The ESC Textbook of

Cardiovascular Imaging
EUROPEAN SOCIETY OF CARDIOLOGY PUBLICATIONS
The ESC Textbook of Cardiovascular Medicine (Third Edition)
Edited by A. John Camm, Thomas F. Lüscher, Gerald Maurer, and Patrick W. Serruys
The ESC Textbook of Preventive Cardiology
Edited by Stephan Gielen, Guy De Backer, Massimo Piepoli, and David Wood
The EHRA Book of Pacemaker, ICD, and CRT Troubleshooting: Case-​based learning with multiple choice questions
Edited by Harran Burri, Carsten Israel, and Jean-​Claude Deharo
The EACVI Echo Handbook
Edited by Patrizio Lancellotti and Bernard Cosyns
The ESC Handbook of Preventive Cardiology: Putting prevention into practice
Edited by Catriona Jennings, Ian Graham, and Stephan Gielen
The EACVI Textbook of Echocardiography (Second Edition)
Edited by Patrizio Lancellotti, José Luis Zamorano, Gilbert Habib, and Luigi Badano
The EHRA Book of Interventional Electrophysiology: Case-​based learning with multiple choice questions
Edited by Hein Heidbuchel, Matthias Duytschaever, and Harran Burri
The ESC Textbook of Vascular Biology
Edited by Robert Krams and Magnus Bäck
The ESC Textbook of Cardiovascular Development
Edited by José Maria Pérez-​Pomares and Robert Kelly
The EACVI Textbook of Cardiovascular Magnetic Resonance
Edited by Massimo Lombardi, Sven Plein, Steffen Petersen, Chiara Bucciarelli-​Ducci, Emanuela R. Valsangiacomo Buechel, Cristina Basso,
and Victor Ferrari
The ESC Textbook of Sports Cardiology
Edited by Antonio Pelliccia, Hein Heidbuchel, Domenico Corrado, Mats Börjesson, and Sanjay Sharma
The ESC Handbook of Cardiac Rehabilitation
Edited by Ana Abreu, Jean-​Paul Schmid, and Massimo Piepoli
The ESC Textbook of Intensive and Acute Cardiovascular Care (Third Edition)
Edited by Marco Tubaro, Pascal Vranckx, Eric Bonnefoy-Cudraz, Susanna Price, and Christiaan Vrints
The ESC Textbook of Cardiovascular Imaging (Third Edition)
Edited by José Luis Zamorano, Jeroen J. Bax, Juhani Knuuti, Patrizio Lancellotti, Fausto J. Pinto, Bogdan A. Popescu, and Udo Sechtem
The ESC Textbook of
Cardiovascular
Imaging
THIRD EDITION

EDITED BY
José Luis Zamorano
Jeroen J. Bax
Juhani Knuuti
Patrizio Lancellotti
Fausto J. Pinto
Bogdan A. Popescu
Udo Sechtem

1
3
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First Edition published in 2010
Second Edition published in 2015
Third Edition published in 2021
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 ​Preface
With great pleasure we would like to introduce the third edition
of The ESC Textbook of Cardiovascular Imaging. Cardiovascular
imaging is the cornerstone of non-​invasive diagnosis in cardi-
ology. The continuous development of all techniques implies the
need for continuous medical education.
The third edition of The ESC Textbook of Cardiovascular Imaging
includes new and updated chapters that explain the utility of the
different imaging modalities in the diagnosis of all relevant and
major cardiovascular diseases.
The clinically oriented text is accompanied by images and in-
sights of the everyday practice of these techniques, prepared by
experienced and well-​known cardiovascular imagers who have
dedicated long hours and commitment to prepare the chapters
included in this edition.
We hope that cardiologists, trainees, and cardiovascular
imagers find in this book the knowledge and expertise to cope
with the challenges faced in their daily practice.
As editors, we have tried to harmonize all chapters in order
to obtain an easy reading of all chapters. Images were carefully
selected to better understand the text. On behalf of all the edi-
tors, we would like to express our gratitude to all authors and
to Claudia Balseca as Editors’ Assistant. All of them worked ex-
tremely hard to make this third book possible.
We want to dedicate our work to the victims of COVID-​19
and their families, especially to our beloved friend Prof Maurizio
Galderisi, who was a co-​author in this book.
José Luis Zamorano
Jeroen J. Bax
Juhani Knuuti
Patrizio Lancellotti
Fausto J. Pinto
Bogdan A. Popescu
Udo Sechtem
 Free personal online access
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 Contents

Symbols and abbreviations  xi 6.2 Assessment of myocardial function by

Contributors xv speckle-​tracking echocardiography   103
Thor Edvardsen, Lars Gunnar Klaeboe, Ewa Szymczyk,
and Jarosław D. Kasprzak

SECTION 1 Contrast echocardiography  111

7
Roxy Senior, Harald Becher, Fausto J. Pinto,
Technical aspects of imaging  and Rajdeep S. Khattar

1 Conventional echocardiography—​basic Echocardiography in the cath lab: Fusion imaging

8
principles  3 and use of intracardiac echocardiography  121
Andreas Hagendorff, Stephan Stobe, Covadonga Fernández-​Golfín and José Luis Zamorano
and Bhupendar Tayal
New technical developments in nuclear cardiology
9
2 Nuclear cardiology (PET and SPECT)—​basic and hybrid imaging  129
principles  41 Antti Saraste, Sharmila Dorbala, and Juhani Knuuti
Danilo Neglia, Riccardo Liga, Stephan G. Nekolla,
Frank M. Bengel, Ornella Rimoldi, New technical developments in Cardiac CT:
10
and Paolo G. Camici Anatomy, fractional flow reserve (FFR), and
machine learning  145
3 Cardiac CT—​basic principles  57 Stephan Achenbach, Jonathan Leipsic, and James Min
Gianluca Pontone and Filippo Cademartiri
4 CMR—​basic principles  67
Jan Bogaert, Rolf Symons, and Jeremy Wright SECTION 3
5 Training and competence in cardiovascular Valvular heart disease 
imaging  79
Kevin Fox and Marcelo F. Di Carli Aortic valve stenosis  161
11
Philippe Pibarot, Helmut Baumgartner,
Marie-​Annick Clavel, Nancy Côté, and Stefan Orwat

SECTION 2 Aortic valve regurgitation  181

12
Julien Magne and Patrizio Lancellotti
New technical developments in imaging
techniques  Mitral valve stenosis  191
13
Ferande Peters and Eric Brochet
New developments in echocardiography/​
6 Mitral valve regurgitation  199
14
Advanced echocardiography  87 Daniel Rodríguez Muñoz, Kyriakos Yiangou,
6.1 Three-​dimensional echocardiography   87 and José Luis Zamorano
Silvia Gianstefani and Mark J. Monaghan
viii C onte n ts

Tricuspid and pulmonary valve disease  211

15 27 Nuclear cardiology and detection of coronary
Denisa Muraru and Elif Leyla Sade artery disease  403
Richard Underwood, James Stirrup, and Danilo Neglia
Multiple and mixed valvular heart disease  223
16
Philippe Unger and Madalina Garbi 28 PET-​CT and detection of coronary artery
disease  421
Intraoperative transoesophageal
17
Marcelo F. Di Carli
echocardiography for valvular surgery  233
Joseph F. Maalouf and Hector I. Michelena 29 MDCT and detection of coronary artery
disease  435
Valvular prostheses  251
18
Stephan Achenbach and Pál Maurovich-​Horvat
Luigi P. Badano and Denisa Muraru
30 CMR and detection of coronary artery
Endocarditis  271
19
Daniel Rodríguez Muñoz and Álvaro Marco del Castillo
disease  447
Eike Nagel, Juerg Schwitter, and Sven Plein
31 Non-invasive Imaging of the vulnerable
atherosclerotic plaque  467
SECTION 4
Rong Bing, David E. Newby, Jagat Narula,
Procedures in the intensive and Marc R. Dweck
cardiovascular care unit  32 Imaging of microvascular disease  481
Paolo G. Camici and Ornella Rimoldi
Imaging- guided transseptal puncture and
20
transcatheter closure of patent foramen ovale/
atrial septal defect, ventricular septal defect, and
paravalvular leaks  287 SECTION 6
Itzhak Kronzon, Juan Manuel Monteagudo,
Heart failure 
Francesco F. Faletra, Priti Mehla, and Muhamed Saric
Imaging for electrophysiological procedures  303
21 Evaluation of systolic LV function and
33
Louisa O’Neill, Iain Sim, John Whitaker, Steven Williams, LV mechanics  497
Henry Chubb, Pál Maurovich-​Horvat, Mark O’Neill, Rainer Hoffmann and Frank A. Flachskampf
and Reza Razavi
Evaluation of left ventricular diastolic
34
Transcatheter aortic valve implantation  315
22 function  507
Arnold C.T. Ng, Victoria Delgado, and Jeroen J. Bax Bogdan A. Popescu, Carmen C. Beladan, and
Maurizio Galderisi†
Transcatheter mitral valve interventions  337
23
Nina C. Wunderlich, Robert J. Siegel, Ronak Rajani, Imaging of the right heart  519
35
and Nir Flint Lawrence Rudski, Petros Nihoyannopoulos, and
Sarah Blissett
Transcatheter tricuspid valve repair/​
24
replacement  361 Assessment of viability  545
36
Rebecca T. Hahn Luc A. Pierard, Paola Gargiulo, Pasquale Perrone-​Filardi,
Bernhard Gerber, and Joseph B. Selvanayagam
Transcatheter pulmonic valve replacement  377
25
Kuberan Pushparajah and Alessandra Frigiola Imaging cardiac innervation  565
37
Albert Flotats and Ignasi Carrió
Cardiac resynchronization therapy: Selection of
38
SECTION 5 candidates  577
Victoria Delgado and Jens-​Uwe Voigt
Coronary artery disease 
Cardiac resynchronization therapy: Optimization
39
26 Echocardiography and detection of coronary and follow-​up  587
artery disease  395 Marta Sitges and Erwan Donal
Thor Edvardsen, Marta Sitges, and Rosa Sicari
 C on t e n ts ix

Echocardiography evaluation in extracorporeal

40 Myocarditis  715
48
support  599 Ali Yilmaz, Heiko Mahrholdt, and Udo Sechtem
Susanna Price and Alessia Gambaro
Cardiac masses and tumours  731
49
Cardiac imaging in cardio-​oncology  613
41 Teresa López-​Fernández and Peter Buser
Riccardo Asteggiano, Patrizio Lancellotti,
Maurizio Galderisi†, Stephane Ederhy, and Marie Moonen

SECTION 9
Aortic disease: aneurysm and
SECTION 7
dissection 
Cardiomyopathies 
50 The role of echocardiography  747
Hypertrophic cardiomyopathy  629
42 Arturo Evangelista and Gisela Teixidó-​Turà
Nuno Cardim, Alexandra Toste, and Robin Nijveldt
51 Aortic disease: Aneurysm and dissection—​role
Infiltrative cardiomyopathy  645
43 of CMR  757
Massimo Lombardi, Silvia Pica, Antonella Camporeale, Jose F. Rodriguez-​Palomares and Arturo Evangelista
Alessia Gimelli, and Dudley J. Pennell
52 Aortic disease: Aneurysm and dissection—​role
Dilated cardiomyopathy  661
44 of MSCT  771
Upasana Tayal, Sanjay Prasad, Tjeerd Germans, Rocío Hinojar and Raimund Erbel
and Albert C. van Rossum
Other genetic and acquired
45
cardiomyopathies  681 SECTION 10
Kristina Haugaa and Perry Elliott
Adult congenital heart disease 
The role of echocardiography in adult
53
SECTION 8 congenital heart disease  783
Peri-​myocardial disease  Lindsay A. Smith, Mark K. Friedberg,
and Luc Mertens
Pericardial effusion and cardiac tamponade  697
46 The role of CMR and MSCT  809
54
Allan Klein, Bernard Cosyns, and Aldo L. Schenone Giovanni Di Salvo and Francesca R. Pluchinotta
Constrictive pericarditis  707
47
Alida L.P. Caforio, Maurizio Galderisi†, Massimo Imazio,
Renzo Marcolongo, Yehuda Adler, and Ciro Santoro Index  823
 Symbols and abbreviations
z video
E cross reference
9 additional online material
M website
AC arrhythmogenic cardiomyopathy/​attenuation
correction
AccT acceleration time
ACE angiotensin-​converting  enzyme
ACR American College of Radiology
ACS acute coronary syndromes
AF atrial fibrillation
åICD implantable cardioverter defibrillator
Ar atrial re­verse velocity
AR aortic regurgitation
ARVC arrhythmogenic right ventricular
cardiomyopathy
AS aortic stenosis
ASD atrial septal defect
ASE American Society of Echocardiography
ASO amplatzer septal occluder
AV aortic valve/​atrial valve
AVA aortic valve area
AVS aortic valve stenosis
BAV bicuspid aortic valve
BMI body mass index
BNP B-​type natriuretic peptide
BSA body surface area
CAC coronary artery calcium
CAD coronary artery disease
CAV cardiac allograft vasculopathy
CBF coronary blood flow
CCT cardiac computed tomography
CCTA coronary computed tomography angiography
CFR case fatality rate/​coronary flow reserve
CHF congestive heart failure
CIED cardiac implantable electrical devices
CLT Classroom and Laboratory Training
CM contrast material
CMD coronary microvascular dysfunction
CMR cardiac magnetic resonance
CPT cold pressure testing
CRT cardiac resynchronization therapy
CSA cross-​sectional  area
CT computed tomography
CTA computed tomography angiography
CTCA computed tomography coronary angiography
CTP computed tomography myocardial perfusion
CW colour wave/​continuous wave
CWD colour wave Doppler
CZT cadmium zinc telluride
DECT dual-​energy computed tomography
DOPS Direct Observation of Practical Skills
DSCT dual-​source computed tomography
DSE dobutamine stress echocardiography
EACTS European Association for Cardio-​Thoracic
Surgery
EACVI European Association of Cardiovascular
Imaging
EAM electro-​anatomical mapping
EANM European Association of Nuclear Medicine
EAPC European Association of Preventive Cardiology
ECMO extracorporeal membrane oxygenation
ECNC European Council of Nuclear Cardiology
ECV extracellular volume
ED effective radiation dose
ED external diameter
EDIC Echo Dobutamine International Cooperative
EDT E wave decel­eration time
EDV end-​diastolic  volume
EF ejection fraction
EOA effective orifice area
EPIC Echo-​Persantine International Cooperative
ERO effective regurgitant orifice
EROA effective regurgitant orifice area
ESC European Society of Cardiology
ESCR European Society of Cardiac Radiology
ESCR European Society of Cardiovascular Radiology
ESV end-​systolic  volume
xii Symb ols an d Abbreviations
EVEREST Endovascular Valve Edge-​to-​Edge REpair Study
FAC fractional area change
FBP filtered back-​projection
FF forward flow
FFA free fatty acid
FFR fractional flow reserve
FO fossa ovalis
FOV field of view
FWLS free wall longitudinal strain
GCV GREAT cardiac vein
GLS global longitudinal left ventricular strain
GLS global longitudinal strain
HCM hypertrophic cardiomyopathy
HF heart failure
HFA Heart Failure Association
HFpEF heart failure with preserved ejection fraction
HLA horizontal long axis
HR heart rate
HU Hounsfield Units
HVD heart valve disease
IAEA International Atomic Energy Agency
ICA invasive coronary angiography
ICU intensive care unit
IDR iodine delivery rate
INCAPS IAEA Nuclear Cardiology Protocols
Cross-​Sectional  Study
IOD internal orifice diameter
IRIS iterative reconstruction in image space
IVC inferior vena cava
IVRT isovolumic relaxation time
IVUS intravascular ultrasound
LA left atrium
LA long axis
LAA left atrial appendage
LAD left anterior descending
LAP left atrial pressure
LAV left atrial volume
LAVi LA volume indexed to body surface area
LBBB left bundle branch block
LD left disc
LDL low-​density lipoprotein
LGE late gadolinium enhancement
LMV left marginal vein
LOR line-​of response
LS longitudinal strain
LV left ventricle
LVAD left ventricular assistance device
LVFP left ventricular filling pressure
LVEDD left ventricle end-​diastolic dimension
LVEDP left ventricular end-diastolic pressure
LVEF left ventricular ejection fraction
LVESV left ventricular end-​systolic volume
LVOT left ventricular outflow tract
MACE major adverse cardiovascular events
MAD mitral annular disjunction
MAPSE mitral annular plane systolic excursion
MBF myocardial blood flow
MCE myocardial contrast echocardiography
MCQ multiple choice question
MDCT multidetector-​row computed tomography
MESA Multi-​Ethnic Study of Atherosclerosis
MFR myocardial flow reserve
MI mechanical index
MI myocardial infarction
MIP maximum intensity projections
MPI myocardial performance index/​myocardial
perfusion imaging
MPRI myocardial perfusion reserve index
MR mitral regurgitation
MRA magnetic resonance angiography
MRCA magnetic resonance coronary angiography
MRI magnetic resonance imaging
MS mitral stenosis
MV mitral valve
MVA mitral valve area
MVO microvascular obstruction
NASCI North American Society for Cardiovascular
Imaging
NBE National Board of Echocardiography
NMR nuclear magnetic resonance
NYHA New York Heart Association
OCT optical coherence tomography
OR operating room
PA pulmonary artery
PAH pulmonary arterial hypertension
PAP pulmonary arterial pressure
PASP pulmonary artery systolic pressure
PCWP pulmonary capillary wedge pressure
PE pulmonary embolism
PET positron emission tomography
PFO patent foramen ovalis
PH pulmonary hypertension
PHT pressure half-​time
PISA proximal isovelocity surface area
PIV posterior interventricular vein
PLARC paravalvular Leak Academic Research
Consortium
PPL referred to as periprosthetic leak
PR pulmonary regurgitation
PS pulmonary stenosis
PSF point spread function
PSIR phase-​sensitive inversion recovery
PSS post-​systolic shortening
PV pulmonary valve
PVI pulmonary vein isolation
PVLV posterior vein of the left ventricle
PVR pulmonary vascular resistance
PW pulsed wave

QA quality assurance
RA right artery
RAP right atrial pressure
RCA right coronary artery
RD right disc
RF regurgitant flow
RF regurgitant fraction
RIMP right-​sided index of myocardial performance
ROI region of interest
ROS reactive oxygen species
RPM revolutions per minute
RV right ventricle
RVAD right ventricular assist device
RVEF right ventricular ejection fraction
RVOT right ventricular outflow tract
RVSP right ventricular systolic pressure
SAM systolic anterior motion
SARF severe acute respiratory failure
SCCT Society of Cardiovascular Computed
Tomography
SCD sudden cardiac death
SCMR Society for Cardiovascular Magnetic Resonance
SD standard deviation
SE stress echocardiography
SHD structural heart disease
SL septal leaflet
SNR signal-​to-​noise  ratio
SPAMM spatial modulation of magnetization
SPECT single photon emission computed tomography
SRD sewing ring diameter
SSFP steady-​state free precession
Sym b ol s a n d A b b rev iat i on s xiii
STE speckle tracking echocardiography
SV stroke volume
SVC superior vena cava
TA tricuspid annular
TAC time-​activity  curves
TAD tissue annulus diameter
TAPSE tricuspid annular plane systolic excursion
TAVI transcatheter aortic valve implantation
TAVR transcatheter aortic valve replacement
TOE transoesophageal echocardiography
TI the optimal inversion
TOF tetralogy of Fallot
TOF time of flight
TR tricuspid regurgitation
TTDE the feasibility of transthoracic doppler
echocardiography
TV tricuspid valve
USPIO ultrasmall superparamagnetic iron oxide
VA ventricular arrhythmias
VAD ventricular assist device
VC vena contracta
VHD valvular heart disease
VLA vertical long axis
VSD ventricular septal defect
VT velocity time
VT ventricular tachycardia
VTI velocity-​time integral
WISE Women’s Ischemia Syndrome Evaluation
 Contributors
Stephan Achenbach
Department of Cardiology, Friedrich-Alexander University
Erlangen-Nürnberg, Erlangen, Germany
Yehuda Adler
The Gertner Institute, Sheba Medical Center, affiliated to
Sackler Medical School, Tel Aviv University and the College for
Academic Studies, Tel Aviv, Israel
Riccardo Asteggiano, MD, FESC
Adjunct Professor, Faculty of Medicine, Insubria University,
Varese, Italy; LARC (Laboratorio Analisi e Ricerca Clinica),
Turin, Italy
Luigi P. Badano, MD, PhD, FESC, FACC, Honorary FASE,
Honorary FEACVI
Professor of Cardiovascular Medicine, University of Milano-​
Bicocca; Director of the Cardiovascular Imaging Unit,
Department of Cardiovascular, Neural and Metabolic Sciences;
Istituto Auxologico Italiano, IRCCS, Milano, Italy; Istituto
Auxologico Italiano, IRCCS, Cardiology Unit, Department
of Cardiovascular, Neural and Metabolic Sciences, San Luca
Hospital, and Department of Medicine and Surgery, University
of Milano-​Bicocca, Piazzale Brescia, MI, Italy
Helmut Baumgartner, MD
Department of Cardiology III, Adult Congenital and Valvular
Heart Disease, University Hospital Muenster, Muenster, Germany
Jeroen J. Bax, MD, PhD
Professor of Cardiology, Head Department of Non-invasive
Imaging, Leiden University Medical Center, The Netherlands
Harald Becher, MD, PhD, FRCP
Professor of Medicine, ABACUS, Mazankowski Alberta
Heart Institute, University of Alberta Hospital, Edmonton,
Alberta, Canada
Carmen C. Beladan, MD, PhD
University of Medicine and Pharmacy ‘Carol Davila’—​
Euroecolab, Emergency Institute for Cardiovascular Diseases
‘Prof. Dr. C. C. Iliescu’, Bucharest, Romania
Frank M. Bengel, MD, Univ. Prof. Dr. med.
Director, Department of Nuclear Medicine, Hannover Medical
School, Hannover, Germany
Rong Bing, MBBS
Doctor, Department of Centre for Cardiovascular Science,
University of Edinburgh, Edinburgh, UK
Sarah Blissett, MD, MHPE
Cardiologist, London Health Sciences Centre, London, Canada;
Assistant Professor (Medicine), Western University, London,
Canada; Researcher, Centre for Education Research and
Innovation, Schulich School of Medicine and Dentistry, Western
University, London, Canada
Jan Bogaert, MD, PhD
Faculty of Medicine, Department of Imaging and Pathology,
University Hospitals Leuven, Leuven, Belgium
Eric Brochet
Department of Cardiology, University Hospital Bichat, Paris,
France
Peter Buser, MD
Department of Cardiology, University Hospital Basel, Basel,
Switzerland
Filippo Cademartiri, MD, PhD
Chairman Prof. Dr., Department of Radiology, Area Vasta 1—​
ASUR Marche, Urbino, PU, Italy
Alida L.P. Caforio, MD, PhD, FESC
Cardiologist, Department of Cardiac, Thoracic, Vascular
Sciences and Public Health, University of Padova, Padova, Italy
Paolo G. Camici, MD, FESC, FAHA, FACC, FRCP
Professor of Cardiology, Department of Cardiovascular Research
Center, San Raffaele Hospital and Vita Salute University,
Milan, Italy
Antonella Camporeale, MD, PhD
Multimodality Cardiac Imaging Section, I.R.C.C:S., Policlinico
San Donato, Milan, Italy
xvi C ontribu tors
Nuno Cardim, MD, PhD
Head Echo Lab, Department of Cardiology, Hospital da Luz,
Lisbon, Portugal
Ignasi Carrió, MD, FEBNM, FESC, FRCP
Professor of Nuclear Medicine, Universitat Autònoma de
Barcelona, Director, Nuclear Medicine Department, Hospital de
la Santa Creu i Sant Pau, Barcelona, Spain
Henry Chubb
Division of Pediatric Cardiology, Department of Pediatrics,
Stanford University, USA
Marie-​Annick Clavel, DVM, PhD
Associate Professor, Department of Medicine, Laval University,
Canada Research Chair on Women’s Valvular Heart Health,
Institut Universitaire de Cardiologie et de Pneumologie de
Québec, QC, Canada
Bernard Cosyns, MD, PhD, FESC, FEACVI
Cardiology Department, Centrum voor hart en vaatziekten,
Universitair ziekehuis Brussel, 101 laarbeeklaan 1090 Brussels,
Belgium
Nancy Côté, PhD
Institut Universitaire de cardiologie te de Pneumologie de
Québec, Québec, Canada
Álvaro Marco del Castillo, MD 
Victoria Delgado, MD, PhD
Cardiologist, Department of Cardiology, Leiden University
Medical Center, Leiden, the Netherlands
Marcelo F. Di Carli, MD
Executive Director, Cardiovascular Imaging, Department of
Radiology and Medicine, Brigham and Women’s Hospital,
Boston, MA, USA, and Family Professor of Radiology and
Medicine, Women’s Hospital, Seltzer, Harvard Medical School,
Boston, MA, USA
Giovanni Di Salvo, MD, PhD, MSc, FESC, FEACVI, FISC
Professor and Director, Department of Paediatric Cardiology
and Congenital Heart Disease, University of Padua, Padua, Italy;
Honorary Consultant Royal Brompton Hospital, London, UK
Erwan Donal, MD, PhD
Cardiology & INSERM1099, University Hospital, University
Rennes-​1,  France
Sharmila Dorbala, MD
Division of Nuclear Medicine, Department of Radiology,
Brigham and Women’s Hospital, Boston, MA, USA
Marc R. Dweck, MD, PhD
Professor, Department of BHF Centre for Cardiovascular
Science, University of Edinburgh, Edinburgh, UK
Stephane Ederhy
Department of Cardiology, AP-HP, Saint-Antoine Hospital,
Sorbonne University, Paris, France
Thor Edvardsen, MD, PhD
Professor, Department of Cardiology, Oslo University Hospital,
Oslo, Norway
Perry Elliott
Chair of Cardiovascular Medicine, University College London,
London, UK
Raimund Erbel, MD, FAHA, FESC, FASE, FACC
Medical Informatics, Biometry and Epidemiology, University
Clinic, Universitat Duisburg-Essen, Essen, Germany
Arturo Evangelista, MD, FESC
Institut de Recerca Vall d’Hebron (VHIR), Coordinator of
Valvular and Aortic Research Unit, Hospital Universitari Vall
d’Hebron, Barcelona, Spain
Francesco F. Faletra, MD
Director of Cardiac Imaging Service, Cardiocentro Ticino
Lugano, Switzerland
Covadonga Fernández-​Golfín, MD
Cardiac Imaging Unit Coordinator, Cardiology Department,
Ramón y Cajal University Hospital, Madrid, Spain
Frank A. Flachskampf, MD, FESC, FACC
Professor, Department of Medical Sciences, Uppsala University,
Uppsala, Sweden
Nir Flint, MD
Attending Cardiologist, Echocardiography Lab, Division of
Cardiology, Tel-​Aviv Sourasky Medical Center, Sackler Faculty
of Medicine, Tel-​Aviv University, Tel-​Aviv, Israel
Albert Flotats, MD
Consultant, Department of Nuclear Medicine, Hospital de la
Santa Creu i Sant Pau, Barcelona, Spain
Kevin Fox, MD, FRCP, FESC
Consultant Cardiologist, Department of Cardiology, Imperial
College Healthcare NHS Trust, London, Middlesex, UK
Mark K. Friedberg, MD
Professor, The Hospital for Sick Children, The University of
Toronto, Toronto, ON, Canada
Alessandra Frigiola, MD, MD(res), FRCP
Consultant Cardiologist—​ACHD specialist, Cardiovascular,
ACHD, Guy’s & St Thomas’ Hospital, NHS Foundation Trust,
London, UK
Maurizio Galderisi, MD†
Professor of Medicine, Department of Advanced Biomedical
Sciences, Federico II University Hospital, Naples, Italy
Alessia Gambaro, MD
Cardiology Division, Department of Medicine, University of
Verona, Verona, Italy
Madalina Garbi, MD, MA
Consultant Cardiologist, Department of Cardiology, Royal
Papworth Hospital, Cambridge, UK

Paola Gargiulo, MD, PhD
Department of Advanced Biomedical Sciences, Federico II
University, Naples, Italy
Bernhard Gerber, MD, PhD, FESC, FACC, FAHA
Professor of Medicine, Cardiology Division, Department of
Cardiovascular Diseases, Cliniques Universitaires St. Luc UC
Louvain, Brussels, Belgium
Tjeerd Germans, MD, PhD
Cardiologist, Department of Cardiology, Amsterdam University
Medical Center, Amsterdam, the Netherlands
Silvia Gianstefani, MD  Cardiologist, Cardiothoracic and Vascular Department,
Alessia Gimelli, MD
Fondazione Toscana Gabriele Monasterio, Pisa, Italy
Andreas Hagendorff, MD
Professor, Department of Cardiology, University Hospital
Leipzig, Leipzig, Germany  Teresa López-​Fernández, MD
Rebecca T. Hahn, MD, FESC
Department of Medicine, Division of Cardiology/​New York
Presbyterian Hospital, New York-​Presbyterian/​Columbia
University Medical Center, New York, NY, USA
Kristina Haugaa, MD 
Rocío Hinojar, MD
Ramón y Cajal University Hospital, Madrid, Spain
Rainer Hoffmann, MD
Professor, Department of Cardiology, Bonifatius Hospital
Lingen, Lingen, Germany
Massimo Imazio, MD, FESC
Multimodality Cardiac Imaging Section, IRCCS Policlinico San
Donato, Milan, Italy
Jarosław D. Kasprzak, MD, PhD
Professor of Medicine, Department and Chair of Cardiology,
Bieganski Hospital, Medical University of Lodz, Lodz, Poland
Rajdeep S. Khattar, DM, FRCP, FACC, FESC
Consultant Cardiologist and Honorary Clinical Senior Lecturer,
Royal Brompton and Harefield NHS Trust, and National Heart
and Lung Institute, Imperial College, London, UK
Lars Gunnar Klaeboe 
Allan Klein, MD, FRCP(C), FACC, FAHA, FASE
Professor of Medicine, Cleveland Clinic Lerner College of
Medicine of Case Western Reserve University, ​Director, Center
for the Diagnosis and Treatment of Pericardial Diseases, Section
of Cardiovascular Imaging, Department of Cardiovascular
Medicine, Heart, Vascular, and Thoracic Institute, Cleveland
Clinic, Cleveland, OH, USA
Juhani Knuuti, MD, PhD, FESC
Turku PET Centre, Turku University Hospital and University of
Turku, Turku, Finland
C on t ri bu tor s xvii
Itzhak Kronzon, MD, FASE, FESC, FACC, FAHA, FCCP
Professor of Cardiovascular Medicine, Hofstra University,
NY, USA
Patrizio Lancellotti
Professor, Head of Department, Department of Cardiology,
University of Liège Hospital, Liège, Belgium
Jonathan Leipsic, MD, FRCPC, MSCCT
Physician, Department of Imaging and Cardiology, UBC,
Vancouver, BC, Canada
Riccardo Liga, MD, PhD
University Hospital of Pisa, Pisa, Italy
Massimo Lombardi, MD, FESC, PhD
Head, Multimodality Cardiac Imaging Section, I.R.C.C.S
Policlinico San Donato, Milan, Italy
Senior Consultant Cardiologist, Department of Cardiology, La
PAz University Hospital, IdiPAZ Research Institue, Ciber CV,
Madrid, Spain
Joseph F. Maalouf, MD, FAHA, FACC, FASE
Professor of Medicine, Director of Interventional
Echocardiography, Consultant in Cardiovascular Diseases,
Department of Cardiovascular Medicine, Mayo Clinic,
Rochester, MN, USA
Julien Magne, PhD
Department of Cardiology, CHU de Limoges, Limoges, France
Heiko Mahrholdt
Professor Doctor, Head of Imaging, Department of Cardiology,
Robert Bosch Medical Center, Stuttgart, BW, Germany
Renzo Marcolongo, MD
Senior Staff Physician, Department of Medicine, Azienda
Ospedale Università Padova, Padova, Italy
Pál Maurovich-​Horvat, MD 
Priti Mehla, MD
Lenox Hill Hospital, New York, NY, USA
Luc Mertens, MD, PhD
Professor of Paediatrics, Department of Cardiology, The
Hospital for Sick Children, University of Toronto, Toronto,
ON, Canada
Hector I. Michelena, MD, FACC, FASE, FESC
Professor of Medicine, Department of Cardiovascular Medicine,
Mayo Clinic, Rochester, MN, USA
James Min, MD 
Mark J. Monaghan, PhD, FRCP (Hon), FACC, FESC
Director of Non-​Invasive Cardiology, King’s College Hospital,
Denmark Hill, London, UK
xviii C ontribu tors
Juan Manuel Monteagudo, MD
Department of Cardiology, University Hospital Ramón y Cajal,
Madrid, Spain
Marie Moonen, MD, PhD
University Hospital Sart Tilman, GIGA Cardiovascular Sciences,
Department of Cardiology, Liege, Belgium
Daniel Rodríguez Muñoz, MD, PhD
Consultant, Department of Cardiology, Hospital Universitario
12 de Octubre, Madrid, Spain
Denisa Muraru, MD, PhD, FESC, FACC, FASE
Department of Medicine and Surgery, University of Milano-
Bicocca, Istituto Auxologico Italiano, IRCCS, Milan, Italy
Eike Nagel, MD 
Jagat Narula, MD, PhD, MACC
Philip J. and Harriet L. Goodhart Chair of Medicine, Professor
of Medicine, Radiology and Health System Design & Global
Health, Chief, Division of Cardiology, Mount Sinai Hospital
Morningside; Associate Dean for Global Health, Icahn School
of Medicine at Mount Sinai, Executive Editor, Journal of the
American College of Cardiology; Vice President Elect, World
Heart Federation, New York, NY, USA
Danilo Neglia, MD
Fondazione Toscana G. Monasterio, Via G. Moruzzi, Pisa, Italy
Stephan G. Nekolla, PhD, FESC
Adjunct Teaching Professor, Nuklearmedizinische Klinik und
Poliklinik, Klinikum rechts der Isar der Technischen Universität
München, and Deutsches Zentrum für Herz-​Kreislauf-​Forschung
e.V. Partner site Munich Heart Alliance, München, Germany
David E. Newby
Centre for Cardiovascular Science, University of Edinburgh,
Edinburgh, UK
Arnold C.T. Ng
Princess Alexandra Hospital, Brisbane, Queensland, Australia;
Faculty of Medicine, South Western Sydney Clinical School, the
University of New South Wales, Australia
Petros Nihoyannopoulos, MD 
Robin Nijveldt, MD, PhD, FESC
Cardiologist, Department of Cardiology, Radboud University
Medical Center, Nijmegen, the Netherlands
Louisa O’Neill
King’s College London, UK; Guy’s and St Thomas NHS
Foundation Trust, London, UK
Mark O’Neill, MD 
Stefan Orwat, MD
Consultant Cardiologist, Adult Congenital and Valvular Heart
Disease Department, University of Muenster, Muenster, Germany
Dudley J. Pennell, MD, FRCP, FACC, FESC, FRCR, FAHA,
FMedSci, FSCMR
National Heart and Lung Institute, Imperial College, Royal
Brompton and Harefield NHS Foundation Trust, London, UK
Pasquale Perrone-​Filardi
Department of Clinical Medicine, Cardiovascular and
Immunology Sciences, Federico II University, Naples, Italy
Ferande Peters, MBBCH, FCP (SA), FACC, FESC, FRCP
Senior Cardiologist, Associate Professor, Flora Hospital,
Cardiovascular Pathophysiology and Genomics Unit,
University of the Witwatersrand, Johannesburg, South Africa
Philippe Pibarot, DVM, PhD, FESC, FACC, FAHA, FCCS
Head of Cardiology Research, Department of Cardiology,
Institut Universitaire de Cardiologie et de Pneumologie de
Québec/​Québec Heart & Lung Institute, Laval University,
Québec, QC, Canada
Silvia Pica, MD
Multimodality Cardiac Imaging Section, I.R.C.C:S., Policlinico
San Donato, Milan, Italy
Luc A. Pierard, MD, PhD, FESC
Honorary Professor of Medicine, Department of Cardiology,
University of Liège, Liège, Belgium
Fausto J. Pinto, MD, PhD, FESC, FACC, FASE, FSCAI
Head of Department, Department of Cardiovascular Medicine,
University Hospital, Universidade de Lisboa, Lisbon, Portugal
Sven Plein, MD, PhD, FRCP
Professor, British Heart Foundation Professor of Cardiovascular
Imaging, Leeds Institute of Cardiovascular and Metabolic
Medicine, University of Leeds, Leeds, UK
Francesca R. Pluchinotta, MD
Consultant of Pediatric Cardiology and Adult Congenital Heart
Disease, Multimodality Cardiac Imaging Unit, IRCCS Policlinico
San Donato, Milan, Italy
Gianluca Pontone, MD, PhD
Director, Department of Cardiovascular Imaging, Centro
Cardiologico Monzino, IRCCS, Milan, Italy
Bogdan A. Popescu, MD, PhD, FESC, FACC
Professor of Cardiology, University of Medicine and Pharmacy
‘Carol Davila’—​Euroecolab, Head of Cardiology Department,
Emergency Institute for Cardiovascular Diseases ‘Prof. Dr. C. C.
Iliescu’, Bucharest, Romania
Sanjay Prasad, MD 
Susanna Price, MD, PhD
Professor of Cardiology and Intensive Care, Adult Intensive Care
Unit, Royal Brompton Hospital, London, UK
Kuberan Pushparajah, MD 

Ronak Rajani, BM, DM, FRCP, FESC, FSCCT, FACC
Department of Cardiology, Guy’s and St Thomas’ NHS
Foundation Trust, London, UK
Reza Razavi, MD 
Ornella Rimoldi, MD
IBFM, Consiglio Nazionale delle Ricerche, Segrate, Italy
Jose F. Rodriguez-​Palomares, MD, PhD
Director of Cardiovascular Imaging Department, Department of
Cardiology, Vall Hebrón Hospital, Barcelona, Catalonia, Spain
Lawrence Rudski, MD, FRCPC
Director, Azrieli Heart Center, Jewish General Hospital, McGill
University, Montreal, QC, Canada
Elif Leyla Sade, MD
Professor of Cardiology, Department of Cardiology, Baskent
University, Ankara, Turkey
Ciro Santoro, MD
Department of Advanced Biomedical Science, Federico II,
University Hospital, Naples, Italy
Antti Saraste, MD, PhD, FESC
Professor, Chief Cardiologist, Heart Center, Turku University
Hospital, Turku, Finland
Muhamed Saric, MD, PhD
Director, Noninvasive Cardiology, Professor of Medicine,
Leon H. Charney Division of Cardiology, New York University
Langone Health, New York, NY
Aldo L. Schenone, MD
Chief Cardiovascular Imaging Fellow
Section of Non Invasive Cardiovascular Imaging,
Department of Radiology
Brigham and Women’s Hospital, Harvard Medical School,
Boston, MA, USA
Juerg Schwitter, MD
Full Professor, Cardiovascular Department, University Hospital
Lausanne, CHUV, Faculty of Biology and Medicine, Lausanne
University, Lausanne, VD, Switzerland
Udo Sechtem, MD
Associate Professor of Cardiology, Cardiologicum and Robert-​
Bosch-​Krankenhaus, Stuttgart, Germany
Joseph B. Selvanayagam, MD, PhD
Professor in Cardiovascular Medicine, Flinders University,
Adelaide, Australia
Roxy Senior, MD, DM, FRCP, FACC, FESC
Consultant Cardiologist and Professor of Cardiology, Department
of Cardiology, Royal Brompton Hospital, London, UK
Rosa Sicari, MD, PhD
Research Director, Department of Biomedicine, Institute of
Clinical Physiology, Pisa, PI, Italy
C on t ri bu tor s xix
Robert J. Siegel, MD, FACC
Kennamer Chair in Cardiac Ultrasound, Medical Director,
Clinic for Hypertrophic Cardiomyopathy and Aortopathies;
Director, Cardiac Noninvasive Laboratory; Professor of
Medicine, Cedars-​Sinai Medical Center and UCLA School of
Medicine, CA, USA
Iain Sim, MD
Clinical Research Fellow in Cardiology, King’s College
London, UK
Marta Sitges, MD, PhD
Director, Cardiovascular Institute, Hospital Clinic, Professor of
Medicine, University of Barcelona, Barcelona, Spain
Lindsay A. Smith
University Hospital Southampton, Southampton, UK
James Stirrup, DLM, MD(Res), FSCCT, FRCP
Consultant Cardiologist, Department of Cardiology, Royal
Berkshire NHS Foundation Trust, London, UK
Stephan Stobe, MD 
Rolf Symons, MD, PhD
Department of Imaging and Pathology, Faculty of Medicine,
University Hospitals Leuven, KU Leuven, Leuven, Belgium
Ewa Szymczyk, MD 
Bhupendar Tayal, MD 
Upasana Tayal, MD 
Gisela Teixidó-​Turà, MD, PhD, FESC
Vall d’Hebron Research Institute, Hospital Universitari Vall
d’Hebron, CIBER-​CV, Barcelona, Spain
Alexandra Toste, MD
Hospital da Luz, Inherited Cardiovascular Diseases &
Hypertrophic Cardiomyopathy Center, Affiliated Professor at
NOVA Medical School, Lisbon, Portugal
Richard Underwood, MA, DM, FRCP, FRCR
Emeritus Professor of Cardiac Imaging, National Heart and
Lung Institute, Imperial College London, London, UK
Philippe Unger, MD, PhD
Head of Department, Department of Cardiology, CHU Saint-​
Pierre, Université Libre de Bruxelles, Brussels, Belgium
Albert C. van Rossum, MD, PhD
Department of Cardiology, Amsterdam University Medical
Centers, Amsterdam, the Netherlands
Jens-​Uwe Voigt, MD, PhD, FESC
Head of Echocardiography, Department of Cardiovascular
Diseases, University Hospitals Leuven, Leuven, Belgium
John Whitaker
Division of Imaging Sciences and Biomedical Engineering,
King’s College, London, UK
xx C ontribu tors

Steven Williams Kyriakos Yiangou, MD, MSc, FESC, FACC, FEACVI

Division of Imaging Sciences and Biomedical Engineering,
King’s College, London, UK
Jeremy Wright, MBBS, FRACP
Cardiologist, Greenslopes Private Hospital, Brisbane, Australia
Nina C. Wunderlich, MD
Head of Noninvasive Cardiology, Department of Cardiology,
Cardiovascular Center Darmstadt, Darmstadt, Hessen, Germany
Cardiologist, President Cyprus Society of Cardiology
Ali Yilmaz, MD
Department of Cardiology, Division of Cardiovascular Imaging,
University Hospital Münster, Germany 
José Luis Zamorano, MD, PhD
Head of Cardiology, University Hospital Ramon y Canal,
Madrid, Spain
 SECTION 1

Technical aspects of
imaging

1 Conventional echocardiography—​basic principles  3

Andreas Hagendorff, Stephan Stobe, and Bhupendar Tayal
2 Nuclear cardiology (PET and SPECT)—​basic principles  41
Danilo Neglia, Riccardo Liga, Stephan G. Nekolla, Frank M. Bengel, Ornella Rimoldi, and
Paolo G. Camici
3 Cardiac CT—​basic principles  57
Gianluca Pontone and Filippo Cademartiri
4 CMR—​basic principles  67
Jan Bogaert, Rolf Symons, and Jeremy Wright
5 Training and competence in cardiovascular imaging  79
Kevin Fox and Marcelo F. Di Carli

Contents
Introduction  3
Principles of transthoracic
echocardiography—​practical aspects  3
Principles of image optimization and
identification of artefacts—​practical
aspects  7
Standardized data acquisition in
transthoracic echocardiography  7
Principles of transoesophageal
echocardiography—​practical
aspects  24
Standardized data acquisition in
transoesophageal echocardiography  28
Standard values in transthoracic and
transoesophageal echocardiography  37
M-​mode measurements  37
Two-​dimensional measurements  38
Pulsed spectral Doppler measurements  38
Continuous wave Doppler measurements  38
Pulsed spectral tissue Doppler
measurements  38
Acknowledgements  40
CHAPTER 1
Conventional
echocardiography—​basic
principles
Andreas Hagendorff, Stephan Stobe,
and Bhupendar Tayal
Introduction
Echocardiography is an imaging technique that enables accurate assessment of car-
diac structures and cardiac function. Conventional echocardiography involves different
modalities—​especially the M-​mode, the 2D, and colour Doppler, as well as the pulsed-​
wave and continuous wave Doppler. The M-​mode illustrates the reflections of a single
sound beam plotted against time. 2D echocardiography enables the documentation of
views, which represent characteristic sectional planes of the moving heart during one
heart cycle. Colour Doppler echocardiography adds the information of blood flow to
the 2D cineloop. Pulsed-​wave Doppler is the acquisition of a local blood flow spectrum
of a defined region represented by the dimension of the sample volume, whereas con-
tinuous wave Doppler displays the blood flow spectrum of all measured blood flow vel-
ocities along a straight line sound beam from its beginning to the end. The handling of
the transducer has to be target-​oriented, stable with respect to the imaging targets, and
coordinated with respect to angle differences between the defined views to use all these
modalities correctly to get optimal image quality of the cineloops and spectra.
Thus, the focus of this chapter will be a mainly practically oriented description of scan-
ning technique in transthoracic and transoesophageal echocardiography.
The echocardiographic documentation requires image optimization and ultrasound
machines, which fulfil the international laboratory standards in echocardiography. Thus,
the equipment has to be minimally capable to enable broadband 2D imaging, M-​mode
imaging, pulsed and continuous wave Doppler, as well as colour-​coded imaging, pulsed
tissue Doppler imaging, and complete digital storage capability. In addition, the ultra-
sound system has to have all technical possibilities for transoesophageal, contrast, and
stress echocardiography. An electrocardiographic (ECG) recording should generally be
performed in order to be able to capture complete heart cycles according to the ECG
trigger. This chapter is written in accordance with the current international guidelines
and recommendations [1–​7].
Principles of transthoracic echocardiography—​
practical aspects
The main principle of echocardiographic scanning is an exact or best possible manual
control of the region of interest during the technical procedure. This principle includes
the ability to move a certain cardiac structure within the scan sector from the left to
the right and vice versa without losing the cardiac structures of the selected sectional
4 CHAPTER 1   C on v ent ional ech o cardio gr a phy — basi c pri n ci pl es
plane. In addition, this aspect is documented by the ability to ro-
tate the transducer exactly about 60 or 90° without losing the de-
fined cardiac structure in the centre of the primary scan sector
before rotating. In other words, the visualization of cardiac struc-
tures in the centre of the scan sector has to be combined with
the technical skill of the investigator to change only one plane
within the spatial coordinates to achieve accurate characteriza-
tion and documentation of the target cardiac structure. Thus, the
easy message of transthoracic echocardiography is scanning by
tilting without flipping and rotating, by flipping without tilting
and rotating, as well as by rotating without tilting and flipping.
This sounds easy, but it requires a stable transducer position next
to the skin of the patient, an absolutely stable guiding of the trans-
ducer, and a stereotactic manual control of the transducer.
Regarding these aspects it is surprising that the finger position
of holding a transducer has almost never been described in lec-
tures and books about echocardiography, whereas in every book
about musical instruments instructions of hand and finger posi-
tions, and illustrations of fingering charts are given.
In transthoracic echocardiography there is a complex inter-
action between the eyes, the brain, and the hand muscles to co-
ordinate looking to a monitor to detect incongruities between
the actual view and defined views and to correct them by manual
manoeuvres to get the standardized views. Thus, it is like ‘seeing’
the heart with your hands. A basic position of the transducer in
the hand is necessary to get the orientation for the scan procedure
for an easy, but controlled change of a sectional plane. This im-
plies that a defined holding of the transducer is always linked to a
Fig. 1.1  Correct relaxed holding of the transducer using the right hand. The transducer lies on the fourth and fifth finger without any muscle tension (a), the
pulp of the thumb only has contact to the notch of the transducer (b). The pulps of the fourth and fifth finger have contact to the skin (c) and the feeling of
this transducer holding is combined with the parasternal log axis view (d).
defined hand position which has to be linked with a defined view.
In echocardiography in adult patients, the echocardiographic in-
vestigation normally starts with the left parasternal approach. It is
obvious that the basic holding of the transducer should be linked
to the long-​axis view of the left ventricle. In consequence, all pos-
sible long-​axis views that can be acquired between the position of
the left parasternal and the apical approach should be linked to
this defined hand-​holding of the transducer. If you change your
basic position of holding the transducer during the scanning pro-
cedure of the same sectional plane, the imagination and associ-
ation of the individual coordinates of the heart within the thorax
will be lost by the investigator, which means that he will become
disoriented or blind during scanning.
It has to be mentioned and emphasized, that scanning is possible
with the right as well as with the left hand. The argument for a cor-
rect scanning technique is always the acquisition of standardized
images with high image quality. Thus, echocardiographic scanning
can be performed as the investigator is, or has been, taught how
to do it. The author of this chapter, however, scans with the right
hand. Thus, the images of how to hold the transducer and adjust the
finger positions are shown for right-​hand scanners.
To get a stable position for the transducer holding, all fingers
are generally lifted and not extended. The pulps of the fourth
and fifth fingers conveniently lie on the small edge of the trans-
ducer without any muscle tension (E Fig. 1.1a). The pulp of
the thumb is con­veniently placed on the notch of the transducer
without any muscle tension (E Fig. 1.1b). This convenient re-
laxed transducer holding has to be conceptionally combined with
 Principles of t r a n sthor aci c echo ca rdi o g r a phy — pr acti c a l aspe c ts 5

Fig. 1.2  Examples of inconveniently holding the transducer. In (a) the fourth and fifth finger are between the transducer and the skin like writing with a
pencil. No stable contact to the skin results in non-​stabilization of the transducer. In (b) the holding is like encompassing a horizontal bar. Thus, rotation of the
transducer is not performed by the hand—​it has to be done by the shoulder and/​or cubital joint. In (c) the thumb is too extended and the pulp of the thumb
is not at the notch causing a blind feeling when moving or rotating the transducer. In addition, the mistake in Fig. 1.2a is also seen. In (d) no finger has contact to
the skin. Thus, every trembling of the hand is bridged to the transducer and consequently to the images on the monitor. It is also not possible to get a basis for a
defined flipping, tilting, and rotation, because the starting position is not stable.

the basic position of the transducer in the parasternal long-​axis
view of the heart (E Fig. 1.1c, d). The loss of the feeling for the
notch and extended or tensed fingers in the starting position
will induce discomfort and restrict the degrees of freedom for
the movement of the transducer. Thus, wrong transducer hold-
ings (E Fig. 1.2a–​d) will lead to disorientation and difficulties
in fine-​tuning for adjusting correct standardized views. An often
observed mistake is not to fix the fourth and fifth finger on the
skin of the patient, leading to an unstable transducer position.
With tilting over the small edge using the transducer holding of
this starting position in the long-​axis view, the mitral valve, for
example, can be moved from the right to the left and vice versa
without losing the long-​axis view.
A clockwise rotation of the transducer from the starting pos-
ition is easy (E Fig. 1.3a), because there is free space to turn
the thumb clockwise by bending backwards the fourth and fifth
fingers (E Fig. 1.3b, c). A 90° rotation is easily possible and thus,
you will get the feeling of rotating exactly 90° clockwise at the
left parasternal window to visualize a correct short-​axis view (E
Fig. 1.3d).
After acquisition of the necessary parasternal short-​axis views
the transducer is rotated counterclockwise back to the cor-
rect long-​axis view. The correct position of the apical window
and the correct apical long-​axis view can be achieved by sliding
down from the parasternal window to the apex without losing
the sectional plane of the long-​axis view (E Fig. 1.4). At the
end of this movement the right hand can support itself against
the thorax with the complete auricular finger (E Figs. 1.5a, b).
Fingers placed between the transducer and the thorax in this pos-
ition will disturb or inhibit the correct documentation of apical
standard views by positioning the transducer too perpendicular
to the body surface inducing a right twisted position of the heart
within the scan sector and/​or foreshortening views. Without
tilting and flipping the correct apical long-​axis view, a clockwise
rotation of exactly 60° can be performed (E Fig. 1.5c) to visu-
alize a correct 2-​chamber view (E Fig. 1.5d).
Combining a defined transducer holding always with the long-​
axis view and getting the stable feeling for this combination are
the prerequisites for target-​controlled scanning and the accurate
assessment of cardiac structures. It is obvious that minimal ma-
nipulations of the transducer position can be easily performed
and stably fixed using the correct scanning technique. Thus, a
correct scanning technique is the prerequisite for images with at
least best possible image quality.
The aim of a sufficient transthoracic, and also transoesophageal,
echocardiographic investigation should be an almost reprodu-
cible standardized documentation, which enables an accurate
diagnostic analysis for correct decision-​making. A standardiza-
tion of the documentation enables a comparison between cur-
rent and previous findings to detect changes, improvements, or
6 CHAPTER 1   C on v ent ional ech o cardio gr a phy — basi c pri n ci pl es

Fig. 1.3  Starting with the correct holding of the transducer for displaying the parasternal long-​axis view (a) the transducer is exactly rotated 90° clockwise (b),
after this movement the pulp of the thumb is at the broad side of the transducer at the top and the third finger is at the broad side of the transducer at the
bottom (b), while the fourth and fifth finger are retracted (c), but they have still contact to the skin. This holding is linked with all parasternal short-​axis views (d).

Fig. 1.4  Photo composition of the transducer holding for the different long-​axis views between the standardized parasternal approach and the standardized
apical approach. On the left side the different holdings at the correct parasternal position, at a position between the parasternal and apical position, as well as at
the correct apical position are shown. In the centre the photomontage of all transducer holdings is shown documenting the plane of all long-​axis views. On the
right side the corresponding views are shown.
 Standardized data ac qu i si ti on i n tr a n sthor aci c echo ca rdi o g r a ph y
Fig. 1.5  With the transducer holding of the parasternal long-​axis view
the hand is slid down to the apical long-​axis view (a). At the position of
the apical long-​axis view the fourth and fifth finger still remain on the skin.
In addition, the complete ulnar area of the fifth finger is placed in position
against the thorax for scanning from the apical approach (a). This transducer
holding is linked with the apical long-​axis view (b). A clockwise rotation of
60° without tilting and flipping has to be done (c) to get the correct apical
2-​chamber view (d).
deterioration of the cardiac state in follow-​ups. Furthermore, the
more standardization is present, the more intra-​and interobserver
variability is reduced. The basis for the correct configuration of an
echocardiographic data acquisition and examination—​including
data acquisition, data documentation, data storage, interpretation,
and reporting of the results—​as well as the correct measurements
and calculations of numerical values in echocardiography is pro-
vided by already published national and international guidelines
and position papers.
Principles of image optimization and
identification of artefacts—​practical
aspects
The echocardiographic images of all modalities are reconstructed
by modern techniques using the physical properties of the ultra-
sound waves interacting with the cardiac and thoracic tissue.
Thus, basic knowledge about the physics of ultrasound is neces-
sary to understand the image reconstruction—​especially with
respect to the possibilities of imaging optimization and the iden-
tification or detection of artefacts.
Ultrasound waves (E Fig. 1.6a–​f ) (E Fig. 1.7a–​d) in echocar-
diography are generated by voltage-​induced vibrations of piezo-
electric crystals of the transducers forming an ultrasound beam
7
which interacts with the tissue. The mapping of cardiac struc-
tures depends on the reflection of the ultrasound waves due to the
travel time between transducer and the respective reflexion zone
and its way back as well as the intensity of reflection. However, re-
flection is only one interaction with the tissue. Refraction, disper-
sion, and attenuation are also contributors to the image quality of
the reconstructed cardiac structures. Thus, acoustic impedances
and the orientation of boundaries in relation to the ultrasound
beams between two different tissues have major impacts on the
receiving ultrasound signals at the transducer for the final image
reconstruction.
With respect to the acoustic window in each patient the
imaging settings have to be altered and optimized to illustrate
the respective cardiac structures in an adequate fashion. The
most important issue to get an optimal image quality is the cor-
rect positioning of the transducer. The most important technical
factors influencing echocardiographic parameters are listed in
E Table 1.1.
Artefacts in echocardiography are created by the interactions of
ultrasound waves with the tissue and by the image reconstruction
algorithms due to beam formation properties. Despite the visual-
ization of artefacts being compatible with the physical laws of re-
flection and refraction, artefacts are not consistent with the usual
assumptions of ultrasound imaging. The common assumptions
of ultrasound imaging are (1) ultrasound travel time is related to
a specific speed (1540m/​s), (2) ultrasound waves are attenuated
uniformly, (3) acoustic reflection of ultrasound waves occurs just
once at a reflector after transmission and (4) the ultrasound trans-
mission is formed by a main thin beam.
Artefacts will be created mainly in the presence of strong
reflectors causing multiple reflections between the reflectors.
Artefacts have to be recognized to avoid misinterpretations.
Sometimes artefacts can be avoided or minimized by chan-
ging the ultrasound settings or by changing the scanning mo-
dalities (E Fig. 1.8a–​c, Fig. 1.9a–​f, Fig. 1.10a–​d, Fig. 1.11a–​d,
Fig. 1.12a–​d). The common artefacts observed in 2D-​, spectral,
and colour Doppler echocardiography are listed and described
in E Table 1.2.
Standardized data acquisition in
transthoracic echocardiography
Left parasternal and apical scanning should normally be per-
formed in left lateral position of the patient.
The transthoracic echocardiographic examination should
start with the correct documentation of the conventional two-​
dimensional left parasternal long-​axis view of the left ventricle
(E Fig. 1.13a–​b). This sectional plane is characterized by the
centre of the mitral valve, the centre of the aortic valve, as well
as by the ‘imaginary’ cardiac apex, which cannot be visualized
from the parasternal approach due to the superposition of the
left lung. The following anatomical structures are visualized by
8 CHAPTER 1   C on v ent ional ech o cardio gr a phy — basi c pri n ci pl es

Fig. 1.6  Impact of ultrasound frequency on 2D-​echocardiography: parasternal long-​a xis view in the same patient using low (a) and high (b)
frequencies—​transoesophageal long-​axis view in the same patient using low (c) and high (d) frequencies (better spatial resolution with higher frequencies,
but less penetration). Impact of ultrasound frequency on Doppler echocardiography: transmittal pulsed-​wave Doppler spectrum with low (e) and high
(f) frequencies (sharper contours with higher frequencies, but less penetration). Impact of gain and low velocity reject on Doppler echocardiography:
transaortic continuous wave Doppler spectrum with low (e) and high (f) gain and adjusted low velocity reject (f) (better contour detection of the velocity
spectrum after adjustment)

the parasternal long-​axis view. In the nearfield of the transducer,
the first myocardial structure is the free right ventricular wall—​
normally parts of the right ventricular outflow tract. The left ven-
tricular cavity in the longitudinal section is surrounded by the
midbasal anteroseptal and posterior regions of the left ventricle.
The mitral valve is sliced in the centre of the valve plane nearly
perpendicularly to the commissure. The aortic valve is also sliced
in the centre of the valve in longitudinal direction. The aortic root
and the proximal part of the ascending aorta are longitudinally
intersected. Behind the aortic root the left atrium is longitudin-
ally intersected. The posterior left ventricular wall is bordered by
the posterior epicardium and the diaphragm. The far field of the
parasternal long-​axis view should include the cross-​section of
the descending aorta behind the left atrium. A standardized left
parasternal long-​axis view can be verified by the following display
of the heart within the sector. The mitral valve has to be centred
in the scanning sector. Then, the ventral boundary of the mid-​
anteroseptal region of the left ventricle on the left side has to be
in line with the ventral boundary of the ascending aorta on the
right side of the sector. Furthermore, the check of the correct lon-
gitudinal parasternal long-​axis view should include the ascending
aorta visualized as a tube and not as an oblique section, the cen-
tral valve separation of the mitral and aortic valves, as well as the
missing of papillary muscles. If papillary muscles are sliced, the
sectional plane is not in the centre of the left cavity, which corres-
ponds to a non-​standardized view. For qualitative assessment of
flow phenomena at the mitral and aortic valves, as well as for the
detection of perimembranous ventricular septal defects, a colour-​
coded 2D cineloop of the left parasternal long-​axis view can be
added to the documentation (E Fig. 1.13c–​d).
With respect to the documentation of the right heart, tilting the
transducer to the sternal regions enables the visualization of the
right ventricular inflow tract with a longitudinal sectional plane
through the tricuspid valve (E Fig. 1.14a–​b). Tilting the long-​
axis view to the lateral regions of the heart enables the visualiza-
tion of the right ventricular outflow tract with the longitudinal
 Standardized data ac qu i si ti on i n tr a n sthor aci c echo ca rdi o g r a ph y 9

Fig. 1.7  Impact of ultrasound frequency on colour Doppler

echocardiography: apical long-​axis view in a patient with
mitral regurgitation using adjusted (a) and too high (b)
Doppler frequency (jet area is not visualized with too high
frequencies due to loss of penetration). Impact of colour
pixel size on colour Doppler echocardiography: parasternal
long-​axis view in a patient with aortic regurgitation using
adjusted (c) and smoothed (b) Doppler settings (jet area
and vena contracta are enlarged with wrong ultrasound
settings—​right image).

Table 1.1  Targets for imaging optimization in echocardiography

Imaging Target: physical background
and explanation for image
reconstruction
2D-​axial spatial resolution—​axial
resolution in the direction of the
alignment of the ultrasound beam is
very good (M-​Mode). Spatial resolution
is related to ultrasound frequency and
the bandwidth of the transducer.
2D-​axial lateral resolution—​lateral
resolution is less than axial resolution
and depends on the density of
ultrasound beams (and secondary to
ultrasound frequency).
2D-​Contrast—​contrast will be
influenced by penetration and by the
grey-​scale range.
Button of the ultrasound machine and
its alterations
Ultrasound frequency—​the higher the
ultrasound frequency the better the
spatial resolution. The bandwidth of the
transducer cannot be changed.
Angle size—​the smaller the angle the
better the lateral spatial resolution.
Ultrasound frequency—​The better
penetration (e.g. by decreasing ultrasound
frequency) the better the contrast.
Compression—​the lower the compression
(= less grey levels in a predefined range)
the better the contrast.
Potential important effects of
diagnosis
With poor spatial resolution
delineation of reflections are
suboptimal. Thus, distances
and areas will be measured too
small than they normally can be
visualized.
With poor lateral resolution
distances between reflection
boundaries will be measured too
small (e.g. left ventricular outflow
tract), reflection zones itself will
be measured too broad (e.g.
coaptation length of the aortic valve
in a parasternal long-​axis view).
Increasing contrast enhances the
risk of non-​detection of structures
with low echogenicity, e.g. abscess
formation in patients with
endocarditis or recently originated
thrombus formations.
Optimization of the image
quality and potential adverse
effects
Use higher ultrasound frequencies
to get sharper images. However,
loss of ultrasound penetration
is related to the increasing
ultrasound frequencies.
Measurements of cardiac
structures should be measured
preferably in axial direction.
If measurements in lateral
orientation have to be performed,
the smallest angle should be used.
Depending on the excellence of
the acoustic window the 2D grey
levels have to be adjusted carefully
with respect to the potential
diagnosis. In cases of doubt higher
compression in the presence of
sufficient penetration is better.
(continued)
10 CHAPTER 1   C on v ent ional ech o cardio gr a phy — basi c pri n ci pl es
Table 1.1  Continued
Imaging Target: physical background
and explanation for image
reconstruction
2D-​Brightness—​brightness of the
ultrasound image is influenced by the
brightness of the surrounding. The
more light in the surroundings, the
more brightness is necessary to detect
cardiac structures.
Sharpness of the pw-​and cw Doppler
spectrum—​the sharpness of the
Doppler spectrum is influenced by
multiple ultrasound settings.
Brightness of colour-​coded Doppler
signal in relation to the grey-​scale
image—​the more brightness of colour,
the more overlay of the tissue by the
colour.
Blood flow velocities of the colour-​
coded Doppler signal—​the lower the
blood flow velocities, the darker the
colour-​coded Doppler signal.
Sharpness of the colour-​coded Doppler Colour Doppler ultrasound frequency—​
signal in relation to the grey-​scale
image—​the sharpness of the colour
Doppler signal is influenced by multiple
ultrasound settings.
Colour low velocity reject—​the higher
Smoothing algorithm of the colour
Button of the ultrasound machine and
its alterations
2D gain—​the higher the gain, the brighter With increasing gain distances
and thicker the reflection patterns of the and areas will be measured too
ultrasound image.
Doppler frequency—​the higher the
Doppler frequency, the better the
sharpness of the spectrum.
Scale—​the better the adjustment of the
signal amplitude to the scale, the better
the resolution of the spectrum.
Low velocity reject—​the higher low
velocity reject, the less tissue Doppler
signals. It has to be adjusted with
alterations of the scale.
Sample volume—​The larger the sample
volume, the brighter the pw Doppler
signal and the lower the sharpness.
Doppler gain—​the higher the Doppler
gain, the brighter the spectrum.
Doppler compression—​the lower the
compression, the brighter the spectrum.
Colour Doppler gain—​the higher the
colour Doppler gain, the higher the
intensity of the colour and the more
overlay of tissue by the colour is present.
Colour Doppler Scale—​low blood flow
velocities will be better visualized with
decreasing colour Doppler scale.
the higher the colour Doppler
frequency, the better the elucidation
and sharpness of the colour signal, but
the less penetration of the colour signal.
low velocity reject, the brighter the
colour signal.
signals—​the colour pixels can be
smoothed with respect to radial and
lateral resolution. The more smoothing,
the brighter the pixels.
Potential important effects of
diagnosis
small than they normally can be
visualized. With decreasing gain
structures cannot be detected in
bright surroundings.
With increasing Doppler frequencies
penetration will be reduced.
Thus, depending on the acoustic
properties and by using inadequate
adjustment of scale, low velocity
reject and gain, signals can be lost
out of the detection range. With
decreasing compression maximum
velocities in pw Doppler spectra will
not be visualized, if the alignment of
the ultrasound beam is not exactly
in the regions of the central blood
flow with the highest velocities.
With increasing colour Doppler
gain distances and areas will be
measured too large than they
normally can be visualized (e.g.
especially jet flow areas). Blood flow
jet formations of turbulences will
be better visualized perpendicular
to the ultrasound beam due
to the better axial resolution in
comparison to the lateral resolution
(e.g. vena contracta of a mitral
regurgitation in the parasternal
long-​axis view).
With decreasing colour Doppler
scale low flow regions will be better
elucidated with colour. Thus, flow
areas in cardiac cavities will be
depicted larger than using higher
Doppler scales (e.g. especially jet
flow areas).
If the sharpness of the colour-​coded
Doppler signal is not optimized,
all important semi-​quantitative
parameters of grading valvular
heart diseases, e.g. vena contracta,
proximal convergence areas,
regurgitant orifice areas will be
determined too large.
Optimization of the image
quality and potential adverse
effects
In dark rooms, e.g. a typical
ultrasound laboratory, normally
lower gain settings should be
used than in bright rooms, e.g.
in the theatre or emergency
department.
In general, Doppler spectra have
to be adjusted with an optimal
alignment to the central blood
stream. In cases of doubt avoid
ranges of lower compression and
adjust Doppler frequencies and
sample volume (if pw Doppler
is used) with respect to the
penetration of the ultrasound.
Colour Doppler gain has to be
adjusted at clear boundaries
to tissue. Normally adjustment
should be performed in the
left ventricular outflow tract.
Overlapping of colour and
tissue should be minimized to
a distance of about 1 mm with
respect to the penetration and
quality of the acoustic window.
Colour Doppler scale has
to be adjusted to the flow
phenomenon which has to be
analysed. Thus, if venous flow
should be visualized, normally
lower colour Doppler scales will
be used than in the presence of
high flow conditions.
The sharpness of the colour-​
coded Doppler signal has
to be adjusted to the flow
phenomenon which has to be
analysed. The most challenging
problem is the loss of colour
penetration by the attempts to
improve the signal quality. Thus,
in cases of doubt avoid ranges
no smoothing algorithms should
be used and an adequate colour
signal has to be visualized in the
region of interest when colour
Doppler frequency is increased.
 Standardized data ac qu i si ti on i n tr a n sthor aci c echo ca rdi o g r a ph y
sectional plane through the pulmonary valve (E Fig. 1.14c–​d).
These views should also be documented using colour-​coded 2D
cineloops (E Fig. 1.14e–​h).
The 90° clockwise rotation of the transducer from the trans-
ducer position of the correctly set parasternal long-​axis view
will lead to sectional short-​axis views of the heart. The correct
transducer position to display standardized parasternal short-​
axis views using conventional transthoracic echocardiography
is documented by a M-​mode sweep (E Fig. 1.15a). Parasternal
short-​axis views should be documented with respect to an ac-
curate definition of the plane according to cardiac structures,
which enables a high reproducibility of each view. Short-​axis
views are defined by the accurate cross-​section through the left
ventricular attachment of the papillary muscles (E Fig. 1.15b),
through the papillary muscles (E Fig. 1.15c), through the chord
heads, as well as the chord strands (E Fig. 1.15d), through the
mitral valve (E Fig. 1.15e), through the interatrial septum and
the left ventricular outflow tract (E Fig. 1.15f), through the
aortic valve (E Fig. 1.15g), the aortic root and the proximal
ascending aorta (E Fig. 1.15h), as well as by a nearly longitu-
dinal plane through the pulmonary trunk and the bifurcation
of the pulmonary arteries (E Fig. 1.15i). The acquisition of a
correct M-​mode sweep is performed within 6–​12 cardiac cycles
using the cursor in the centre line of all parasternal short-​axis
11
Fig. 1.8  Impact of colour pixel size on colour Doppler
echocardiography: apical long-​axis view in a patient with mitral
regurgitation using adjusted (c) and smoothed (b) Doppler
settings (jet area and vena contracta is enlarged with wrong
ultrasound settings—​right image). Impact on 2D-​gain on
Doppler echocardiography: apical long-​axis view in a patient
with mitral regurgitation using adjusted (a) and too high (b) 2D-​
gain (jet area and vena contracta are not visualized with too high
2D-​gain settings).
views by scanning through the left ventricle over the long axis
of the left ventricle by tilting the transducer starting from the
short-​axis view between the papillary muscles up to the cranial
short-​axis view of the centrally intersected aortic valve and as-
cending aorta (E Fig. 1.15a). By deriving M-​modes and M-​
mode sweeps in the short axis, it can always be checked whether
the left heart is sliced exactly in its centre line or only a secant
view of the left ventricle is documented. This fact favours the ac-
quisition of M-​modes using short-​axis views instead of a long-​
axis view. The correct transducer position is documented in the
M-​mode sweep by a horizontal line between the border of the
ventral septum and the border of the ventral ascending aorta.
The alternative to document the correct transducer position in
the long-​axis view simultaneously to the short-​axis views is only
possible by biplane scanning. The problem of isolated short-​axis
views is the fact that the transducer position is too much lateral
or caudal, which causes an oval conformation of the ventricular
wall at the level of the left ventricle. The consequence for meas-
urements of left ventricular dimensions and wall thicknesses is
that the left ventricular cavity is measured too large and the ven-
tricular wall is measured too thick (E Fig. 1.16).
For training aspects and to document manual skills of target-​
oriented scanning, the correct acquisition of the M-​mode sweep
should be integrated into the educational process like a driver’s
12 CHAPTER 1   C on v ent ional ech o cardio gr a phy — basi c pri n ci pl es
(a)
Fig. 1.9  Impact of the Nyquist limit (scale) on colour
Doppler echocardiography: apical long-​axis view in a patient
with mitral regurgitation with different colour scales—​
maximum velocity of 11 cm/​s presents all flow signals above
the Nyquist limit (a), maximum velocity of 44 cm/​s presents
adequate blue flow signals in the ventricle during systole,
but overall turbulences in the left atrium (b) and maximum
velocity of 66 cm/​s presents flow signals of the regurgitation
adequately to the velocities of the jet (c). Impact of the
Nyquist limit (scale) on the proximal convergence areas in
colour Doppler echocardiography: zooming of an apical (d)
long-​axis view in a patient with mitral regurgitation with
different colour scales—​with increasing scale from 37 cm/​s
(d) to 48 cm/​s (e) and 58 cm/​s (f) the radius of the proximal
convergence zone becomes smaller.
licence for echocardiography. For clinical practice the correct M-​
mode sweep represents a characteristic profile of the individual
human heart.
According to European recommendations, however, it is not
mandatory to acquire the M-​mode sweep. The standard docu-
mentation includes only parasternal short-​ axis views at the
mid-​papillary level, at the mitral valve level and at the aortic
level. In all parasternal short-​axis views the centre of the left ven-
tricle or the aortic valve should be in the middle of the scanning
sector. Near the transducer the parasternal short-​axis view at the
mid-​papillary level (E Fig. 1.17a–​d) shows the free right ven-
tricular wall, the right ventricular cavity, all mid-​segments of
the left ventricular wall (near the transducer: anteroseptal—​0°;
then clockwise: anterior—​ 60°; lateral—​ 120°; posterior—​ 180°;
inferior—​240°; inferoseptal—​300°), the left ventricular cavity, the
anterolateral transversal mid-​papillary muscle between 60° and
90° at the inner wall of the left ventricle and the posteromedial
transversal mid-​papillary muscle between 210° and 240° at the
inner wall of the left ventricle. The parasternal short-​axis view
at the mitral valve level (E Fig. 1.18a–​d) shows the free wall of
the right ventricular outflow tract, the cavity of the right ven-
tricular outflow tract, all basal segments of the left ventricular
wall and the left ventricular cavity, near the transducer in the left
(b) (c)
(e) (f)
ventricular cavity the anterior mitral leaflet, which is anatomic-
ally one leaflet but can be described by three portions (the A1-​
scallop near the anterolateral left ventricular wall, the A2-​scallop
in the centre of the anterior mitral leaflet, the A3-​scallops near the
posteromedial left ventricular wall) and far from the transducer
in the left ventricular cavity the posterior mitral leaflet, which is
divided anatomically into three scallops (the P1-​scallop near the
anterolateral left ventricular wall, the P2-​scallop in the centre of
the posterior mitral leaflet, the P3-​scallops near the posteromedial
left ventricular wall). The parasternal short-​axis view at the aortic
valve level (E  Fig. 1.19a–​d) is characterized by the following car-
diac structures. The basal free wall of the right ventricular out-
flow tract is near the transducer. The right ventricular cavity is
bounded on the left side of the sector by the tricuspid valve and
on the right side by the pulmonary valve. The aortic valve is in
the centre of the sector behind the right ventricle. During dia-
stole the right coronary cusp is ventrally located, the left coronary
cusp is between 60° and 180°, and the non-​coronary cusp is be-
tween 180° and 300°. Close to the commissure between the right
and the left coronary cusp at the aortic valve annulus, the dorsal
cusp of the longitudinally intersected pulmonary valve is located.
Close to the commissure between the right and the non-​coronary
cusp at the aortic valve annulus, the septal leaflet of the tricuspid
 Standardized data ac qu i si ti on i n tr a n sthor aci c echo ca rdi o g r a ph y 13

Fig. 1.10  Parasternal short-​axis view (a) and a corresponding M-​Mode (b) with increased depth to document reverberation artefacts due to strong reflectors.
The epicardium represents one strong reflector (thick red arrow) causing a reverberation signal in the far field (thin red arrow) as well as comet tail artefacts
(yellow arrows). In addition the mirroring of the posterior wall is shown (green lines). In the M-​Mode the parallel movement of the artefact in relation to the
reflector is labelled by the red arrows. The biplane parasternal view with the short axis characterized by the white line in the parasternal view documents again
the strong reflector (red arrow), comet tail artefacts (yellow arrows) and mirror artefacts (green lines). In addition the reverberations of the mitral valve are seen
in the long axis as well as in the short-​axis view (blue arrows). It has to be mentioned that the mitral valve as the reflector is not visualized in the short-​axis view
(c). A reverberation artefact mimicking a dissection membrane in the ascending aorta is shown in (d).

valve is located. At the far side of the aortic valve, the left atrium
is shown. Close to the aortic valve annulus, near to the non-​
coronary cusp, the perpendicular intersected interatrial septum is
located. Between the aortic valve and the left atrium, the fibrotic
aorticomitral junction is located. Between the interatrial septum
and the tricuspid valve is the right atrium.
It has to be mentioned that all parasternal short-​axis views dis-
play the cardiac structures mirror-​inverted.
The colour-​coded short-​axis views through the mitral and
aortic valve are additionally suitable for qualitative analysis of
the location of mitral valve regurgitation and semi-​quantification
of aortic valve regurgitation by analysing the regurgitant orifice
during diastole.
From the parasternal approach, colour-​coded and pulsed
spectral Doppler imaging of the right ventricular outflow tract
or the pulmonary valve should be generally added to a standard
documentation in order to calculate the cardiac output of the
right heart and to estimate the pulmonary pressure by acceler-
ation time and the morphology of the flow profile, retrospect-
ively (E Fig. 1.20a–​e). If pulmonary regurgitation is present,
and right heart or pulmonary diseases are suspected, a con-
tinuous wave Doppler spectrum through the pulmonary valve
should be documented to estimate end-​diastolic and mean pul-
monary pressure by the end-​diastolic and maximal velocities of
the regurgitant flow.
The locating of the transducer directly at the cardiac apex is
essential for the documentation of the correct apical sectional
planes. This is possible by guiding the transducer to the correct
apical position by sliding in caudolateral direction on the skin of
the patient from the correct transducer position of a standardized
parasternal long-​axis view to the correct transducer position of a
standardized apical long-​axis view (E Fig. 1.21). The apical long-​
axis view is characterized by the same cardiac structures as the
parasternal long-​axis view (E Fig. 1.21). The standardized apical
14 CHAPTER 1   C on v ent ional ech o cardio gr a phy — basi c pri n ci pl es

Fig. 1.11  Transoesophageal simultaneous 2D-​

and colour-​coded Doppler short-​axis views of the
descending aorta. The distal aortic wall represents
a strong reflector (red arrow). Comet tail artefacts
are labelled by yellow arrows. The mirror artefact of
the colour flow (green line) is shown by the different
colour signal in red inside the aorta and in blue inside
the artefact of the aortic cavity. Near field clutter
in a transoesophageal 2D-​short-​axis view of the
descending aorta is presented in (b). Mirror artefacts
of the aortic valve within the right ventricular
outflow tract (green lines) are shown in (c). In a
corresponding biplane transoesophageal colour-​
coded view the colour mirror artefacts of the aortic
regurgitation (green lines) are shown in (d).

long-​axis view is additionally characterized by the tip of the car-
diac apex, which is directly below the transducer surface and the
centre of the mitral valve in the centreline of the scanning sector.
The centred display of the left ventricle is essential for the correct
documentation of the apical 2-​and 4-​chamber view by rotation
of the transducer without tilting and flipping at the correct apical
transducer position. If the centreline of the left ventricle is not
centred in the sector of the apical long-​axis view, rotation of the
transducer obviously will produce foreshortening views of other
sectional planes of the left ventricle.
Oblique apical views in normal hearts and failing standardiza-
tion can be checked by the configuration of the apical shape of
the left ventricular cavity. In normal hearts with a normal elec-
trocardiogram, the apex of the left cavity shows a peaked, ‘gothic’
configuration (early ‘gothic’ in the 4-​chamber view, mid ‘gothic’
in the long-​axis view, and late ‘gothic’ in the 2-​chamber view).
In normal hearts a ‘Romanic’ configuration is obtained due to
foreshortening views.
Due to guiding to the apical transducer position by sliding down
from the parasternal long-​axis view to the apical long-​axis view,
the apical transthoracic echocardiographic examination should
start with the two-​dimensional imaging of the left ventricle in the
apical long-​axis view (E Fig. 1.21a–​b). The apical long-​axis view
of the left ventricle is normally perpendicular to the commissure
of the mitral valve. Thus, the long-​axis view shows the functional
division of the left ventricle into the complete inflow chamber
during diastole at fully opened mitral valve and the movement of
the anterior mitral leaflet close to the anterior septal wall, as well
as into the complete outflow chamber during systole by complete
closure of the mitral valve. Monoplane planimetry of the left ven-
tricle is performed using the apical long-​axis view for estimation
of global left ventricular function by determination of the ejection
fraction. The apical long-​axis view is also used for visual analysis
of regional wall motion in the posterior and anteroseptal regions,
as well as for morphological evaluation of the mid scallops of the
mitral valve (A2-​/​P2-​scallop).
The 2D-​view is followed by the colour-​coded apical long-​axis
view (E Fig. 1.21c–​d) to assess mitral and aortic valve function
qualitatively. Because the long-​axis view shows best the blood flow
direction into and out of the left ventricle, determinations of prox-
imal jet width or vena contracta, as well as proximal isovelocity
surface areas in the presence of turbulent flow at the mitral
and aortic valve can usually be well performed in this sectional
plane—​especially for central mitral and aortic lesions. According
to guidelines, jet morphology and jet size of mitral and aortic
regurgitation is not recommended anymore for assessing the
 Standardized data ac qu i si ti on i n tr a n sthor aci c echo ca rdi o g r a ph y 15

Fig. 1.12  Profile view of a Medtronic Hall

prosthetic valve in mitral position (a) presenting
mirror artefacts (green lines) and attenuation
artefacts (blue arrows). In the perpendicular view
(b) refraction artefacts can be demonstrated
(red arrow). The prosthesis itself acts as the
strong reflector producing all artefacts. The
transoesophageal long-​axis view of a mechanical
prosthesis in aortic position (c and d) displays
the mirror artefact of the prosthesis projected
into the right ventricular outflow tract is shown
in c. In addition the side lobe artefact of the
distal part of the prosthesis is shown in d.

Table 1.2  Common artefacts observed in echocardiography

Artefact type Mechanism of the generation of
the artefact
Reverberation Reflection of proportions of the ultrasound
artefact wave on its way back to the transducer
by a second or multiple strong reflectors.
The interpretation of the artificial reflected
structure by assuming normal ultrasound wave
propagation is creating a second image or
multiple additional images in a larger distance
of the real image—​The distance between the
real image of the reflected structure and the
artefacts correspond to the distance between
the structure and the reflectors.
Comet tail Several repetitive strong reflectors can create
artefact a complex reverberation. Two or more strong
reflectors which are very close to each other
induce multiple reflections of the sound
wave between each other. Thus, transit times
between the reflectors induce multiple images
behind the true structure.
Identification of artefact
(including examples)
Strong reflector(s) should be identified
by parallel movement of the artefact(s)
and the true structure as well as by higher
echogenicity of the true structure in
comparison to the artefact (false ‘thrombus
formation’ in the left atrium and left atrial
appendage, false dissection flap in the
ascending aorta, false intracardiac tumours).
Strong reflectors at the origin of the
comet tails should be detected to explain
the phenomenon (aortic wall, posterior
epicardium in the parasternal view,
mechanical valves, leads of cardiac devices,
lung comets).
Mitigation of the problem
Alteration and changing of the transducer
position to avoid the strong reflectors
within the scanning plane.
It is important to mention that the
reflectors have not to be documented
in the sectional plane. Due to the
three-​dimensional propagation of the
ultrasound waves the strong reflectors
can be detected only by rotation of the
sectional plane.
Alteration and changing of the transducer
position to document the changing of
the position of the comet tail artefacts.
Normally these artefacts are easily to
identify. However, they impede the view
behind the origin of these artefacts.

(continued)
16 CHAPTER 1   C on v ent ional ech o cardio gr a phy — basi c pri n ci pl es

Table 1.2  Continued

Artefact type Mechanism of the generation of
the artefact
Mirror image The mechanism of mirror images is similar
artefact to reverberation artefacts. Again, a strong
reflector—​normally in the presence of a good
acoustic window—​is necessary to produce
mirroring. The ultrasound wave reflected from
distal strong reflector will be again reflected by
the cardiac structures on its way back, which
produces an image formation of an identical
mirror-​inverted image distal to the original
structure.
Side lobe Side lobe artefacts are related to the ultrasound
artefact beam properties and the ultrasound equipment,
because the side lobe reflections will be analysed
as central lobe reflections. Thus, a broad signal
with the curvature of the radius of the sector will
be created. Thus, the original structure is enlarged
on both sides producing a circumferential arc like
structure.
Beam width Beam width artefacts are also related to the
artefact ultrasound beam properties. The ultrasound
beam is hourglass shaped with the most
narrowing at the focal zone. If a strong reflector is
present in the near or far field, which have poorer
lateral and elevation resolution, this reflector can
produce an artefact in the focus region.
Refraction Refraction often occurs at strong reflectors with
artefact curved surface which are not perpendicular to
the ultrasound beam lines. Thus, some structures
act like a lens and the reflected waves are bent.
Thus, a second structure from a different location
is visualized.
Attenuation Acoustic shadowing is characterized by a strong
artefact reflector which impedes the view behind it. The
surface of the strong reflector is usually extremely
bright and distal to this signal the attenuating
is visualized as a dark comet-​like structure.
Multiple reflectors in the near field can produce
attenuation by reverberation in the far field.
Near field clutter These artefacts are induced by repeated
artefact oscillation of the transducer itself.
Identification of artefact
(including examples)
Mirror artefacts can be identified by
parallel mirror-​inverted movements of
cardiac structures. The most common
strong reflectors of mirror images
are the posterior epicardium in the
parasternal view and the wall of the
descending aorta in transoesophageal
echocardiography.
(Mirror artefacts mimic pleural effusion or
descending aneurysms in the far field).
This artefact is characterized by a very
strong reflector and the circular artefact
lines. (misinterpretation of e.g. vegetations imaging.
in calcified heart valves, of dissection flaps
in the ascending aorta, of flow signals
through the interatrial septum mimicking a
foramen ovale).
The detection of a strong reflector is
helpful for the explanation of beam width
artefact. Beam artefacts will be observed
in the presence of severe calcifications,
pacemaker leads and prosthetic valves.
(misinterpretation of vegetations or
thrombus formation in cardiac cavities).
Refraction artefacts will be depicted as
doubled images—​mostly mirror-​inverted.
Duplication of the prosthetic valves in
projection into cardiac cavities are the most
observed refraction artefacts. Moreover,
it is easy to recognize as anatomically the
duplicated structure cannot exist.
Calcification, ribs, and metallic material are
examples of inducing acoustic shadowing.
Lung tissue and breast implants can induce
bright attenuation artefacts.
Near field clutter has to be assumed in
all diffuse signals in the near field. Often
apical left ventricular thrombus formation
is assumed in apical views or aortic and left
atrial appendage thrombus formation in
transoesophageal echocardiography.
Mitigation of the problem
Alterations and changing the angulation
of the scanning plane can mitigate the
effects of the strong reflector.
Changing of the imaging modalities
between harmonic and fundamental
Alteration of the acoustic window and
changing of the focus area. In addition
sometimes reducing of 2D gain can be
helpful.
Double images can be avoided by
scanning from different positions. If the
surface of the reflectors is almost parallel
to the ultrasound beam, the artefact will
disappear.
The occurrence of these artefacts can
only be avoided by scanning with other
planes beside the reflectors. Sometimes in
the presence of shadowing increasing of
2D gain can be helpful.
Near field clutter can be mitigated
by switching from fundamental to
harmonic imaging in transoesophageal
echocardiography. It can be unmasked
by elucidating the respective cavity
by colour flow Doppler or contrast
echocardiography.

severity of mitral and aortic regurgitation. The derivations of the
pulsed-​wave Doppler spectra of the inflow and outflow tract of the
left ventricle should be performed in the apical long-​axis view due
to the clear positioning of the sample volumes (E Fig. 1.21e–​f ).
The sample volume of the pulsed-​wave Doppler spectrum at the
mitral valve for characterizing left ventricular inflow should be
positioned in the region of the transition of the mitral leaflets to
the chord strands (about 10–​15 mm towards the ventricle from
the mitral valve plane) in the centre of the flow direction into the
left ventricle. High-​quality pulsed-​wave Doppler spectra are de-
picted by bright contours at the maximum velocities. The sample
volume of the pulsed-​wave Doppler spectrum at the left ven-
tricular outflow tract has to be positioned in front of the aortic
valve (about 5–​10 mm towards the left ventricle from the aortic
valve plane).
The pulsed-​wave Doppler spectrum of the left ventricular in-
flow is necessary for characterization of diastolic function by
the E/​A-​ratio, as well as for calculation of E/​E′; the pulsed-​wave
 Standardized data ac qu i si ti on i n tr a n sthor aci c echo ca rdi o g r a ph y 17

Fig. 1.13  Standardized grey-​scale parasternal long-​axis view during systole (a) and diastole (c), as well as the corresponding colour-​coded images during systole
(b) and diastole (d). Additional comments in the text.

Fig. 1.14  Illustration for display of the right ventricular inflow tract and right ventricular outflow tract. Starting from the standardized parasternal long-​axis view
(red arrow and red surrounding), the right ventricular inflow tract is displayed by medial tilting (green arrow and green surrounding) of the sectional plane (a—​
systole, b—​diastole), the right ventricular outflow tract by lateral tilting (blue arrow and blue surrounding) of the sectional plane (c—​systole, d—​diastole). The
corresponding colour-​coded views are displayed in (e–​h). Additional comments in the text.
Fig. 1.15  Display of a standardized M-​mode sweep (a). The correct transducer position is documented by the M-​mode sweep by a horizontal line between
the ventral border of the anteroseptal septum and the ventral border of the aortic root (dotted line). Short-​axis views are defined by the accurate cross-​section
through the left ventricular attachment of the papillary muscles (b), through the papillary muscles (c), through the chord heads as well as the chord strands
(d), through the mitral valve (e), through the interatrial septum and the left ventricular outflow tract (f), through the aortic valve (g), the aortic root and the
proximal ascending aorta (h), as well as by a nearly longitudinal plane through the pulmonary trunk and the bifurcation of the pulmonary arteries (i). The red
arrows show the position of the respective short-​axis view in a M-​mode sweep. Additional comments in the text.

Fig. 1.16  Illustration of potential errors of measurements for left ventricular dimensions and wall thicknesses due to non-​standardization. If the parasternal
transducer position is too caudal and/​or too lateral, the aortic root drops down on the right side of the sector. This induces too large dimensions of the left
ventricular cavity and of the wall thickness (left side—​differences are displayed by the white arrows). Measurements using long-​axis views can be performed
using secant-​like sectional planes which induce too small dimensions of the left ventricular cavity and too large dimensions of the wall thickness (right side—​
differences are displayed by the white arrows). Additional comments in the text.
Standardized data ac qu i si ti on i n tr a n sthor aci c echo ca rdi o g r a ph y 19

Fig. 1.17  The standardized parasternal short-​axis

view at the mid-​papillary level. Additional comments
in the text.

Fig. 1.18  The standardized

parasternal short-​axis view at
the mitral valve level. Additional
comments in the text.
20 CHAPTER 1   C on v ent ional ech o cardio gr a phy — basi c pri n ci pl es
Fig. 1.19  The standardized parasternal short-​axis view at the aortic valve level. Additional comments in the text.
Doppler spectrum of the left ventricular outflow tract is manda-
tory for calculation of cardiac output or shunt volumes in case of
communication defects, as well as for calculation of aortic sten-
otic valve area according to the continuity equation.
In the presence of turbulences at the mitral and aortic valves,
the standard documentation should be completed by continuous
wave Doppler spectra over the mitral and the aortic valves. The
continuous wave Doppler spectrum over the mitral valve is ne-
cessary for determination of the velocity time integral in the
presence of mitral valve stenosis for determination of mean and
maximum pressure gradients, the determination of the stenotic
and regurgitant velocities, as well as for calculation of the par-
ameter dp/​dt for estimation of global left ventricular function.
The continuous wave Doppler spectrum over the aortic valve is
necessary for estimating aortic stenosis severity by determining
the mean and maximum pressure gradients and for calculation
of aortic stenotic valve area according to the continuity equation.
For semi-​quantification of aortic regurgitation, the pressure half-​
time method is used at the deceleration border of the regurgitant
velocities.
By an approximately 60° clockwise rotation of the transducer,
starting from the standardized apical long-​axis view, the correct
apical 2-​chamber view is obtained (E Fig. 1.22a–​b). The sec-
tional plane of the apical 2-​chamber view is characterized by
the left ventricular cavity tip, the inferior left ventricular wall
at the left side of the cavity, the anterior left ventricular wall at
the right side of the cavity, the centre of the mitral valve in its
commissural plane, the cross-​sectional coronary sinus in the re-
gion of the inferior mitral ring, the left atrium and the left atrial
auricle cranial to the mitral ring and the opening of the upper
left pulmonary vein cranial to the left atrial auricle. Near the
anterior region the P1-​scallop of the mitral valve is depicted,
near the inferior region the P3-​scallop. In the centre of the mi-
tral valve the A2-​scallop is normally seen. The apical 2-​chamber
view is used for visual assessment of global and regional left
ventricular function in the inferior and anterior regions of the
left ventricular wall and for the morphological evaluation of the
mitral valve. The colour-​coded 2-​chamber view is suitable for
characterization of the defect localization in mitral valve regur-
gitation (E Fig. 1.22c–​d).
 Standardized data ac qu i si ti on i n tr a n sthor aci c echo ca rdi o g r a ph y 21

Fig. 1.20  The standardized parasternal short-​axis view through the pulmonary valve and the pulmonary trunk at systole (a) and diastole (b). The
corresponding colour-​coded views are displayed in (c) and (d). In (e) the pulsed-​wave Doppler spectrum of the right ventricular outflow tract is shown.
Additional comments in the text.

After modifying the hand position of the transducer to enable
a further approximately 60° clockwise rotation of the transducer,
this isolated rotation will be performed from the correctly set
apical 2-​chamber view to get the standardized apical 4-​chamber
view (E Fig. 1.23a–​b). The correct apical 4-​chamber view is
characterized by the left ventricular cavity tip, the inferoseptal
left ventricular wall at the left side of the cavity, the lateral left
ventricular wall at the right side of the cavity, the centre of the
mitral valve (A2-​scallop, P2-​scallop near to the P1-​scallop), the
interventricular and interatrial septum, the cardiac crux, the
septal and the anterior leaflet of the tricuspid valve, the inflow
tract of the right ventricle, the free right ventricular wall and the
left and right atrium. It is essential that the origin of the anterior
mitral leaflet and the septal leaflet of the tricuspid valve is almost
at the same point near the cardiac crux. The standardized 4-​
chamber view does not show parts of the left ventricular outflow
tract or the longitudinal sectional plane of the coronary sinus. The
apical 4-​chamber view is used for visual assessment of global and
regional left ventricular function in the inferoseptal and lateral re-
gions of the left ventricular wall and for the morphological evalu-
ation of the central mitral valve.
Using the 2-​and 4-​chamber views, quantitative assessment of
left ventricular function is performed by left ventricular volume
analysis and determination of left ventricular ejection fraction
using the Simpson’s rule. It is recommended to check the longitu-
dinal length of the ventricle at end-​diastole in both views before
starting planimetry. If, for example, the longitudinal length of the
4-​chamber view is more shortened than 10 mm in comparison to
the 2-​chamber view, it is obvious that the 4-​chamber view has to
be foreshortened.
The colour-​coded 4-​chamber view (E Fig. 1.23c–​d) is ne-
cessary for characterization of the defect localization in mi-
tral valve regurgitation and for semi-​ quantification of the
tricuspid valve regurgitation by its vena contracta (E Fig.
1.24a–​c; E Fig. 1.24d–​f ). For complete semi-​quantification of
tricuspid valve regurgitation its vena contracta has to be add-
itionally measured in the apical right ventricular inflow tract
view derived by tilting the apical long-​axis view to the medial
regions (E Fig. 1.24g–​i). In the presence of turbulences at the
tricuspid valve, the continuous wave Doppler spectra over the
tricuspid valve have to be documented. The continuous wave
Doppler spectrum over the tricuspid valve is necessary for
22 CHAPTER 1   C on v ent ional ech o cardio gr a phy — basi c pri n ci pl es
Fig. 1.21  Standardized grey-​scale apical long-​axis view during systole (a) and diastole (b), as well as the corresponding colour-​coded images during systole
(c) and diastole (d). The pulsed-​wave Doppler spectrum of the left ventricular inflow through the mitral valve (e) and of the left ventricular outflow tract (f) is
displayed in the middle of the illustration. Additional comments in the text.
estimating the right ventricular systolic pressure according to
the simplified Bernoulli equation, which corresponds to the
systolic pulmonary pressure if no pulmonary stenosis is pre-
sent. Furthermore, the maximum velocity of tricuspid valve
regurgitation is necessary for estimation of the pulmonary
valvular resistance.
The 4-​chamber view is also used for the acquisition of the
pulsed tissue Doppler spectra for the calculation of E/​E′. The
sample volume is positioned at the basal inferoseptal and lat-
eral myocardium near the mitral annulus (E Fig. 1.25a–​d).
E′ for calculation of the E/​E′-​ratio is the mean E′ of both
values determined at the basal inferoseptal and lateral left ven-
tricular wall. The 4-​chamber view is also used for grey-​scale
and colour-​coded imaging of the upper right pulmonary vein
for documentation of the pulsed-​wave Doppler spectrum of
the pulmonary vein flow for analysis of diastolic function.
The sample volume has to be positioned into the left atrium
10–​15 mm ahead of the entry of the pulmonary vein. The
pulsed-​wave Doppler spectrum has to be acquired in low pulse
repetition frequency mode to prevent overlapping of the
signals of the flow through the mitral valve and the signals of
the pulmonary vein (E Fig. 1.26a–​e).
For the documentation of the anterolateral and posteromedial
commissure of the mitral valve, two further oblique views of
the apical 4-​chamber view have to be adjusted (E Fig. 1.27).
The documentation of the P3/​A3 scallops of the mitral valve (=
posteromedial commissure) is performed by tilting the trans-
ducer to the dorsal region of the left ventricle, which will show
the dorsal mitral annulus with the target structure of a longi-
tudinal section of the coronary sinus (E Fig. 1.27a–​d). The
documentation of the P1/​A1 scallops of the mitral valve (= an-
terolateral commissure) is possible by tilting the transducer to
the ventral region of the left ventricle, which will show the 5-​
chamber view (E Fig. 1.27e–​h). In the 5-​chamber view the left
ventricular outflow tract and parts of the aortic valve are visu-
alized. The 5-​chamber view is an oblique view through the left
ventricle, which shows the anteroseptal and anterolateral basal
segments of the left ventricular wall and the inferoseptal and
lateral apical segments of the left ventricle. The target structure
of the 5-​chamber view is the left ventricular outflow tract. Both
 Standardized data ac qu i si ti on i n tr a n sthor aci c echo ca rdi o g r a ph y
views should also be documented using colour-​coded Doppler
to analyse the localization of mitral valve regurgitation.
Subcostal and suprasternal scanning should be performed with
the patient in strict supine position.
Subcostal scanning should start with the subcostal 4-​chamber
view, which is easily adjusted by holding the transducer with the
orientation of the notch in the same direction as in the apical
23
Fig. 1.22  Standardized grey-​scale
apical 2-​chamber view during systole
(a) and diastole (b), as well as the
corresponding colour-​coded images
during systole (c) and diastole (d).
Additional comments in the text.
4-​chamber view during inspiration of the patient (E Fig. 1.28a–​
b). The subcostal 4-​chamber view shows the same cardiac struc-
tures as the apical 4-​chamber view. A counter-​clockwise rotation
shows the subcostal short-​axis views. The perpendicular view
to the interatrial septum in the subcostal short-​axis view of the
aortic valve is suitable for the detection of interatrial communica-
tion defects by colour-​coded Doppler imaging (E Fig. 1.28c–​f ).
24 CHAPTER 1   C on v ent ional ech o cardio gr a phy — basi c pri n ci pl es

Fig. 1.23  Standardized grey-​scale

apical 4-​chamber view during systole
(a) and diastole (b), as well as the
corresponding colour-​coded images
during systole (c) and diastole (d).
Additional comments in the text.

Subcostal short-​axis views of the mitral valve and the left ven-
tricle at mid-​papillary level can replace the parasternal short-​axis
views for analysis of the heart if the parasternal window is not
sufficient (E Fig. 1.29a–​h). The right ventricular inflow and out-
flow tract, as well as the pulmonary trunk and the pulmonary
bifurcation can be well visualized by the subcostal approach.
Due to the excellent Doppler angle, Doppler spectra through the
pulmonary valve can be achieved in this view (E Fig. 1.30a–​e).
By counter-​clockwise rotation from the subcostal 4-​chamber
view the longitudinal section of the inferior caval vein should be
documented for estimation of the preload of the right ventricle
(E Fig. 1.31a–​b). In the presence of normal right atrial pressure,
the central venous pressure is normal, which can be documented
by pulsatile wall movement and a complete breath-​dependent in-
spiratory collapse of the inferior caval vein. The right atrial pres-
sure is increased in patients with cardiac stasis on the right side,
documented by partial collapse or a complete loss of collapse of
the inferior caval vein during deep inspiration.
Principles of transoesophageal
echocardiography—​practical aspects
A transthoracic echocardiography should be generally performed
prior to a transoesophageal echocardiography, if it is possible.
The main reason for the transthoracic pre-​examination in adult
 Principles of t rans oes ophag ea l echo ca rdi o g r a phy — pr acti c a l aspe c ts 25

Fig. 1.24  The colour-​coded four-​chamber view for qualitative and semi-​quantitative analysis of tricuspid valve regurgitation during systole (a) and diastole
(b). The continuous wave Doppler spectrum of tricuspid valve regurgitation is given in (c). For semi-​quantification of moderate and severe tricuspid valve
regurgitation two views are necessary. In an example of a combined tricuspid valve disease the colour-​coded 4-​chamber view is displayed during systole (d) and
diastole (e), as well as the view of the right ventricular inflow tract by medial tilting from the apical long-​axis view during systole (g) and diastole (h). In both
views the vena contracta of a tricuspid valve regurgitation has to be determined for semi-​quantification during systole. The corresponding continuous wave
Doppler spectra of the tricuspid valve regurgitation are given in (f) and (i). Additional comments in the text.

patients is the fact that multiple cineloops and Doppler spectra
can be achieved and documented in a high and often better
image quality in the transthoracic than in the transoesophageal
approach. This mainly concerns the short-​axis views of the left
ventricle and the mitral valve, which often will be visualized by
oblique views in the transgastric documentation and the Doppler
spectra of the left heart, which will not show optimal Doppler
angulations in the transoesophageal echocardiography. This is
very important for all calculations using Doppler parameters. If
these parameters are falsified by incorrect Doppler angulations,
calculation of pressure gradients, stroke volumes, shunt volumes,
and stenotic areas using the Bernoulli or continuity equation will
be wrong. Therefore it is obvious that a sufficient transthoracic
echocardiography prior to the transoesophageal investigation
can significantly shorten the procedure time of transoesophageal
echocardiography.
For transoesophageal echocardiography some prerequisites
have to be fulfilled. The preparation of the patient for the pro-
cedure includes an ECG, blood pressure and oxygen saturation
monitoring, a venous line for sedation, contrast administration,
drug administration in the event of complications, the availability
of emergency and resuscitation equipment, as well as a suction
system. The patient should have an empty stomach, dental fixtures
should be removed and a bite guard should be used to protect the
shaft of the probe. A local oropharyngeal anaesthesia with lido-
caine spray is often sufficient for intubation of the oesophagus.
If additional sedation is needed, intravenous administration of
midazolam (0.075 mg/​kg) can be added in stable patients. It is
obvious that lower sedation doses should be used in patients with
severe heart failure or in patients with other compromising dis-
eases. The transoesophageal echocardiography is normally per-
formed in the left lateral position. During intubation of the probe,
26 CHAPTER 1   C on v ent ional ech o cardio gr a phy — basi c pri n ci pl es

Fig. 1.25  Illustration of a colour-​coded tissue Doppler 4-​chamber view during systole (a) and diastole (b) and the corresponding tissue pulsed-​wave Doppler
spectra at the basal septal (c) and lateral (d) myocardium near the mitral annulus. Additional comments in the text.

Fig. 1.26  Illustration of a deep grey-​scale 4-​chamber view during systole (a) and diastole (b) and the corresponding colour-​coded 4-​chamber view during systole
(c) and diastole (d). The pulsed-​wave Doppler spectrum of the flow in the right upper pulmonary vein is displayed in (e). Additional comments in the text.
 Principles of t rans oes ophag ea l echo ca rdi o g r a phy — pr acti c a l aspe c ts 27

Fig. 1.27  Illustration for analysis of mitral valve regurgitation affecting the commissures. In the middle of the illustration the standardized 4-​chamber view is
displayed during diastole and during systole (red surrounding) and its sectional plane is displayed in a parasternal short-​axis view (red arrow). For analysis of the
posteromedial commissure the transducer has to be tilted to the dorsal region of the left ventricle showing a longitudinal section through the coronary sinus.
The illustration shows the corresponding colour-​coded images during systole (a) and diastole (b), as well as the grey-​scale images during systole (c) and diastole
(d). For analysis of the anterolateral commissure the transducer has to be tilted to the ventral region of the left ventricle showing the left ventricular outflow
tract. The illustration shows the corresponding colour-​coded images during systole (e) and diastole (f), as well as the grey-​scale images during systole (g) and
diastole (h). Additional comments in the text.

the tip of the probe has to be unlocked, regarding flexion and ex-
tension, to avoid injury to the oesophageal wall. After the exam-
ination the probe has to be disinfected as well as inspected for
damage according to the international guidelines.
The insertion of the probe is the most uncomfortable mo-
ment for the awake or slightly sedated patient. Assistance during
the intubation is helpful to enable the most convenient mode
of introduction of the probe (E Figs. 1.26–​1.27). The user-​
operated actuator should be held by the assistant directly above
the patient in the vertical direction with the shaft leading down-
wards (E Fig. 1.33a–​b). Then, the shaft is touched by the op-
erator with the right hand at the distal shaft near the movable
tip (E Fig. 1.33b–​c). The distal ending of the unlocked probe
is curved and adapted to the curvature of the oropharynx (E
Fig. 1.33c). The left hand of the operator is free for manipulating
the tip of the probe during introduction to the oral cavity. The
advantage of this setting is that by pushing the probe forward
into the oesophagus, the tip, as well as the shaft, of the probe
will follow the natural course of the upper pharyngeal isthmus
without inducing unnecessary forces to the wall of the pharynx
and the upper oesophagus. The fingers of the left hand will guide
the tip of the probe. If the bite guard has to be positioned be-
tween the teeth during insertion, the second finger should be laid
across the tongue. Then, the probe can be fixed to the back of the
pharynx, but positioned at the ridge in the middle of the tongue
for the best possibility of introduction into the proximal oe-
sophagus (E Fig. 1.34a). If the patient tolerates the introduction
procedure without the bite guard, the second and third finger can
be used for introduction of the probe to fix the probe at the ridge
in the middle of the tongue (E Fig. 1.34b). The bite guard, which
during this manoeuvre was at the shaft of the probe, should be
positioned between the teeth after insertion of the probe.
28 CHAPTER 1   C on v ent ional ech o cardio gr a phy — basi c pri n ci pl es
Fig. 1.28  Standardized grey-​scale apical 4-​chamber view during systole (a) and diastole (b). Standardized subcostal short-​axis view at the aortic valve level
during systole (c) and diastole (d), as well as the corresponding colour-​coded images during systole (e) and diastole (f). Additional comments in the text.
Standardized data acquisition in
transoesophageal echocardiography
The sequence of the transoesophageal image acquisition
and documentation depends on the individual situation. If
there is no time limit due to emergency, cardiac or respira-
tory failure, cough or vomiting, agitation or high tempera-
ture, the transoesophageal investigation can be performed
according to anatomical issues starting with the transgastric
views followed by the oesophageal views with retraction of
the probe. If there is a time limit, the investigation should
focus on the target lesion and additional important find-
ings. In conventional settings with high-​quality transthoracic
pre-​investigations and sufficient acquisition of all necessary
Doppler spectra by the transthoracic approach, documenta-
tion of the transgastric views can normally be spared with re-
spect to the patient’s comfort. Important medical indications
for a transoesophageal echocardiography are the accurate visu-
alization of cardiac structures, which cannot be analysed by
transthoracic echocardiography, and the clarification of issues
which were the cause for the transoesophageal procedure.
Then, depending on the patient’s tolerance and further cir-
cumstances, the transoesophageal study should be performed
completely, if it is possible.
Most of the transoesophageal cardiac views are character-
ized by the left atrium nearest to the transducer. All standard
views should be documented as 2D grey-​scale cineloops, as well
as colour-​coded 2D cineloops, to document flow phenomena
at the valves or other special cardiac structures. Due to the
higher frequencies used in transoesophageal echocardiography,
the spatial resolution is normally better than in transthoracic
echocardiography. The small layers of the oesophageal and left
atrial wall result in an almost direct proximity to the heart. Thus,
transoesophageal echocardiography is normally performed in
the fundamental mode due to the absence of tissue interferences
of the ultrasound.
The transoesophageal study should normally start in the
transverse position (0°) with a 5-​chamber view or an oblique
foreshortened 4-​chamber view in the lower transoesophageal
 Standardized data ac qu i si ti on i n tr a n s oes ophag ea l echo ca rdi o g r a ph y 29

Fig. 1.29  Standardized subcostal short-​axis view at the mitral valve level during diastole (a) and systole (b), as well as the corresponding colour-​coded
images during diastole (c) and systole (d). Standardized subcostal short-​axis view at the mid-​papillary level during diastole (e) and systole (f), as well as the
corresponding colour-​coded images during diastole (g) and systole (h). Additional comments in the text.

Fig. 1.30  The standardized subcostal short-​axis view through the pulmonary valve and the pulmonary trunk at diastole (a) and systole (b). The corresponding
colour-​coded views are displayed in (c) and (d). In (e) the pulsed-​wave Doppler spectrum of the right ventricular outflow tract is shown. Additional comments
in the text.
Fig. 1.31  The subcostal longitudinal
view of the inferior caval vein during
expiration (a) and inspiration (b).
Additional comments in the text.

Fig. 1.32  The suprasternal view of

the aortic arch using grey-​scale mode
(a) and colour-​coded imaging (b).
Additional comments in the text.

Fig. 1.33  Holding of the actuator and the shaft of the transoesophageal probe at the beginning of the investigation. An assistant during the intubation is
helpful to enable the most convenient mode of introduction of the probe (a). The user-​operated actuator should be held by the assistant directly above the
patient in a vertical direction with the shaft leading downwards (a). The shaft is touched by the operator with the right hand at the distal shaft near the movable
tip (b). The distal ending of the unlocked probe is curved to adapt to the curvature of the oropharynx (c). Additional comments in the text.
 Standardized data ac qu i si ti on i n tr a n s oes ophag ea l echo ca rdi o g r a ph y 31

Fig. 1.34  Directly before introducing the probe the left hand of the operator is free for manipulating the tip of the probe during introduction to the oral cavity.
The fingers of the left hand will guide the tip of the probe. If the bite guard has to be positioned between the teeth during insertion, the second finger should
be laid across the tongue (a). Then, the probe can be fixed to the back of the pharynx, but positioned at the ridge in the middle of the tongue with the best
possibility to introduce into the proximal oesophagus. If the patient can tolerate the introduction procedure without the bite guard, the second and third fingers
can be used for introduction of the probe to fix the probe at the ridge in the middle of the tongue (b). Additional comments in the text.

approach (E Fig. 1.35a–​d). With a minimal deeper insertion of
the probe, the longitudinal section of the coronary sinus can be
visualized (E Fig. 1.35e–​h). The standardized 4-​chamber view is
obtained by a rotation of the plane of about 0°–​40° (E Fig. 1.36a–​
b), straightening the tip of the probe and retracting the probe to
the mid-​oesophageal window to get the apex into the centre of the
scanning sector. The transoesophageal 2-​chamber view is shown
by rotating the plane a further 60° without any movement of the
tip and/​or the shaft (60°–​100°) (E Fig. 1.36c–​d). Then, the left
ventricular apex is still in the centreline of the scanning sector. The
transoesophageal long-​axis view is obtained by further plane rota-
tion of about 60° (120°–​160°) (E Fig. 1.36e–​f ). The angle distance
between the views is like in transthoracic echocardiography—​60°
if the left ventricular apex is in the centre of the scanning sector.
If this is not possible and the left ventricular apex is rotating from
the right side of the sector in the 4-​chamber view to the left side
of the sector in the long-​axis view, which occurs if the correct
position in the upper oesophagus cannot be achieved, the angle
differences between the planes of the left ventricle will change.
This is the reason why the 2-​chamber view in transoesophageal
echocardiography often seems to be perpendicular to the long-​
axis view. The normal 60°-​angle difference between the standard-
ized views of the left ventricle can be documented by the triplane
approach, which will show exactly the standardized views with
60°-​angle difference if the left ventricular apex is centred in the
scanning sector (E Fig. 1.36g–​h).
An oblique 2-​chamber view, which is obtained by deflecting
the tip of the probe, normally enables the documentation of
a longitudinal section of the left atrial appendage and the
upper left pulmonary vein (E Fig. 1.37a–​e). This view is
used for acquisition of the pulsed-​wave Doppler spectra of
the velocities of the left atrial appendage and the pulmonary
venous inflow. The Doppler spectrum of the velocities of left
atrial appendage is necessary for risk estimation of thrombo-
embolic events and the Doppler spectrum of the pulmonary
vein is necessary for analysis of diastolic function, as well as
for estimation of the severity of mitral valve regurgitation.
The left atrial appendage should be visualized at least in a
second plane perpendicular to this view to detect possible
thrombus formations. Using conventional echocardiography,
the left atrial appendage has to be positioned in the centre of
the sector by deflecting the probe (E Fig. 1.38a–​c). Using
multidimensional probes, this second plane can be achieved
by the biplane scanning mode.
The aortic short-​axis view is also obtained by further flexion of
the tip of the probe taking the 2-​chamber view as the starting view.
In addition to the morphological analysis of the aortic valve, the
aortic short-​axis view (E Figs. 1.31d and 1.32a) also shows the
region of the oval fossa to detect a patent foramen ovale, which is
located at the connection of the interatrial septum with the aortic
valve annulus. With rotation from 50–​75° to 120–​135° the lon-
gitudinal intersected channel of the patent foramen ovale can be
visualized (E Fig. 1.38d–​f). In addition, colour-​coded Doppler
can be used or contrast can be administrated to document a com-
munication defect. An additional long-​axis view of the aortic valve
(120–​135°) should be documented from the most upper oesopha-
geal approach to display the best possible view of the ascending
aorta (E Fig. 1.39b). The perpendicular short-​axis view of the as-
cending aorta (again 60–​75°) displays the cross-​sected ascending
aorta, as well as the bifurcation and origin of the right pulmonary
artery (E Fig. 1.39c–​d). With a clockwise rotation of the probe
shaft, the cross-​sected superior caval vein is behind the right upper
pulmonary vein (E Fig. 1.39e–​f ). This view is necessary for the
detection of upper sinus venosus atrial defects.
By rotating the shaft of the transoesophageal probe clockwise
from the aortic long-​axis view, the bicaval view can be achieved
(E Fig. 1.40a–​b). The bicaval view of the right atrium displays the
left atrium at the top followed by the interatrial septum, which is
longitudinally intersected and is seen as a nearly horizontal struc-
ture. Distal to the interatrial septum the right atrium is displayed.
Located on the right side of the sector the orifice of the superior
caval vein and the right atrial appendage can be documented, on
the left side of the sector the orifice of the inferior caval vein en-
ters the right atrium.
The transgastric views will be achieved after positioning the tip
of the probe in the upper stomach. For the transgastric approach
harmonic imaging is often superior to fundamental imaging due to
the larger near field and the longer distance between the transducer
Fig. 1.35  The mid-​oesophageal 5-​chamber view during systole (a) and diastole (b) and the corresponding colour-​coded views during systole (c) and diastole (d).
A slight deeper insertion of the probe at 0° displays the inflow of the coronary sinus. The following views of the right atrium and the right ventricular inflow tract are
displayed in grey-​scale mode during systole (e) and diastole (f) and in colour-​coded mode during systole (g) and diastole (h). Additional comments in the text.

Fig. 1.36  The mid-​oesophageal 4-​chamber view during systole (a) and diastole (b), the mid-​oesophageal 2-​chamber view during systole (c) and diastole (d),
the mid-​oesophageal long-​axis view during systole (e) and diastole (f) and the simultaneous triplane views during systole (g) and diastole (h) to document
that angle differences between mid-​oesophageal standardized views with the left ventricular apex near the centreline of the sector are about 60° like the
transthoracic views. Additional comments in the text.
 Standardized data ac qu i si ti on i n tr a n s oes ophag ea l echo ca rdi o g r a ph y 33

Fig. 1.37  Oblique mid-​oesophageal 2-​chamber view (a) for visualization of the left atrial appendage (LAA) and the upper left pulmonary vein. The upper left
pulmonary vein is displayed at the right side of the sector by positioning of the LAA in the centre of the sector (b). Colour-​coded imaging of the pulmonary vein
(c) facilitates the positioning of the sample volume for flow measurements. In the middle of the figure the pulsed-​wave Doppler spectra of the flow in the LAA
with sinus rhythm (e) and in the upper left pulmonary vein (e) are displayed. Additional comments in the text.

and the cardiac structures. The investigation starts with a short-​
axis view of the left ventricle at the mid-​papillary level (0°) (E
Fig. 1.40c–​d). If the left ventricle is displayed centrally in the sector,
the perpendicular view shows the transgastric left ventricular 2-​
chamber view (90°) with the apex on the left side and the mitral
valve on the right side (E Fig. 1.40e–​f ). The inferior wall is in the
near field, the anterior wall in the far field. The transgastric long-​
axis view can be displayed by further rotation of the probe to 100°–​
130° and a minor clockwise rotation of the shaft, which displays the
aortic valve on the right side of the sector in the far field (E Fig.
1.41a–​f ). The inflow tract of the right ventricle is also visualized by
the perpendicular view (90°) to the left ventricular short-​axis view
(0°) after centring the right ventricle in the sector before rotating
(E Fig. 1.42a–​d). The transgastric right ventricular longitudinal
view displays the right ventricular apex on the left side and the right
atrium and the tricuspid valve on the right side of the sector. A fur-
ther rotation of the probe to 110°–​140° and a minor rotation of the
shaft enables the visualization of the inflow and outflow tracts of
the right ventricle. The outflow tract and the pulmonary valve are
nearly centred in the far field in this view.
The transgastric short-​axis view of the mitral valve is a tech-
nically difficult view. Often only an oblique view of the mitral
valve can be displayed. The short-​axis view of the mitral valve is
achieved by slightly withdrawing the probe at 0°–​20° from the
mid-​papillary short-​axis view and simultaneous anteflexion of the
probe. In this view the anterior mitral leaflet is on the left side of
the sector and the posterior leaflet on the right side of the sector.
The posteromedial commissure (A3/​P3) is in the near field, the an-
terolateral commissure (A1/​P1) in the far field (E Fig. 1.43a–​d).
A second possibility to visualize the left ventricular out-
flow tract is by deep intubation into the gastric fundus with
consecutive anteflexion of the tip of the probe. Using this ap-
proach, the deep transgastric long-​axis view at about 0° and the
deep transgastric 5-​chamber view can be achieved at about
120°–​140° (E Fig. 1.44a–​f). The deep transgastric long-​axis
view displays the right ventricular outflow tract on the left side
of the sector, the left ventricle on the right side of the sector
in the near field, and the aortic valve centrally in the far field.
Sometimes the transversely intersected aortic root and proximal
ascending aorta are visualized.
After the documentation of the cardiac structures and the
ascending aorta at the end of the transoesophageal investi-
gation, the probe is turned into the opposite direction to the
heart by rotating the shaft about 90°. Starting in the deep oe-
sophagus at the diaphragm, the descending aorta is scanned
using short-​axis views (0°) during withdrawal of the probe to
the upper oesophagus. In the region of the separation of the left
subclavian artery, the probe has to be rotated (10–​60°) to dis-
play the descending aorta in short-​axis views (E Fig. 1.45a–​b).
The aortic arch is displayed in a short-​axis view after rotation
of about 90°. Scanning of the descending aorta is necessary for
the detection of plaque ruptures and other aortic pathologies. If
pathological findings are present, additional long-​axis views of
the descending aorta should be documented.
Fig. 1.38  Biplane documentation of a normal left atrial appendage (a, b) and the corresponding pulsed-​wave Doppler spectrum during atrial fibrillation (c).
Documentation of the oval fossa in a short-​axis view at the aortic root level (d). By rotation of the plane to 90° (e) and 107° (f) the channel between the septum
primum and secundum is displayed. Additional comments in the text.

Fig. 1.39  Mid-​transoesophageal short-​axis view of the aortic valve (a). Upper transoesophageal long-​axis view of the ascending aorta (b). Upper
transoesophageal views of the ascending aorta and pulmonary artery, as well as the superior caval vein. The short-​axis view of the aortic root and the pulmonary
bifurcation is displayed in grey-​scale (c) and colour-​coded mode (d). The short-​axis view of the superior caval vein and the upper right pulmonary vein is
displayed in grey-​scale (e) and colour-​coded mode (f). Additional comments in the text.
 Standardized data ac qu i si ti on i n tr a n s oes ophag ea l echo ca rdi o g r a ph y 35

Fig. 1.40  Mid-​transoesophageal bicaval view during systole (a) and diastole (b). Transgastric short-​axis view at the mid-​papillary level during systole (c) and
diastole (d). Transgastric 2-​chamber view during systole (e) and diastole (f). Additional comments in the text.

Fig. 1.41  Transgastric long-​axis view during systole (a) and diastole (b), as well as the corresponding colour-​coded views (c, d). The transgastric colour-​coded
long-​axis view in a patient with hypertrophic cardiomyopathy with increased systolic (e) and diastolic flow (f). Additional comments in the text.
36 CHAPTER 1   C on v ent ional ech o cardio gr a phy — basi c pri n ci pl es

Fig. 1.42  Transgastric right ventricular inflow and outflow

tract during systole (a) and diastole (b) and the corresponding
colour-​coded views (c, d). Additional comments in the text.

Fig. 1.43  Transgastric short-​axis views at the mitral valve

level. Two slightly different sectional planes of the mitral
valve are displayed during systole (a, c) and diastole (b, d).
Additional comments in the text.
 Standard valu es in t ransthor aci c a n d tr a n s oes ophag ea l echo ca rdi o g r a ph y 37

Fig. 1.44  Deep transgastric long-​axis view during systole (a) and diastole (b) and the corresponding colour-​coded views (c, d). Further colour-​coded views of a
patient with hypertrophic cardiomyopathy are displayed during systole (e) and diastole (f). Additional comments in the text.

Fig. 1.45  Mid-​oesophageal short-​

axis view (a) and long-​axis view (b)
of the descending aorta. Additional
comments in the text.

wall thicknesses, as well as aortic root and left atrial dimensions.

Standard values in transthoracic and For wall thickness measurements to calculate left ventricular
transoesophageal echocardiography mass according to the Penn-​convention and for left ventricular
diameter measurements for calculation of the left ventricular
M-​mode measurements ejection fraction according to the Teichholz equation, the myo-
M-​mode measurements in conventional echocardiography are cardial borders will be labelled inner-​edge-​to-​inner-​edge without
mainly performed for analysis of left ventricular dimensions and endo-​and epicardium at the maximum peak of the R-​wave of
38 CHAPTER 1   C on v ent ional ech o cardio gr a phy — basi c pri n ci pl es

the electrocardiogram. In contrast, according to the American Table 1.3  Echocardiographic parameters and standard values used
Society of Echocardiography convention, measurements of the to quantify cardiac dimensions and function
left ventricular wall will be performed leading-​edge-​to-​leading-​
Echocardiographic parameter Standard value
edge at the beginning of the QRS complex. In Europe the meas-
urements are normally performed inner-​edge-​to-​inner-​edge. Left ventricular wall thickness (M-​mode/​2D) 6–​11 mm
Measurements were performed at a ventricular level between the Left ventricular end-​diastolic diameter 39–​59  mm
transition of the papillary muscles to the chords. (M-​mode/​2D) 22–​32  mm/​m2
25–​33 mm/​m
Left atrial diameter is measured at the time point of early dia-
stole behind the aortic root. Aortic root diameter is measured Right ventricular wall thickness (M-​mode/​2D) <5 mm
inner-​edge-​to-​inner-​edge during mid-​systole at the time interval Right ventricular diameter (M-​mode/​2D) <25 mm
of aortic valve separation. Left ventricular end-​diastolic volume (2D) 56–​155  ml
Right ventricular diameter is measured in the M-​mode at the 35–​75 ml/​m2
mitral valve level during end-​diastole. Left ventricular end-​systolic volume (2D) 19–​58  ml
12–​30 ml/​m2
Two-​dimensional measurements Left ventricular ejection fraction (2D) >55%
Two-​dimensional measurements of left atrial and left ventricular Left ventricular outflow tract diameter 18–​31 mm
volumes and function are performed by planimetry of both cav- Right ventricular outflow tract and aortic 17–​23 mm
ities in the standardized apical 2-​and 4-​chamber view during dia- annulus diameter
stole and systole using Simpson’s rule. Right ventricular base-​to apex-​length 71–​79 mm
Right atrial and ventricular size is conventionally determined
Basal right ventricular diameter 20–​28 mm
by the longitudinal and transverse diameter of the right atrium
Right ventricular diastolic area 11–​28 cm2
and the right ventricular inflow tract in the standardized apical 4-​
chamber view. Right ventricular function is estimated by planim- Right ventricular fractional area change 32–​60%
etry of the right ventricular inflow tract in the standardized apical Left atrial diameter (M-​mode/​2D) 27–​40  mm
4-​chamber view during diastole and systole for determination of 15–​23 mm/​m2
right ventricular fractional area change. Left atrial volume (atrial end-​diastole) (2D) 22–​58  ml
The diameter of the left ventricular outflow tract is normally <34 ml/​m2
measured in a standardized parasternal long-​axis view due to a Aortic root diameter (M-​mode/​2D) <39 mm
better spatial resolution than in the apical long-​axis view. Right atrial minor axis diameter (2D) 29–​45  mm
Inferior caval vein diameter is measured in the subcostal longi- 17–​25 mm/​m2
tudinal view during expiration and inspiration. Inferior caval vein diameter (2D) <17 mm
E/​A-​ratio >1
Pulsed spectral Doppler measurements
Deceleration time <200 ms
Pulsed spectral Doppler measurements are performed using the
A-​wave velocity of the pulmonary vein <35 cm/​s
spectra of the mitral valve inflow and the left ventricular outflow
tract. In normal hearts the dimension of the left ventricular out- A-​wave duration <120 ms
flow tract is almost the same as the dimension of the aortic valve E′-​wave velocity >8 cm/​s
annulus. For the left ventricular inflow, maximum velocities of E/​E′-​ratio <8
the E-​and A-​wave, the E/​A-​ratio and the deceleration time of the
E-​wave are measured.
For estimation of diastolic function, the pulsed-​wave Doppler spec-
trum of the pulmonary vein flow is analysed for determination of the
retrograde maximum A-​wave velocity and the A-​wave duration. aortic valve using the continuous wave Doppler spectra, if veloci-
ties are increased.
Continuous wave Doppler measurements
Continuous wave Doppler measurements are performed in all Pulsed spectral tissue Doppler measurements
spectra documenting turbulences. This is especially important Pulsed spectral tissue Doppler measurements are performed in
in valve pathologies. In normal hearts only the continuous wave the inferoseptal and lateral region of the mitral valve annulus to
Doppler spectrum of a mild tricuspid regurgitation is used for es- determine the velocity of E′ and the E/​E′-​ratio.
timation of systolic pulmonary pressure. The maximum and mean Standard values for these measurements are given in E
velocities, as well as maximum and mean gradients calculated by Table 1.3.
the velocity time integrals, will be measured for the mitral valve The standard digital acquisition for transthoracic and
inflow and left ventricular outflow tract, or the flow through the transoesophageal echocardiography is given in E Table 1.4.
Table 1.4  Standard digital acquisition for transthoracic and transoesophageal echocardiography. The mandatory documentation is labelled
in bold. 2D—​two-​dimensional; pw—​pulsed-​wave Doppler; cw—​continuous wave Doppler; IAS—​interatrial septum; TTE—​transthoracic
echocardiography.

View Data type

Parasternal long-​axis view of the left ventricle (2D/​colour-​coded) Cineloop
Parasternal long-​axis view at the mid-​papillary level (2D/​M-​mode) Cineloop
Parasternal long-​axis view at the mitral valve level (2D/​colour-​coded) Cineloop
Parasternal long-​axis view at the aortic valve level (2D/​colour-​coded/​M-​mode) Cineloop
M-​mode sweep M-​Mode
Parasternal right ventricular inflow tract (2D/​colour-​coded) Cineloop
Parasternal right ventricular outflow tract (2D/​colour-​coded) Cineloop
Right ventricular outflow tract velocities (pw Doppler) pw Doppler
Apical long-​axis view (2D/​colour-​coded, optional tissue colour-​coded) Cineloop
Transmitral velocities (pw Doppler/​in the presence of turbulences—​cw Doppler) pw Doppler
cw Doppler
Left ventricular outflow tract velocities (pw Doppler) pw Doppler
Transaortic velocities (in the presence of turbulences—​cw Doppler) cw Doppler
Apical 2-​chamber view (2D/​colour-​coded, optional tissue colour-​coded) Cineloop
Apical 4-​chamber view (2D/​colour-​coded, optional tissue colour-​coded) Cineloop
Tricuspid valve regurgitant velocities (cw Doppler) cw Doppler
Tissue pulsed-​wave Doppler velocities (inferoseptal, lateral—​4-​chamber view) pw Doppler
Right pulmonary vein velocities pw Doppler
Subcostal 4-​chamber view—​IAS (2D/​colour-​coded) Cineloop
Subcostal short-​axis view at the mitral valve level (2D/​colour-​coded) Cineloop
Subcostal short-​axis view at the aortic valve level (2D/​colour-​coded) Cineloop
Subcostal longitudinal view of the inferior caval vein during breathing (2D) Cineloop
Suprasternal view of the aortic arch (2D/​colour-​coded) Cineloop
Mid-​transoesophageal 4-​chamber view (2D/​colour-​coded) Cineloop
Mid-​transoesophageal 2-​chamber view (2D/​colour-​coded) Cineloop
Mid-​transoesophageal long-​axis view (2D/​colour-​coded) Cineloop
Mid-​transoesophageal short-​axis view at the aortic valve level (2D/​colour-​coded) Cineloop
Mid-​transoesophageal view of the left atrial appendage (2D/​colour-​coded) and its perpendicular view Cineloop
Left atrial appendage velocities (pw Doppler) pw Doppler
Left upper pulmonary vein velocities (pw Doppler) pw Doppler
Mid-​oesophageal bicaval view (2D) Cineloop
Upper oesophageal aortic short-​axis view Cineloop
Upper oesophageal superior caval vein axis view Cineloop
Upper oesophageal aortic long-​axis view Cineloop
Mid-​oesophageal short-​axis view of the descending aorta (2D) Cineloop
Mid-​oesophageal long-​axis view of the descending aorta (2D) Cineloop
Transgastric short-​axis view at the mid-​papillary level (2D) if TTE not possible Cineloop
Transgastric 2-​chamber view (2D/​colour-​coded) if TTE not possible Cineloop
Transgastric long-​axis view (2D/​colour-​coded) if TTE not possible Cineloop
Transgastric view of the right ventricular inflow and outflow tract (2D/​colour-​coded) if TTE not possible Cineloop
Transgastric short-​axis view at the mitral valve level (2D/​colour-​coded) if TTE not possible Cineloop
Deep transgastric 5-​chamber view (2D/​colour-​coded) if TTE not possible Cineloop
Deep transgastric long-​axis view (2D/​colour-​coded) if TTE not possible Cineloop
Transmitral velocities in the deep transgastric 5-​chamber view (pw Doppler/​in the presence of pw Doppler
turbulences—​cw Doppler) if TTE not possible cw Doppler
Left ventricular outflow tract velocities in the transgastric long-​axis view (pw Doppler) if TTE not possible pw Doppler
Transaortic velocities in the transgastric long-​axis view (in the presence of turbulences—​cw Doppler) if TTE not possible cw Doppler
40 CHAPTER 1   C on v ent ional ech o cardio gr a phy — basi c pri n ci pl es
Acknowledgements
The photos and the photo composition are performed by Stefan
Straube, Public Relations Department, University Hospital
AöR Leipzig, Germany.
References
1. Flachskampf FA, Decoodt P, Fraser AG, et al. Recommendations
for performing transoesophageal echocardiography. Eur J Echocardio­
graphy 2001; 2: 8–​21.
2. Lang R, Bierig M, Devereux R, et al. Recommendations for chamber
quantification. Eur J Echocardiography 2006; 7: 79–​108.
3. Nihoyannopoulos P, Fox K, Fraser A, et al. EAE laboratory standards
and accreditation. Eur J Echocardiography 2007; 8: 80–​7.
4. Evangelista A, Flachskampf F, Lancellotti P, et al. European Association
of Echocardiography recommendations for standardization of per-
formance, digital storage and reporting of echocardiographic studies.
Eur J Echocardiography 2008; 9: 438–​48.
All persons on the photos have given consent to be
published.
5. Hagendorff A. Transthoracic echocardiography in adult patients—​
a proposal for documenting a standardized investigation. Eur J
Ultrasound 2008; 29: 2–​31.
6. Nagueh SF, Appleton CP, Gillebert TC, et al. Recommendations for
the evaluation of left ventricular diastolic function by echocardiog-
raphy. Eur J Echocardiography 2009; 10: 165–​93.
7. Flachskampf FA, Badano L, Daniel WG, et al. Recommendations
for transoesophageal echocardiography: update 2010. Eur J
Echocardiography 2010; 11: 557–​76.
 CHAPTER 2

Nuclear cardiology
(PET and SPECT)—​basic
principles
Danilo Neglia, Riccardo Liga,
Stephan G. Nekolla, Frank M. Bengel,
Ornella Rimoldi, and Paolo G. Camici

Contents
Introduction  41
Introduction
Technical aspects: physics and data Radionuclide imaging of the heart is well established for the clinical diagnostic and prog-
analysis  41 nostic workup of coronary artery disease. Myocardial perfusion single photon emission
SPECT  42
PET  44 computed tomography (SPECT) has been the mainstay of cardiovascular radionuclide
Acquisition  45 applications for decades and its usefulness is supported by a very large body of evidence
Data correction  46
[1]‌. Positron emission tomography (PET) is an advanced radionuclide technique that
Current procedures and clinical applications
of nuclear cardiac imaging  46 has also been available for decades. In contrast to SPECT, PET has long been considered
SPECT  46 mainly a research tool due to its methodological complexity. But owing to several devel-
PET  48 opments, it has penetrated the clinical arena [2].
Recent trends  49
Conclusion  51 Nuclear cardiology techniques are considered robust, accurate, and reliable for clinical
imaging of heart disease. Yet, in a continuous effort to minimize radiation burden and
improve comfort for patients while maximizing the available information for the refer-
ring physician, nuclear imaging technology has progressed towards higher sensitivity
and spatial resolution [3]‌, and the use of novel, highly specific radiotracers [4]. While
nuclear cardiology will continue to play a key role for the assessment of myocardial per-
fusion, function, and viability, its unique and evolving features for molecular imaging
will add new opportunities for more specific, personalized preventive and therapeutic
decision-​making.
This chapter will outline the basic aspects of SPECT and PET as the two key nuclear
cardiology techniques. Technical aspects of image acquisition will be discussed first. A
brief overview on current application of radionuclide imaging procedures will then be
given, and the chapter will be concluded by an outlook on novel developments.

Technical aspects: physics and data analysis

After the injection of a radiotracer into the patient, it accumulates in the heart and other
parts of the body depending on its physiological properties. During distribution and ac-
cumulation, the radioactive decay is permanently ongoing and the resulting high-​energy
photons escaping the body are detected. Depending on the fact whether gamma emitters
(SPECT) or positron-​emitters (PET) are used, the method of detection is fundamentally
different but both were developed already in the 1960s [5, 6].
42 CHAPTER 2   Nuc le a r cardiol o gy (PET and SPECT) — basi c pri n ci pl es
SPECT
From the 1950s on, radioisotopes were used to investigate myo-
cardial blood flow with (now rather exotic) isotopes such as 84Rb,
42
K, and 129Cs [7]‌. These non-​imaging approaches were later re-
fined with planar scintigraphy: for the heart, it was used to gen-
erate projection images of the distribution of radio-​agents [5, 8].
In such a setup a collimator (basically a layer of lead with many,
small holes) is in front of a crystal converting the high-​energy
photons to light pulses. Those are converted with photomulti-
pliers to electrical signals which then generate finally a projec-
tion image—​optionally from different angles to optimally show
the heart [9]. However, this suffered from the general disad-
vantage of all projection images, the superimposition of struc-
tures. The solution to this were basically a series of projection
images with the camera head rotating around the patient’s body
[10] (E Fig. 2.1). The initial approach used only a single head
but dual and even triple camera configurations became widely
available in the 1980s. The collimators balance detection sensi-
tivity (i.e. large hole diameter) and optimize spatial resolution
(i.e. small hole diameter). For practical imaging, the patient is
typically positioned supine on the table, although prone posi-
tioning has been shown to be useful for reducing attenuation
artefacts [11].
As for any other tomographic acquisition, the projection
(or raw) data is reconstructed with dedicated algorithms into
transaxial images for subsequent analysis and interpretation. This
stack of transaxial images builds a data volume which encom-
passes the tracer’s distribution in the body during typically 10 to
20 minutes. The used analytical algorithms were, for many dec-
ades, the so-​called filtered back-​projection (FBP) or—​after more
Fig. 2.1  Basic 90° configuration for cardiac imaging of a dual head
SPECT system. The gamma camera detector heads, typically consisting
of a collimator, sodium-​iodine crystal, and photomultipliers, rotate in a
semicircular fashion around the chest and create images in multiple positions
(‘step-​and-​shoot’).
powerful computer systems became available in the late 1990s—​
iterative reconstruction algorithms. Those, (simply speaking) try
to numerically match the acquired data to the image, thus sup-
pressing noise and improving image quality. The optimization of
image reconstruction algorithms is a still ongoing process and is
improved by taking more and more information of the data acqui-
sition process into consideration [12]. However, it is important to
note that the visual appearance of the image is possibly affected
by all innovations in the data acquisition and reconstruction pro-
cess and thorough validation is required prior to wider use in a
clinical setting.
In any case, patient motion during the acquisition induces in-
consistencies for image reconstruction and needs ideally be cor-
rected by software. In the next step, the fact that a data volume
was acquired is of special relevance for cardiac imaging. As the
heart is tilted with two axes in the body, a computational re-​
orientation along the left ventricular short and long axes is pos-
sible to facilitate review of myocardial tracer distribution and
comparison of rest and stress studies on a single report page
thus allowing very rapid assessment of normal and abnormal
tracer distribution (EFig. 2.2). This is a major advantage of
nuclear imaging of the heart. In addition, software tools have
been developed which employ contour detection algorithms
and circumferential profiles to create so-​called polar maps from
the tomographic images [13–​15]. These polar maps are a two-​
dimensional display of the three-​dimensional tracer distribu-
tion throughout the myocardium which facilitate comparison
of patient data with normal databases, semiquantitative ana-
lysis of defect sizes, and machine learning approaches [16–​18]
(EFig. 2.3a).
Electrocardiographic (ECG) gating
ECG-​gated acquisition of perfusion SPECT studies has become
a standard procedure. Basically, every detected photon is noted
with its position within the RR cycle. After the completion of
the scan, all events are sorted into so-​called gated bins, which
splits the average RR cycle retrospectively into typically eight
or sixteen equidistant slots and the respective number of data
volumes are reconstructed. Thus, this is not a (near)- real time
gating technique as found in ultrasound imaging or MRI, but
it generates average gated images over the complete acquisition
duration—​thus a fairly stable heart rhythm is required.
This approach has two major advantages over non-​gated ac-
quisition: First, ECG-​gating allows quantitative estimates of left
ventricular (LV) ejection fraction (EF) and volumes, as well as
regional evaluation of LV wall motion [19]. Second, ECG-​gating
may improve the diagnostic accuracy of perfusion imaging in the
event of attenuation artefacts (which is discussed in more detail
in the next paragraph) [20]. Since these artefacts may appear as
perfusion defects, their normal regional wall motion prevents a
wrong interpretation.
It should be noted that functional gated SPECT acquired after
stress shows the contracting LV at post-​stress conditions with
the stress perfusion patterns, although sometimes, transient wall
 Techn i ca l aspects : physi cs a n d data a na lysi s
(a)
(b)
motion abnormality and visually dilated LV and reduced EF
(myocardial stunning) may persist and be observed during the
acquisition phase, up to 90 min or even later after the resolution
of ischaemia [21] (EFig. 2.3b).
For the assessment of contractile function, software packages
are commercially available. They generate semi-​ automatically
or automatically 3D myocardial contours throughout the car-
diac cycle. From these contours quantitative regional and global
parameters are calculated (EFig. 2.3b). It is important to note
that—​although individual packages were validated, e.g. against
MRI—​the performance differs between them and for serial as-
sessment the same software should be used [22].
Attenuation correction (AC)
Attenuation of high-​energy photons in the body leads to a non-​
uniform reduction in the apparent activity in the myocardium
and consequentially to artefacts. Basically, photons from the
anterior LV wall have a higher probability to leave the body
unscattered (i.e. without changes in their direction) through the
chest wall as compared to photons from the inferior wall due
to a longer travel distance. Additionally, (primarily) Compton
scatter of radiation within the body and in the detector (photo-​
electric scatter) degrades image contrast and potentially affects
the accurate quantification of activity. Among those factors,
photon attenuation has the most significant effect. The amount
43
(c)
Fig. 2.2  Typical representation of a rest/​stress
myocardial SPECT study. (a) Summed images:
display of matched stress and rest tomographic
images, reangulated along the short and long
axes of the left ventricle for visual analysis. (b)
Same layout as (a) but here the gated post-stress
images are displayed in systole (upper rows) and
diastole (lower rows) with (c) the corresponding
3D displays.
of attenuation depends on the type of tissue (soft tissue, bone,
or lung), the energy of the radiation, and the length of travel
for the photon, i.e. thickness of the body. Hence, correction for
body attenuation requires the regional distribution of attenu-
ating materials. While many schemes for the generation of
the attenuation characteristics have been reported [23], now-
adays the attenuation map of a patient is generated using the
computed tomography (CT) in hybrid systems. Software and
hardware methods used in these systems vary significantly
from one vendor to another, but it has been documented for
several systems that attenuation combined with scatter correc-
tion improves image quality and image interpretation [24–​26].
However, and this holds true for SPECT and PET, the alignment
between the CT used for the correction and the SPECT data
must be carefully quality controlled as misalignments induce
artefacts on their own [27].
Systematic data analysis
For adequate interpretation of myocardial perfusion images, a
structured visual review of the projection data and reconstructed
images is warranted [28]. The system of reviewing comprises sev-
eral levels. First, projection data are reviewed to identify motion
artefacts and assess tracer distribution in organs other than the
heart which potentially effects the reconstructed myocardial up-
take due e.g. to scatter from extra-​cardiac activity such as liver
44 CHAPTER 2   Nuc le a r cardiol o gy (PET and SPECT) — basi c pri n ci pl es

(a)

STRESS REST
(b)

Fig. 2.3  (a) Representative 99mTc-​Tetrofosmine

SPECT images showing reversible perfusion
abnormalities induced by pharmacological stress
(Regadenoson) in the anterior-​apical region of
the LV myocardium (vascular territory of the
left anterior descending coronary artery). (b)
Analysis of the gated images acquired after stress
(left panel) and at rest (right panel) demonstrate
persistent regional ‘stunning’ of the LV apex with
moderate impairment of global systolic function
and relaxation (PFR) in the post-​stress conditions as EF: 48% EF: 54%
compared with resting conditions. EDV: 95 mL, EDV: 88 mL,
Courtesy of Dr. A Gimelli, Nuclear medicine department ESV: 54 mL ESV: 42 mL
Fondazione Toscana G. Monasterio, Pisa. PFR: 2.00 EDV/sec PFR: 2.40 EDV/sec

or gut. Next, re-​orientated tomographic images are reviewed detection (or electronic collimation) was developed already in
without and, if available, with attenuation/​scatter compensation
the late 1950s and was actually used in the 1960s for cardiac
and gated cine data. Then, semiquantitative polar maps are re- imaging [29]. As both of these photons need to leave the body,
viewed and used in order to strengthen the visual impression of the probability of such an event is much less towards the centre
tomographic image readout. Finally, the impression of the image of the body as compared to SPECT and renders non-​attenuation
readout is integrated with stress performance and with clinical corrected cardiac PET images almost useless. Thus, it was real-
data and should be reported in a standardized format. ized already in the 1980s that AC is mandatory [30]. Again, as
in AC-​SPECT, the real distribution of attenuating tissue needs
PET to be incorporated into the image reconstruction and yields—​
There are methodological differences between conventional together with sophisticated calibration scans—​the true, quan-
SPECT and PET. The foremost difference is the positron-​ titative tracer distribution within every voxel in the body (unit:
emitting isotope. A positron is emitted which annihilates with Bq/​ml). Secondly, much shorter lived positron-​emitting radio-
an electron and emits two 511keV photons which leave the body isotopes are being utilized allowing more flexibility of imaging
in almost opposite directions. In other words, not the positron protocols and biologic targets, but at the same time increasing
but the annihilation photons are detected. Their coincident the complexity and limiting the availability of the methodology.
 Techn i ca l aspects : physi cs a n d data a na lysi s 45

Third, as organs like the heart or the brain fit more or less com-
pletely in the field of view of even the early PET scanners, dy-
namic imaging with tracer injections within the scanner is a
hallmark of PET imaging since the beginning. The image recon-
struction of such a temporal series of volumes allows the gen-
eration of time-​activity curves (TAC) of target tissue and blood
which then are analysed with e.g. compartmental models to cal-
culate parameters such as the absolute myocardial blood flow
(unit: ml/​min/​g).
Acquisition
Annihilation. Positron-​emitting radioisotopes are generated ei-
ther by elution generators (82Rb, 68Ga) or by cyclotrons, which
accelerate protons or deuterons interacting with target atoms to
produce ‘proton rich’ radioisotopes (11C, 18F, 13N, 15O). During
decay, a proton in the nucleus converts to a neutron and a positron
is emitted. Under the influence of surrounding atomic electrons,
the positron is slowed down until a close interaction with an elec-
tron is possible, followed by their annihilation and the emission
of two 511keV photons (EFig. 2.4). Compared to radionuclides
emitting single photons such as 99mTc with 140keV, the 511 keV
photons show less tissue attenuation and gives PET higher de-
tection efficiency and basically better image quality (EFig. 2.5).
However, this comes at the price of increased complexity.
Coincidence detection. As mentioned earlier, both annihilation
photons leave ideally the body and are detected almost simultan-
eously by two (out of many thousands) detector elements sur-
rounding the body. As photons travel with the speed of light, this
so-​called coincidence window is only a few nanoseconds wide
and requires complex hardware. When detected, the two events
define the so-​called line-​of response (LOR) and a large number of
these LORs can be sorted in order to generate projection images.
If such an event happens, true, scattered, or random coincidences
are found and are subject for further, sophisticated processing
(EFig. 2.4). In the early days of PET, the transaxial coverage
was only a few centimetres, which made cardiac imaging for di-
lated ventricles quite challenging. Today’s scanners allow a axial
coverage of up to 25 cm.

Positron decay and PET Scanner Coincidence detection

annihilation
13 N
7

+
511
keV
– 511
+ keV

(a) Time axis

(b) True Coincidence

Crystal Crystal

Scattered Event
Crystal Crystal

Random Event
Crystal Crystal

Fig. 2.4  (a) Schematics of the annihilation process: the positron is emitted from the nucleus, travel a few millimetres depending on the tissue density
and then annihilates with an electron with the emission of two 511keV photons. (b) Schematic setup of three key elements of PET imaging: two
photons arise from an annihilation events (red circle) and are identified by two detectors. Both signals are processed in the coincidence electronics
and are accepted as they happen in very close temporal proximity (1–​5 nanoseconds). The line between the detectors for this particular decay event
is line-​of-​response (LOR). Three types of coincidence events are also shown: the true one, a scatter event, and a random one. Their separation is
implemented with real time electronics capable of processing these events.
46 CHAPTER 2   Nuc le a r cardiol o gy (PET and SPECT) — basi c pri n ci pl es
Data correction
To exploit the potential of PET to be truly quantitative, several
elements are needed:
Normalization. The geometry of a PET system with its thousands
of components (crystals, photomultipliers, etc.) introduces
regional variation in the detection sensitivity due to slightly
different properties of the individual parts. Normalization cor-
rects for this by measuring a homogeneously filled phantom
with a known amount of activity.
Dead time. The response time of a detector system is finite and
this becomes an issue if many 100s of MBq is injected into a
patient—​ not untypical for dynamic myocardial perfusion
studies [31, 32]. This might be because of the electronics delay
or if more than one photon strikes a detector within its re-
solving time and is rejected. New lutetium oxyorthosilicate
(LSO), Lutetium-​ yttrium (LYSO) and cerium-​ doped gado-
linium oxyorthosilicate (GSO:Ce) crystals have higher light
output and shorter decay constants, which result in improved
spatial resolution and reduction of random coincidences af-
fecting the counting rate capabilities of the system. Still, satur-
ation might occur in the described settings and the then used
corrections factors are important to watch.
Attenuation. Until the introduction of PET/​CT systems in the
early 2000s, an external, rotating positron-​emitting source has
been used to measure the attenuating factor before adminis-
tration of radioactivity in standalone PET scanners. Basically,
this created a 511keV, low resolution ‘CT’ image for AC which
could take up to 15 minutes acquisition time [33–​35]. With
the advent of hybrid PET-​CT, a CT scan provides a substitute
for this speeding up the process considerably from minutes to
seconds [36, 37]. However, as the duration of a CT is of a few
seconds, a new problem was found: patient motion (cardiac, re-
spiratory, other voluntary and involuntary), resulted in poten-
tial misalignment of CT and PET which needs careful quality
control [38].
Scattered, Random Coincidences, and Time-​of-​flight. Although the
high-​energy of annihilation photons, scatter remains an issue
especially for cardiac imaging as many well perfused structures
are found in the thorax. Fortunately, today’s scanners incorp-
orate highly optimized algorithms to address this. Still, the
majority of PET/​CT systems were designed for rather low ac-
tivity settings in oncological imaging. Thus, especially dynamic
perfusion scans require attention for the amount of tracer in-
jected [39]. The progress in PET scanner technology resulted
in the introduction of the so-​called time-​of-​flight technique.
Although initially tailored to improve oncologic imaging of
small lesions in obese patients, also cardiac imaging can profit
(EFig. 2.5).
Motion. A very important consequence of the high temporal reso-
lution in modern, high sensitivity, scanners is that it makes ef-
fective motion correction possible. ECG-​gating is a standard
procedure for PET and studies have also been carried out
using respiratory gating, making the monitoring of and the
(a) (b)
(c) (d)
Fig. 2.5  Example of a cardiac 3D PET image with 13NH3. (a) CT transmission
image. (b) High statistic PET data reconstructed—​3D OSEM point spread
function (PSF) and time of flight (TOF), spatial resolution FWHM 2 mm.
(c) Low statistic PET data reconstruction for comparison—​3D filter-​back
projection, Hanning Filter spatial resolution FWHM 4.3 mm. (d) Co-​registration
of PET and CT images, motion corrected.
Courtesy of Dr. L Gianolli and Dr. V. Bettinardi Nuclear medicine department Ospedale
San Raffaele Milan.
correction for both cardiac and respiratory movements of the
patient feasible [40–​42].
Partial Volume. Despite the technological developments in PET,
basic physical characteristics imply that its spatial resolution
is limited due to the travel length of the positron prior to the
annihilation and the finite size of the detector crystals. Thus,
the signal in a particular region will be ‘diluted’ due to the
presence of surrounding tissues—​there will be a ‘spillover’ of
radioactivity between adjacent structures. The same is true
for SPECT, which usually has an approximately 2-​fold lower
spatial resolution compared to PET (approx. 8 mm vs. 4 mm).
Combination of transmission and emission data has been used
to correct for this effect in the myocardium and PET and CT or
MRI images have been combined to enable corrections at last
on an experimental basis [43, 44].
Current procedures and clinical
applications of nuclear cardiac
imaging
SPECT
SPECT represents one of the most frequently performed non-​
invasive imaging to evaluate patients with suspected or known
coronary artery disease (CAD) [45, 46], allowing to identify pa-
tients at risk of future cardiac events and to guide clinical decision
making [47]. More recently, SPECT with 123I-​MIBG has been used
for the functional assessment of myocardial sympathetic innerv-
ation in patients with heart failure and/​or malignant ventricular
 Cu rrent pro cedu res a n d cl i n i ca l a ppl i cati on s of nu cl ea r ca rdiac i m ag i n g 47

arrhythmias, for both risk stratification and guiding interven- amenable to ablation even in areas with normal endocavitary
tional procedures [48, 49]. voltage [58] (EFig. 2.6).
Radiolabelled phosphate derivatives (i.e. 99mTc-​pyrophosphate)
Myocardial perfusion are gaining increasing relevance to diagnose cardiac amyloidosis,
For perfusion imaging with SPECT, thallium-​201 (201Tl) and
two technetium-​ 99m (99mTc) labelled compounds (Sestamibi (a)
and Tetrofosmin) are available (E Fig. 2.3) [50, 51]. 201Tl shows
overall better tracer-​ kinetic properties than 99mTc-​labelled
radiopharmaceuticals, but its longer half-​life and a higher radi-
ation exposure has discouraged its use in clinical practice [45].
99m
Tc-​
sestamibi and tetrofosmin are lipophilic compounds
that diffuse through the capillary and cell membranes and are
trapped in the mitochondria of the myocytes. While tetrofosmin
is extracted less avidly than sestamibi, it shows a more rapid
subdiaphragmatic clearance, thus the image quality of the two
compounds is comparable [52, 53]. The high photon energy and
the short half-​life of 99mTc allows the administration of higher
activities to the patient, improving image quality and reducing
attenuation and scatter [45, 46]. The extraction of both 99mTc-​
labelled tracers as a function of myocardial blood flow is less avid
than 201Tl, plateauing at higher flows [53], potentially reducing
the accuracy of SPECT imaging in the case of minimal alterations
of regional perfusion.
Acquisition of images with 99mTc-​Sestamibi and Tetrofosmin usu-
ally begins 15–​60 min after the injection to allow for hepatobiliary
clearance. Rest examination after nitrate administration is advo-
cated to improve the assessment of myocardial viability and avoid
underestimation in areas with reduced resting perfusion [54].
(b)
Myocardial function
The assessment of ventricular function is feasible through ECG-​
gated acquisitions [20, 55]. Equilibrium radionuclide ventricul-
ography is performed after 99mTc-​labelling of red blood cells and
allows the quantification of both systolic and diastolic functional
parameters (i.e. peak filling rate) with high accuracy and reprodu-
cibility [56]. LV-​EF measurement with equilibrium radionuclide
ventriculography is one of the methods-​of-​choice for monitoring
of cardiotoxicity in patients on anticancer drugs [56]. In patients
with suspected CAD, integrating the amount of ischaemia and the
LV functional impairment improves stratification of patients into
low, intermediate, and high risk of cardiac death [55] (EFig. 2.3).

Molecular imaging
123
I-​meta-​iodobenzylguanidine (MIBG) was developed from the
neuron-​blocking agent guanethidine. Uptake of 123I-​MIBG into
neuronal vesicles is achieved mainly through the uptake-​1 mech-
anism of norepinephrine (NE), then the tracer is not metabolized
and remains trapped [57]. Two static anterior planar acquisitions
are generally obtained (at 15 min and 4 h after injection). The
primary parameter calculated is the heart-​to-​mediastinum ratio Fig. 2.6  Example of dual tracer SPECT scans obtained by 99mTc-​Tetrofosmine
to assess myocardial perfusion and 123I-​MIBG to assess cardiac adrenergic
on the delayed images. Impaired cardiac adrenergic innervation innervation in a patient with ventricular arrhythmias. An area of preserved
as assessed by 123I-​MIBG imaging is strongly related to major perfusion with abnormal innervation is evidenced in the inferoposterior wall of
adverse cardiovascular events (MACE) in patients with HF in- the LV (a) corresponding to abnormal potentials at electro-​anatomic mapping
dependently of its cause [48]. In patients with ventricular ar- where ablation procedure was performed (b).
Courtesy of Dr. A Gimelli, Nuclear medicine department Fondazione Toscana G.
rhythmias 123I-​MIBG uptake defects identify myocardial regions Monasterio, Pisa.
48 CHAPTER 2   Nuc le a r cardiol o gy (PET and SPECT) — basi c pri n ci pl es
binding specifically to amyloid fibres probably via a calcium-​
mediated mechanism [59]. Their superior specificity for
transthyretin amyloid, allows the differential diagnosis with light-​
chain amyloidosis, including relevant prognostic and therapeutic
implications [58].
PET
The current clinical applications of PET imaging in cardiology
include three main fields: (1) myocardial blood flow (MBF);
(2) myocardial metabolism and inflammation; (3) molecular
imaging.
Myocardial blood flow
The measurement of MBF in ml/​g/​min by PET requires the intra-
venous injection of a positron-​ emitting perfusion tracer and
dynamic acquisition of images of the radiotracer, which passes
through the central circulatory system and is extracted in the
myocardium. Tracer-​kinetic models are then applied to correct
for physical decay of the radioisotope, partial volume effect, and
spillover to yield regional and global MBF values.
Three tracers are currently used for PET imaging: 15O-​labelled
water (H215O) [60, 61], 13N-​labelled ammonia (13NH3) [30, 62]
and 82Rubidium (82Rb) [63]. For both 13NH3 and H215O produc-
tion an on-​site cyclotron is required. H215O is a diffusible tracer
and its myocardial uptake is proportional to flow, making it ideal
for MBF quantitation [61]. The very short half-​life (2 min) and
the immediate washout from myocardial tissue limit the count
density and the quality of static images, requiring automated pro-
cessing to obtain MBF distribution images [64]. 13NH3 is meta-
bolically extracted and retained in the myocardium, showing an
uptake that is proportional to flow at lower-​intermediate flow
rate, while becoming non-​linear at higher flows [65–​67]. Using
appropriate kinetic models, 13NH3 allows accurate quantitation
of MBF and, due to its trapping in the myocardial cells and a
longer physical half-​life (9.8 min), yields high quality myocar-
dial perfusion images. In human subjects, both tracers provide
similar absolute MBF information [68] and both allow repeated
measurements in the same session [67, 69]. 82Rb is produced by
a Strontium-​82/​82Rb generator that generally requires replace-
ment once a month. Despite the limitation of a more prominent
nonlinear myocardial uptake with increasing blood flow, both
semiquantitive and fully quantitative measurements of myocar-
dial perfusion with 82Rb have proven feasible on a large scale
providing incremental risk estimation of cardiac and all-​cause
death in patients with known or suspected CAD [70–​73]. More
recently, 18F-​labelled PET perfusion tracers have been validated
[74–​76]. 18F-​ BMS747158-​ 02 (flurpiridaz) is the most prom-
ising, showing a relatively long half-​life (110 minutes) and high
extraction at first pass. These characteristics may allow both
qualitative and quantitative assessment of MBF and facilitate
the use in clinical routine [77]. Whichever the tracer used, PET
myocardial perfusion imaging (MPI) has the unique ability to
evaluate both qualitative abnormalities of regional myocardial
perfusion and to measure regional and global MBF in absolute
terms. Regional perfusion defects clearly indicate stenotic or oc-
cluded coronary arteries. In the case of diffuse atherosclerosis,
endothelial and/​or microvascular dysfunction, only full quanti-
fication can detect global ischaemia independently of detectable
regional perfusion defects [78, 79]. Coronary microvascular
dysfunction often coexists with epicardial coronary artery le-
sions and aggravate the impairment of hyperaemic MBF [80].
In view of the excellent image quality and full quantification of
MBF, PET has shown a superior diagnostic power to identify
functionally significant coronary lesions in patients with stable
angina [81–​83]. Globally impaired MBF and MBF reserve are
strong independent prognosticators of adverse outcome in pa-
tients with ischaemic heart disease [84, 85]. In asymptomatic
patients, the use of quantitative PET is able to detect the impact
of cardiovascular risk factors on MBF [61] [84, 85] and to pre-
dict MACE [86]. In addition, quantitative PET is particularly
effective in cardiomyopathies, characterized by a diffuse im-
pairment of MBF reserve, e.g. in hypertrophic or dilated car-
diomyopathy [87–​89]. Hybrid and fusion PET/CT and SPECT/
CT, IMHO imaging, with or without quantitation of MBF and
MBF reserve, can help to discriminate functionally significant
obstructive coronary disease, diffuse atherosclerotic and/​ or
microvascular coronary disease, and risk stratify patients [90–​
92] (EFig. 2.7).
Myocardial metabolism and inflammation
In the post-​absorptive state, the heart relies mainly on oxidation
of free fatty acid (FFA) as its main source of high-​energy phos-
phates while glucose uptake and oxidation are low. In the fed
state, glucose uptake is high and accounts for majority of the
concurrent oxygen uptake [93]. The factors that regulate myocar-
dial substrate utilization are complex and depend, in addition to
substrate concentration, upon multiple factors including insulin,
catecholamines, cardiac workload, and oxygen supply [93, 94].
While PET imaging is able to assess multiple aspects of ischaemic
myocardial metabolisms such as reduced FFA utilization [95] and
impaired tricarboxylic acid cycle activity [96], it is widely used
in the clinical setting for the assessment of glucose metabolism
as a marker of ischaemia and viability [97]. Fluorodeoxyglucose
(FDG) is transported into the myocyte by the same trans-​
sarcolemmal carriers (GLUT-​1, GLUT-​4) as glucose and is then
phosphorylated by hexokinase to FDG-​6-​phosphate, which is no
more metabolized. Noninvasive imaging of ischaemia by PET
FDG basically relies on the observation that the uptake of glu-
cose by the myocardium is increased by hypoxia and mild to
moderate ischaemia, but decreased by chronic severe ischaemia
and abolished in scarred myocardium. In patients with post-​
ischaemic myocardial dysfunction, the combination of MPI by
PET or SPECT and metabolic imaging by PET FDG thus allows
to distinguish ischaemic and viable myocardium (mismatch areas
with decreased perfusion and enhanced FDG uptake) from nec-
rotic non-​viable tissue (matched areas with both decreased per-
fusion and FDG uptake) [97–​99] (EFig. 2.8). The use of hybrid
PET/​MRI scanners holds promise for a better characterization
 Cu rrent pro cedu res a n d cl i n i ca l a ppl i cati on s of nu cl ea r ca rdiac i m ag i n g
Fig. 2.7  Three examples of hybrid/​fusion SPECT/CT and PET/CT studies.
In the upper panel a SPECT/CT study in a 57-​year-​old female with typical
angina on effort and normal LV function demonstrating extensive exercise
induced perfusion defect downstream an obstructive left anterior descending
coronary artery (LAD) stenosis. In the middle panel a quantitative PET/CT
study performed in a 67-​year-​old man with dyslipidaemia, borderline
abnormal LV function (LVEF 50%) and diffuse coronary atherosclerosis
demonstrating a global impairment of MBF reserve during dipyridamole
stress. In the lower panel a quantitative PET/CT study performed in a
60-​year-​old man with glucose intolerance, hypertension, moderate-​severe
LV dysfunction (LVEF 33%) and angiographically normal coronary arteries
with diffuse impairment of MBF reserve during dipyridamole stress.
of post-​ischaemic myocardial damage allowing the detection of
subendocardial infarctions [100, 101].
18
F-​FDG imaging of the increased cell metabolism in activated
macrophages and CD4+ T lymphocytes, in fasting conditions
after a fat-​enriched diet, has been exploited to assess active car-
diac inflammation in sarcoidosis. Patients with decreased per-
fusion and increased metabolic signal have the highest event
rate, particularly if right ventricle (RV) is involved [102, 103]
The co-​registration of CT angiography and 18F-​FDG has shown
a good performance for the detection of active disease status in
patients with large vessel vasculitis [104], cardiac prosthesis, and
device infection. It can serve as a surrogate biomarker for as-
sessment of active inflammation and remission after immuno-
suppressive therapy [105, 106] 18F-​FDG uptake has been used to
49
measure atherosclerotic plaque inflammation and vulnerability
[107]. More recently, PET using 18F-​sodium fluoride (18F-​NaF), a
tracer for imaging skeletal diseases, has been shown to visualize
microcalcifications in atherosclerotic plaques of large coronary
and carotid arteries as a potential marker of disease progression
and plaque vulnerability [108].
Molecular imaging
Different tracers have been used to study the autonomic innerv-
ation of the heart. Adrenergic presynaptic sympathetic terminals
have been tested in particular with 11C-​labelled hydroxyephedrine
(11C-​HED) [109], which compete with endogenous noradrenaline
for the uptake-​1 into the presynaptic nerve terminal. Several beta-​
blocking drugs have been labelled with 11C to act as radioligands
for the study of postsynaptic ß-​adrenoceptors. 11C-​(S)-​CGP12177
is a non-​selective ß-​adrenoceptor antagonist which is particularly
suited for PET studies due to its high affinity and low lipophilicity,
thus enabling the functional receptor pool on the cell surface to
be studied [110]. In ischaemic heart disease, reduced regional
11
C-​HED retention may exceed the presence and extent of perfu-
sion defects reflecting either complete denervation or abnormal
presynaptic neuronal function in areas of viable myocardium,
due to higher susceptibility to ischaemia of neurons as opposed
to cardiomyocytes. In patients with heart failure, an increased
adrenergic drive together with an impaired presynaptic uptake-​
1 function may downregulate β-​adrenoceptors. Clinical studies
have demonstrated diffuse downregulation of 11C-​(S)-​CGP12177-​
derived β-​adrenoceptor density in hypertrophic cardiomyopathy
[111, 112] and in congestive heart failure [113].
Several investigational tracers have been proposed to diag-
nose cardiac amyloidosis with PET 11C-​Pittsburgh Compound B
(PIB), 18F-​Florbetapir, and 18F-​Florbetaben [114].
Recent trends
Novel dedicated SPECT cameras
Economic pressure, competition from other modalities, chan-
ging patient cohorts with an increasing body mass index (BMI),
and a growing awareness of patient exposure to ionizing radi-
ation have triggered the development of novel cardiac SPECT
technology which has been introduced in recent years. Several
manufacturers have integrated semiconductor detector materials
such as cadmium-​zinc-​telluride (CZT) and dedicated collima-
tors [115]. Together with improved reconstruction algorithms the
latter resulted in increased speed and accuracy of conventional
gamma cameras (EFig. 2.9) [116]. Using both approaches,
imaging times now can be reduced to as much as 10% of that of
previous standard protocols, and/​or injected activity can be re-
duced. It is important to note, however, that both effects are mu-
tually exclusive, with a spectrum of solutions in between, and that
many aspects of optimal acquisition protocols are not yet fully
defined [117].
In general ultra-​fast acquisition protocols are at least of equal
quality when compared to standard gamma camera acquisitions
[118, 119] even if new imaging methods tend to introduce new
artefacts [120, 121].
50 CHAPTER 2   Nuc le a r cardiol o gy (PET and SPECT) — basi c pri n ci pl es

Fig. 2.8  Example of a cardiac PET exam with

13
NH3 as a flow tracer and 18F-​FDG as a metabolic
tracer performed to assess myocardial viability
in a patient with LV dysfunction candidate to
coronary revascularization. The exam documents
an area of flow-​metabolism ‘mismatch’ indicating
viable myocardium in the LAD territory (40% of LV
myocardium) and an area of ‘match’ in the right
coronary artery (RCA) territory indicating scarred
tissue (28% of LV myocardium).

Some of these new systems are suited for dynamic applications
which may facilitate measurements of MBF reserve [122]. These
devices are not limited to perfusion agents but also innervation
imaging with MIBG might profit from the increased sensitivity
[123]. The increased energy resolution of CZT detector also allow
the development of sophisticated dual isotope protocols [124].
Reduction of radiation dose
The success and high frequency of noninvasive testing in CAD
have contributed to an increasingly critical perception of radi-
ation exposure from nuclear cardiology [125–​127]. Increased
gamma camera sensitivity through new solid-​state detector ma-
terials and novel camera designs allows for a significant reduction
of injected radiotracer dose, which reduces radiation exposure
to the patient paralleling similar advances in CT [128]. When
combining such novel technology with a stress only imaging ap-
proach, the average injected dose per patient can be potentially
reduced to around one mSv [129, 130].
Likewise, PET uses shorter lived radiotracers and thus results
in lower radiation exposure when compared to SPECT [131]. Due
to its success in oncological imaging, more and more powerful
PET systems are available for clinical application, allowing for re-
duction of injected dose preserving image quality.
Integrated PET/​MRI
Even before the availability of commercial systems for clinical
use since 2011, integrated PET/​MRI was eagerly awaited for car-
diac applications [132, 133]. After addressing the fundamental
problem of AC in absence of a direct assessment of radio-​density
[134, 135], the success still appears to be limited. The primary
reasons are high systems costs, complex protocols, and rather
long scan durations. Still, cardiac PET/​MRI could be attractive
as the use of this modality in single organ applications has the
potential to shorten the scan times due to parallel assessment of
parameters. From the technical perspective, motion detection
and thus correction is feasible without any extra radiation burden

in order to increase the effective resolution of PET and integrate
with imaging of the epicardial vessels [136]. Especially its use in
inflammatory diseases where the increased scanning costs are less
relevant in comparison to the total cost of treatment, offer signifi-
cant potential [137–​139].
Conclusion
Radionuclide imaging techniques are well established for imaging
of myocardial function, perfusion, viability, and biologic mech-
anisms. The tracer principle—​the attachment of a radioisotope
to a biomolecule in order to follow its distribution throughout
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 CHAPTER 3

Cardiac CT—​basic
principles
Gianluca Pontone and Filippo Cademartiri

Contents Introduction
Introduction  57
Basic principles of a computed tomography In the last three decades, several technologies were introduced in cardiology to allow a
system  57 non-​invasive evaluation of cardiac anatomy, function, perfusion, and metabolism with
ECG synchronized acquisition mode  59 billions of tests performed per year. A great contribution derives from cardiac computed
Spatial resolution and scan coverage  60
tomography (CCT) that was introduced in the field of cardiac imaging in late 1990s,
Temporal resolution  60
Image noise  61 showing a promising performance to rule out coronary artery disease (CAD) [1]‌and to
Dual-​energy computed tomography  62 stratify the risk of adverse cardiac events [2–​4]. Therefore, a deep knowledge of the basic
Contrast material  63 principles that are beyond this technology is useful for cardiologists to better understand
Radiation exposure  63 this disrupting imaging modality that change is status from investigative tool into a tech-
Patient selection  63 nique for daily practice.

Basic principles of a computed tomography system

A standard CT equipment is based on a X-​ray source, producing a narrow X-​ray beam
with different widths depending on the number of slices, that is coupled with matrix
detector with different number of detector rows (E Fig. 3.1) [5]‌. The X-​ray source and
matrix detector rotate simultaneously around the patient while the table moves (helical
scan modality) or while the table remains stationary (axial scan modality). Data acqui-
sition requires an X-​ray source that produces a collimated X-​ray beam that goes through
an anatomical section where some of the photons are absorbed (EFig. 3.1). The attenu-
ation consists in the reduction of the number of X-​ray photons able to reach the detector
on the other side of the X-​ray source, that depends mainly by the atomic density of
the tissues and by the energy of the photons. The attenuated X-​rays collected by de-
tectors located on the opposite side of X-​ray source are then converted into digital data
and they become attenuation values expressed as Hounsfield Units (HU). This physical
phenomenon occurred for a large number of projections performed during each half
rotation of the tube. To determine an adequate level energy of the photons tube current
and tube voltage are both crucial parameters to be settled in the CCT acquisition. To
limit the attenuation of X-​ray, high tube current, and tube voltage should be desirable.
Unfortunately, the effective radiation dose (ED) increases linearly with tube current and
with the voltage squared. Therefore these parameters need to be at the lowest level ex-
pected to reach good image quality for a specific diagnostic aim reaching a trade-​off be-
tween image noise and contrast resolution. For this reason, individual weight-​adapted
protocols have been successfully applied by adjusting tube voltage and tube current to
the patient’s body mass index or chest diameter. Alternatively, a ‘noise-​based’ approach
58 CHAPTER 3   C ardiac CT—basic principle s

GANTRY
Rotating direction
ROTATION TIME

Rotating
ECG- x-ray source
TRIGGERING Fan-shaped
MODALITY x-ray beam NUMBER OF X-RAY SOURCE

TUBE VOLTAGE and

TUBE CURRENT

ADAPTIVE ITERATIVE
RECONSTRUCTION
ALGORITHM

MODULATION DOSE
Rotating ECG-TRIGGERED
x-ray detectors
Motorized table

SCAN LENGHT
TABLE SPEED
MOVEMENT
(PITCH) NUMBER OF SLICES

Fig. 3.1  Standard cardiac computed tomography equipment. An X-​ray source is coupled with matrix detector with different rows based on the different
scanner. The X-​ray source and matrix detector rotate simultaneously around the patient while the table moves (helical scan modality) or while the table remains
stationary (axial scan modality). All variables contributing to image production are listed in the figure.
Reproduced from Brenner DJ, Hall EJ. Computed tomography— an increasing source of radiation exposure. N Engl J Med. 2007;357(22):2277–2284. doi:10.1056/ NEJMra072149 with
permission from Massachusetts Medical Society.

to define the best scanning parameters was described and con-
sisting in the noise measurement on precontrol scan with tube
voltage and tube current adapted to the noise measured [6].
According to the above description of basic principles of CCT,
the most common definitions used in daily practice are here
provide:
a) Tube current represents the number of photons that are pro-
duced and that actually run through the patient and it is ex-
pressed in milliAmpere per second (mAs). A higher mAs
improves the contrast-​to-​noise ratio (e.g. image quality and
specifically contrast resolution).
b) Tube voltage represents the energy of each photon of the beam
and it is expressed in kiloVolt (kV). Photons with higher en-
ergy are more likely to cross structures with higher densities
such as calcifications, bone, metal.
c) Field of view (FOV) represents the size of the image that is going
to be reconstructed. A small FOV increases in-​plane spatial
resolution when spatial resolution of the raw data is below or
equal the minimum value of the FOV; FOV is generally square
or a circle.
d) Image matrix represents the number of pixels that are recon-
structed in one image and is generally constant for CT (i.e. 512
× 512 pixel).
e) Spatial resolution is defined as the capability to separate two
neighbouring pixels (or voxels in the third dimension) and it
roughly corresponds to the width of matrix detector.
f ) Temporal resolution represents the minimum time required to
generate one single axial image and it corresponds to the half of
gantry rotation time 180° of gantry or tube/​detector rotation;
this is different in dual-​source CT scanners because they only
require 90° of rotation. Hence, given the same rotation time,
a dual-​source CT has double temporal resolution (i.e. twice
as fast).
g) Contrast resolution represents the capability to separate two
neighbouring attenuation values expressed in HU with a given
background noise.
h) Table feed is defined as the speed of patient’s translation along
the z-​axis (Cranio-​caudal or longitudinal direction).
i) Collimation is defined as the beam width along the longitudinal
axis at the scanner iso-​centre.
j) Scan pitch is conventionally defined as the ratio between the
table feed and the slice/​beam collimation. More commonly
beam collimation is used since the slice collimation has to do
with individual slice/​detector width and number of detectors.
Low pitch (i.e. <1) means multiple acquisitions across the same
geometrical region.

ECG synchronized acquisition mode
The standard CCT technology requires acquisition of data
set over multiple heart cycles to fully image cardiac structure.
Therefore, it is essential that all data are acquired/​reconstructed
during the same cardiac phase and this is only possible using an
ECG synchronized acquisition. There are two main methods of
ECG synchronization: retrospective ECG gating (or helical/​spiral
low-​pitch acquisition) and prospective ECG triggering (or axial/​
step-​and-​shoot acquisition).
Retrospective ECG gating or helical acquisition: The acquisi-
tion of image is continuous during the cardiac cycle as showed
in EFigure 3.2 [7]‌. Once the data have been acquired, they can
be reconstructed in any phase of the cardiac cycle by shifting the
initial point of the image reconstruction window relative to the R-​
wave. Therefore, the combination of z-​interpolation and cardiac
gating enable a stack of parallel tomographic images to be gener-
ated which represent the heart in the same phase of the cardiac
cycle [7]. The aim of this strategy is to retrospectively extract the
data set corresponding to the phase when cardiac motion is at a
minimum. To obtain images in the diastolic phase, some operators
reconstruct the images in relation to the phase (i.e. % of the R-​R
interval) of the cardiac cycle (typically between 70% and 80% of the
R-​R interval), whereas others use the time window of the absolute
interval after or prior to the peak of the R-​wave [8] (EFig. 3.3).
Retrospective ECG gating allows to have all cardiac phases and to
select the one with less motion artefacts. However, the combination
of backward-​looking measurement of R-​wave timing and spiral
scanning during table motion requires very low pitch (range 0.15–​
0.35), and traditional cone beam reconstruction with increase in
radiation dose. For this reason tube current modulation technique
can be applied. Because residual cardiac motion is high during sys-
tole and low during diastole, the ‘useful’ radiation dose usually falls
in mid-​to-​end diastole phase which corresponds to 15–​30% of the
overall radiation burden. According to this principle, the highest
Systolic Early diastolic Late diastolic
Fig. 3.2  Retrospective ECG triggering. This technique consists of a
continuous spiral scanning of the heart with simultaneous ECG recording.
Using this technique, tube current is applied during all cardiac cycle with
increase of radiation exposure.
EC G sy n chron i z ed ac qu i si t i on   mode 59
R R R R
(a)
60% 60%
(b)
+650ms +650ms +650ms
(c)
–350ms –350ms –350ms
Fig. 3.3  Cardiac phase selection in retrospective ECG-​triggering acquisition.
The figure depicts different strategies for cardiac phase selection in ECG-​
triggering acquisition gating in MDCT coronary angiography. (a) Percentage
relative delay: the software calculates the distance from one R-​wave to the
next to the next and positions the time window at a defined point based on
the percentage of the entire R-​R interval. (b) Absolute delay: with this strategy
the time window is placed according to a fixed delay time after the previous
R-​wave. (c) Absolute reverse delay: with this strategy the window is placed
with a fixed time delay prior to the next R-​wave.
tube current to reach the best image quality is delivered only during
end diastole, while it is reduced by 80–​95% in the remaining phases
of the cardiac cycle. During the scan, the desired mA modula-
tion window is prospectively determined by the operator (range
30–​80% of cardiac cycle). For high heart rate (HR), retrospective
ECG gating with ‘multisegment reconstruction algorithm’ has been
proposed (i.e. multiple partial datasets from different consecutive
heart beats are averaged to generate each cross-​sectional image) as-
suming an improvement of temporal resolution [9]. However, the
assumption falls short in predicting that each and every heartbeat is
exactly the same. In normal condition this never happens because
heartbeats are all slightly different due to cardiac chamber filling as
well as diaphragm position continuously changing throughout the
apnoea required during the CCT scan.
Prospective ECG triggering or axial acquisition: The first geom-
etry for ECG synchronization applied to tomographic scanners
was prospective ECG triggering. In particular, this technique was
applied to an older technology (electron beam CT) that could
rely on a very high temporal resolution in the range of 50–​100
ms. This technique suffered from low spatial and contrast reso-
lution and the field of applications was mainly quantification of
coronary artery calcium (i.e. Calcium Score). In the last 10 years
CT technology developed newer scanners with higher temporal
resolution that allowed to apply prospective ECG triggering also
for CCT [10]. This technique applies forward-​looking prediction
of R-​wave timing with static table during acquisition (EFig. 3.4).
The crucial point of this acquisition relies on the accurate predic-
tion of the R-​R duration based on the evaluation of the previous
cardiac cycles. During ECG analysis, the table moves to the next
position, and waits for the subsequent QRS trigger to initiate the
scan that is performed without table movement. The process is
repeated until the entire volume of interest is covered. This means
60 CHAPTER 3   C ardiac CT—basic principle s
Prospective ECG-triggering
50%
R to R interval
ECG
X-ray
Fig. 3.4  Prospective ECG triggering. It is based on sequential scanning
(also called ‘step-​and-​shoot’ mode). With this scanning, the table remains
stationary while the X-​ray tube rotates around the patient and is advanced
for the subsequent scan only when data acquisition is completed obtaining
a significant reduction of total X-​ray exposure time. Radiation are delivered
only within the phase of the cardiac cycle that has been decided prior to the
initiation of the scan. It requires very low heart rate and/​or very high temporal
resolution to guarantee adequate image quality.
that radiation is only administered at one predefined time window
of the cardiac cycle with non-​spiral scanning. Consequently, in a
prospective acquisition, the exposure time is optimized and radi-
ation dose is lower as compared to retrospective acquisition. The
main disadvantage of axial acquisition is that only a short diastolic
phase is acquired and therefore a HR control is mandatory for
prospective ECG triggering [10]. Another source of inconsistency
is a situation with high beat-​to-​beat HR variability. If high HR is
an absolute contraindication for prospective ECG triggering, the
limitation of HR variability can be overcome using larger window
acquisition to improve interpretability of the images by providing
additional cardiac phases with a concomitant increase in radi-
ation dose [10]. The second limitation is that discrete nature of
the prospective ECG-​triggering acquisition mode may result in
transition artefacts between axial shots. Finally, a further limita-
tion is the scan length and the impossibility to perform functional
evaluation, unless a very wide acquisition window is applied.
Spatial resolution and scan coverage
With the recent technical innovations two important goals were
reached: the improvement of spatial resolution and a larger ana-
tomical coverage during the scan. Currently, the maximum phys-
ical spatial resolution corresponds to the minimum detector
array width (i.e. 0.5 mm). Detector technologies have developed
in different directions providing solutions able to increase spa-
tial resolution without compromising image quality with signifi-
cant noise. In this field the developments are difficult because a
smaller detector entails a smaller surface, which result in a lower
number of photons reaching the target, given all other parameters
constant, which result in a lower and noisier signal. Therefore,
making a small detector in itself is not actually the issue, but the
issue is to keep images readable with smaller detectors and to
avoid a consistent increase in radiation dose that would compen-
sate the smaller target area for the photons.
The second important step forward was the introduction of pro-
gressively wider detector coverage CCT scanner. Cranio-​caudal
coverage of 64-​slice CCT is typically around 40 mm. As conse-
quence, multiple beats are required to image the full heart, re-
gardless the ECG synchronization technique. The development of
wide area detector [11] enabled greater coverage per gantry semi-​
rotation and the extension from 64-​slices multidetector computed
tomography (MDCT) to 256-​detector row or 320-​detector row
system reaching a 160 mm of coverage in the z-​direction. Both
detector geometries allow a comprehensive anatomic imaging of
the whole heart and coronary vessels in a single heartbeat in axial
scan mode (EFig. 3.5). Several advantages can be associated with
these scanners. First, they eliminate ‘stair-​step’ artefacts. Second,
the fast acquisition of the entire cardiac volume allows the contrast
bolus to be imaged at a single time point so that intravenous con-
trast material volume can be reduced. Third, these scanners pre-
sent a significant opportunity to expand the utilization of low dose
CCT also in patients with higher HR. Finally, these scanners were
proved to be ready for advanced application in CCT such as the
use in atrial fibrillation patient [12] or stress myocardial perfusion
[13] with similar diagnostic accuracy of fractional flow reserve CT
derived [14].
Temporal resolution
Temporal resolution has been for a long period of time the main
limitation of CCT. Indeed, with the standard single-​tube technology
the maximum temporal resolution achievable is 135 msec which is
significantly higher than the ideal <50 msec temporal resolution
requested to image coronary arteries to avoid blurring of vessel im-
ages even at high and irregular HR [15]. To compensate this limita-
tion, a reduction of patient’s HR with different drug protocols were
usually performed before CCT scan, but unfortunately, an ideal
HR for CCT is achieved not in all patients in the daily practice.
Therefore, in patients with high HR or HR variability, to reach a
good image quality is still challenging for the standard technology.
A milestone in the improvement of temporal resolution was
the introduction of dual-​source computed tomography (DSCT).
The technology combines two systems consisting of one tube
and one detector array each, arranged within the same gantry at
a 90° offset, so that a one-​quarter rotation is sufficient to sample
X-​ray transmission data over 180° of projections, reaching a
temporal resolution of 66 msec with third generation DSCT
scanner (EFig. 3.6). This high temporal resolution allows fast
volume scanning with pitch values up to 3.2 (which means that
whole heart is acquired within the same end-​diastolic phase of
a single heartbeat). Due to the high pitch value, no redundant
data are acquired. Images reconstructed with this scan mode have
image quality comparable to those acquired with a pitch of 1.0
[16]. Therefore, the DSCT system can be operated in two ways.
First, it can work at increased pitch without synchronization to
the patient’s ECG. Using a pitch value ranging from 1.5 to 3.2.
Second, the patient’s ECG can be used to trigger the start of table
motion and the start of the high-​pitch spiral scan in such a way

Fig. 3.5  Whole-​heart CCT scanner. The 256-​CCT has 912 × 256 (cranio-​caudal) elements, each approximately of 0.5–​0.6 mm with cranio-​caudal coverage
ranging between 128 mm and 160 mm per rotation. The 320-​CCT system used a detector element consisting of 320 × 0.5 mm detector and provides 160 mm
of coverage in the z-​direction. Both scanners allow a comprehensive anatomic imaging of the whole heart and coronary vessel in a single heartbeat in cime non-​
spiral scan mode without ECG gating.
Reproduced from Pontone, G., How to Reduce the Radiation Burden in Cardiac CT, in Marzullo, P., and Mariani, G., eds. From Basic Cardiac Imaging to Image Fusion, © Springer 2013
with permission from Springer Nature.
that the heart will be imaged starting at a preselected phase of
the patient’s cardiac cycle. Previous studies with DSCT demon-
strated that image quality and diagnostic accuracy remain un-
changed by systematic HR control while coronary visualization
significantly improves as compared to 64-​slice single-​source CCT
[17]. Clinical benefits are more relevant for example in the exam-
ination of patients with limited ability to cooperate in holding
still, such as in thoracic, paediatric, and emergency applications.
Detector B
34 cm
Detector A
Fig. 3.6  Dual-​source computed tomography system (DSCT). This scanner
combines two arrays consisting of one tube and one detector each, arranged
within the same gantry at a 90° offset, so that a one-​quarter rotation is
sufficient to sample X-​ray transmission data over 180° of projections. With
the third DSCT generation a temporal resolution of 66 msec is reached.
Source data from Flohr TG, Leng S, Yu L, et al. Dual-​source spiral CT with pitch up to 3.2
and 75 ms temporal resolution: image reconstruction and assessment of image quality.
Medical physics 2009;36:5641–​53.
Im ag e   n oi se 61
64-slice MDCT
256-slice MDCT
320-slice MDCT
Image noise
CCT usually use a class of algorithm called filtered back-​projection
to provide cardiac images. In this algorithm, each projection data
is calibrated, filtered, back-​projected, weighted, and when the last
projection view has finally been processed, the reconstruction is
complete, and reconstructed images are generated. Unfortunately,
FBP are much sensitive to noise. Therefore any effort to reduce ED
of patient by reducing tube voltage and tube current needs to keep
in account the concomitant noise increase. Recently, as an alterna-
tive to FBP, iterative reconstruction algorithms were introduced to
compensate the increase image noise produced at low tube current
and tube voltage settings. It is bases on an estimation process that
mimics, as much as possible, the process in real CT scanning in
which X-​ray photons traverse through the object and reach the de-
tector. In other words with this algorithm, it is assumed that noise
is not homogeneously distributed across the entire image but the
matrix algebra is used to selectively identify and then subtract
noise from the image with a mathematic model. The result is a less
noisy image than with FBP techniques. Leipsic et al [18] showed
that although the largest reduction in noise was observed with
100% of iterative reconstruction, a level ranging between 40% and
60% appeared to provide optimal image quality. Similarly, Pontone
et al. showed lower noise (–​15%), higher signal-​to-​noise (+21%)
and contrast-​to-​noise (+22%) ratio, and better feasibility (97% vs.
91%) with 40% iterative reconstruction versus FBP with similar
results also confirmed in the last generation algorithms [19].
62 CHAPTER 3   C ardiac CT—basic principle s

whereas the bottom layer detector absorbs higher-​energy X-​ray

Dual-​energy computed tomography photons; (4) Canon/​Toshiba: a single X-​ray source, with fast
tube voltage switching, thereby close to GE Healthcare design.
The standard CCT equipment is characterized by a single poly-
The tube voltage level is altered between consecutive gantry ro-
chromatic energy levels of photons set usually ranging between
tations, instead of acquiring projection views in a single gantry
120 to 140 kVp based on body mass index of patients. More re-
rotation. A summary of different technical option is provided in
cently, dual-​energy computed tomography (DECT) system was
E Figure 3.7 [20]. Mostly DECT applications are still experi-
introduced in the clinical practice. It consists in a scanner produ-
mental or preclinical. One potential application of DECT is in
cing energy levels of photons ranging between 80 to 140 kVp for
the field of myocardial perfusion. Given the ability of DECT to
the acquisition of low-​and high-​energy-​dependent tissue attenu-
allow differentiation of iodine attenuation profile, it allows the
ation profiles, respectively [20]. The exploitation of two polychro-
mapping of iodine distribution in the myocardium as a surrogate
matic energy spectra by DECT can be achieved by four different
semi-​quantitative marker for perfusion. Several studies suggest
solutions: (1) Siemens Healthineers: dual-​source CT scanners
that the addition of myocardial perfusion with DECT may de-
with two tubes and two detector arrays using two different tube
crease the number of false-​positive results CCT which is in line
voltage settings, which allows the simultaneous acquisition of
with the observations seen for hybrid scanner [21]. A second po-
two different data sets with low (80-​kV) and high (140-​kV) tube
tential clinical application in cardiac imaging is coronary plaque
voltages; (2) GE Healthcare: this approach involves using a CT
characterization. One of the main aims of CCT is to identify the
scanner with a single X-​ray source, which rapidly switches be-
features of high-​risk plaque prone to rupture that are presence
tween 80 kV and 140 kV in a single gantry rotation; (3) Philips
of positive remodelling, low attenuation plaque and spotty cal-
Healthcare: detector design entails dual layer detector array (i.e.
cification [22]. However, a considerable overlap in HU between
sandwich detector technology) composed of different mater-
lipid-​rich and fibrous-​rich non-​calcified plaques was observed.
ials. The top layer detector absorbs low-​energy X-​ray photons,
DECT may overcome these limitations thanks to its capability to

(a)
80 kVp
2 Tubes + Detectors
Tube Spectra
140 SIEMENS
# x-rays

140 kVp 80 Dual Source

Energy
(b)
1 Tube + 1 Detector
Tube Spectra 140 kVp 140
# x-rays

80

80 kVp kV Switching
Energy
(c) 1 2
Dual-Layer Detector
Detector Absorption
# x-rays

1 2

Dual-Layer

Energy
(d)
Gantry Roration TOSHIBA

kVp Switching Between

High Tube Voltage Gantry Rotations

Low Tube Voltage

Fig. 3.7  Schematic illustration of four different dual energy computed tomography approaches. (a) Two tubes that operate at two different tube voltage
settings, which allows the simultaneous acquisition of two different data sets with low (100-​kV) and high (140-​kV) tube voltages; (b) CT scanner with a single X-​
ray source, which rapidly switches between 80 kV and 140 kV in a single gantry rotation; (c) The two detectors are superimposed and are composed of different
materials. The top layer detector absorbs low-​energy X-​ray photons, whereas the bottom layer detector absorbs higher-​energy X-​ray photons; (d) A single X-​ray
source, with fast tube voltage switching. The tube voltage level is altered between consecutive gantry rotations, instead of acquiring projection views in a single
gantry rotation.
Reproduced from Danad I, Fayad ZA, Willemink MJ, Min JK. New applications of cardiac computed tomography: dual-​energy, spectral, and molecular CT imaging. JACC Cardiovasc
Imaging. 2015;8(6):710–​23. doi:10.1016/​j.jcmg.2015.03.005 with permission from Elsevier.
 Pati en t se l e c t i on 63

perform material decomposition. However in this field further drugs) and ability to maintain breath-​hold for a period compat-
studies should be addressed. ible with the scan time. Both these criteria are aimed at avoiding
motion artefacts. Even though CCT can be diagnostic with a
higher HR, motion artefacts progressively reduce the number of
Contrast material segments which can be correctly visualized. The second criterion
aims at avoiding artefacts associated with respiratory motion.
Iodinated non-​ionic contrast material (CM) is the elective intra- In addition patients with known allergies to iodinated contrast
venous (IV) agent in CCT, used to increase the contrast resolution agent, severe renal insufficiency (serum creatinine >120 mmol/​
between vessels and vascularized structures and the remaining L), pregnancy, respiratory failure, and unstable clinical condi-
surroundings. The IV administration of CM has developed and tions should be excluded from CCT. Once the patient is selected,
modified over time, following mainly the development of CT the scan parameters should be defined. Despite there are several
scanners. The aim of a proper CT angiography of the coronary differences among the different technologies, the ideal protocol
arteries is to obtain the highest intravascular contrast enhance- should enable high spatial resolution (thin collimation), high
ment while using the minimum volume [23]. In fact, Iodinated temporal resolution (fast gantry rotation) and low radiation dose
CM can affect renal function in patients with already significantly a good signal-​to-​noise ratio. The main scan parameters are listed
decreased renal excretion performance. CM can also be a source in ETable 3.1. In all patients with resting HR<65 beats/​min be-
of allergic reaction for a minor group of patients, for which, most fore CCT, a pretreatment is required mainly if standard 64-​slice
of the times, it is very difficult to predict a future allergic reaction.
The protocol for IV CM administration takes into account sev-
eral variables including; patient’s size (i.e. height/​weight, body Table 3.1  Scan and reconstruction parameters
mass index [BMI], BSA), Global Cardiac Function/​Index, quality
of the IV access (usually a large antecubital vein), length of the Scan
apnoea during angiographic phase, kiloVoltage of the CT ac- Detectors 64–​312
quisition, presence of coronary artery stent(s). In general, with Collimation 0.5–​0.6 mm
state of the art CT equipment it is possible to obtain diagnostic
KiloVolt 80–​120
image quality with a volume of 50 ml administered at a rate of
MilliAmpere/​sec (range) 400–​900
4–​5 ml/​s and pushed by saline chaser of the same volume and
with the same rate [24]. A higher concentration of iodine is de- Rotation time 270–​330 ms
sirable within the injected CM to obtain with more ease a high Tube current modulation Systolic
intravascular enhancement [25]. Lately, the progressive reduction Effective temporal resolution 66–​65 ms
of kiloVoltage has allowed to decrease the need for higher IV rate
Effective spatial resolution 0.3 × 0.3 × 0.4 mm
and CM volume due to the improved performance of CM attenu-
Pitch 0.2–​3.2
ation at lower kiloVoltages.
Scan time <1 sec–​12 s
Reconstrution
Radiation exposure Effective slice width 0.5–​0.75 mm
Temporal windows (‘hot spots’) 40–​80% cardiac cycle
Cardiac CT is a diagnostic technique based on X-​rays and there-
fore radiation protection has always been an important factor in FOV 140–​180 mm
the technical and clinical development of the method. Currently, Matrix 512 × 512
when we consider optimal standard conditions for CCT the radi- Contrast Material
ation dose required is quite low a can sometimes even be below 1 Synchronization Test bolus/​bolus tracking/​fluoroscopy
mSv. On one hand the approach should always follow the rule that trigger
we need to use only the minimum amount of radiation required Region of interest (ROI) Ascending aorta or left atrium/​left
for the diagnosis; on the other hand it is necessary to perform a ventricle
diagnostic CCT scan without trading accuracy or confidence of Threshold in the ROI +100 HU
the results. This is important especially if we consider the current
Pre-​delay 1.7 sec–​10 s
and future role of CCT in the clinical field.
CM volume 50–​100 ml
CM rate 4–​6 ml/​s

Patient selection Iodine concentration 320–​400 mgI/​ml

Bolus chaser 40–50 ml @ 4–​6 ml/​s
Despite the latest technologies allow to scan any kind of patient
Venous access Antecubital
regardless the HR, normal inclusion criteria with standard 64-​
slice scanner are usually HR<65 bpm (spontaneous or induced by Total administration time Variable
64 CHAPTER 3   C ardiac CT—basic principle s
scanner is used. Several drug protocols were described in litera-
ture including p.o. or i.v. beta-​blocker (metoprolol p.o. 100 mg 1
hour before the scan or metoprolol i.v. with a titration dose up to
15–​20 mg). Also a pretreatment with oral ivabradine (5–​7.5 mg
twice per day since 3–​4 days before the scan) [13]. In addition
to chronotropic therapy, the use of sublingual nitrates is highly
recommended to improve the size of coronary arteries and there-
fore the image quality. Moreover, each patient should perform a
breath-​hold test to evaluate the heart rate variability (HRv) cal-
culated as the standard deviation (SD) from the average HR. All
patients received a variable dose of contrast agent based on the
BMI of patients and the scan length ranging between 50 and 100
ml (iodine concentration suggestion ranging between 50 and 100
ml) through an antecubital vein at an infusion rate of 4–​6 ml/​s,
followed by 40 ml of bolus chaser at an infusion rate of 4–​6 ml/​
sec (ETable 3.1). To correct timing of acquisition can be decided
based on three different techniques [26]: a) Test bolus: this tech-
nique is based on the calculation of the transit time between the
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Accuracy of multidetector spiral computed tomography in detecting
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5. Brenner DJ, Hall EJ. Computed tomography—​an increasing source
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site of injection and the ascending aorta using a small volume of
CM as a test bolus (usually 10–​15 ml) [23]. Unfortunately, it was
proved that there is not a direct correlation between the delay cal-
culate with the test bolus and the peak enhancement during the
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side if the heart the patient is invited to breath-​hold and when the
contrast agent fills the left side the scan is started. It is important
to underline that with this technique the delay to start the scan
should be set up at minimum delay.
12. Andreini D, Pontone G, Mushtaq S, et al. Atrial fibrillation: diag-
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diac computed tomography: dual-​energy, spectral, and molecular
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21. Ko SM, Choi JW, Song MG, et al. Myocardial perfusion imaging
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Re f e re n c e s 65
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25. Cademartiri F, Mollet NR, van der Lugt A, et al. Intravenous con-
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Contents
Introduction to MRI physics  67
Contraindications to MRI  67
MRI contrast agents  68
Pulse sequences  68
Cardiac motion  69
Respiratory motion  69
Cardiac function  69
Cardiac morphology and tissue
characterization  71
A non-​contrast-​enhanced tissue
characterization  71
Contrast-​enhanced tissue
characterization  73
Myocardial perfusion  74
Velocity-​encoded  CMR  75
MR angiography  75
Conclusions  77
CHAPTER 4
CMR—​basic principles
Jan Bogaert, Rolf Symons, and Jeremy Wright
Introduction to MRI physics
Magnetic resonance imaging (MRI), formerly called nuclear magnetic resonance (NMR),
relies on the physical properties of hydrogen nuclei (protons). These protons, abundantly
present in the human body, have an intrinsic ‘spin’. When a patient is brought into a high-​
strength magnetic field, the ‘spins’ of the human body align with the direction of the
magnetic field [1]‌. Application of a radiofrequency (RF) pulse can excite the spins and
perturb their alignment, with vector components in line with the magnetic field (longi-
tudinal magnetization) and perpendicular to the field (transverse magnetization). These
spins gradually return to their resting state (relax), and in the process create RF signals
which are used to create an image. The magnitude of signal arising from the tissue is
mainly influenced by two relaxation times (T1 and T2), proton density, and movement
of the protons (blood flow) [2].
T1 is the time constant describing the return of longitudinal magnetization to baseline,
and T2 is the time constant describing return of transverse magnetization to baseline.
Note that T1 and T2 of a proton are independent, and vary according to the local envir-
onment of the proton (i.e. the tissue). This phenomenon enables the excellent soft-​tissue
discrimination seen in MRI images. Fat and water are at the extremes of T1 and T2 re-
laxation times. Fat has short T1 and T2, whereas water has long T1 and T2 times. T1-​
weighted images exploit the differences in T1-​relaxation behaviour between tissues. For
instance, fat has a hyperintense (‘bright’) appearance, fluid has a hypointense (‘dark’) ap-
pearance, while myocardial tissue is iso-​intense (‘grey’). In comparison, on T2-​weighted
images fluid has a bright appearance, while fat has a less bright appearance.
Image formation also requires understanding of the origin of a particular signal in the
patient. This is achieved by application of magnetic field gradients in a process called spa-
tial encoding, a detailed discussion of this can be found in any basic MR textbook. For
any image ‘slice’ the raw data acquired are called ‘k-​space’ [3]‌, and consists of multiple
‘lines’ of data (typically between 128 and 256). To generate an image, the k-​space data
undergo a complex mathematical process called Fourier transformation. The key concept
of this transformation is the centre of k-​space contains image contrast information, while
image resolution is governed by the periphery of k-​space [4].
Contraindications to MRI
There is an ever-​expanding variety of implanted medical devices which may interact with
the powerful main and gradient magnetic fields imposed by CMR. First, ferromagnetic
68 CHAPTER 4   C MR — basic principles
materials in medical devices are susceptible to the force and
torque generated by the magnetic field and the risk of device dis-
location ultimately depends on the balance between its fixation
and its ferromagnetic properties, the magnetic field strength, and
its distance to the magnetic field [5]‌. Second, implant heating
due to transition of electromagnetic energy may lead to tissue
damage [6]. Third, electromagnetic interference with electronic
devices such as pacemakers and implantable cardioverter defibril-
lators (ICDs) may result in loss of function of changes in pacing
properties [7]. Finally, image artefacts induced by the presence
of medical implants may degrade image quality to such a degree
that erroneous diagnoses are made with inappropriate treatment
[8]. Therefore, medical devices have traditionally been viewed as
a contraindication for CMR. However, major efforts have been
made to implement device modifications to improve MRI com-
patibility and ultimately, as with every other medical decision,
the risk-​benefit of CMR has to be balanced for each individual
patient. An extensive review of CMR in patients with medical de-
vices is beyond the scope of this chapter, but can be found else-
where [9]. In brief, sternal wires, most prosthetic cardiac valves,
coronary stents, orthopaedic implants, and surgical clips are no
contraindications to CMR. The situation with implantable cardiac
devices is complex. Permanent pacemakers and defibrillators are
a contraindication to routine MRI as deaths and device malfunc-
tion have been reported [10]. However, many studies report safe
MRI scanning of patients with pacemakers and defibrillators. The
new MRI conditional pacemaker generator and lead systems can
safely have MRI [11]. Older pacemakers and all current defibrilla-
tors are classified as MRI unsafe, but under certain circumstances
can still undergo MRI [12]. Implanted loop recorders (e.g. Reveal,
Copyright) are MRI conditional, though data may be erased by
the scan. All implants must be confirmed as MRI safe, condi-
tional, or unsafe before the patient enters the scanner. The brief
summary recommendations in this chapter are therefore not to
be followed blindly or be considered appropriate for all patients.
CMR images are advised to contact the device manufacturer in
order to obtain up-​to-​date safety information to ensure patient
safety.
Pregnancy is not a contraindication to MRI when no
gadolinium-​based contrast agents are used, and no harm to a
developing foetus has been documented. However, it is prudent
to only perform MRI on pregnant patients if the information is
required prior to delivery and ultrasound is inadequate [10].
MRI contrast agents
Contrast agents are often used in assessing both patients with
ischaemic and non-​ischaemic heart disease patients with CMR.
The most commonly used contrast agents contain chelates of the
lanthanide metal element gadolinium with multidentate ligands
(e.g. Gd-​DTPA or Gd-​DOTA). These are non-​specific contrast
agents that distribute throughout the extracellular space, and
are renally excreted in an unchanged form. They shorten the T1
relaxation times of tissues, and therefore result in an increase
in signal intensity on T1-​weighted images (lesser effect on T2).
The typical dose is 0.1–​0.2 mmol/​kg (~1,530 ml). Side effects are
very rare, and these contrast agents have proven to be much safer
than the iodinated contrast agents used for conventional X-​ray.
However, precautions are still necessary. Gadolinium-​containing
contrast agents do not cause renal dysfunction, but should be
avoided in patients with GFR <60 ml/​min/​1.73 m2 because of
the recently observed association with nephrogenic systemic fi-
brosis and deposition in multiple tissues, mostly the brain [13,
14]. Gadolinium should be avoided in patients with haemolytic
and sickle cell anaemia, and use during pregnancy is discouraged.
In lactating women, a small amount of gadolinium may be ex-
creted into breast milk and absorbed by the infant, so it is prudent
to express and discard breast milk for 24 hours after injection. It
is important to note that assessment of cardiac structure, global
and regional myocardial function, valve function, coronary angi-
ography, and flow quantification can be performed without ad-
ministration of contrast.
Pulse sequences
A pulse sequence is a carefully timed series of RF pulses and mag-
netic field gradients, and provides the raw information filling the
k-​space. The two broad families of pulse sequences are spin-​echo
and gradient echo [1, 2].
In spin-​echo sequences a 90-​degree RF pulse is applied to the
selected slice, so that the resting longitudinal magnetization (Z)
is entirely flipped into the transverse (XY) plane. The transverse
magnetization begins to dephase then a 180-​degree RF pulse is
applied. This causes the transverse magnetization to partially
rephase and produce a spin ‘echo’, filling one line of k-​space. This
rephasing 180-​degree pulse can be repeated multiple times to ac-
quire multiple lines of k-​space, this is known as fast or turbo spin-​
echo. Excellent quality images can be obtained, with T1, T2, or
proton-​density weighting. The main drawback of these sequences
is the long time required to fill k-​space.
In contrast, gradient-​echo pulse sequences utilize a smaller
initial RF pulse (usually between 10 degrees and 90 degrees),
and then apply magnetic field gradients to rephase the magnetic
moments to produce a signal known as a ‘gradient’ echo. These
sequences can produce images with T1, T2, or proton-​density
weighting. The main advantage of gradient-​echo sequences is that
gradient-​echoes can be generated very quickly, so that scan times
are reduced. The main disadvantage is an increased susceptibility
to artefacts.
Imaging speed is a key concern in cardiac MRI, and parallel
imaging is often used to reduce scan times or improve temporal
resolution [15, 16]. The vendors have slightly different parallel
imaging techniques—​SENSE (Philips), ASSET (General Electric),
GRAPPA (Siemens). They all rely upon multiple-​element coils
which allow undersampling of k-​space, and allow for a 2–​3-​fold re-
duction in scan times. The main disadvantage of parallel imaging
is a reduced signal-​to-​noise ratio (SNR). Compressed sensing is
a more recent development which significantly accelerates CMR
 Ca rdiac f un c t i on 69

acquisitions by acquiring less data through undersampling of prescribed and navigator efficiency, these scans take 5–​15 min to
the k-​space [17]. Using a multitude of algorithms, CMR images acquire.
can be compressed with compression ratios of 9:1 to 25:1 while We will now discuss the specific sequences used for assessment
maintaining diagnostic information. As the images will be com- of cardiac function, cardiac morphology, perfusion, viability, and
pressed anyway, it turns out one does not have to acquire all the MR angiography.
data in the first place (i.e. fill the k-​space completely), but the image
can also be reconstructed from a small (‘compressed’) number of
measurements. Initial studies using compressed sensing demon- Cardiac function
strate its potential for CMR where functional cine images of the
entire LV may be acquired within a single breath-​hold [18]. The balanced steady-​ state free procession (b-​ SSFP) sequence
is the mainstay of functional assessment [20]. There are several
Cardiac motion monikers; balanced FFE (Philips), FIESTA (General Electric),
TrueFISP (Siemens). The resultant images are not T1-​or T2-​
As with other imaging modalities, CMR data acquisition is
weighted, rather the signal intensity depends upon the ratio of
synchronized to cardiac motion using the electrical activity
T2/​T1 in addition to flow. Therefore blood, water, and fat all ap-
of the heart. The magnetic field exerts a significant magneto-​
pear bright.
hydrodynamic effect on the surface electrocardiogram (ECG),
Similar to other cardiac imaging techniques, cardiac function
resulting in a voltage artefact in the ST segment of the ECG.
is usually studied along the standard cardiac imaging planes.
Reliable R-​wave detection is possible using a vector cardiogram
To obtain these imaging planes, imaging is started with a set of
[19] (VCG), but reliable ST/​T wave monitoring is not possible.
single-​phase localizer scout views in the axial, coronal, and sa-
The VCG can be used for either prospective triggering or retro-
gittal planes. These planes are used to determine the vertical long
spective gating. Prospective triggering is typically used for single
axis (VLA)—​a plane prescribed on the axial images through the
phase acquisitions, i.e. a static image of the heart at a single point
apex of the LV and the middle of the mitral valve (E Fig. 4.1a).
in the cardiac cycle. Information is acquired at a specific interval
On this image a second cine sequence is prescribed in the hori-
after the R-​wave, usually chosen to coincide with diastasis (when
zontal long axis (HLA)—​transecting the LV apex and the middle
the heart is relatively still). In patients with poor VCG quality,
of the mitral valve (E Fig. 4.1b). It can be of interest to acquire
peripheral pulse gating is usually a good alternative.
one extra cine image in ‘pseudo-​short-​axis’ direction between the
Multiphase acquisitions are used to acquire dynamic informa-
vertical and HLA. Prescribing on this image a plane connecting
tion such as cine MRI. Here data is acquired throughout the car-
the middle of the lateral LV wall with the right ventricle (RV) at
diac cycle, and is reconstructed with retrospective reference to the
the angle between the inferior and lateral part of the RV free wall,
VCG. Usually the cardiac cycle is divided into 20–​30 phases. One
generally provides a perfect 4-​chamber view (E Fig. 4.1b).
image is reconstructed for each phase, and the resulting images
Now the LV short axis can be prescribed, perpendicular to both
are displayed as a cine loop. Real-​time cine MRI images can be
the VLA and HLA or 4-​chamber view. The ventricles are encom-
acquired by increasing the parallel imaging factor and reducing
passed in a stack of 10–​12 contiguous slices in short-​axis direction
the spatial resolution or by using compressed sensing. With these
(E Fig. 4.1c–​d). The end-​diastolic and end-​systolic frames are
sequences it is possible to obtain diagnostic images in patients
selected, and then the endocardial and epicardial contours are de-
who cannot hold their breath, and in those with very irregular
lineated. This allows calculation of global functional parameters;
cardiac rhythms (when normal cine images are often suboptimal).
end-​diastolic volume (EDV), end-​systolic volume (ESV), stroke
volume (SV) and ejection fraction (EF), and myocardial mass.
Respiratory motion This is the reference standard for in-​vivo assessment of myocar-
Most CMR images are obtained during breath-​holds, typically of dial volume, global function, and mass [21]. Regional function
10–​15 seconds duration. Although end-​inspiratory breath-​hold is assessed qualitatively and quantitatively. Qualitative evaluation
may be more comfortable and can be held longer, breath-​hold at of LV contractility is reported using the 17-​segment model pro-
the end of gentle expiration is more consistent (minimizing slice posed by the American Society of Echocardiography [22].
misregistration), less likely to provoke ectopy and therefore pref- This stack of short-​axis slices can also be used to quantify RV
erable. Administration of oxygen may be of help in patients ex- volumes. However, as the tricuspid valve is often difficult to define
periencing shortness of breath. in short-​axis direction, horizontal long-​axis, or axial, transverse
The use of a navigator-​echo during free breathing is an al- images are often preferred. Other views routinely assessed are the
ternative method of image acquisition, and is typically used LV inflow/​outflow tract view connecting the mitral and aortic
for high-​ resolution imaging such as coronary angiography. valve and the LV apex. Optional views can be obtained to study
The navigator-​echo is typically positioned on the right hemi-​ cardiac valves or specific parts of the left/​right ventricle.
diaphragm to monitor respiratory motion. The patient is Valvular function can also be assessed with cine imaging. The
instructed to breathe regularly and consistently, and image in- valve leaflets are easily seen (E Fig. 4.2) and mechanisms of dys-
formation is only acquired when the diaphragm is in a prede- function identified. Although the b-​SSFP sequence is designed to
termined position (e.g. end expiration). Depending on the scan be relatively flow ‘insensitive’, turbulent flow through stenotic or
70 CHAPTER 4   C MR — basic principles

(a) (b)

(c) (d)

Fig. 4.1  Assessment of cardiac function. A b-​SSFP cine sequence is used for functional assessment (only end-​diastolic frames are shown here). From the
localizer scout images the VLA plane is prescribed (a). A plane perpendicular to the VLA produces the HLA (b). The LV short-​axis plane can now be prescribed,
perpendicular to both the VLA and HLA (c). The LV is encompassed by a stack of slices in the short-​axis plane (d) to enable quantification of ventricular
volumes and assessment of global and regional systolic function. LV = left ventricle; LA = left atrium; RV = right ventricle; RA = right atrium; VLA = vertical long
axis; HLA = horizontal long axis.

(a) (b)

Fig. 4.2  Assessment of valve morphology. Valve morphology and function can be qualitatively assessed with b-​SSFP cine imaging. Short-​axis images of the
aortic valve at end diastole (a) and mid-​systole (b) demonstrate a trileaflet aortic valve with thin leaflets that open normally.
 Ca rdiac morphol o g y a n d ti s su e cha r ac t e ri z at i on
(a)
Fig. 4.3  CMR-​tagging. Example of SPAMM (spatial modulation of magnetization) Tagging in a patient with asymmetric septal hypertrophic cardiomyopathy.
Basal short-​axis image (a), and horizontal long-​axis image (b). Both images represent early systole. The myocardium initially is shown as a square pattern. Regional
myocardial contraction patterns can be analysed by the deformation pattern of these ‘squares’ throughout the cardiac cycle.
regurgitant valves is visible. The regurgitant fraction of an isolated
valve lesion can be calculated from the difference between LV and
RV SV. Further assessment of valve dysfunction will be discussed
in the section on velocity-​encoded CMR.
Myocardial tagging is another CMR technique useful in func-
tional analysis [23]. A grid or tag of lines on the myocardium is
transiently created, and these lines track the underlying myo-
cardial deformation (E Fig. 4.3). These images can be ana-
lysed qualitatively and quantitatively, e.g. strain analysis, but the
elaborate post-​processing required for quantitative analysis has
largely confined it to the research setting. As an alternative, novel
post-​processing algorithms using optical flow technology or non-​
rigid elastic registration technology, allows to quantify global and
regional myocardial strain on routinely acquired SSFP cine im-
ages (E Fig. 4.4) [24, 25]. Strain calculation is hereby not limited
to the ventricles, but can be acquired in the atria as well.
Cardiac morphology and tissue
characterization
A non-​contrast-​enhanced tissue
characterization
One of the unique features of cardiac MRI is its potential for non-​
invasive tissue characterization, including gross cardiac morph-
ology as well as in-​depth quantitative phenotyping. Although
traditionally for this purpose static sequences are used, it should
be mentioned that tissue characterization is also possible with dy-
namic cine images. First of all, the spontaneous high contrast be-
tween blood and surrounding myocardium provides high quality
anatomic images exquisitely visualizing the smallest anatomical
details such as the endomyocardial trabeculations. Secondly, in
particular after contrast administration focal myocardial path-
ology, such as in the setting of acute myocardial infarction, can be
generally very well depicted at post-​contrast cine images.
For cardiac tissue characterization, traditionally sequences
are T1-​or T2-​weighted—​proton density sequences in contrast
71
(b)
to other organs are not routinely used in cardiac imaging. These
sequences are ‘qualitative’ in the sense that the signal intensity
differs between normal and abnormal tissue. To further enhance
differentiation blood is typically made black by two 180-​degree
inversion prepulses (double inversion recovery) [26]. A third in-
version prepulse can also be applied, to suppress the (high) signal
arising from fat. T1-​weighted images typically provide excellent
delineation of cardiac anatomy (E Fig. 4.5a), but with the advent
of SSFP cine images are often not routinely acquired anymore.
However, they are still of interest to study the pericardium and
aortic wall, to depict fatty infiltration of the myocardium and in
patients with cardiac tumours. In contrast, T2-​weighted images
provide unique information about free water content—​MRI is the
only imaging modality that can non-​invasively detect myocardial
oedema, for example in patients with acute myocardial infarction
or acute myocarditis [27]. This sequence is also very useful for
depicting oedema of the pericardial layers in inflammatory peri-
carditis as well in patients with cardiac tumours (E Fig. 4.5b).
As relaxation times are tissue-​specific, sequences have been
designed allowing to quantify relaxation times on a pixel-​base,
i.e. the so-​called (parametric) myocardial mapping which can
be T1-​, T2-​, and T2*-​based. These sequences are typically two-​
dimensional though recently also three-​dimensional sequences
have been proposed.
For example, T2* is the time constant reflecting T2 relaxation
and dephasing owing to local magnetic field inhomogeneities
[28]. Typically, a single-​phase LV short-​axis slice is acquired mul-
tiple times (usually 6–​9), each at a different echo time. A region
of interest is delineated, signal intensity vs. echo time is plotted,
and the resulting curve used to calculate the absolute relaxation
time. Shortening of the T2* relaxation time occurs in the presence
of myocardial iron deposition such in in patients with haemo-
chromatosis. T2* has been extensively validated for assessment of
iron content in the liver and myocardium [22]. This biomarker—​
of great use to early diagnose and follow-​up haemochromatosis
patients—​yields also important prognostic value [29]. T2 map-
ping is ideal to quantify an increased amount of myocardial water,
a condition which can be focal (e.g. acute myocardial infarction)
72 CHAPTER 4   C MR — basic principles

(a) (b)

(c) (d)

Fig. 4.4  Multiparametric imaging in hypertrophic cardiomyopathy. A 17-​year-​old patient with obstructive asymmetric septal hypertrophic
cardiomyopathy. Horizontal long-​axis cine (a) shows important hypertrophy of the entire ventricular septum (*) extending to LV and RV apex. Feature
tracking analysis of longitudinal LV strain (b), using arrows to indicate strain orientation and magnitude, shows strongly diminished strains in the
thickened septum (white arrows) while the strain in the lateral LV wall are well preserved. Colour-​coded native T1 map in horizontal long axis (c). Normal
T1 values at 1.5 T magnet (Philips Ingenia) are 998 +/​–​19 ms). In this patient values (measured in septum) were 1,038 ms, which can also be appreciated
well by assessing the colour, i.e. normal values green-​yellow, in contrast to decreased values (green-​blue) and increased values (red to white). At LGE CMR
(d) a large area of inhomogeneous and irregular defined strong enhancement is visible in the apical half of the septum (arrows), reflecting important
replacement fibrosis.

(a) (b) (c)

Fig. 4.5  Comprehensive tissue characterization in a patient with inflammatory-​effusive pericarditis. A 45-​year-​old woman with Crohn’s disease presenting with
respiratory-​related chest pain, inflammatory biomarkers, and pericardial fluid at transthoracic echocardiography. T1-​weighted dark-​blood fast spin-​echo image
in transverse orientation shows diffuse thickened pericardium (arrows) (a). Note the difference between the fluid component ‘dark’ and the thickened layers
(grey). T2-​weighted dark-​blood fast spin-​echo image in short-​axis shows diffuse high signal in the inner and outer pericardial layer (arrows), reflecting important
pericardial oedema (secondary to pericardial inflammation). The pericardial fluid on this sequence has a dark appearance (maximal width 8 mm). Short-​axis LGE
image (c), using a phase-​sensitive inversion recovery (PSIR) technique, shows strong enhancement of both pericardial layers. The intrapericardial space in contrast
does not show uptake of contrast and is shown as dark (*).
 Ca rdiac morphol o g y a n d ti s su e cha r ac t e ri z at i on
(a) (b)
Fig. 4.6  Comprehensive CMR in cardiac amyloidosis. A 60-​year-​old man with ATTR cardiac amyloidosis presenting with biventricular hypertrophy. Native
T1 mapping (a) shows increased T1 values (1,081–​1,121 ms) (normal values 998 +/​–​19 ms, 1.5 T Philips Ingenia). Post-​contrast T1 map (b). This can be used
to calculate ECV map. LGE image (c) shows strong, mostly subendocardial enhancement in left and right ventricle, as well as in both atria. Limited pericardial
effusion.
or diffuse (e.g. diffuse myocarditis, humoral rejection in heart
transplant patients) [30].
Nowadays T1 mapping has become part of a routine clinical
cardiac MRI exam, offering not infrequently unique informa-
tion with regard to the myocardial composition. To calculate
T1-​relaxation time, several images are acquired with different
inversion times allowing to reconstruct a T1 relaxation curve.
Several approaches and sequences are currently available, but an
in-​depth discussion is beyond the scope of this chapter [31]. T1
relaxation times are decreased in the presence of increased myo-
cardial lipids such as Anderson–​Fabry disease or post-​infarction
lipomatous metaplasia, but also in conditions of increased iron
content [32, 33]. A recent study has shown that shortening of
T1-​relaxation may be more sensitive than T2* relaxation time
to depict very early stages of haemochromatosis [33]. Increased
T1 values may be found focally or more generalized throughout
the myocardium in a wide range of myocardial diseases [32].
Pathologic substrates for increased T1 values include for example
myocardial oedema, inflammation, necrosis, fibrosis, and depos-
ition of amyloid deposition (E Fig. 4.6). Although not specific,
as part of a comprehensive exam, the findings at T1 mapping
are most helpful in diagnosis/​differential diagnosis making (E
Fig. 4.4c and Fig. 4.6a).
Contrast-​enhanced tissue characterization
Contrast-​enhanced inversion recovery (CE-​IR) MRI has caused
a paradigm shift in non-​invasive myocardial tissue character-
ization. The technique is best known as delayed or late contrast/​
gadolinium enhancement imaging, as images are typically ac-
quired 10 to 20 minutes after intravenous administration of
gadolinium chelates, which is the optimal time to discriminate
between normal and abnormal myocardium. This technique has
rapidly become the reference standard for in-​vivo assessment of
myocardial infarction in both the acute and chronic phase, but
73
(c)
is nowadays widely used for non-​ischaemic myocardial diseases
and pericardial diseases as well (E Fig. 4.7). It has been exten-
sively evaluated in animal and human studies [34–​36] and can
accurately measure infarction within 1 g.
The mechanism of accumulation of contrast within infarcted
tissue is incompletely understood. Regarding acute infarction, it
is thought that myocardial cell membrane rupture allows gado-
linium to diffuse into the intracellular space (it must be noted
that gadolinium is an extracellular contrast agent) [37]. The
greater distribution area, concomitant myocardial oedema, and
altered contrast kinetics result in hyperenhancement relative to
the normal myocardium. The mechanism of contrast accumula-
tion within chronic infarcts is thought due to increased interstitial
space between collagen fibres, combined with slower wash-​in and
wash-​out contrast kinetics of infarct tissue compared to normal
myocardium [38].
The CE-​IR technique consists of first applying an inversion RF
prepulse [39]. As the ‘spins’ of a tissue ‘relax’ towards their resting
state, they pass through a point where they have zero longitudinal
magnetization. If image information is acquired at this point no
signal will arise from these spins which are ‘nulled’ and appear
dark on the resultant image. This delay between the inversion
prepulse and image acquisition is called the inversion time (TI).
Typically, we choose to null the signal of normal myocardium,
while infarcted or scarred myocardium has a bright signal be-
cause of the gadolinium within it (E Fig. 4.7a). The TI to null
normal myocardium is variable and depends upon patient weight,
contrast dose, renal function, and time-​point after injection of the
contrast. Choosing the correct TI is crucial to maximize the con-
trast between normal and abnormal myocardium and to prevent
image artefacts. Look Locker and TI-​scouting pulse sequences are
available to help choose the ideal TI. The problem of selecting the
correct TI can be overcome by using phase-​sensitive inversion re-
covery (PS-​IR) imaging (E Fig. 4.5c) [40].
74 CHAPTER 4   C MR — basic principles
(a)
Fig. 4.7  Applications of contrast-​enhanced CMR. A 57-​year-​old man with acute transmural infarction in lateral LV wall (a, mid-​ventricular short-​axis). Note
the presence of a large no-​reflow zone in the inner half of the lateral wall. A 45-​year-​old patient with fever and acute chest pain presenting with subepicardial
enhancement (arrows) in the laterobasal LV wall (b). This pattern is highly suggestive of acute (inflammatory) myocarditis.
2D and 3D acquisition schemes are available. 3D acquisitions
enable imaging of the entire heart in a single breath-​hold with
a high SNR, but are prone to image blurring [41]. In contrast,
2D sequences acquire one slice per breath-​hold (more tiring for
the patient) and has lower SNR. However, despite more image
‘noise’ the 2D images usually provide greater in-​plane spatial
resolution.
As just mentioned, the enhancement at CE-​IR is not specific
for ischaemic injury but can be found in many non-​ischaemic
myocardial diseases, including inflammatory (i.e. myocarditis
(E Fig. 4.7b)), infiltrative diseases (e.g. cardiac amyloidosis)
as well as cardiomyopathies (e.g. hypertrophic (E Fig. 4.4d)
and dilated cardiomyopathy, arrhythmogenic right ventricular
dysplasia). The pattern and location of enhancement provides
valuable information with regard to the ischaemic versus non-​
ischaemic nature [42]. Moreover, the presence and extent yield
prognostic value in several myocardial diseases [43]. The late
gadolinium-​enhanced (LGE) sequence is also of great value in
depicting pericardial inflammation (E Fig. 4.5c), as well as in
characterization of cardiac masses.
A major shortcoming of the CE-​IR MRI technique is the
need for myocardium deemed ‘normal’ as contrast for the
pathologic myocardium, thus limiting its use in diffuse myo-
cardial disease, such as interstitial fibrosis. Here, T1 mapping
may be of great help. First of all, native T1 values in inter-
stitial fibrosis may be—​although not necessarily—​increased.
However, if the T1 mapping is repeated after contrast admin-
istration (normally 10–​20 minutes post-​contrast), the extra-
cellular volume (ECV) can be calculated (E Fig. 4.6b) [31,
43]. The underlying explanation is that gadolinium chelates
distribute in the extracellular space but not intracellularly.
Thus, the shortening in T1 post-​contrast administration of
the myocardium is exclusively caused by shortening of T1 in
the extracellular space (including the vascular component).
Moreover, a similar phenomenon happens in the blood. T1 of
plasma shortens but not the T1 of the red blood cells. If the
(b)
blood haematocrit is known, using the T1 values of blood and
myocardium before and after contrast, the ECV can be calcu-
lated. In normal conditions, ECV ranges 22–​28% and correl-
ates well with histologic measures of collagen deposition [31].
Pathologies such as diffuse interstitial fibrosis and amyloidosis
increase ECV values [44]. However, it should be noted that
ECV values as such do not provide information with regard to
the underlying cause of increased ECV.
Myocardial perfusion
Imaging the first pass of an intravenous injection of a small dose
of contrast can be used to evaluate myocardial perfusion pat-
terns in resting and/​or stress conditions (e.g. during pharmaco-
logic vasodilator stress) such as adenosine, dipyridamole, and
regadenoson [45]. Usually, 3–​5 short-​axis slices of the LV are
obtained to encompass all myocardial segments. An ultra-​fast ac-
quisition scheme is required because each slice is imaged once per
heartbeat immediately after gadolinium contrast (usually injected
at 2 ml/​s followed by a saline flush). The optimal dose of gado-
linium is 0.03–​0.1 mmol/​kg, depending on the sequence used and
whether visual analysis (higher dose) or semi-​quantitative ana-
lysis is planned.
Visual analysis is the most frequently used approach. A perfu-
sion defect is identified as a region of non-​enhancing myocardium
during the first pass of contrast (E Fig. 4.8). The defect is most
pronounced in the subendocardium and has variable transmural
spread. It is critical to differentiate true defects from frequently
encountered dark rim artefacts [45]. Semi-​quantitative assess-
ment is usually performed by analysis of signal intensity-​time
curves. The myocardial perfusion reserve index (MPRI) is calcu-
lated by comparing the myocardial perfusion upslope between
rest and stress [45, 46]. Absolute quantitative assessment of myo-
cardial perfusion can be performed, but is currently largely con-
fined to the research setting.

Fig. 4.8  Adenosine stress first-​pass myocardial perfusion imaging. A short-​
axis slice of the left ventricle at mid-​ventricular level is shown during the first
pass of intravenous gadolinium during adenosine vasodilator stress. There
is a large perfusion defect in the mid-​anterior and antero-​septal segments
(arrows).
Velocity-​encoded  CMR
Velocity-​encoded CMR, also known as phase-​contrast flow
quantification is an established fast and simple method of
measuring blood flow [47]. It is based upon the phenom-
enon that as ‘spins’ flow along a magnetic field gradient, they
acquire a ‘shift’ in their transverse (XY) magnetization. This
shift is proportional to the strength of the magnetic field gra-
dient as well as the flow velocity, which can thus be calculated.
Comparisons with invasive measurements and phantom studies
have demonstrated that the overall error in flow measurement
is <10% [48].
To measure flow through a vessel, first an image slice is pre-
scribed perpendicular to the flow direction. It is important this
slice is within 15 degrees of the true perpendicular plane, other-
wise flow will be significantly underestimated (similar to the
principle of Doppler line-​up in echocardiography). Second, an
appropriate encoding velocity (VENC) is selected, which must
be greater than the highest velocity in the flow otherwise aliasing
will make the data unreliable. The images are acquired during a
15–​20 s breath-​hold, and minor post-​processing produces flow
and velocity data. Flow in any vessel can be assessed, though in
clinical imaging vessels smaller than the pulmonary veins are
rarely quantified.
There are many applications of flow quantification, including
calculation of RV and LV SVs, shunt quantification (Qp:Qs), cal-
culation of valvular regurgitant fraction [49], and assessment of
diastolic function (mitral inflow, pulmonary vein flow, mitral
annular velocities, tricuspid inflow, caval flow) (E Fig. 4.9). In
addition, velocity data enables assessment of pressure gradients
which are crucial for the assessment of stenotic valvular lesions
(E Fig. 4.9) [50].
M R a n g i o g r a ph y 75
In recent years, 4D-​ flow imaging has been proposed as
an appealing method to quantify flow not within one, but in
three orthogonal directions [51]. Depending on the region of
interest, acquisition times are between 5 and 20 minutes, cur-
rently impeding routine clinical use. However, it is a powerful
tool to non-​invasively visualize flow patterns in cardiac cavities,
transvalvular flow as well as intravascular flow. Moreover, infor-
mation can be obtained with regard to pulse wave velocity, wall
shear stress, and kinetic energy. One of the applications is for ex-
ample assessment of complex congenital cardiomyopathies. This
technique certainly will become more integrated in clinical rou-
tine in the near future.
MR angiography
Cardiovascular MRI comprises vascular imaging as well including
coronary artery imaging. Broadly speaking MR angiography can
be non-​contrast or contrast enhanced. Non-​contrast-​enhanced
MR angiography sequences are based on time-​of-​flight or phase-​
contrast principle and can be 2D or 3D dimensional. Flowing
blood yields high contrast while no or minimal signal is obtained
from the surrounding stationary tissues. In contrast, gadolinium-​
enhanced MR angiography relies on the T1 shortening of blood
after intravascular injection of gadolinium chelates [52]. Different
strategies for optimized imaging of the different vessels (e.g. lower
limbs, renal arteries) in the human body have been developed.
In brief, a 3D volume encompassing the vessel(s) of interest is
selected. Next, imaging is started at the moment of first pass of
contrast through the vessel of interest. Nowadays optimal timing
is achieved using real-​time low spatial resolution MRI sequences
allowing to follow the passage of contrast [53]. Moreover, sub-
traction techniques—​using a precontrast 3D scan—​substantially
improve image quality. Post-​processing techniques can be used to
explore the 3D datasets—​including maximum intensity projec-
tions (MIP), multiplanar reformatting (MPR), and volume ren-
dering (EFig. 4.10a).
Coronary artery imaging with MRI has been extensively in-
vestigated but is far more difficult. The principle challenges are
the small size of the coronaries (2–​5 mm), their long tortuous
course, motion (respiratory, cardiac, and individual artery), and
flow. Many MRI techniques have been used, but despite prom-
ising results (E Fig. 4.10b) in the literature [54], MRI is hardly
used for diagnosing coronary artery disease. However, coronary
artery MRI is indicated to assess the anomalous coronary origins
and to follow the aneurysms of Kawasaki disease. Likely the most
important explanation for the decreased interest in coronary
artery MRI is the availability of cardiac computed tomography
(CCT) offering ultra-​fast and reliable coronary artery imaging
with acceptable radiation doses. Besides offering high spatial and
contrast resolution images of the coronary arteries, CCT yields
promise to study the haemodynamic impact of coronary artery
stenoses (e.g. CT-​derived fractional flow reserve, stress myocar-
dial perfusion).
76 CHAPTER 4   C MR — basic principles

(a) (b)

Fig. 4.9  Mixed aortic valve disease. A 49-​year-​

old man with mixed aortic valve disease. Cine
imaging during systole (a) and diastole (b) in LV
outflow tract shows thickened, almost immobile
aortic leaflets with systolic jet and backward
flow (arrows). Velocity-​encoded CMR showed
a systolic peak velocity through the aortic valve
(aortic valve area 0.6 cm2 at planimetry) of 5.37
m/​s corresponding to a gradient of 117 mmHg
(c). During diastole an important regurgitation is
shown (arrow, Panel d) with a regurgitant fraction
of 42%. (c) (d)

(a) (b)

Fig. 4.10  Magnetic resonance angiography. Contrast-​enhanced 3D MR angiography in a patient with aortic coarctation (*) and important collateral circulation
(volume rendered view, a). Non-​contrast-​enhanced 3D coronary MR angiography. A tangential view showing normal origin and proximal courses of the left and
right coronary arteries (b) Ao, aorta.

Conclusions
MRI is a powerful tool for assessment of the cardiovascular
system; indeed, it is the reference standard for the assessment of
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Contents
Summary  79
Introduction  79
The need for training  79
The elements of training  80
Sources of training  80
What makes ‘good training’  80
Competence  80
Models of training programmes and linked
certifications  82
Maintaining competence  82
Performance and quality assurance (QA)  82
Training and competence in multimodality
imaging  83
Future perspectives  83
Conclusion  83
CHAPTER 5
Training and competence in
cardiovascular imaging
Kevin Fox and Marcelo F. Di Carli
Summary
Safe and effective cardiovascular imaging requires a competent trained workforce
practising within a quality assured service. Training programmes are usually linked to
healthcare facilities and competence assessment is undertaken by national training au-
thorities but also by professional societies through certification programmes. The EACVI
has been instrumental in many of the progressive improvements in training and compe-
tence assessment in the last decade. Training requires acquisition of knowledge skill and
professionalism. Knowledge can be acquired through study and lectures or courses and
increasingly through web based resources. Knowledge can be tested in a number of ways
but exams remain an important methodology. Skill and professionalism require time
to progress along a learning curve and are typically assessed using work based assess-
ments. To provide a high performance service requires competent individuals to work
within a quality assured environment. As cardiovascular imaging progresses towards a
multimodality approach, training must similarly adapt.
Introduction
The provision of safe and effective cardiovascular imaging requires a competent trained work-
force practising within a quality assured service. While historically the first cardiac imagers
applied a ‘teach yourself ’ principle, nowadays organized training programmes with objective
assessments of competence are the norm across the cardiovascular imaging modalities. The
EACVI has been instrumental in many of the progressive improvements in training and
competence assessment in the last decade. In this Chapter we review the requirements and
processes for training and competence assessment in cardiovascular imaging.
The need for training
In order to offer best care to patients, cardiologists need to practice to a high standard.
As in any aspect of life this requires training, and ongoing reflective practice. While this
statement is intuitive there are data to show that performance improves with training in
relation to cardiac imaging [1]‌.
Errors in the performance and reporting of imaging studies can have a significant det-
rimental impact on patient care. For example many binary clinical decisions are based
on measurement of ejection fraction. This includes device therapy including defibrilla-
tors, drug therapy, and criteria for the use of potentially cardiotoxic chemotherapy. The
80 CHAPTER 5   Train ing and c ompet ence in ca rdi ovas cu l a r i m ag i n g
inter-​and intraobserver reliability of cardiac imaging parameters
has been studied and shown to be clinically significant in the con-
text of decision making.
Furthermore in research the demonstration of a meaningful
change in a parameter following treatment will be diluted, i.e. the
power reduced, if the measurements cannot be made with pre-
cision. It is possible that negative outcomes in certain trials may
simply have been due to inaccurate measurement [2]‌.
Variability and inaccuracy in cardiac imaging has many causes,
the underlying physics, variable quality data sets, but lack of in-
terpreter skill is often invoked. Although intuitive, it has also been
objectively demonstrated that training improves performance.
The elements of training
There are three key aspects in training a person to practice effect-
ively. These include: (1) acquire appropriate knowledge about the
principles and technical aspects of imaging, (2) develop the skillset
necessary to manage the practical aspects of the task, and (3) de-
velop the clinical expertise to synthesize the knowledge and skill
into effective practice. Given the growing complexity and diversity
of imaging options, developing clinical skills in multiple modalities
is now recognized as a critical component of training to prepare
trainees as effective imaging consultants in the management of car-
diovascular disease (e.g. coronary artery disease, structural heart
disease, cardiomyopathies, etc.). These qualities need to be mapped
against a curriculum to provide a framework for the training.
Sources of training
Supervised hands-​ on training remains a critical and funda-
mental cornerstone of cardiovascular imaging training. Length of
training and numbers of hands-​on procedures have been identi-
fied as important training requirements (ETable 5.1), although
the link between volume and ability is not linear, practical ex-
posure matters and different levels of expertise require a min-
imum number of cases. However simply building up numbers is
not enough and continuous assessment of competence and feed-
back is required to facilitate the learning process.
There are additional complementary training tools. For ex-
ample, learning platforms such as ESCeL offer a comprehensive
multimedia training environment including the capability to
track training, which is continuously updated. Individuals also
learn through their own searches and through knowledge sharing
via social media. For development of practical skills, simulation-​
based learning through increasingly sophisticated simulators
offers an evidence-​based method for skills acquisition [3]‌.
What makes ‘good training’
Identifying all the elements of ‘good’ training is challenging. It is
possible to measure the knowledge of trainees through exams and
also to assess competence. However high quality comprehensive
training involves imparting knowledge, skills, professionalism,
judgement, teamwork, and more. To facilitate this, the concept
of training centres benchmarked against agreed standards have
been developed [4]‌.
Training of trainers has also been an established part of edu-
cational practice. Other qualities including leadership, teaching,
and mentoring abilities are hard to measure but remain critical
components of quality training.
Competence
If we believe that practising at a high level is important, then we
must be able to measure it. It is important to distinguish ‘compe-
tence’ from ‘performance’ and to measure both. In brief, compe-
tence is the ability to perform a task, while performance reflects
practice in the real world. Some individuals may perform badly
in an observed environment (exam nerves) while others perform
badly under the pressure of practice (in emergency situations)
even though they have a high level of competence. Typically
where a gap exists between competence and performance the
problem is unlikely to be knowledge or skill and more profession-
alism, psychology, and the working environment.
Competence in provision of cardiac imaging is typically graded
into three levels. These are summarized in ETable 5.2. Level 1
involves an awareness of the use and role of a test rather than
the ability to perform it. Level 2 competence however implies
a level of competence to undertake basic imaging in common
clinical situations. Level 3 implies an expertise to undertake and
interpret complex cases as well as a leadership, research, and
training role.
Measuring knowledge is typically done through a knowledge-​
based assessment (exam), the commonest type being multiple
choice question (MCQ) based. MCQ tests can be analysed for their
reliability (the ability to discriminate candidates with or without a
specific level of knowledge) and the most popular format is ‘best
of 5’ with 100–​150 questions in the exam. Reliability is improved
with some element of time pressure for candidates. Tests of know-
ledge through vivas have been shown to be unreliable. Increasing
the numbers of examiners each candidate meets helps, but this
represents a significant resource demand. Essay or short answer
questions have proven hard to mark objectively and consistently.
Competence for the practical aspects of cardiac imaging can be
measured in multiple ways. The opinion of a trained supervisor
tracking progress is important. The objectivity of this assessment
can be enhanced by using a more formalized structure, e.g. Direct
Observation of Practical Skills (DOPS) templates. Practical exams
at the end of training can be effective but are resource intensive
and for reliability need multiple ‘stations’ and examiners. The
British Society of Echocardiography has adopted a practical as-
sessment as part of its transthoracic certification process. Testing
practical skill on simulators is gaining in popularity and while
currently mainly used for formative assessment its role in sum-
mative assessment is expanding [3]‌.
 C o m pet e n c e 81

Table 5.1  Examples of training/​credentialing programmes

Professional Minimum duration Advised procedure Knowledge-​based Logbook Recertification

group/​modality of training numbers
EACVI TTE 6 months 350
EACVI/​EACTA TEE Not specified 75
EACVI /​EAPC CHD Not specified 250
EACVI CMR (Level 2) 3 months 150
EACVI CT (Level 2) Not specified 50 live plus 100 on
workstation
ASE/​NBE 6 months TTE: Perform 150 plus
300 supervised
interpretation
TEE: performed and
interpreted at least
50 cases
Stress echo: supervised
and interpreted 100
cases
CBNC 4–​6 months depending 35 hands-​on cases
on lab volume plus a plus 300 cases with
minimum of 700 hours interpretation under
including 80 hours supervision
of Classroom and
Laboratory Training
(CLT) including
radiation safety
CBCCT 4–​6 months Contrast-​enhanced
CT: 150 contrast
cardiovascular CT
examination including
50 hands-​on cases
Non-​contrast CT: 50
cardiovascular CT
examinations
All completed within a
36-​month timeframe
CBCMR 3 months 150 CMR examinations Yes
for 3 months, including 50
hands-​on cases
ASE, American Society of Echocardiography; CB, Canadian Board; CME, continuing medical education;
CHD, congenital heart disease; NBE, National Board of Echocardiography.
assessment requirements
(exam)?
Yes 250 cases incl. 6 with 100–​250 studies per year
submitted images 40–​50 hours CME per year
Yes 75 cases 50 studies per year 50 hours
CME per year
Yes 250 cases plus local 125 studies per year
DOPS 50 hours CME per year
Yes 150 cases 20 hrs and 100 studies every
3 years
Yes 50 live plus 100 on 20 hours CME over 5 yrs 100
workstation scans over 3 years
Yes TTE: Perform 150 plus 15 hours of
300 supervised echocardiography-​dedicated
interpretation CME over 3 years
TEE: performed and 400 2-​Dimensional Echo/​
interpreted at least Doppler studies per year for
50 cases two (2) of the three (3) years
Stress echo: supervised immediately preceding the
and interpreted 100 recertification exam
cases
Yes 35 hands-​on cases 30 hours of CME completed
plus 300 cases with within 36 months of
interpretation under application submission,
supervision including a minimum of 15
nuclear cardiology-​dedicated
CME hours
Yes Contrast-​enhanced Performed and interpreted
CT: 150 contrast 150 clinical cardiovascular CT
cardiovascular CT (contrast) cases in the last 36
examination including months prior to application
50 hands-​on cases submission
Non-​contrast CT: 50 24 hours of CME on
cardiovascular CT Cardiovascular CT topics and
examinations completed no more than 36
All completed within a months prior to application
36-​month timeframe submission
150 CMR examinations TBD
for 3 months, including
50 hands-​on cases

Table 5.2  Levels of competence

Level 1 Experience of selecting the appropriate diagnostic or therapeutic modality and interpreting results or choosing an appropriate treatment
for which the patient should be referred. This level of competency does not include performing a technique, but participation in
procedures during training may be valuable.
Level 2 Level 2 goes beyond Level 1. In addition to the Level 1 requirements, the trainee should acquire practical experience but not as an
independent operator. They should have assisted in or performed a particular technique or procedure under the guidance of a trainer.
This level also applies to circumstances in which the trainee needs to acquire the skills to perform the technique independently, but only
for routine indications in uncomplicated cases.
Level 3 Level 3 goes beyond the requirements for Level 1 and 2. The trainee must be able independently to recognize the indication, perform the
technique or procedure, interpret the data, and manage the complications.
82 CHAPTER 5   Train ing and c ompet ence in ca rdi ovas cu l a r i m ag i n g
The same quality assurance and governance which is applied
to clinical practice must also be applied to the process of compe-
tence assessment.
Models of training programmes and
linked certifications
Different models exist across Europe and North America for the
training and assessment of cardiac imagers [4]‌.
For example, the EACVI offers national training programmes
and certifications for individuals wishing to demonstrate compe-
tence in cardiac imaging modalities. A very similar structure sup-
ported by individual professional society organizations also exists
in the USA. The EACVI certifications all have a common core
structure (E Fig. 5.1).
In the EU, a curriculum is established, usually through expert
consensus. Trainees are asked to identify a supervisor within their
own institution and then to acquire knowledge and skill through
multiple methods. There is a knowledge-​ based assessment
(MCQ exam) which must be passed. Practical capability is as-
sessed through submission of a logbook of supervised procedures
undertaken and/​or reported. The very ‘hands-​on’ nature of echo
means that images obtained by candidates must be submitted for
external independent review. Certification is awarded if all elem-
ents are successfully completed [5]‌.
In the USA, fellows graduating from training programmes
can sit for a certifying examination after their training pro-
gramme director attests that they have fulfilled the national
requirements (Core Cardiovascular Training Statement—​
COCATS) regarding time, number of cases, and other regu-
latory requirements (e.g. radiation safety training for nuclear
cardiology).
Details of individual certifications are shown in ETable 5.1
which also includes details of equivalent certifications from the
USA for comparison.
In the EU, the first certification was offered by the European
Association of Echo in 2003, and the first exam had <50 can-
didates. The number of certifications and the number of suc-
cessful candidates has expanded exponentially and now over
2000 candidates sit exams each year. In the USA, the American
Supervised
learning,
textbooks, courses,
‘e’ materials
Learning
imaging
modality
Fig. 5.1  Outline structure of EACVI certification
Curriculum
processes.
Board of Echocardiography and the Certification Board in
Nuclear Cardiology have been offering certifying examinations
since the mid-​1990s. More recently, the Certification Board of
Cardiovascular Computed Tomography (CT) has begun of-
fering certifying examinations and soon the Certification Board
of Cardiac Magnetic Resonance will do the same. These cer-
tifications do not represent a legal licence to practice but pro-
vide a benchmarked demonstration of competence. In the USA,
subspecialty board certification is becoming a requirement for
reimbursement by payers (e.g. nuclear cardiology). Further bene-
fits of the subspecialty certifications are their role as a stimulus to
continued learning and in creating a family of experts who can
network together.
Maintaining competence
Competence is not static, partly because individual compe-
tence may drift but mainly because cardiac imaging is a dynamic
and evolving field. While national regulations may not require
evidence of ongoing competence, all certifications in cardiac
imaging within the EACVI framework are time limited. Every 5
years certified practitioners must provide evidence of continuing
practice and learning for renewal of certification. Recertification
does not require retaking the exam. In the USA, documentation
of maintenance of competence, which in most cases includes a re-​
certifying examination, is a requirement in most cardiovascular
imaging subspecialties.
Performance and quality
assurance (QA)
As described earlier, competence may not be interchangeable
with performance.
The process of ensuring a high level of performance requires
competent practitioners but in addition audited organizational
effectiveness. Maintaining performance requires QA or prefer-
ably a programme of Continuous Quality Improvement
QA can be defined as the systematic process of ensuring that in-
formation sent out by imaging laboratories is timely, appropriate,
Pass Re-certification
Knowledge Collect log through
Certification
Based book and ongoing
awarded
Assessment submit practice and
(exam) CME

Box 5.1  Elements of a quality assurance programme for a
cardiovascular imaging laboratory
1 Regular (at least annual) assessment of environment and
equipment
2 Regular review of protocols for patient selection, patient
information, indications for studies, triage, and study
performance
3 Regular (annual) audit of parameters of process of care:
Waiting times for studies, waiting times for reports,
proportion of studies fulfilling appropriateness criteria/​
indications, number of studies performed, patient
satisfaction, and feedback
4 Regular (monthly) clinical governance review of safety
5 Documented programme of staff training including internal
and external CME
6 Regular (weekly) meeting to discuss complex or
interesting cases
7 Regular peer review of a proportion of randomly selected
studies through re-​reporting or panel review. Up to 10%
recommended for low volume case load/​less experienced
laboratories and operators. Feedback mechanism for
reporting differences and alert system for high difference
rates/​category 1 or 2 errors
8 Comparison of reports with reports from other imaging
modalities and operative findings
9 Regular programme to assess intra-​and interobserver
variability
and accurate. The elements of a QA programme for an imaging
laboratory are described in E Box 5.1. It is important that a QA
programme for an imaging department is holistic and not just
focussed on the scan. Patient facilities, information, and experi-
ence should all be included. Equipment and emergency proced-
ures should be regularly tested. Image acquisition, measurement,
and reporting should be measured and mechanisms for feedback
of relevant clinical information and outcomes established. In add-
ition to local QA programmes, professional societies have devel-
oped national voluntary participatory programmes. The British
Society of Echocardiography runs a national programme which
involves bi-​annual testing on the reading of echo clips on a dedi-
cated web based platform [6]‌. The undertaking of effective QA
represents a real challenge to departments with busy service com-
mitments but is essential to ensure clinically meaningful reports
are issued.
Further reading
European Society of Cardiology (ESC). Certification programmes. Available
from: https://​w ww.escardio.org/​E ducation/​C areer-​D evelopment/​
Certification
C on c lusi on 83
Training and competence in
multimodality imaging
Cardiovascular imaging is rightly trending to a multimodality
approach aiming to offer patients the best imaging modality or
modalities to answer the clinical question. Currently training and
assessment of competence is unimodality based but this is chan-
ging. The EACVI is committed to promoting a multimodality
approach and with it develop linked curricula and certifications
[7]‌. Effective multimodality imaging requires competent practi-
tioners but also a facilitative infrastructure. This includes ideally
co-​location of imaging modalities and reporting areas, with de-
velopment of integrated software and sharing of expertise through
multidisciplinary teams (MDTs). The multimodality approach
offers many opportunities to enhance training. The basic cardio-
vascular physiology is shared between modalities. Furthermore
CT and cardiac magnetic resonance can accelerate the learning
and understanding of cardiac anatomy when acquiring echocar-
diography skills. Multimodality imaging can aid the characteriza-
tion of unusual structures and pathologies. Overall training time
in multiple modalities is much less than the summation of the
training times for each modality.
Future perspectives
The future of training is likely to involve more on-​line learning
and more use of simulators. There will be an increasing drive to
formalize competence assessment and to monitor and improve
performance through QA.
Within cardiac imaging a multimodality approach will pro-
gress and require changes to the current unimodality training
programmes and certifications.
Conclusion
The development of formalized training in cardiovascular imaging
has been one of the successes of recent years. Organized training pro-
grammes, mapped to consensus developed curricula have allowed
trainees to develop competence which can now be rigorously as-
sessed by national authorities and through certification programmes
offered by professional bodies. However to maintain clinical per-
formance in imaging, which is what really matters, individuals need
to maintain competence, work in a quality assured service and be
prepared to embrace the transition to multimodality imaging.
European Society of Cardiology (ESC). Weblinks to ESCEL: http://​learn.
escardio.org/​Default.aspx
84 CHAPTER 5   Train ing and c ompet ence in ca rdi ovas cu l a r i m ag i n g
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 SECTION 2

New technical
developments in
imaging techniques

6 New developments in echocardiography/​Advanced echocardiography  87

6.1  Three-​dimensional echocardiography  87
Silvia Gianstefani and Mark J. Monaghan
6.2  Assessment of myocardial function by speckle-​tracking echocardiography  103
Thor Edvardsen, Lars Gunnar Klaeboe, Ewa Szymczyk, and Jarosław D. Kasprzak
7 Contrast echocardiography  111
Roxy Senior, Harald Becher, Fausto J. Pinto, and Rajdeep S. Khattar
8 Echocardiography in the cath lab: Fusion imaging and use of intracardiac
echocardiography  121
Covadonga Fernández-​Golfín and José Luis Zamorano
9 New technical developments in nuclear cardiology and hybrid imaging  129
Antti Saraste, Sharmila Dorbala, and Juhani Knuuti
10 New technical developments in cardiac CT: Anatomy, fractional flow reserve (FFR),
and machine learning  145
Stephan Achenbach, Jonathan Leipsic, and James Min
 CHAPTER 6

New developments in
echocardiography/​
Advanced
echocardiography

Contents 6.1  Three-​dimensional echocardiography

Introduction  87
Acquisition techniques  88
Simultaneous multiplane mode  88
Silvia Gianstefani and Mark J. Monaghan
Real-​time 3D mode—​narrow sector  88
Focused wide sector ‘zoom’ mode  88 Acknowledgements to Chiara Palermo
Full-​volume mode (gated or one beat)  88
3D colour Doppler  88
Display of 3D data sets  89
Cropping  89
Post-​acquisition display  89
Introduction
Pitfalls  91 Three-​dimensional echocardiography (3DE) has been around for some time now. It was
Patient selection  91
Data set optimization  91 back in 1974 that investigators first reported the acquisition of 3D ultrasound images of
Optimal views of acquisition  91 the heart [1]‌, but it has not been until the last decade that 3DE has started to enter rou-
Artefacts  91 tine clinical practice.
Stitching artefacts  91
Dropout artefacts  91 The early attempts at this form of imaging were based around computerized recon-
Blurring and blooming artefacts  91 struction from multiple 2D slices, achieved by carefully tracking a transducer through
Railroad-​shaped artefacts  92
Reverberations and shadowing  92 a number of separate 2D planes, acquired over many cardiac cycles. Over subsequent
Gain artefacts  92 years, the technique was gradually refined and improved upon; electrocardiographic
Advantages and limitations of 3D versus (ECG) gating was introduced and free hand scanning gave way to motorized rotary
conventional 2D echocardiography  92 transducers, whose location in space was continually tracked. This approach appeared
Left ventricle  92
Right ventricle  93 to produce accurate chamber volumes [2]‌and relatively impressive images; however,
Left atrium  94 the time involved for reconstruction and the labour-​intensive analysis, not to mention
Mitral valve  94
Aortic valve  95 the large computing requirements, meant that it was the preserve of dedicated research
Tricuspid valve  95 departments.
Pulmonary valve  96 The advent of a sparse matrix array transducer in the early 1990s [3]‌represented a
Transoesophageal echocardiography for
guidance of non-​coronary transcatheter marked improvement. The transducer was capable of obtaining direct volumetric data at
interventions  96 volume rates high enough to demonstrate cardiac motion. Images were presented as 2D
Transcatheter closure of PFO and ASD  96
Percutaneous aortic valve implantation  96
orthogonal planes, and both spatial and temporal resolutions were low. Transducer tech-
Mitral valve clip  97 nology continued to advance and fully sampled matrix array technology facilitated the
Paravalvular leak closure  97 integration of 3DE into clinical practice. These transducers allowed rapid ECG gated or
Percutaneous LA appendage closure  98
real-​time 3D image acquisition with temporal and spatial resolution sufficient for clinical
Developments  98
Fusion imaging  98 applications.
Heart model or Automatic Intelligence to The latest technical advancement consists of the introduction of broadband (5–​1 MHz)
perform 3D analysis  99
single crystal transducers. The electromechanical efficiency of these single crystals is 80–​
Future perspectives  100
100% better than that of the old piezoelectric crystals making them twice as sensitive
and not requiring liquid cooling. This results in enhanced axial resolution, penetration,
and signal-​to-​noise ratio. These transducers allow high-​resolution harmonic imaging
88 CHAPTER 6   N ew devel opments in ech o ca rdi o g r a phy /A dva n ced echo ca rdi o g r a phy
with improved cavity delineation. Matrix array technology uses
multiple rows of crystals to obtain a more uniform resolution
throughout the field of view. Now probes have become smaller
and shaped to fit the hand more comfortably, and to fit within
intercostal spaces to avoid rib shadowing. The efficiency of the
monocrystal matrix array transducers and miniaturization has fa-
cilitated the introduction of transoesophageal (TEE) real-​time 3D
echocardiography: three spatial dimensions plus time (4D).
Acquisition techniques
Improvements in workflow have meant that 3D data acquisition
can be completely incorporated into a standard 2D examination.
Integrated 2D/​ 3D probes for transthoracic echocardiography
(TTE) are commercially available. During an examination it is
only necessary to press a button on the screen to switch between
2D and 3D modes. The current generation of matrix-​phased array
transducers facilitates five main types of image acquisition, which
are available on both TTE and TEE 3D probes. Each of them
differs in spatial and temporal resolution profiles. A complete
understanding of these different live modes and of their potential
and their limitations is crucial in order to appropriately use them
in every specific clinical setting [4–​5]:
◆ Simultaneous multiplane mode.
◆ Real-​time 3D mode—​narrow sector.
◆ Focused wide sector—​‘zoom’.
◆ Full volume—​gated acquisition.
◆ 3D colour flow Doppler.
Simultaneous multiplane mode
Simultaneous multiplane mode is based on the capability to ac-
quire two/​three perpendicular scan planes in a single cardiac
cycle and display them simultaneously. The exact angle of these
slices can be adjusted depending on the structures being imaged.
Colour flow Doppler imaging can also be superimposed onto the
2D images.
Real-​time 3D mode—​narrow sector
Real-​time 3D (RT3D) mode permits the acquisition of a real-​
time, beat-​by-​beat 3D image that can be manipulated live. Due
to high line density and relatively narrow scan volume, this 3D
mode has a high spatial and high temporal resolution. It is par-
ticularly useful for visualization of small structures (valves, small
masses) or to guide interventional procedures where real-​time 3D
imaging is required. However, due to the pyramidal shape of the
volume, additional cropping may be required to obtain an ‘en face’
view of the structure of interest during scanning. With recent de-
velopments in beam forming and data processing techniques it is
now possible to increase the field sector size while maintaining a
reasonable temporal and spatial resolution.
Focused wide sector ‘zoom’ mode
Focused wide sector mode provides a magnified data set of
a specific volume. The region of interest can be manually de-
fined during scanning to obtain a direct view of the structures
and eliminating the need of cropping the volume. This facility
makes the zoom mode the most commonly used acquisition
mode during 3D TEE for examining individual intracardiac
structures. It can be obtained with good resolution in one beat
acquisition; therefore it is not limited by stitching artefacts (as
described later). Nevertheless, it is characterized by a relatively
low temporal resolution (wide scan volume) and a low spatial
resolution (lower line density) so it is important to keep the
zoom volume relatively small to help avoid this. However, if the
volume is too small and doesn’t include reference structures it
may be difficult to correctly orientate the 3D data set due to loss
of spatial orientation.
Full-​volume mode (gated or one beat)
‘Full-​volume’ mode allows the 3D data set to be wide enough
to include the entire heart. The acquisition can be performed
over 2–​6 cardiac cycles gated to the R-​wave and with suspended
respiration, or in true real-​time with one beat full volume ac-
quisition. In the first scenario, the final volume consists of mul-
tiple 3D volumes stitched together (thereby not permitting live
3D viewing). The data set needs cropping and to be analysed
off-​line. Images can then be displayed in a number of ways to
facilitate viewing and analysis of cardiac structures. The stitched
full-​volume mode provides relatively high temporal reso-
lution; however, it is prone to stitching artefacts mainly caused
by translation of the heart during respiration or irregular R–​R
intervals during the volume acquisition time. These limitations
have been overcome by one-​beat full-​volume modality. New 3D
acquisition and parallel processing techniques makes it pos-
sible to analyse, in real-​time structures, using the three perpen-
dicular planes in space with the one beat (real-​time) mode. The
disadvantage of this acquisition modality is a slightly reduced
volume rate and/​or spatial resolution. Full volume is the most
appropriate mode for transthoracic acquisition and quantita-
tive analysis of large volumes, such as the cardiac chambers. It
is possible to acquire an apical data set incorporating all four
cardiac chambers in most patients. In transoesophageal exam-
inations it can be used to include multiple valves or large struc-
tures (such as intracardiac masses).
3D colour Doppler
3D colour Doppler combines volume imaging with colour
Doppler and it is a useful tool for assessing valve regurgitation
(E Fig. 6.1.1) or paravalvular leaks, especially when these are
irregular in size and/​or direction. It can be used in full volume,
zoom modality, and real-​time 3D. The temporal resolution how-
ever is still relatively low.

Display of 3D data sets
Each 3D data set can be displayed and manipulated in different
ways, according to the operator’s needs and preferences. This
helps one to accurately visualize a structure of interest or to obtain
accurate measurements of specific dimensions and volumes.
Cropping
The volume has to be cropped in order to expose the region of
interest (E Fig. 6.1.2). Three-​dimensional cropping can be per-
formed during or after data acquisition. Cropping before acquiring
provides better temporal and spatial resolution and generates the
immediate availability of the cropped image. A wider data set,
cropped after acquisition instead, retains more diagnostic infor-
mation at the expense of loss of spatial and temporal resolution.
Di spl ay of 3 D data   sets 89
Fig. 6.1.1  Aortic valve regurgitation visualized as
vena contracta width along the long axis of aortic
regurgitation jet in anterior-​posterior. After selecting
the best frame for aortic regurgitation (AR) jet
visualization the data set was cropped through the
perpendicular plane of AR from the left ventricular
side to the level of the vena contracta. Therefore,
vena contracta area was visible as the narrowest
region of AR bottom left box.
The procedure consists of manually moving a free cutting tool,
cropping the 3D data set along virtually infinite planes using a
variety of tools, or one can perform the cropping along three
perpendicular axes.
Post-​acquisition display
After the acquisition, a 3DE data set can be visualized and pro-
cessed interactively using a number of 3D visualization and
rendering software tools. 3DE images can be viewed as volume-​
rendered images, surface rendered or wire-​frame display images,
and 2D tomographic slices.
Volume-​rendered  images
Volume rendering provides an ‘en face’ view of intracardiac struc-
tures and their anatomical spatial relationships. It also creates the
possibility of viewing structures simultaneously from opposing
Fig. 6.1.2  Multibeat full volume data set. On the
left side the volume is cropped by a plane parallel
to the mitral valve (MV) annulus to expose the
valves focusing on the MV where there is a flail
of P2 segment. On the right side, the data set is
cropped by a plane perpendicular to the mitral
valve annulus crossing, with Ao, A2, P2 highlighting
the wide flail gap.
LAA, left atrial appendage; Ao, aortic valve; TV,
tricuspid valve.
90 CHAPTER 6   N ew devel opments in ech o ca rdi o g r a phy /A dva n ced echo ca rdi o g r a phy
(a)
Fig. 6.1.3  Simultaneous views of the mitral valve
on the same data set. On the left side the MV is
seen from the left atrial (surgical view) on the right
side from a ventricular perspective. Scallops are
numbered.
LVOT, left ventricular outflow tract.
directions which is not possible by 2DE (E Fig. 6.1.3). It is par-
ticularly useful for evaluating valves and adjacent anatomic struc-
tures. Shading techniques, such as opacification, brightness, and
smoothing, and various colour maps (E Fig. 6.1.4) are used to
generate a 3D display improving the perception of depth and
enhancing the texture of cardiac structures. High-​ definition
photo-​realistic rendering tools have been developed with the
ability to change the position of a pseudo light source on recon-
struction to illuminate structures in different ways and better il-
lustrate anatomical detail.
Surface rendered images
Surface rendering allows the visualization of structures in a solid
appearance. It is mainly used to display models of the ventricles
and of the atria, improving the visual assessment of their volumes
Fig. 6.1.4  An example of different volume rendering of the mitral valve obtained by changing the colour map and the shading techniques. The mitral valve is
imaged in the surgical view.
(b)
and function. It can also be used for tracking and analysing valvular
structures, such as the mitral valve (MV) annulus. The results of the
tracking may be expressed in length, circumference, area, or volu-
metric measurements. It also provides additional information on
timing of events, motion, and displacement. Solid and wire-​frame
surface-​rendering techniques can be combined to appreciate the ex-
tent of cardiac chamber motion and the changes in volume during
the cardiac cycle. In order to obtain the 3D render the endocardium
is traced using a semi-​automatic or fully automatic border detec-
tion algorithm. These contours are combined together to produce
a 3D shape that can be visualized as a solid object or a wire-​frame.
2D tomographic slices
2D tomographic slices’ mode consists of perpendicular 2D views
(coronal, sagittal, and transverse slices) obtained from the same

3D data set displayed simultaneously in a cine-​loop format; or
of multiple 2D parallel tomographic slices. This technique is par-
ticularly useful to facilitate the assessment of regional wall motion
abnormalities in TTE or in 3D stress echocardiography.
Pitfalls
Patient selection
In order to obtain a good-​quality 3D data set it is important to
understand which acquisition modality is most appropriate for
each specific clinical setting. This knowledge comes with ex-
perience and frequent use of 3D technology. 3D zoom or one
beat full-​volume acquisition represent the modality of choice
in patients not capable of breath-​holding or in the presence
of an irregular heart rhythm. This is because they provide a
reasonable volume rate without stitching artefacts related to
translation of the heart during breathing or to irregular car-
diac cycles. On the other hand, in patients in sinus rhythm
and capable of breath-​holding, the stitched 3D full-​volume is
the method of choice to image a large structure (e.g. left ven-
tricle), as it provides in 2 to 6 beats excellent temporal reso-
lution with a data set volume wide enough to contain all the
required information.
Data set optimization
It is not possible to produce a high-​quality diagnostic 3D data set
if the 2D data set is not optimized. Optimal-​gain setting is man-
datory. Low gain could result in drop out, with the risk of elimin-
ating information. On the other hand, a high-​gain setting could
lead to a decrease in resolution, loss of 3D perspective, and arte-
facts. The ‘ideal’ quality 3D data set is a compromise between the
spatial and temporal resolutions achievable. An increased scan
line density will improve spatial resolution; however, this results
in a longer acquisition phase (susceptible to stitching artefacts).
To improve the temporal resolution (volume rate), the sector
size should be minimized, focusing on the volume of interest.
Developments in image acquisition techniques and faster data
processing will help overcome some of these currently necessary
compromises in the future.
Optimal views of acquisition
As with 2D, 3D TTE examinations should be performed from
multiple transducer positions. However, there are specific 3D
views that enable higher temporal and spatial resolution due
to the closer position of a particular structure of interest to
the transducer. The best approach to image the mitral and
aortic valve is from the parasternal long axis window allowing
higher spatial resolution, while the apical approach allows the
‘en face’ visualization of the valve. The apical window is the
most appropriate for the left ventricle (LV) and LA volume
acquisition.
A rt e fac ts 91
Artefacts
Knowledge of the main artefacts in 3D echocardiography is im-
portant for a correct interpretation of the acquired images. The
principal types of artefacts consist of:
◆ Stitching artefacts.
◆ Dropout artefacts.
◆ Blurring and blooming artefacts.
◆ Railroad-​shaped artefacts.
◆ Reverberation and shadowing.
◆ Artefacts related to gain settings.
Stitching artefacts
One of the main limitations of the full-​ volume and colour
Doppler modes is the potential for thin ‘fault lines’ to appear be-
tween the subvolumes after reconstruction. These lines, known
as stitching artefacts, can be caused by irregular R–​R intervals or
by any movement of the heart relative to the transducer during
image acquisition. Stitching artefacts not only impair image
quality, but also hinder analysis and make it challenging to as-
sess patients with an arrhythmia (see z Video 6.1.1). This is a
problem that has been largely overcome by the latest generation
of transducers and software. Volume acquisition times have now
been reduced to such an extent that systems are capable of high
volume rates and full volume 90° by 90° acquisitions, including
3D colour Doppler, all in one cardiac cycle. This abolishes the po-
tential for stitching artefacts, making it easier to accurately image
patients with arrhythmias.
Dropout artefacts
Dropout artefacts are caused by loss of 3D surface information
related to poor echo-​signal intensity of thin intracardiac struc-
tures (i.e. interatrial septum). This typically results in a false ‘hole’.
Discriminating between a true defect and a dropout can be very
challenging and requires experience and sometimes the use of
colour Doppler. To achieve a correct interpretation of dropout
artefacts it is useful to compare 3D volume with 2D views of
the same structure with and without colour Doppler. In order
to minimize this artefact it is important to optimize gain setting
(avoiding over-​gaining) and orientate the structure of interest
perpendicular to the transducer.
Blurring and blooming artefacts
These are mainly caused by inaccurate voxel interpolation be-
tween distant image lines and are inversely proportional to line
density. Blurring refers to the thicker representation of thin struc-
tures (i.e. MV leaflets, mitral subvalvular apparatus). Blooming
refers to un-​sharp or defocussed representation of high echo-​
density structures, mainly artificial structures (i.e. mechanical
prosthesis or pacemaker leads). Blooming and blurring artefacts
commonly coexist.
92 CHAPTER 6   N ew devel opments in ech o ca rdi o g r a phy /A dva n ced echo ca rdi o g r a phy
Railroad-​shaped artefacts
Related to large catheters with wide lumens where two surfaces
are perpendicular to the ultrasound beam and produce strong
echoes. The other two surfaces are tangential, producing very
weak echoes. Therefore the catheter appears made by two linear
structures (railroad-​like image). In order to reduce this artefact,
it may be useful to obtain a view of the catheter perpendicular
to the beam and increase compression (to fill the gap with weak
echoes), add smoothing (reducing roughness) to obtain a cylin-
drical shape, more similar to reality. However, this artefact is so
characteristic of large catheters that it permits unambiguous rec-
ognition of structures.
Reverberations and shadowing
Reverberation is given by reflections of metallic component of cath-
eters and, depending on the perspective, may appear to lengthen
it. Shadowing happens when ultrasound pulses are attenuated by
strong reflecting surfaces (catheters or devices) causing dropout
artefacts, which resemble a lack of tissue. It can be recognized be-
cause it is just beyond the catheter or device, has the same shape
and size, and follows their motion. This artefact can be reduced or
moved rotating, moving, and/​or angulating the transducer.
Gain artefacts
Gain artefacts are related to over-​gaining, which may cause an
effect of smoke or noise that can completely obscure the structure
of interest. In order to avoid this phenomenon and to achieve an
optimal representation, it is advisable to turn up the gain setting
until the smoke appears, then turn it down just to the point where
the smoke has disappeared.
Advantages and limitations
of 3D versus conventional
2D echocardiography
The principal advantage of a direct volumetric acquisition is over-
coming image foreshortening and any geometric assumptions on
Fig. 6.1.5  3D analysis of the left ventricle. Semi-​
automatically detected LV contours are combined
together in order to generate a 3D model of the
left ventricle and LV volume curve throughout the
cardiac cycle. After region of interest are marked
manually, the software automatically traces the
endocardial border. Manual adjustments are
required when the software border detection is
suboptimal. In this case the left ventricle is dilated
with a normal systolic function.
cardiac structures. Moreover, 3DE supplies volumetric informa-
tion of the structure of interest in relation to contiguous cardiac
structures. We have summarized below the main current applica-
tions of 3D echocardiography, comparing it with conventional
2D echocardiography.
Left ventricle
LV quantification is one of the most widespread and one of the
first researched clinical applications of 3DE TTE. 3D imaging
of the LV is free from geometrical assumptions, prevents apical
foreshortening and errors in imaging positioning. In order to
obtain global LV function, semi-​automated border tracking soft-
ware is used to create a mathematical cast of the LV throughout
the cardiac cycle from which volumes and ejection fraction are
extracted, completely dispelling the need for geometric assump-
tions (E Fig. 6.1.5). A number of off-​line software are available
for the analysis of LV global function (volumes and ejection frac-
tion), mass, and regional function. These measurements are now
quick and easy to perform and have been proven to be more ac-
curate than 2D or M-​mode calculations when compared to car-
diac magnetic resonance imaging (CMR) [6–​9] the current gold
standard for mass and volumes. Correlation has been very good
albeit with a tendency for echocardiography to slightly underesti-
mate volumes, mainly due to the difference in endocardial border
visualization [10].
Furthermore, 3DE has better interobserver, intraobserver,
and test–​retest variability [11] than 2D, and has been shown to
have significant clinical impact in different clinical scenario. 3DE
is paramount in the decision-​making and follow up of patients
undergoing sequential left ventricular ejection fraction (LVEF)
and volume quantification during cancer chemotherapy, as it pro-
vides an accurate and reproducible quantification with the lowest
variability [12]. It is very valuable in risk stratification of patients
with LV dysfunction post-​myocardial infarction or heart failure
to guide management with implantable defibrillator placement or
biventricular pacemaker, which requires an accurate and repro-
ducible EF [13–​15].
The mathematical cast described can also be used to pro-
vide regional information. It can be divided into the American
 Advantages and limitat i on s of 3 D ver su s c on ven ti ona l 2 D echo ca rdi o g r a ph y
Society of Echocardiography 17 segment models, and for
each segment a regional ejection fraction can be obtained, as
well as a time to minimum volume. From this data a systolic
dyssynchrony index can be calculated [16], which is based on
the time to minimum volume of all the segments. This tech-
nique gives a measure of the intraventricular mechanical
dyssynchrony. Further subdivision of this model, into over 800
segments, can be performed with the time to peak contraction
of each one colour-​coded. This information can be merged to
give a dynamic parametric image known as a contraction front
map. This technique offers an intuitive display of mechanical
contraction, with an ability to rapidly demonstrate significant
areas of myocardial delay.
Stress echocardiography (SE) is another important aspect of
LV assessment which can now be performed with 3DE, with
or without contrast enhancement. 3D-​SE is feasible and clin-
ically useful in the diagnosis of ischaemia during conventional
2D Dobutamine stress echocardiography (DSE), and it appears
to have better sensitivity compared to 2D SE to detect myo-
cardial ischaemia in the left anterior descending artery (LAD)
territory [17, 18].
3D SE has the potential to overcome the major limitations of
2D SE such as LV foreshortening and difficulties in matching the
same myocardial segment during the different stages of the ac-
quisition protocol [19] offering the great advantage of acquiring
all images from one echo window in a single capture.
A 3D data set allows a multiplane view with the simultaneous
display of all major orthogonal planes (multiplane view) as well as
a multislice view with multiple short-​axis images extracted from
LV apex to base. The overall wall motion is simultaneously as-
sessed in different planes, whereas in 2DE the various planes are
imaged at different times. It can also provide accurate quantitative
93
data such as LVEF and volumes [20]. 3D is also less operator-​
dependent and has reduced interobserver variability compared to
2D [21–​25]. However, 3D spatial and temporal resolution is still
lower than 2D SE, therefore pharmacologic stress testing rather
than exercise imaging is better for accuracy and technically easier
for detecting myocardial ischaemia. Nevertheless, in the latest
generation of single-​beat acquisition and smaller footprint matrix
transducers, the volume rate has improved (40 volumes/​s giving
good temporal resolution); single-​beat acquisition also avoids
stitching artefacts and reduces the acquisition time. Dedicated 3D
stress echo viewers provide semi-​automated, side-​by-​side analysis
of multiple cross-​sections during different stress stages; this saves
data analysis time and may help 3D stress echo become more clin-
ically attractive.
Right ventricle
The complicated geometrical structure and asymmetry of
the right ventricle (RV), both in health and disease, signifi-
cantly limits accurate 2D quantification of size and function.
This chamber is often not explored enough with the standard
RV projections and is subject to misinterpretation with the
modified ones.
3D analysis has been shown to be more accurate, as it does not
rely on geometrical assumptions that may be applied to the right
ventricle improperly [26, 27]. Normal ranges of RV volumes and
right ventricular ejection fraction (RVEF) have been established
[28] and new and more user-​friendly software packages are avail-
able to perform quantitative analysis of 3D data sets of the RV.
Dedicated semi-​automated analysis software create a mathemat-
ical cast and global time–​volume curves similar to the one that
can be created for the LV. RV volumes can be obtained and ejec-
tion fraction calculated (E Fig. 6.1.6).
Fig. 6.1.6  A semi-​automated segmentation
algorithm was used to measure the RV cavity
volume during the cardiac cycle (3D RV cast on the
top centre). User-​defined landmarks are located
at the level of the RV endocardium, the tricuspid
valve plane and RV outflow tract (left side of the
figure). The algorithm computes the deformation
of the 3D model calculating volumes, EF (ejection
fraction), stroke volume (SV), TAPSE, FAC
(fractional area changes) (top right) and RV volume
curve throughout the cardiac cycle (bottom right).
94 CHAPTER 6   N ew devel opments in ech o ca rdi o g r a phy /A dva n ced echo ca rdi o g r a phy
This technique has been validated in vitro [29] and in vivo in
children and adults in different clinical settings, and is accurate
when compared to CMR [30]. The independent prognostic value
of 3DE assessment of RV ejection fraction has been reported
in consecutive patients with various cardiac conditions and the
power of RV ejection fraction to predict cardiac mortality and
major adverse cardiac events (MACE) was higher than that
LVEF [31].
The advantages of 3D imaging over 2D includes improved
interobserver variability and a reduced underestimation of the
RV end-​diastolic and end-​systolic volumes compared to CMR
both in healthy subjects [32] and in RV pathology [33–​ 36].
Moreover using mesh type modelling of the RV obtained by 3DE,
we can measure the relative contribution of the longitudinal and
the radial components to global RV function. With 2D echo we
can realistically only study the longitudinal shortening of the RV.
The acquisition should be guided by a multislice 2D display in
order to ensure that the whole RV (in particular the anterior wall
which is the closest to the sternum) is included in the data set. A
cooperative patient, in sinus rhythm, able to breath-​hold, is key to
avoid stitching artefacts during multibeat full volume acquisition.
However, 3D analysis is still time-​consuming and requires experi-
enced operators and good-​quality data sets in order to produce
reliable measurements.
Left atrium
The left atrium (LA) has three important roles in cardiac per-
formance due to its capability to dilate and remodel in relation to
the LV filling pressures. It works as a contractile pump (delivering
15% to 30% of the entire LV filling), as a reservoir collecting pul-
monary venous return during ventricular systole, and as a con-
duit for the passage of blood from the LA to the LV during early
ventricular diastole. It represents a good marker of the magnitude
and duration of LV systolic and diastolic dysfunction, and it is a
validated prognostic marker [37–​38].
In the most recent guidelines on chamber quantification [32],
volume determinations have been advised over linear dimen-
sions, as they allow accurate assessment of any asymmetric re-
modelling of the LA. 3D TTE has been demonstrated to be more
accurate and reproducible than 2D TTE compared to CMR [39]
and cardiac computed tomography (CT) [40] and has a superior
prognostic ability [41, 42]. However 3D LA measurement, despite
these advantages, are still not used in clinical practice because of
the lack of standardization and the additional time required.
3D TEE has an important role in the assessment of the LA be-
fore ablation procedures [43] and percutaneous closure of LA
appendage. 3D TEE provides an accurate anatomical visualiza-
tion of the atrial structures, such as the LA ridge, LA isthmus,
LA appendage, and pulmonary veins. The LA appendage is com-
plex in shape, elongated, often multilobar, and usually heavily
trabeculated with pectinate muscles. A 3D TEE assessment can be
very useful in this setting. The acquisition of a single 3D volume
overcomes the need to obtain multiple views of the appendage
from different angles, as the 3D data set can be cropped in the
post-​processing phase through an infinite number of planes.
Mitral valve
The MV and the mitral subvalvular apparatus are optimally im-
aged by 3DE with an ‘en face’ view of the valve from both LV and
LA perspectives. This technique is less operator-​dependent as the
entire MV and the spatial relationship of the valve with the sur-
rounding structures can be visualized in a single view.
The view of the MV imaged with an LA perspective is called
‘surgical view’, as it represents what a surgeon sees standing on
the right side of the patient and looking at the MV from an open
LA (see E Fig. 6.1.3(a)). This enormously facilitate an effective
communication with cardiothoracic surgeons, both in the pre-
operative assessment of valve pathology and in evaluation of the
surgical results.
In the setting of mitral regurgitation there is a great benefit of
3D over 2D in different aspects: diagnosis and treatment, particu-
larly in localizing the lesion, identifying the mechanism of regur-
gitation, and quantifying its severity. Data have suggested that a
good 3D TTE can abolish the need for 2D TEE in conditions such
as MV prolapse [44] however 3D transoesophageal approach
provides significantly better images compared to TTE and gives
a better understanding especially in challenging setting such as
commissural pathology and clefts [45]. See z Video 6.1.2.
2D TTE can make it challenging to localize the diseased seg-
ment with precision as it only provides a single plane image,
which can be misleading in correctly identifying the affected
scallop due to the saddle shape of the MV and changes of the spa-
tial relationships of MV apparatus with adjacent structures (i.e.
mitral annular dilatation, or aortic root enlargement) [46].
In the post-​processing phase, it is possible to perform a seg-
mental analysis of each scallop, achieving an anatomically correct
orifice area, assessing the shape and perimeter of MV annulus, and
obtaining functional data with 3D colour Doppler. New volumetric
software allows a quick and accurate measurement for quantifying
MV annular, leaflet, and subvalvular geometry throughout the car-
diac cycle and offers 3D parametric maps with colour grading indi-
cating the degree of leaflet displacement into the LA relative to the
mitral annular plane. These measurements have a role in improving
the identification of MV pathology [47] and subsequently in
improving the planning of mitral valve surgery [48].
Moreover 3D colour Doppler can add important information
on the effective regurgitant orifice area, and on the shape and di-
mension of the vena contracta (VC; elliptical in many patients)
eliminating any geometrical assumption. The 3D VC area correl-
ates also more closely with Doppler-​derived effective regurgitant
orifice area, than 2D VC diameter [49].
In the presence of multiple MR jets the areas of the different
orifices can be planimetered and summated to obtain a more ac-
curate assessment of regurgitation severity.
3D colour Doppler is also very useful in identifying the exact
origin and severity of paravalvular leaks in prosthetic valves,
 Advantages and limitat i on s of 3 D ver su s c on ven ti ona l 2 D echo ca rdi o g r a ph y
which can be very challenging with 2D TEE. Unfortunately, at
present 3D colour Doppler is still limited by a relatively low frame
rate despite multibeat acquisition and breath-​hold.
Finally, 3DE is also superior to 2DE for the quantification of
MV stenosis (MS). MV 3D planimetry is a direct, accurate, and
relatively haemodynamically independent measurement of mi-
tral valve area (MVA) and it is recommended as the method of
choice for assessment of MS by the recent European guidelines
on the management of valve disease [50]. With the simultaneous
display of the three orthogonal planes, it is often possible to opti-
mally position a plane at the MV leaflet tips, thereby obtaining the
smallest MV orifice area. This measurement can be very challen-
ging with 2DE as the operator can never be sure if the ultrasound
plane is truly perpendicular to the funnel of the MV [51].
Aortic valve
The gold standard technique to assess the effective aortic valve
area (AVA) in aortic valve stenosis (AVS) is the continuity equa-
tion, based on the measurement of the transvalvular velocity and
of the LV outflow tract (LVOT) by 2DE. However, the continuity
equation relies on the geometric assumption of LVOT circularity,
which can make the AVA calculation inaccurate, as it has been
shown to be elliptical in many patients [52, 53]. Using a hybrid
technique, with a 3D measurement of the LVOT area, it is possible
to overcome geometrical assumptions and obtain a more reliable
estimation of the AVA in the continuity equation [54, 55].
A correct estimation of AVA can also be achieved by 3D plan-
imetry of the valve [56, 57]. This post-​processing method is based
on an accurate positioning of one of the three orthogonal planes
at the level of the tips of the aortic valve cusps in systole, where
AVA is smallest. The true AVA will be displayed in the perpen-
dicular plane and it is possible to measure it by manual tracing.
This is analogous to the technique described for mitral stenosis.
However, an accurate assessment of the aortic valve can be chal-
lenging due to its small size and to frequent thickening and calci-
fication of the leaflets.
With development of transcatheter aortic valve replacement
(TAVR), atrial valve (AV) assessment by 3D TEE has acquired
a fundamental role as guidance for choosing the optimal pros-
thesis size. 3D TEE enables the operator to accurately assess
annulus dimensions and shape, location, and amount of cal-
cification, aortic root dimensions and distance between the
coronary arteries and the aortic annulus providing invaluable
information [58].
3D TEE sizing for transcatheter aortic valve implantation
(TAVI) procedures has demonstrated a good correlation with CT,
and it can also assess the differences in aortic root geometry in
specific subsets (bicuspid AV).
Recent studies have shown that novel (semi-​)automated 3D
echocardiographic TEE analysis software specially designed
for the aortic root can accurately measure aortic annulus and
root in patients with severe AS, with excellent correlation com-
pared to contrast CT and good concordance with conventional
95
prosthesis sizing charts [59–​61]. These findings may have clin-
ical implications in terms of prosthesis sizing in patients under-
going TAVR, in both the elderly population because of contrast
nephrotoxicity and in the younger population to decrease ex-
posure to radiation.
Tricuspid valve
There is renewed interest on 3DE imaging of the so called ‘for-
gotten valve’. This is likely to be due to the better understanding
of the influence of tricuspid valve (TV) dysfunction on patient
outcomes and due to the recent developments in transcatheter
interventions.
The latest valvular heart disease guidelines [50] suggest (class
IIa) repairing the TV in the presence of tricuspid annular (TA)
dilatation (>40 mm or > 21 mm/​m2) in the setting of surgery for
left-​heart disease. Studies have shown that when surgical repair is
performed based on annulus dilatation rather than on TV regur-
gitation (TR) severity the surgical outcome is improved [62, 63].
Therefore an accurate assessment of TA dimension becomes
fundamental. 3D makes it possible to fully understand and delin-
eate this complex structure which is ellipsoid and saddle-​shaped
with distinct superior points oriented anteriorly and posteriorly
and inferior points oriented medially and laterally. However, with
worsening TR the annulus becomes larger, rounder and flatter
and mainly increases in the septal-​lateral diameter (along its
free wall) than in the anterior-​posterior direction. This has im-
portant clinical implications for planning surgical annuloplasty
techniques [64].
It has been seen that 3D assessment of annular dimensions
correlates to CMR better than 2D which tends to underestimate
it [65]. 3D is also superior to 2D in displaying TV anatomy and
pathology with the visualization of the whole valve from any per-
spective. By 2D it is impossible to assess the commissures, co-
aptation orifice, and perform valve area planimetry plus there is
a significant variability of the leaflets seen in each view. Using a
3D multiplanar reconstruction instead it is possible to accurately
identify each leaflet [66]. See E Figure 6.1.7.
Obtaining a 3D data set of the TV is also of paramount
importance in the presence of a pacemaker lead to establish
if the tricuspid regurgitation may be related to interference
of the electrode with the valve leaflets. By conventional 2DE
the diagnosis of lead-​induced tricuspid regurgitation may be
challenging because of the difficulties in identifying the ana-
tomical relationship between the pacing lead and the tricuspid
leaflets [67].
By 3D colour Doppler it is possible to accurately measure
VC, PISA, and effective regurgitant orifice area (EROA) without
geometrical assumptions. In literature, a poor correlation was
found between the 3D VC area and its width measured by 2DE,
supporting the concept of its irregular geometry [68]. A new
dedicated TA software has been produced and utilized in a re-
cent study [69] to evaluate TA in healthy subjects. It was found
that 2DE and 3D MPR measurements of TA diameters, which
96 CHAPTER 6   N ew devel opments in ech o ca rdi o g r a phy /A dva n ced echo ca rdi o g r a phy
Fig. 6.1.7  Tricuspid valve visualization from the
ventricular aspect.
AL, anterior leaflet; PL, posterior leaflet; SL, septal leaflet.
do not account for the non-​planarity of the TV, underestimate
true 3DE dimensions. Normal ranges were identified, and it
was shown that TA area, perimeter, and dimensions progres-
sively decrease during systole, reaching minimum values in end
systole.
The recent interest in tricuspid percutaneous interventions [70,
71] is expected to increase the need for 3D echo preprocedural
planning (accurate sizing of the valve and accurate annular
measurements), intraprocedural guidance, and postprocedural
assessment.
Pulmonary valve
3D transthoracic assessment of pulmonary valve is considerably
more challenging, primarily because of its location and the thin-
ness of the leaflets. Clinical roles have been researched, but less
well-​delineated.
Transoesophageal echocardiography for
guidance of non-​coronary transcatheter
interventions
3D TEE has gained a new important field of application after the
recent development and diffusion of non-​coronary transcatheter
interventions. 3D echo has become an invaluable diagnostic tool
in procedures such as TAVR, MV clip, atrial septal defect (ASD),
patent foramen ovale (PFO), LA appendage percutaneous closure,
and percutaneous closure of paravalvular leaks. 3D TEE in these
settings is used, sometimes in combination with CT, for optimal
preprocedural assessment. It also provides continuous soft-​tissue
imaging during the intervention (which cannot be provided by
fluoroscopy alone). And it facilitates prompt monitoring of the
final result and possible complications. 3D compared to 2D pro-
vides accurate visualization of devices, balloons, guidewires, and
catheters assessing their position in relation to the surrounding
cardiac anatomy [72]. It allows continuous real-​time imaging of
structures of interest, avoiding the necessity to constantly change
the angle of acquisition in order to detect the position of cath-
eters, wires, and balloons.
Transcatheter closure of PFO and ASD
PFO and ASD closure are now widely performed procedures. In
the majority of the cases a combination of fluoroscopy and TEE
is used to guide and monitor the device deployment and to as-
sess the final result (see z Video 6.1.3). 3D TEE has great cap-
ability in this setting as it provides anatomical views and leads to
an accurate estimation of the shape and dimensions of the defect
without the necessity of mental reconstruction. Moreover, 3DE
supplies information about surrounding structures (such as the
aortic rim and pulmonary veins, etc.) representing the most ac-
curate periprocedural imaging tool.
Percutaneous aortic valve implantation
The guidelines on the Use of Echocardiography in Transcatheter
Interventions for Valvular Heart Disease [73] recommend TEE
prior to TAVR if there are any concerns on the assessment of
the aortic root anatomy, aortic annular size, or number of cusps
(E Fig. 6.1.8). Accurate sizing of the aortic annulus is critical
to TAVR procedural success. The views obtained by 2D TEE are
limited to a short-​axis view and a long-​axis view of the struc-
tures (annulus, aortic root). 3D TEE overcomes this limitation by
providing a true anatomical visualization of the whole annulus
 Advantages and limitat i on s of 3 D ver su s c on ven ti ona l 2 D echo ca rdi o g r a ph y 97

Fig. 6.1.8  Automated 3D image analysis of a 3D

TEE image of the aortic and mitral valve showing
superimposition of a 3D wire-​mesh model of
the valve structures. This model is dynamic and
therefore moves with the heart, tracking the
anatomical aspects of the valve. Automated
measurements of various aspects of the valve
anatomy are derived by the software which
removes the variability introduced by manual
measurements.

leading to more accurate sizing. It is fundamental in determining Mitral valve clip

the distance between the annulus and the ostium of the right and
Mitral valve clip (edge-​to-​edge repair) is a treatment option in
left coronary arteries to avoid ostial occlusion during the valve
the setting of severe degenerative or functional MV regurgi-
deployment. As previously mentioned, 3D TEE measurements
tation in patients unsuitable for open heart surgery [76, 77].
have been shown to correlate very well with CT and the two
The device is delivered via percutaneous femoral venous trans-​
techniques can be considered interchangeable. During the pro-
septal access. The mitral clip grasps the scallops of the MV cre-
cedure, 3D TEE can supply continuous monitoring of prosthesis
ating a double orifice, which increases the leaflet coaptation and
position. Once the valve is implanted, 3D colour flow provides
thereby reduces the degree of regurgitation. This technique is
important information on presence, location, and severity of re-
an echocardiographically guided interventional procedure: TEE
sidual valvular and paravalvular leaks. Cropping the 3DE data set
guides the transseptal puncture and optimal alignment of the de-
ensures a perpendicular imaging plane to the jet origin enabling
vice. 3D TEE compared with 2D furnishes an anatomical view
accurate measurement of its circumferential extent and planim-
of the interatrial septum for the interatrial septal puncture and
etry of its effective regurgitant orifice area [74]. However the low
provides an ‘en face’ view of the MV, which is particularly helpful
spatial and temporal resolutions of 3D colour flow are still rela-
in monitoring the perpendicular orientation of the clip to the
tive limitations.
MV coaptation line. Moreover, with 3D colour Doppler it is pos-
3D TEE is also fundamental in planning and monitoring
sible to more accurately assess the severity and the position of the
the procedure of percutaneous valve-​in-​valve therapy, which
regurgitant jets before and after clip positioning and to determine
has become an important treatment for a failing bioprosthesis
if a second or even third clip is needed.
in patients who cannot have redo surgery. 3DE is extremely
useful in the assessment of LVOT geometry and in the meas-
urement of the true internal diameter of the existing valve, es- Paravalvular leak closure
pecially when the valve size and type are unknown. Even in the In paravalvular leak (PVL) closure, 3D and 3D colour Doppler
setting of a known type of bioprosthesis, the manufacturer and are particularly useful for correct identification of size and lo-
true internal diameters could differ, because manufacturer’s cation of the leak(s). The superiority of 3D TEE over 2D TEE
charts potentially result in overestimation of the real internal in monitoring this procedure relies on obtaining anatomical
diameter [75] and the presence of fibrosis and valve calcifica- views of the PVL and of the closure device in relation to the
tion can reduce the true internal diameter. Choosing the right surrounding structures. A 3D volume data set allows the oper-
valve-​in-​valve size is necessary for a good procedural result ator to directly measure the area of dehiscence and to correctly
and to avoid complications such as central or paravalvular size the device. Confirmation with 3D colour mapping is cru-
aortic regurgitation, valve embolization, or coronary artery cial to avoid misdiagnosis. RT3DE is fundamental in guiding
obstruction. the trans-​septal puncture if needed and helping the wire and
98 CHAPTER 6   N ew devel opments in ech o ca rdi o g r a phy /A dva n ced echo ca rdi o g r a phy

the guide catheter through the defect. During deployment 3D
TEE helps to ensure proper seating of the device. 3DE assesses
the function of the prosthetic valve to ensure that there is no
obstruction by the device to the opening and closing of the pros-
thetic leaflets/​discs and it may also be helpful in excluding cor-
onary ostia coverage in aortic PVL. After release, 3D TEE colour
is performed to assess if there are residual leaks and if a second
plug is needed.
Percutaneous LA appendage closure
Percutaneous left atrial appendage (LAA) occlusion/​exclusion
devices are growing in popularity as a potential option for stroke
risk reduction in patients ineligible or at high risk for systemic
anticoagulation.
On the market there are different types of devices. The most
popular among them require a purely endocardial approach
(Watchman and Amulet) where a trans-​septally delivered nit-
inol structure is placed in the LAA orifice, thereby excluding the
LAA from the systemic circulation. 3D TEE has an important
role in identifying LAA size, anatomic orientation, relationship
to the interatrial septum and its complex anatomy (often com-
posed of multiple lobes): orifice, neck region, body, and apex.
The anatomic definition of LAA ‘orifice’ is different from the ‘ori-
fice’ defined as the landing zone for various LAA occluder de-
vices; obtaining the right measurement is obviously essential for
the subsequent sizing. 2DTEE may be misleading in measuring
the landing zone, often oval shaped, as it can obtain only one
diameter. This limitation can be overcome using 3D multiplanar
reconstruction: two long axes of the LAA are aligned to visu-
alize the short-​axis plane of the LAA, allowing precise measure-
ment of the landing zone diameter. 3D TEE should be preferred
for the correct sizing of LAA closure devices as it can provide
full view of the LAA without radiation exposure and contrast
administration.
RT3D TEE is essential in guiding the trans-​septal puncture (in
the inferoposterior part of the septum allowing the most direct
route to antero-​laterally located LAA) in guiding the catheters
and assessing of results of the procedure. 3D TEE is also particu-
larly helpful in exclude complications such as: peridevice leaks
(associated with increased risk for thromboembolism), embol-
ization, or shifting position of the device possibly uncovering an
LAA lobe, thrombus formation on the left atrial side of the device,
residual shunt across the interatrial septum.
Developments
Fusion imaging
Percutaneous approaches as treatment for structural heart dis-
ease are becoming more complex and widespread. The combin-
ation between 3D TEE and fluoroscopy is becoming essential in
order to guide such interventions. In the crowded setting of the
cardiac catheter lab, these two modalities are usually displayed
on separate screens and handled by physicians with different ex-
pertise, requiring mental reconstruction to merge the informa-
tion obtained from echo and fluoroscopy.
Echocardiographic-​ fluoroscopic fusion imaging, recently
introduced in clinical practice, has the ability to overcome this
issue synchronizing soft-​tissue information (TTE) and precise
visualization of catheters and devices (fluoroscopy) in a single
view (E Fig. 6.1.9). A very innovative function allows tagging
the anatomical structure of interest on both echocardiographic

Fig. 6.1.9  Spatial co-​registration of a 3D TEE probe in a fluoroscopy field during structural interventions facilitates fusion and superimposition of 3D or 2D
images on top of the fluoroscopy image in real-​time. The echo image can be made semi-​translucent so the fluoroscopy details of catheters and devices etc.
can be seen together with soft-​tissue information and both images are spatially co-​registered, irrespective of the fluoroscopy angle and TEE probe position.
In this example, a 3D TEE image of the aortic valve complex is superimposed onto the fluoroscopy during a TAVI procedure. Details and positioning of the
TAVI valve and delivery catheter are seen simultaneously with the soft-​tissue images from the echo. This facilitates accurate valve (or device) positioning and
means that these procedures can be performed without the use of contrast media when required.
 Dev e l op m e n ts 99

and fluoroscopic images. This tool is strategic in identifying
anatomical landmarks to guide trans-​septal puncture, landing
zones for device positioning or facilitate the steering of the
guidewire through defects. Before a trans-​septal puncture, for
example, the optimal site of puncture can be identified on 3D
TEE positioning the marker on each echo view of the biplane
modality. After validation, the marker is directly superimposed
onto the fluoroscopic view. The interventional cardiologist then
uses the marker on the screen to position the puncture needle.
This technique is extremely promising potentially increasing
procedural safety, shortening procedural duration, reducing
radiation exposure, and reducing contrast usage. 3D Fusion
imaging is rapidly becoming the default imaging technique
to guide many structural interventions, not just trans-​septal
puncture.
Heart model or Automatic Intelligence to
perform 3D analysis
3D TTE cardiac chamber quantification is known to be superior
to 2D TTE measurements, however, its use in clinical practice is
limited likely because of time required and lack of 3D expertise.
HeartModel™ is a software that using anatomical intelligence
performs a fully automated analysis, pressing only one button
(E Fig. 6.1.10). It provides LV volumes, SV, and LVEF and LA
volumetric quantification plus LV mass in a dynamic presenta-
tion from 3D TTE data sets, thereby improving workflow with
minimum training. LA volumes and LV mass are simultaneously
measured from the same 3D data set without the need of LA fo-
cused views to minimize foreshortening. An adaptive algorithm
automatically detects the endocardial surfaces adjusting to
various imaging conditions, including variations in ventricular
shape and data set orientation and dropout. It identifies LV end
diastole from ECG and determines a global end-​diastolic shape
which is used in combination with motion detection to deter-
mine an end-​systolic cavity. Preliminary end-​systolic and end-​
diastolic LV and LA models are then built in conjunction with
information from a database of LA and LV end-​diastolic and
end-​systolic shapes from approximately 1,000 3D TTE data sets
of different image quality, obtained from patients with a wide
range of function and morphologies. The final model is then
displayed with the possibility to manually edit the contours if
necessary. A recent study [78] showed that automated chamber
quantification analysis can provide accurate, reproducible sim-
ultaneous 3D measurements of LVEDV, LVESV, LVEF, LV mass
and left atrial volume (LAV) comparable to CMR potentially
further reducing subjectivity and improving workflow, redu-
cing the duration of examination. The main limitations consist
of image quality as a minimum number of visible endocardial
border segments are necessary for a reasonable estimation of
chamber volumes. This technique is soon to be expanded to
include automated assessment of the RV and right artery (RA)
so that all four cardiac chambers can be simultaneously and
quickly analysed from a single-​beat full-​volume data set. This

Fig. 6.1.10  Automated analysis, using artificial intelligence, of an apical 3D TTE full-​volume data set incorporating all four cardiac chambers. The software,
using prelearned data sets, has automatically recognized all the salient anatomical features of the left heart and has measured and displayed, in a dynamic
graphical manner, left ventricular and left atrial volumes. In addition, it has automatically calculated left ventricular mass. In this example, the volumes have been
calculated from a single cardiac cycle, however it is possible for the software to perform an analysis from multiple cardiac cycles and display an average.
100 CHAPTER 6   N ew devel opments in ech o ca rdi o g r a phy /A dva n ced echo ca rdi o g r a phy

Fig. 6.1.11  The left-​hand panel is a 3D TEE image of a failed bioprosthetic mitral valve replacement, seen from the surgical (left atrial) perspective using
conventional 3D, surface rendered, processing. On the right-​hand side is the same valve imaged using photo-​realistic processing (TrueVue) where the position
of the light source is seen as a white dot on the image. The enhanced visualization, together with the controllable light source positioning and consequent
shadowing, improves the visual appreciation of the abnormal valve morphology.

will represent a significant improvement in 3D echo workflow
and should further encourage integration of the technique into
routine clinical practice.
Future perspectives
Research efforts are to achieve the highest spatial and volume
rates in a single-​beat acquisition. Direct volumetric acquisitions
allow the possibility of fusion imaging with CMR, computed
tomography, and SPECT. Quantification of regional LV-​RV
shape analysis is now possible and allows the differentiation of
normal from pressure overloaded ventricles. The integration
between fluoroscopic, TEE data with 3D anatomical intelli-
gence allows delimitation of cardiac cavities for optimal visual-
ization of the heart position and orientation on the fluoroscopy
screen.
As previously mentioned, photo-​realistic realization adds pre-
cise soft-​tissue appreciation to the 3D data set (E Fig. 6.1.11).
By illuminating tissue details with a virtual and moveable light
source it creates an improved depth perception and can help with
the communication of complicated information obtained by 3D
data sets thereby potentially improving the diagnostic power
of 3DE.

Further reading
Buck T, Franke A, Monaghan MJ (eds.). Three-​dimensional Echocardio­
graphy, 2nd edn. Berlin Heidelberg: Springer, 2015.
Galderisi M, Cosyns B, Edvardsen T, et al. Standardization of adult
transthoracic echocardiography reporting in agreement with recent
chamber quantification, diastolic function, and heart valve disease
recommendations: an expert consensus document of the European
Association of Cardiovascular Imaging. Eur Heart J Cardiovasc
Imaging 2017; 18: 1301–​10.
Zamorano JL, Badano LP, Bruce C, et al. EAE/​ASE recommendations
for the use of echocardiography in new transcatheter interventions for
valvular heart disease. Eur Heart J 2011; 32: 2189–​214.

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9 For additional multimedia materials please visit the online version of the book at M oxfordmedicine.com/esccvimaging3
6.2  Assessment of myocardial function by speckle-​tracking
echocardiography
Thor Edvardsen, Lars Gunnar Klaeboe, Ewa Szymczyk, and Jarosław D. Kasprzak
Contents
Assessment of myocardial deformation using echocardiography  103
Clinical applications of strain echocardiography  106
Assessment of left ventricular function  106
Early detection of LV dysfunction  106
Assessment of myocardial function in the presence of pathological
remodelling  106
Cardio-​oncology  107
Ischaemic heart disease  107
STE assessment of regional myocardial function  108
STE assessment of right ventricular function  108
STE assessment of atrial function  108
Assessment of myocardial
deformation using echocardiography
Myocardial deformation or strain (ε) is the universal prop-
erty of contracting cardiac muscle. Deformation is defined in
physics as relative change of length (and is therefore unitless
and usually given as percentage) and in cardiac imaging it is
thus algebraically negative for shortening or positive for thick-
ening. There are several definitions of strain—​ L agrangian
∑ ∆L
strain ε L = refers to a fixed baseline distance and
L0 ∆L
Eulerian (or natural) strain ε E =
L ∑
–​to a dynamically
changing reference length, representing a time integral
of strain rate (which can be obtained by tissue Doppler).
Measurements of strains are usually obtained by greyscale
image quantification modality—​speckle-​tracking echocardiog-
raphy (STE) which analyses myocardial motion by tracking
and matching naturally occurring markers of myocardial
103
75. Condemi F, Bapat VN, Gianstefani S, et al. Validation of
transesophageal echocardiographic in vitro measurements for
bioprosthetic aortic valves: implications for percutaneous valve-​
in-​valve therapy. J Am Soc Echocardiogr 2016; 29: 267–​75.
76. Feldman T, Kar S, Rinaldi M, et al. Percutaneous mitral repair with
the MitraClip system: safety and midterm durability in the initial
EVEREST (Endovascular Valve Edge-​to-​Edge REpair Study) cohort.
J Am Coll Cardiol 2009; 54: 686–​94.
77. Feldman T, Foster E, Glower DD, et al. EVEREST II Investigators.
Percutaneous repair or surgery for mitral regurgitation. N Engl J Med
2011; 364: 1395–​406.
78. Tsang W, Salgo IS, Medvedofsky D, et al. Transthoracic 3D echocardio-
graphic left heart chamber quantification using an automated adaptive
analytics algorithm. JACC Cardiovasc Imaging 2016; 9: 769–​82.
texture, described as speckles. Echocardiographic speckles
represent interference pattern of subtle myocardial scatters
and can be followed from frame to frame by dedicated soft-
ware to define the displacement of the myocardium within the
interval between consecutive frames (inverse of frame rate).
For clinical purposes strain is classified relative to the long axis
of specific cardiac cavity—​as longitudinal, circumferential, or ra-
dial strain which may be used to calculate secondary parameters
such as area strain (product of longitudinal and circumferential
strain) or myocardial work. Typically, deformation data are pre-
sented as (E Fig. 6.2.1):
◆ colour-​ coded map overlaid on greyscale two-​ dimensional
(2D) image
◆ curvilinear  M-​mode
◆ ‘bull’s eye plots’ or polar maps supplemented by segmental or
averaged percent deformation values
◆ strain curves—​segmental or averaged global
Systolic deformation of cardiac wall consists of longitudinal
and circumferential shortening and radial thickening (E Fig.
6.2.2). This deformation can be measured in vivo with echocar-
diography (and also with magnetic resonance imaging) and has
been introduced to clinical practice as the parameter of con-
tractility and synchrony. After early M-​mode attempts, one of
the first practical methods to quantify strain was tissue Doppler
that allowed to record local velocity differences at high frame
rates (around 100 Hz) and convert them into Eulerian strain
rate which could be integrated to calculate strain. However,
STE has soon become the preferred way of calculating strain
(Lagrangian). Image acquisition for longitudinal strain includes
recording three apical views (or simultaneous triplane imaging
104 CHAPTER 6   N ew devel opments in ech o ca rdi o g r a phy /A dva n ced echo ca rdi o g r a phy

Fig. 6.2.1  STE assessment of regional myocardial function and timing of ventricular contraction
Left panel: Cardiac amyloidosis with severely reduced global longitudinal strain (-​9%). Regional longitudinal function is markedly reduced in the basal segments
and preserved in the apical segments causing the typical ‘apical sparing’ of longitudinal strain as shown in bulls-​eye plot (red ).
Middle panel: Typical LBBB mechanical activation. Due to early septal activation, the septum contracts before opening of the aortic valve (AVC), causing an
inward septal motion (the septal flash) that coincides with early stretching of the lateral wall giving rise to an opposing wall motion in early systole (yellow
arrows). The septal flash is often combined with apical rocking, the rightward-​leftward motion sequence of the apex transverse to the long axis, due to early
septal activation and delayed lateral wall contraction (white arrow).
Right panel: Hypertrophic cardiomyopathy with LVEF 60% with signs of myocardial dysfunction as indicated by abnormal GLS (–​16%), and prolonged
mechanical dispersion (88 m) reflecting a heterogeneous contraction pattern. White horizontal arrows represent segmental contraction duration.

Fig. 6.2.2  Identification of strain vectors: left ventricular longitudinal (yellow arrow), radial (red arrow) and circumferential (blue arrow) strain and right
ventricular free wall strain (purple) with synchronous (square red-​blue curvilinear M-​mode map) but severely depressed longitudinal shortening calculated in
standard three-​level segmentation scheme (–​10%).
 Assessment of m yo ca rdia l defor m ati on u si n g echo ca rdi o g r a ph y
using matrix probe) in greyscale with optimized image quality
and frame rate reaching 60–​80 Hz (no less than 40 Hz). For
circumferential and radial strain and for rotational mechanics,
short-​axis images should be obtained at basal, middle, and ap-
ical level of the left ventricle (LV). Three-​dimensional (3D) full-​
volume acquisitions of the ventricles with volume rates optimally
above 20 Hz (ideally 30–​50 Hz) can be also used.
STE allows calculation of strain in any direction within the
image sector but the most reliable values are obtained along the
beam line. Deformation values are thus geometrically dependent,
with highest strain obtained in subendocardium. Recent versions
of STE software from different vendors have been standardized
[1]‌which improved intervendor measurements agreement for
longitudinal endocardial strain [2]. Other calculations (e.g. 3D
strain) remain vendor specific.
For the standardized clinical assessment of the ventricles
subendocardial strain values have been proposed, with averaged
global longitudinal left ventricular strain (GLS) being the most estab-
lished practical parameter. GLS can be understood as relative systolic
shortening of subendocardial contour reflecting longitudinal fibres
dysfunction, occurring from the early stages of LV diseases. STE
allows for discrimination between normal, active myocardial seg-
mental deformation versus passive displacement of a dysfunctional
myocardial segment due to adjacent segment tethering and global
cardiac motion. Strain is defined as the percentage change in the di-
mension of myocardial segment. Positive values are related to length-
ening, thickening, or clockwise rotation, whereas negative values are
related to shortening, thinning, or counterclockwise rotation.
As the myocardium shortens during systole, the longitudinal
strain has negative value but when there is pathological stretch or
lengthening of the myocardium, it becomes positive. GLS has a
negative sign but is also reported as an absolute value. Normal vent-
ricles usually show GLS 18–​25%; or for the single value >20% (or,
precisely <–​20%). Left ventricular shortening is slightly higher in
apical than in basal segments (usually up to 2% absolute difference).
Strain calculation can also be applied to the right ventricle (RV) or
atria. Normal strain of free RV wall is usually >23% (or <–​23%) [3]‌.
Fig. 6.2.3  Example of evaluation of advanced myocardial mechanics based on 3D LV data set—​quantification of 3D radial strain (left panel) and left ventricular
rotation (twist—​right panel)
105
Segmental strain curves are less robust but qualitative patterns
may be used for differentiation of cardiomyopathies or used to
establish ventricular asynchrony. Circumferential strain reflects
reduction in the circumference of the LV wall (usually < –​20–​
22%) whereas radial strain corresponds with systolic thickening
along the LV radius (usually >40%). Radial or circumferential
strain have limited clinical application (identification of systolic
asynchrony by radial strain), and along with layer strain, rotation
quantification, or 3D strain remain much less standardized. 3D
strain offers unique potential for quantifying all parameters re-
flecting true spatial deformation of myocardium based on a single
volumetric data set (E Fig. 6.2.3), but clinical value has to be
established and obtaining high quality of datasets consistently re-
mains a challenge.
Measurements of strain are usually performed using semi-​
automated software. Manual corrections and visual inspection are
frequently needed to ensure correct image tracking. The region of
interest should correspond to LV myocardial thickness, and default
thickness has been proposed for the RV (5 mm) and for the atrial
wall (3 mm) [4]‌. Longitudinal strain curve is characterized by sev-
eral critical parameters, with peak systolic strain representing the
contribution of longitudinal fibres contraction in a given segment
to ejecting blood. End-​diastole (mitral valve closure or its approxi-
mation by electrocardiogram [ECG]) should be used as starting
point within the cardiac cycle, and end-​systole based on aortic
valve closure must be marked for analysis (E Fig. 6.2.1). Timing
of nadirs (maximum shortening) of regional strain curves depends
on contraction synchrony (strain dispersion can be defined as the
standard deviation of segmental shortening times). The presence
of post-​systolic shortening with amplitude exceeding 1/​5 of total
strain represents tardokinesis, occurring in ischaemia, dysfunc-
tion with viability, or left bundle branch block. This phenomenon
may follow positive early systolic strain due to longitudinal fibre
stretch, e.g. in left bundle branch block (LBBB). Recently, strain
was combined with blood pressure to emulate invasive pressure-​
volume loops and estimate regional and global myocardial work
index as well as LV work efficiency (E Fig. 6.2.4) [5].
106 CHAPTER 6   N ew devel opments in ech o ca rdi o g r a phy /A dva n ced echo ca rdi o g r a phy
Fig. 6.2.4  Example of calculation of regional myocardial work based on longitudinal LV strain. The plot in top left shows strain-​pressure curve—​red: global with
reduced LV efficacy due to left bundle branch block; green: abnormal regional curve of dyssynchronous septal segment with work wasting.
Clinical applications of strain
echocardiography
Current clinical applications of strain echocardiography include
detection of subclinical myocardial disease (e.g. in aortic stenosis,
cancer therapeutics–​related cardiac dysfunction (CTRCD) or LV
hypertrophy), identification of specific abnormal deformation
patterns (e.g. in amyloidosis) and detection of regional abnormal-
ities (e.g. related to segmental myocardial disease, cardiac asyn-
chrony, or arrhythmic risk). Calculation of RV free wall strain is
a promising systolic functional parameter and can be used as a
robust prognostic parameter in a wide range of myocardial dis-
eases, similarly to LV strain.
Assessment of left ventricular
function
STE enables quantitative assessment of LV deformation in mul-
tiple directions. Only GLS obtained from the apical 2-​, 3-​and 4-​
chamber views offers the feasibility and reproducibility needed to
improve assessment of LV systolic function beyond the conven-
tionally used LV ejection fraction (EF). A peak GLS of approxi-
mately –​20 ± 2% has been suggested as what can be expected in
healthy persons [6]‌, while values within the –​16% to –​18% range
represent a grey zone. Impairment of GLS, on the other hand, has
been consistently linked to adverse outcome across the spectrum
of cardiac disease, being particularly useful in detecting early myo-
cardial dysfunction in heart failure with preserved EF (HFpEF),
cardiomyopathies, ischaemic heart disease, and valvular diseases,
and after treatment with antineoplastic agents [7–​11].
Early detection of LV dysfunction
left ventricular ejection fraction (LVEF) is an inaccurate measure
of LV systolic function that may remain within the normal range
until late in the disease process. Abnormal GLS, however, may
be found in a variety of cardiac conditions and signals preclin-
ical LV dysfunction in the absence of symptoms. GLS impairment
indicative of latent myocardial dysfunction is not uncommon in
asymptomatic diabetic and hypertensive patients and confers in-
creased cardiovascular risk [12]. Detection of heart failure with
preserved EF (HFpEF) currently relies on complimentary assess-
ment of diastolic function which is not always straightforward.
GLS is more user-​friendly to evaluate than traditional diastolic
markers, is frequently abnormal in HFpEF and reflects the se-
verity of diastolic dysfunction. Furthermore, impaired GLS is a
risk marker of cardiac death and mortality independent of clinical
predictors, LVEF and diastolic function in HFpEF [5]‌. In severe
aortic stenosis, the most frequent valvular disease, a normal GLS
is rare even in asymptomatic patients with severe AS and LVEF >
50% [13] signalling latent LV dysfunction. Several reports dem-
onstrate how GLS might be a better indicator of timing of valvular
intervention compared to EF in patients with asymptomatic AS
and paradoxical low flow—​low gradient AS [12, 14, 15].
Assessment of myocardial function
in the presence of pathological
remodelling
STE-​derived GLS is a particularly useful method to evaluate LV
function in the presence of pathological remodelling, in which

conventional volume-​based methods may provide an incorrect
estimate of myocardial performance. Moreover, disease-​specific
strain patterns may identify the underlying aetiology of heart
disease. In hypertrophic cardiomyopathy (HCM) areas with im-
paired strain correspond to areas with fibrosis or increased wall
thickness, typically identified by impaired septal strain on bull’s
eye plots. The sensitivity of myocardial strain imaging may fa-
cilitate diagnosis and management in early stages of HCM [10].
Abnormal strain may also be found in mutation positive family
members before the development of phenotypic HCM (E Fig.
6.2.1, right panel) [10]. GLS is the strongest independent pre-
dictor of ventricular arrhythmias, future heart failure, and all-​
cause mortality in HCM with preserved LVEF7. In later stages
of HCM, LVEF may still be normal although systolic function as
measured by GLS is severely depressed.
Differentiating HCM from other cardiac conditions with in-
creased wall thickness such as athlete’s heart, cardiac amyloidosis,
and Fabry disease is challenging. Normal GLS in an athlete makes
physiological athletic remodelling more likely than underlying
myocardial disease [16]. In cardiac amyloidosis, the basal segmental
predilection site for amyloid deposition may be identified by the
characteristic strain pattern of ‘apical sparing’ reflecting a progres-
sive impairment of longitudinal shortening from the apex to the
basal left ventricular segments (E Fig. 6.2.1, left panel). Apical
sparing is highly sensitive and specific for cardiac amyloidosis while
isolated posterolateral defects are typical of Fabry disease [17].
Cardio-​oncology
GLS holds a central role in recommendations for monitoring of
LV function in patients at risk of cancer therapeutics–​related car-
diac dysfunction (CTRCD). Accurate assessment of LV function
is essential to uncover true cardiotoxicity that influence deci-
sion making regarding cessation of potential lifesaving therapy.
Fig. 6.2.5  Patient with acute myocardial infarction due to occlusion of left anterior descending coronary artery and typical ischaemic longitudinal strain
features in adjacent septal and apical segments, including early systolic lengthening of apical-​septal (green) and apical-​lateral (purple) segments (yellow arrow)
and post-​systolic shortening in mid-​septal (light blue), apical-​septal (green) and apical-​lateral (purple) segments (white arrows) and a non-​uniform reduction of
longitudinal strain (polar map or bull’s eye plot).
I s cha em i c hea rt di se ase 107
Acknowledging GLS as a feasible and accurate tool capable of
CTRCD-​prognostication the ASE/​EACVI consensus statement
has accommodated a relative percentage impairment in GLS of
>15% from baseline as a possible early detection of subclinical
LV dysfunction that might lead to CTRCD [18]. This means that
a reduction in absolute GLS values from 18% at baseline to 15%
is suspicious for subclinical LV dysfunction and very likely to be
of clinical relevance. These patients should therefore have a car-
diology consultation and must be followed closely and regularly
between the therapeutic oncological interventions. It will be im-
portant to acknowledge that the same vendor-​specific ultrasound
machine should be used when applying STE in the longitudinal
follow-​up of patients with cancer. In comparison, CTRCD as-
sessed by LVEF is defined as a decrease of more than 10% to
subnormal reference values (LVEF <53%) in asymptomatic indi-
viduals or a symptomatic decrease of more than 5% in LVEF fol-
lowing cancer treatment, regardless of baseline values.
Ischaemic heart disease
STE is particularly useful in the acute setting of coronary artery
disease (CAD) when LVEF is normal or wall motion abnormal-
ities are not visible. As the subendocardial longitudinally oriented
muscle fibres are vulnerable to ischaemia, early systolic length-
ening, and post-​systolic shortening [19] in adjacent myocardial
segments, or reduced strain corresponding to coronary supply
territories are longitudinal strain features suggestive of ischaemia
(E Fig. 6.2.5). A faster interventional strategy facilitated by
strain imaging in myocardial infarction where ECG is not sensi-
tive enough to detect coronary occlusion has been demonstrated
to be beneficial [20]. Furthermore, GLS has been shown to be
better than LVEF in prediction of all-​cause mortality and infarct
size after myocardial infarction [21].
108 CHAPTER 6   N ew devel opments in ech o ca rdi o g r a phy /A dva n ced echo ca rdi o g r a phy

STE assessment of regional myocardial function
STE assessment of longitudinal strain provides additional in-
formation regarding heterogeneity and timing of ventricular
contraction beyond regional myocardial function. However, the
assessment of regional function [22] has lower reproducibility
than GLS and must be used with caution. Experienced operators
can delineate the typical, dyssynchronous STE contraction pat-
tern of LBBB activation (E Fig. 6.2.1, middle panel), while in-
formation regarding more subtle mechanical dyssynchrony can
be obtained by STE assessment of the time course of segmental
strain. Mechanical dispersion, the intersegmental variability of
contraction duration, reflects subtle contraction heterogeneity
that might be related to myocardial fibrosis [23] and possibly also
to electrophysiological heterogeneity (E Fig. 6.2.1, right panel).
STE assessment of right ventricular
function
The complex RV geometry only allows 2D STE assessment of
longitudinal function. Nevertheless, RV longitudinal strain
seems to offer a more sensitive and accurate assessment of RV
function than the conventionally used tricuspid annular plane
systolic excursion (TAPSE), tissue Doppler derived tricuspid an-
nular systolic velocity, or the fractional area change [24]. Current
recommendations suggest that RV longitudinal strain is assessed
in the RV free wall from base to apex visualized in the focused
RV chamber view [1, 3]. Furthermore, a RV free wall strain worse
than—​20% is likely to be abnormal. Although RV 2D strain has
potential as a valid tool in the diagnosis of RV systolic dysfunc-
tion, standardization efforts, and dedicated software are still
awaited.
STE assessment of atrial function
The left atrium is a reservoir for pulmonary venous return during
LV systole and a conduit for the subsequent early diastolic LV
filling that occurs prior to the onset of late diastolic atrial con-
traction. Left atrial (LA) longitudinal strain is calculated as the
longitudinal strain obtained from a non-​foreshortened apical
four-​chamber view and reported separately for the reservoir, con-
duit, and contraction phase [20] (E Fig. 6.2.2). The use of the
QRS complex (R-​R gating) as the initiation of the strain calcu-
lation is recommended, as all strain values will be positive and
the two peaks of the strain curves correspond to reservoir and
atrial contractile function, respectively (E Fig. 6.2.2, left panel).
LA reservoir strain is the best validated parameter and decreases
significantly with more severe diastolic dysfunction. Although
promising for future diastolic evaluation, further validation of
atrial strain is needed [2, 3].

Fig. 6.2.6  Assessment of left atrial strains.

Left panel: The recommended R-​R gated atrial strain protocol using the QRS complex as the initiation of the strain curve results in positive strains for reservoir
and atrial contractile function. The difference between reservoir strain and atrial contractile strain corresponds to left atrial conduit function. Right panel: P-​P
gated strain protocol included for comparison. A = late diastolic mitral flow velocity; Ctr = atrial contraction phase; ε = strain; E = early diastolic mitral inflow
velocity; MVC = mitral valve closure; MVO = mitral valve opening.

References
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standard for 2D speckle tracking echocardiography: consensus
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formation imaging. Eur Heart J Cardiovasc Imaging 2015; 16: 1–​11.
2. Yang H, Marwick TH, Fukuda N, Oe H, Saito M, Thomas JD, Negishi
K. Improvement in strain concordance between two major vendors
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3. Galderisi M, Cosyns B, Edvardsen T, et al. EACVI Scientific
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4. Badano LP, Kolias TJ, Muraru D, et al. Standardization of left atrial,
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dimensional speckle tracking echocardiography: a consensus
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deformation imaging. Eur Heart J Cardiovasc Imaging 2018; 19:
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Contents
Introduction  111
Contrast agents  111
Physical principles of contrast
echocardiography  112
Contrast-​specific imaging modalities  112
Left ventricular opacification  113
Left ventricular volumes and ejection
fraction  113
Regional wall motion assessment and stress
echocardiography  114
Safety of ultrasound contrast agents  115
Cost-​effectiveness of ultrasound contrast
agents  115
Limitations of contrast echocardiography
for left ventricular opacification  116
Myocardial contrast echocardiography  116
Physical principles of myocardial contrast
echocardiography  116
Assessment of myocardial blood flow and
coronary flow reserve  117
Stress testing with myocardial contrast
echocardiography  117
Detection of coronary artery disease  117
Assessment of myocardial viability  118
Assessment of cardiac masses  118
Limitations of myocardial contrast
echocardiography  118
Future perspectives  118
Conclusion  118
CHAPTER 7
Contrast echocardiography
Roxy Senior, Harald Becher, Fausto J. Pinto,
and Rajdeep S. Khattar
Introduction
Despite the advances in two-​dimensional image quality with high resolution ultra-
sound transducers and use of harmonic imaging, a significant minority of patients
have suboptimal echocardiographic images. Moreover, the need for very good left
ventricular (LV) endocardial definition is vital in stress echocardiography, but the
visualization of all LV segments is not possible in up to a third of patients. These
limitations have prompted the development of ultrasound contrast agents to enhance
LV endocardial border definition. Since the 1990s, stabilized microbubble ultrasound
contrast agents have been developed which can pass through the pulmonary circu-
lation intact. This has been coupled with modifications in ultrasound technology to
better visualize the microbubbles in the LV cavity and myocardium with standard
ultrasound equipment [1]‌. Consequently, over the last two decades, a large evidence
base has evolved along with published guidelines for the use of contrast agents in a
variety of settings [2–​4].
Contrast agents
The current generation of ultrasound contrast agents consists of acoustically-​active gas
filled microspheres which are designed to increase the signal strength of ultrasound
waves [5–​7]. The microbubbles are smaller than the capillaries in the lungs allowing
transit from the venous to the arterial side of the circulation by intravenous injection.
The microbubbles are composed of a high molecular weight gas encapsulated by an outer
shell. To prevent dissolution of the microbubble, a low solubility, high molecular weight
gas is used, and the compressibility of the gas enables the microbubbles to be efficient
acoustic reflectors. The composition of the outer shell determines the stability of the
microbubble and the shell is coated with a biocompatible surfactant to minimize reac-
tion. As the microbubbles remain intravascular at all times, they act as red blood cell
tracers.
The three contrast agents currently approved for clinical use are Sonovue, Luminity,
and Optison [5–​7] (E Table 7.1). The most widely used contrast agent in Europe is
Sonovue, followed by Optison and Luminity. In the USA, Sonovue is marketed as
Lumason, and Luminity as Definity. These contrast agents are administered intraven-
ously either by bolus injection or continuous infusion. A slow bolus injection of 0.2–​
0.5 ml of ultrasound contrast is usually sufficient to obtain images of LV structure and
function in the standard views. A continuous infusion is sometimes preferred in more
112 CHAPTER 7   C on trast ech o cardio graph y

Table 7.1  Characteristics of commercially available ultrasound contrast agents

SONOVUE/​LUMASON LUMINITY/​DEFINITY OPTISON

Gas Sulphur hexafluoride Perfluoropropane Perfluoropropane
Shell Lipid/​surfactant Lipid/​surfactant Albumin
Size 2.5 um 1.1–​3.3 um 3–​4.5 um
Manufacturer Bracco Diagnostics Lantheus Medical Imaging GE Healthcare

challenging cases to provide stable conditions for image acquisi-
tion or to assess myocardial perfusion.
Physical principles of contrast
echocardiography
In order to properly perform and interpret a contrast echo study,
it is important to understand the physical interactions between
ultrasound, myocardial tissue, and contrast agents [1, 8]. The fre-
quency at which sound waves leave the transducer is known as the
incident or fundamental frequency. Myocardial tissue is capable
of reflecting an equal and opposite frequency and this is known
as a linear response. Consequently, standard 2D imaging origin-
ally involved the ultrasound receiver transmitting and receiving
ultrasound impulses of the same frequency, known as funda-
mental imaging. However, ultrasound waves become distorted on
passing through the body as they encounter tissues of differing
composition and density. This may change the waveform and gen-
erate frequencies different from the incident frequency. These are
harmonic frequencies and include subharmonic, ultraharmonic,
and multiples of the fundamental frequency (E Fig. 7.1). The
strongest harmonic signals are multiples of the fundamental fre-
quency. A non-​linear response is one in which a structure reflects
different frequencies to the incident frequency. When an ultra-
sound wave encounters a microbubble, it alternately compresses
the microbubble on the positive pressure, and expands it on the
negative pressure (E Fig. 7.2). During the expansion phase, a
microbubble’s radius can increase by as much as several hundred
percent. During the contraction phase, a microbubble’s radius is
limited by the gas inside the bubble, making it less compressible.
This results in an asymmetric-​nonlinear microbubble oscillation.
Instead of producing a sinusoidal echo with a clean frequency
spectrum like the transmitted signal, it produces an asymmetric
waveform which can be utilized to enhance the signals from the
microbubbles and effectively distinguish them from the sur-
rounding tissue.
Contrast-​specific imaging modalities
Harmonic imaging was originally introduced to enhance the de-
tection of ultrasound contrast agents because of the non-​linear
scattering properties of microbubbles. However, harmonic
imaging was also found to enhance imaging of the myocardium
as myocardial tissue has both linear and non-​linear properties.

6 MHz

3 MHz 6 MHz

3 MHz 0 Fundamental
3 MHz
6 MHz 6 MHz
−10
Sub harmonic 2nd harmonic
Power (Db)

−20
3 MHz Ultra harmonic
−30

−40

−50
1 2 3 4 5 6
−60
Frequency/MHz

Fig. 7.1  Harmonic imaging. The transducer transmits ultrasound waves of a given fundamental frequency (3 MHz) and receives signals of varying frequencies
caused by a non-​linear response from the tissues and ultrasound microbubbles. These are harmonic frequencies and include subharmonic, ultraharmonic,
and multiples of the fundamental frequency. Ultrasound microbubbles produce a greater non-​linear response than the myocardium and the strongest of the
harmonic frequencies are multiples of the fundamental frequency.

(a) (b) (c)
Fig. 7.2  (a–​e) Changes in volume of a lipid shell microbubble during exposure to ultrasound waves, with compression during high pressure and expansion
during low pressure phases.
Courtesy of N De Jong, Erasmus University.
Nevertheless, microbubbles have greater non-​linearity than myo-
cardial tissue and by virtue of this difference, a number of tech-
niques have been developed to help distinguish microbubbles
from the surrounding tissue [1, 2].
Tissues and microbubbles differ in behaviour depending
upon the power of the ultrasound signal emitted. The mechan-
ical index (MI) is a measure of the power generated by an ultra-
sound transducer within an acoustic field. Harmonic imaging
of the myocardium requires a relatively high MI of >0.8 and so
standard non-​contrast 2D imaging is performed at these settings.
For contrast imaging, the higher the MI above 0.5, the greater the
likelihood of microbubble disruption. Consequently, real-​time
imaging of contrast requires an intermediate to low MI to main-
tain microbubble integrity. Moreover, because microbubbles have
greater non-​linearity than the myocardium, visualization of con-
trast remains good at these lower ultrasound intensities, whereas
tissue harmonics are reduced. Therefore, at a low MI setting,
the contrast-​to-​tissue ratio is higher than at high MI and using
more contrast-​specific imaging modalities, this helps to elim-
inate the tissue signal. These imaging modalities include power
pulse inversion, power modulation and cadence (or coherent)
contrast imaging [2]‌. These techniques use ultrasound cancel-
lation techniques that rely on the fact that, at low ultrasound
energy levels, myocardial tissue has essentially linear whereas
microbubbles have non-​ linear ultrasound scattering proper-
ties. When using these imaging modalities, the linear reflections
from the myocardium are effectively suppressed and the image is
(a) (b)
L eft ven tri cu l a r opac i f i c at i on 113
(d) (e)
completely dark, until contrast is administered. The appearance
of contrast then provides very effective LV endocardial border en-
hancement, as it demonstrates a sharp demarcation between the
contrast-​enhanced cavity and the dark myocardium. At an MI of
about 0.1 or below, the microbubbles are minimally destroyed,
yet give a good contrast signal compared to MI >0.2 where con-
trast is typically destroyed at the apex causing a swirling effect.
Contrast-​specific imaging modalities should be applied in accord-
ance with current American Society of Echocardiography (ASE)
and European Association of Cardiovascular Imaging (EACVI)
recommendations  [2–​4].
Left ventricular opacification
Left ventricular volumes and ejection fraction
Although harmonic imaging has improved 2D image quality, a
significant proportion of studies do not have adequate images
of all segments of the LV myocardium. The proportion of sub-
optimal studies depends on the population studied and the most
challenging patients include those with morbid obesity, chronic
lung disease, and in the intensive care setting. Under these cir-
cumstances, the efficacy of ultrasound contrast agents in enhan-
cing LV endocardial border definition has been well established
(E Fig. 7.3), and guidelines recommend the use of contrast when
two or more contiguous LV segments are not adequately visual-
ized on standard imaging [3, 4] (E Box 7.1).
Fig. 7.3  (a) Standard non-​enhanced apical four-​
chamber view with poor endocardial views of the
apex and lateral wall. (b) Contrast-​enhanced images
clearly delineating all LV endocardial borders.
114 CHAPTER 7   C on trast ech o cardio graph y
Box 7.1  Indications for contrast echocardiography
◆ When two or more contiguous LV segments are not clearly
visualized
When clinical management depends on accurate measure-
◆
ments of left ventricular ejection fraction (LVEF), irrespective
of image quality
When apical pathology is suspected but non-​contrast images
◆
are suboptimal
For perfusion assessment of cardiac masses
◆
During TOE for exclusion of left atrial appendage thrombus
◆
when non-​contrast images are inconclusive
Delineation of aortic pathology when non-​contrast images
◆
are suboptimal
During thoracic endovascular aortic repair procedures when
◆
non-​contrast images are suboptimal
During stress echocardiography when two or more con-
◆
tiguous segments are not visualized for assessment of
wall motion
Assessment of myocardial perfusion in patients undergoing
◆
dobutamine or vasodilator stress echocardiography or in high
risk patients undergoing physiological stress for improved
diagnosis and risk stratification of CAD
Contrast echocardiography improves the evaluation of LV
function providing more accurate and reproducible meas-
urements of volumes and ejection fraction (EF). In multiple
comparative studies, EF measurements derived from 2D con-
trast echocardiography and non-​ contrast echocardiography
were similar to reference methods, but the interobserver and
intraobserver variabilities of contrast echocardiography were
superior to non-​contrast echocardiography, and similar to car-
diac magnetic resonance imaging [9, 10]. The superior repro-
ducibility of 2D contrast echocardiography becomes important
when clinical management depends on accurate measurements
of EF, for example, in those receiving anticancer drug therapies
or in those under consideration for potentially life-​saving but
expensive device therapies. Notably, LV measurements derived
from contrast echocardiography tend to be higher than those
measured from non-​enhanced images due to better tracking
of the endocardial surface of the true compacted myocardium.
In the recent recommendations for chamber quantification,
normal values of EF and LV volumes were given for conven-
tional echocardiography but not for contrast echocardiography
[11]. Nevertheless, for contrast echocardiographic studies, it
would be reasonable to apply the same normal values of EF,
but not for LV volumes. With regard to 3D echocardiography,
limited single-​centre studies suggest an improved accuracy
of EF measurements with contrast, but the data are incon-
sistent and interobserver variability may be increased [3, 4].
More studies are needed to establish the role of 3D contrast
echocardiography.
Regional wall motion assessment and stress
echocardiography
The use of contrast agents is also beneficial in the assessment
of regional wall motion, improving the accuracy of detection
of abnormalities and reducing interobserver variability. In
stress echocardiography, contrast agents have been shown to
improve visualization of regional wall motion abnormalities,
enhance diagnostic accuracy of the test, reduce interobserver
variability of interpretation, and increase reader confidence
in study interpretation [12–​14]. Moreover, the use of contrast
improves the ability of obtaining a diagnostic test, with a feasi-
bility of 96% even in those with morbid obesity [15]. The high
feasibility of a diagnostic test results in reduced downstream
costs. In a study of patients with troponin-​negative acute
chest pain, it has been estimated that by reducing the need
for further investigation and enabling rapid discharge from
hospital, contrast enhancement of suboptimal images during
stress echocardiography could result in a saving of $238 per
patient [16].
Assessment of left ventricular structure and
cardiac masses
Contrast echocardiography is particularly useful for delin-
eating apical pathology because standard tissue harmonic
imaging is unable to overcome the noise, clutter, and reverber-
ation artefacts in the near field. The use of contrast echocardi-
ography to exclude or detect apical thrombus when standard
echocardiography is inconclusive is a common indication
for the test and the benefit of contrast echocardiography in
this setting has been well demonstrated (E Fig. 7.4a) [17,
18]. The technique is also helpful for detecting other apical
pathology such as LV non-​compaction (E Fig. 7.4b), hyper-
trophic cardiomyopathy (E Fig. 7.4c), myocardial rupture, or
LV pseudoaneurysm. The use of myocardial contrast echocar-
diography (MCE) to differentiate thrombus from a vascular
mass is discussed next.
Other indications
Contrast echocardiography may play a role in the detection
of aortic diseases such as dissection, thrombus formation,
and focal aneurysms or pseudoaneurysms, particularly when
standard images are suboptimal or raise the suspicion of disease
[19, 20]. The use of contrast-​enhanced transoesophageal echo-
cardiography may improve the detection of leaks in patients
undergoing thoracic endovascular aortic repair procedures
[21]. Transoesophageal echocardiography is often indicated for
exclusion of left atrial appendage thrombus. Ultrasound con-
trast agents may be considered when standard images are in-
conclusive [22], but contrast-​specific imaging modalities are not
available on several transoesophageal echocardiography (TOE)
probes and more fundamentally, differentiation from myocar-
dial trabeculations within the left atrial appendage cavity may
be difficult.
 C o st- effecti ven es s of u ltr as ou n d c on tr ast   ag e n ts 115

(a) (b) (c)

Fig. 7.4  Examples of pathological findings with contrast echocardiography (non-​contrast images on the upper panel and contrast-​enhanced images on the
lower panel). (a) Upper panel shows very poor echocardiographic images of a patient in the intense care unit following presentation with chest pain and an
embolic phenomenon to the left arm. Contrast enhancement shows a left ventricular apical thrombus (arrow) and a thin and akinetic apex and lateral wall in
mid-​systole. (b) Unenhanced and contrast-​enhanced images of the left ventricle of a young woman who presented with acute heart failure. The contrast images
confirm marked trabeculation and a thin lateral wall and apex (arrows) consistent with non-​compaction. (c) Inadequate views of the apex on standard harmonic
imaging in a middle-​aged man with an ECG showing lateral T wave inversion. The contrast images show a hypertrophied apex (arrow) consistent with apical
hypertrophic cardiomyopathy.

Safety of ultrasound contrast Cost-​effectiveness of ultrasound

agents
Side effects to ultrasound contrast agents are extremely rare, but
when they occur are usually mild and transient. Serious allergic
reactions have been reported with an incidence of approxi-
mately 1 in 10,000 cases. Absolute contra-​indications for the ad-
ministration of contrast agents include known hypersensitivity
to the agent, bidirectional, or right to left intracardiac shunting
and adult respiratory distress syndrome. Despite initial con-
cerns, contrast agents have been shown to be safe in pulmonary
hypertension [23]. Contrast agents should be used with cau-
tion in patients with cardiovascular haemodynamic instability.
Intracoronary administration of contrast is not approved, but
has been reported widely in guiding alcohol septal ablation in
patients with hypertrophic cardiomyopathy and LV outflow
tract obstruction. The safety of ultrasound contrast agents has
not been established in children.
contrast agents
Many studies have evaluated the cost-​effectiveness of using ultra-
sound contrast agents in patients with technically inadequate
echocardiographic images both for resting and stress echocardi-
ography. The use of contrast agents has been shown to enhance
decision-​making, shorten time to diagnosis, and improve work-
flow by reducing the time needed to image patients with difficult
acoustic windows. Kurt et al. performed a comprehensive study
on the impact of contrast echocardiography on clinical manage-
ment in 623 patients with technically difficult echocardiographic
studies [24]. Contrast echocardiography reduced the number of
technically difficult studies from 86.7% to 9.8%, and uninterpret-
able studies from 11.7% to 0.3%. The number of LV segments
visualized with contrast improved from 11.6 to 16.8 and exclusion
of thrombus was vastly improved. Additional diagnostic proced-
ures were avoided in one-​third of patients and drug management
116 CHAPTER 7   C on trast ech o cardio graph y
was altered in 10% of patients, with an estimated cost saving of
$122 per patient. The use of contrast is also highly feasible and
cost-​effective when used in conjunction with stress echocardiog-
raphy, reducing the number of non-​diagnostic tests, improving
risk stratification, and reducing downstream costs [25, 26].
Limitations of contrast
echocardiography for left
ventricular opacification
Contrast echocardiography may be associated with a number
of artefacts that can be overcome by simple manoeuvres when
properly recognized. When contrast is injected, the initial high
volume of microbubbles in the near field may lead to attenuation
in the deeper part of the imaging sector. This can be overcome
by delaying image acquisition for 20–​30 seconds. Blooming
artefacts refer to a lack of differentiation between the LV cavity
and the myocardium due to an intense concentration of contrast
or an inappropriately high gain setting early after injection. This
type of artefact can be resolved by delaying image acquisition
until the contrast is more evenly distributed in the cavity and
then adjusting the gain setting to obtain a sharp demarcation
of the endocardial border. Swirling of contrast may occur in the
apex resulting from excessive microbubble destruction or too
low a dose of contrast; administering more contrast is an easy
solution.
The additional cost of contrast may deter its use in many
echo labs, but subsequent cost savings have been well dem-
onstrated. However, contrast agents remain underutilized
primarily for logistical reasons. Important factors that might
increase the uptake of contrast agents include structured
training in contrast echocardiography, intravenous cannula-
tion training for sonographers and cardiologist support within
the echo lab [27].
ECG
Flash
End-systolic triggered imaging
Fig. 7.5  Myocardial contrast echocardiography with end-​systolic triggered imaging. After flash bubble destruction, the uptake of microbubbles in the
myocardium is imaged as snapshots in end-​systole when the myocardium is at its thickest. The temporal appearance of microbubbles can be assessed in a
region of interest in the myocardium to provide a quantitative assessment of myocardial blood flow (modified from reference 1).
Source data from Contrast echocardiography toolbox. http://​www.escardio.org/​Guidelines-​&-​Education/​Practice-​tools/​EACVI-​toolboxes/​Contrast-​Echo/​
Contrast-​Echocardiography-​Box.
Myocardial contrast
echocardiography
After transit through the LV cavity, microbubbles enter the
epicardial coronary arteries and coronary microcirculation.
MCE uses the best available imaging settings to visualize the
microbubbles within the myocardium and thereby assess myo-
cardial perfusion [1]‌.
Physical principles of myocardial contrast
echocardiography
As discussed earlier, high MI contrast imaging leads to early de-
struction of microbubbles and therefore does not permit con-
tinuous real-​time imaging. Real-​time imaging uses a very low
MI generating sufficient signal from microbubbles, minimizing
microbubble destruction, and suppressing myocardial tissue
[1]‌. Microbubbles can be intentionally destroyed by a ‘flash’ of
high MI ultrasound pulses and contrast replenishment within
the myocardium may then be observed at a low MI to allow
qualitative and quantitative assessment of myocardial perfusion
(E Fig. 7.5). The two biggest advantages of this method are
firstly that real-​time assessment of both wall motion and per-
fusion are possible and secondly, since there is less microbubble
destruction, a smaller amount of contrast is used. Whereas
bolus injections of ultrasound contrast are good enough for LV
opacification, a steady-​state concentration of microbubbles is
needed for the assessment of myocardial perfusion, and so a con-
tinuous infusion is required.
By the use of triggered imaging, myocardial perfusion may also
be assessed separately from wall motion. End-​systolic triggering
is preferred firstly because the myocardium is at its thickest in
systole and thus the area of interest is largest at this time point.
Secondly, arterioles and venules are maximally compressed, so
one is predominantly imaging microbubble uptake by capillaries,
and finally there is a reduced incidence of artefacts.
β  microbubble velocity
Peak value, A
Video
Intensity
Time
Myocardial blood flow = A × β

Assessment of myocardial blood flow and
coronary flow reserve
The myocardial vasculature comprises only 12% of the
myocardium. Therefore, myocardial opacification is less intense
than cavity opacification, providing excellent differentiation be-
tween the two for endocardial delineation. Approximately 90%
of myocardial blood volume resides within the capillaries and so
myocardial perfusion is defined as tissue blood flow at capillary
level. Its two components are capillary blood volume and red
blood cell velocity. When the entire myocardium is fully satur-
ated during a continuous infusion of microbubbles, the signal
intensity denotes the capillary blood volume [28]. Following
destruction of microbubbles with a flash of high-​ power
imaging, the rate of replenishment of microbubbles within the
myocardium represents blood velocity. The product of peak
microbubble intensity (myocardial blood volume) and their rate
of appearance (blood velocity) equates to myocardial blood flow
[29]. If a graph is drawn plotting contrast video intensity against
time, an exponential curve is obtained. Mathematical analysis
reveals that the plateau represents the peak myocardial blood
volume (denoted A) and the initial slope of the curve is the
microbubble velocity (denoted β). A × β then gives myocardial
blood flow (E Fig. 7.5).
Myocardial blood flow can be calculated at rest and stress, and
the ratio represents coronary flow reserve (CFR). It has been
shown that MCE-​derived CFR is very similar to that derived from
positron emission tomography [30]. Changes in CFR can assess
both the presence and severity of coronary artery disease (CAD)
and can also be used in various other conditions. Contrast agents
can also be used to enhance pulsed wave Doppler signals of the
left anterior descending artery in the evaluation of CFR during
vasodilator stress [31].
Stress testing with myocardial contrast
echocardiography
Stress testing with contrast for myocardial perfusion can be
performed by either exercise or pharmacological methods in a
similar manner to stress echocardiography. For the assessment of
myocardial perfusion, pure arterial vasodilators (dipyridamole,
(a) (b) (c)
Fig. 7.6  Assessment of myocardial ischaemia with treadmill exercise and myocardial contrast echocardiography using triggered imaging in end-​systole. (a)
shows normal perfusion during a steady-​state continuous infusion of ultrasound contrast microbubbles immediately after exercise. (b) shows the delivery of
a high energy impulse (flash) which destroys the microbubbles in the myocardium as shown in (c). Replenishment of microbubbles within the myocardium
is then observed over subsequent cardiac cycles (d–​f ). Uptake of microbubbles in the apex and distal lateral wall is delayed (d) but fills in subsequent cardiac
cycles (e, f) indicating reversible ischaemia in this region.
M yo ca rdia l c on tr ast echo ca rdi o g r a ph y 117
adenosine or regadenoson) are preferred. However, MCE may
also be performed with dobutamine or even exercise.
The interpretation of MCE images requires an understanding
of coronary pathophysiology and ultrasound imaging of con-
trast [1]‌. Microbubbles flow through capillaries at a rate of ap-
proximately 1 mm/​sec. The ‘elevation’ or depth of an ultrasound
beam from a conventional transducer is 5 mm. At a speed of 1
mm/​sec, this means that approximately 5 seconds are required
for the entire ultrasound beam to fill with microbubbles after
high MI-​impulse destruction. With a resting heart rate of 60–​
80 bpm, approximately one cardiac cycle per second, it would
therefore take five cycles for the microbubbles to fill the imaged
myocardium. A healthy individual should be able to increase
resting myocardial blood flow up to 4–​5 times normal at peak
hyperaemia, increasing the speed of microbubbles to about 5
mm/​sec, meaning that they would replenish the ultrasound
beam width in one second (as opposed to the 5 seconds at rest).
If a vasodilator is used for stress, there is little change in heart
rate, so that one second represents one cycle, and so complete
microbubble replenishment should occur within one cycle.
However, if exercise or dobutamine are used, the heart rate
will have increased to over 120 bpm depending on target heart
rate, meaning that there are now at least two cardiac cycles per
second, so one would allow 2–​3 cardiac cycles to see complete
bubble replenishment.
Detection of coronary artery disease
The delayed appearance of contrast with reduced contrast inten-
sity during stress is the hallmark of flow-​limiting CAD in MCE
(E Fig. 7.6) [28]. The diagnostic accuracy of MCE is similar
whether using vasodilator agents, inotropic agents, or exercise,
approximating to sensitivities of 83–​88%, and specificities of
77–​79% [4]‌. A meta-​analysis of eight studies and two recent
large, multicentre trials comparing the diagnostic efficacy of
MCE versus single-​photon emission computerized tomography
(SPECT) imaging have shown higher sensitivity of MCE for the
detection of CAD, but lower specificity than SPECT [32]. The
higher sensitivity may reflect the ability to detect reductions in
myocardial blood velocity and not just myocardial blood volume,
along with better spatial resolution than SPECT imaging. The
(d) (e) (f)
118 CHAPTER 7   C on trast ech o cardio graph y
lower specificity may be due to the detection of abnormalities re-
lated to microvascular disease and imaging artefacts.
The simultaneous assessment of wall motion and perfusion by
MCE during stress echocardiography has been shown to improve
the sensitivity for the detection of CAD over regional wall mo-
tion analysis alone [4]‌. A large body of evidence shows that this
translates into a better prediction of clinical outcome [33, 34] and
that this can be reproduced in a day-​to-​day clinical stress echo
service [35].
The detection of an acute coronary syndrome may be improved
by using MCE over and above the triad of clinical data, electro-
cardiographic (ECG), and cardiac biomarkers allowing the rapid
and simultaneous evaluation of wall motion and perfusion at the
bedside [36]. Studies have shown that resting and stress myo-
cardial perfusion and function with MCE provide incremental
prognostic information in patients with a suspected acute cor-
onary syndrome [37]. Normal function and perfusion confer an
excellent clinical outcome [38]. Based on this evidence, EACVI
guidelines recommend the use of MCE in all patients referred for
dobutamine or vasodilator stress echocardiography, and high risk
patients undergoing exercise echocardiography.
Assessment of myocardial viability
Low-​ dose dobutamine echocardiography is an established
technique for the detection of myocardial viability in patients
with LV dysfunction due to CAD with a sensitivity of 80% and
specificity of 78%. The contractile response to dobutamine de-
pends on an intact microvascular circulation and myocardial
blood flow reserve. However, MCE needs merely to demon-
strate microvascular integrity and so may be more sensitive for
detecting myocardial viability in dobutamine non-​responsive
myocardium. From a total of 10 studies, MCE has a sensitivity
of 87% and specificity of 50% [39] similar to nuclear techniques
for predicting the recovery of contractile function following
revascularization.
Assessment of cardiac masses
Intracardiac thrombus may be difficult to distinguish from car-
diac tumours particularly when adjoining normally contracting
myocardium. Under these circumstances, the use of MCE to
assess perfusion within the mass may be helpful [18]. The pres-
ence of significant vascularity would point to a cardiac tumour,
whereas the absence of perfusion would make thrombus more
likely, albeit not completely exclude an avascular tumour.
Limitations of myocardial contrast
echocardiography
MCE has a number of limitations that have prevented its more
widespread use. Obtaining images of good diagnostic quality
requires a good understanding of the interaction between
microbubbles and ultrasound with a command of the correct
machine settings. The contrast infusion rate, gain adjustments,
and flash settings need to be optimized for each individual
patient making the procedure more technically challenging.
Variation in microbubble concentration and lack of uniformity
of ultrasound power in the area of interest may influence the
contrast intensity. The latter may be reduced at the basal seg-
ments of the LV because ultrasound power is weakest in the far
field, thereby giving rise to false perfusion defects. In the near
field false perfusion defects may occur for the opposite reason
as ultrasound power is strongest at the apex leading to greater
destruction of microbubbles in this region. Despite these chal-
lenges, with appropriate training, diagnostic images are feas-
ible in the vast majority of patients with good reproducibility of
interpretation [40].
Future perspectives
Despite the large body of evidence for contrast echocardiography,
the technique remains underutilized for many reasons including
inadequate knowledge of contrast use, lack of structured training
for administering contrast, lack of availability of personnel for
intravenous cannulation, time pressure, inadequate medical
supervision, perceived safety concerns, and cost implications.
These issues need to be addressed by greater advocacy for the use
of contrast by senior clinical personnel, more attention to logis-
tical considerations in daily practice and an emphasis on the cost
benefit of using contrast.
Whereas high quality contrast studies for LV opacification are
relatively simple to perform, myocardial perfusion assessment re-
quires a higher level of technical expertise. Further refinements
are needed to improve image quality, reduce artefacts and study
whether techniques for bolus injection can be developed to re-
duce the time and cost of perfusion studies. Further research is
also needed to develop the use of contrast agents in 3D echocar-
diography and strain imaging.
Conclusion
Refinements in ultrasound contrast agents and advances in ultra-
sound technology have enabled contrast echocardiography to be-
come a routinely used technique for improving the assessment
of LV structure and function in those with suboptimal images.
The use of contrast agents provides more reliable measurements
of LV volumes and EF, with improved interpretation of regional
wall motion and better delineation of structural abnormalities.
When used in stress echocardiography, contrast agents improve
the feasibility and reader interpretation of the test. This leads to
enhanced decision-​making, shortened time to diagnosis, and re-
duced downstream costs from alternative tests. Over two decades
of experience has reaffirmed the safety of contrast agents with ex-
panding indications for their use. Finally, a bedside assessment
of regional wall motion and myocardial perfusion may be made
simultaneously in the evaluation of myocardial ischaemia and
viability during stress echocardiography.

Further reading
European Society of Cardiology (ESC). EACVI Contrast
Echocardiography Imaging Toolkit. Available from: https://​www.
escardio.org/​Education/​Practice-​Tools/​EACVI-​toolboxes/​Contrast-​
Echo/​Contrast-​Echocardiography-​Box
Porter TR, Abdelmoneim S, Belcik JT, et al. Guidelines for the cardiac
sonographer in the performance of contrast echocardiography: a
focused update from the American Society of Echocardiography. J Am
Soc Echocardiogr 2014; 27: 797–​810.
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Echo/​Contrast-​Echocardiography-​Box
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 CHAPTER 8

Echocardiography in the
cath lab: Fusion imaging
and use of intracardiac
echocardiography
Covadonga Fernández-​Golfín and
José Luis Zamorano

Contents Introduction
Introduction  121
Fusion imaging  121 Percutaneous treatment of different structural heart disease has experienced enormous
Echocardiography–​fluoroscopy fusion growth in recent years, as the complexity of lesions and clinical profile of the patients
imaging  121
Transcatheter aortic valve replacement  123 treated continually increase. Imaging plays a key role in this scenario with expanding
Transeptal puncture  124 applications and requirements, both in procedural planning, during the procedure, and
Left atrial appendage closure  124 in the follow up.
MitraClip procedure  125
Paravalvular leak closure  125 Echocardiography, both two-​dimensional and three-​dimensional (2D and 3D), is the
Intracardiac echocardiography  125 imaging modality most used to guide these interventions since it is fast, accessible, and
Future perspectives  127 provides real-​time detailed anatomic information of the different structures from different
Conclusions  127 views. In most cases transoesophageal echocardiography (TEE) is used, but in some centres
and depending on the type of procedure, intracardiac echocardiography (IE) may be used
as well. However, fluoroscopy is still needed. Interventionalists are used to working with
fluoroscopy where they feel comfortable and safe during the procedures. Moreover, cath-
eters and wires as well as calcified structures or previous implanted devices are best visu-
alized with fluoroscopy imaging, due to its excellent temporal resolution. For this reason
procedures rely on both imaging techniques, which complement each other.

Fusion imaging
Fusion imaging is defined as the combination of two imaging modalities that result in a
single unique image, which provides incremental diagnosis information. Taking into
account the strengths and weakness of the different imaging modalities to guide interven-
tional procedures, fusion technology has emerged as an attractive alternative in the cath lab
to achieve safer and faster procedures with greater operator confidence and higher success
rate [1–​6]. At the moment, there are two fusion-​imaging modalities available in the cath
lab: echocardiography–​fluoroscopy fusion imaging and computed-​tomography fluoroscopy
imaging. In the present chapter, we will focus on echocardiography-​based fusion technology.

Echocardiography–​fluoroscopy fusion imaging

This type of fusion imaging combines live X-​ray and live echo images in a single image.
The system is able to co-​register ‘live’ 2D/​3D echocardiography and X-​ray images by
122 CHAPTER 8   Fusion imaging and u se of in tr aca rdiac echo ca rdi o g r a phy
Fig. 8.1  EchoNavigator screen with the four
possible views. Upper left free echo free view,
upper right echo view, bottom left echo C-​arm
view and bottom right X-​ray view. Both free view
and C-​arm view have cropping tools that can be
used inside the cath lab by the interventionalist.
the automated localization of the TEE probe in the fluoroscopic
field with a two-​step process. The first step consists of the de-
tection of the probe by an algorithm that scans the entire X-​ray
frame for the presence of a TEE probe, using a technique based
on the edge models of the object of interest. The second step is the
tracking phase, when the position of the probe is continuously
updated. Obtained images can be shown on the same display, in
up to four views. The echo view shows the ultrasonography im-
ages that can only be manipulated by the echocardiographer; the
free view also displays echocardiographic images that can be ro-
tated, zoomed, or cropped by the echocardiographer or the inter-
ventionists by using a sterile tableside control. The C-​arm view,
with the echocardiography image in the same orientation as the
C-​arm gantry, and the X-​ray view, where the actual fluoroscopic
view is displayed are shown in E Figure 8.1. The TEE probe has
to be central in this view for a correct co-​registration. When the
angulation of the probe and thus the co-​registration is not correct
(as when the echocardiographer moves the probe out of the field),
Fig. 8.2  Mitral paravalvular leak closure
procedure. Right, 3D echo image with markers
positioned in the leak location (two paravalvular
leaks); left, X-​ray image showing markers in the
exact leak position in the mitral prostheses ring.
the fusion is not possible. All changes in position and rotation of
the probe are detected by the system and updated on the fluoro-
scopic view [1–​6].
Once both images are synchronized, different tools are avail-
able. The system also allows the placement of markers in real
time on specific anatomical regions of interest on echocardiog-
raphy images; these markers will be automatically displayed and
updated on the fluoroscopy image in real time and can be used
for guidance during the procedure (E Fig. 8.2). Customization
of the reference markers is possible with colour and labels, so
any desired anatomical landmark needed for a certain procedure
may be identified at the beginning of the procedure, which saves
time and increases operator confidence. Apart from landmark
identification, true fusion imaging is achieved by activation of
the simultaneous echo and X-​ray view (E Fig. 8.3). Both 2D
and 3D images can be added to the fluoroscopic image and be
changed in real time, depending on procedure step. Moreover,
both the intensity and gain of each modality can be adjusted
 Echo ca rdi o g r a phy –flu oro s c op y fu si on i m ag i n g
so the operator can decide on the type of image: more echo or
more fluoroscopy, through adjusting the transparency of the
ultrasound image. In the case of 3D imaging, cropping is also
available and may be used to get the best-​synchronized fusion
image (E Fig. 8.4).
These types of fusion systems overcome the limitations of each
imaging modality used alone. A better understanding and iden-
tification of the different cardiac structures is achieved, allowing
a better communication between interventionalists and imagers.
It may be used in almost every procedure, being of special use in
certain steps as we discuss next.
Transcatheter aortic valve replacement
During a transcatheter aortic valve replacement (TAVI) procedure
fusion imaging enables marking of the aortic annulus, which
helps in identifying where the prosthesis should be deployed.
123
Fig. 8.3  TAVI procedure. Left, fusion image with
X-​ray and 2D echo images superimposed during
TAVI procedure. Right, 3D echo view of the
left ventricular outflow tract during prostheses
implantation.
When using fusion systems, firstly a real-​time 3D image of the
aortic valve is presented in the echocardiography and free real-​
time views. Cropping tools are used to identify the level of the
aortic annulus. X-​plane 2D images can also be used for aortic an-
nulus identification. Once identified, markers in the form of dots
or ellipses can be set at the level of the annulus. Alignment of
the aortic annulus markers enables selection of the fluoroscopy
plane that lies perpendicular to the annulus, where prosthesis de-
ployment should be performed (E Fig. 8.5). The intervention-
ists for prosthesis deployment guidance can therefore use them.
Complete fusion with echocardiography and fluoroscopy image
overlay may be used as well for deployment, with or without an-
nulus markers (E Figs. 8.3 and 8.4). Fusion imaging in TAVI
procedures is especially useful in those cases where aortic valve
calcification is not so extensive, or in those procedures where less
contrast use is warranted.
Fig. 8.4  TAVI procedure. Left, fusion image with
X-​ray and echo images combined in a single view.
Right, 3D echo images. Cropping of the 3D image
in the fusion image is performed to achieve the
best possible fusion image with fluoroscopy.
124 CHAPTER 8   Fusion imaging and u se of in tr aca rdiac echo ca rdi o g r a phy

Fig. 8.5  Markers are positioned at the level of the

aortic annulus in the three aortic cusps in the echo
view (right image). The markers are aligned in the
free echo view (left) to define one of the possible
projections for valve deployment.

Transeptal puncture
Transeptal puncture (TP) is a part of many procedures for the
percutaneous treatment of different structural heart disease [1,
2]. Depending on the procedure, a certain puncture location
in the fossa ovalis is needed and TEE is mandatory to guar-
antee a safe and optimal TP. Fusion image systems are espe-
cially helpful in this part of the procedure. Fusion imaging in
the bicaval view (E Fig. 8.6) enables the operator to directly
visualize and follow the catheter coming down the superior
vena cava until it reaches the fossa ovalis [7–​9]. No fluoro-
scopic anatomical references or extra catheters and contrast
use are needed with this type of guidance. Moreover, a specific
area of the fossa ovalis can be marked so the exact ideal punc-
ture position can be displayed for the interventionalists. Once
the puncture is performed, a marker of the crossing plane in
the septum can be set; so by looking at the fluoro, the operator
knows if the catheter is in the left atrium and how much cath-
eter is inside without having to go back and forth with the echo
image during the procedure.
Left atrial appendage closure
The left atrial appendage is a soft structure that lacks fluoro-
scopic references if contrast is not used. TEE echocardiography
is essential during the procedure, first for the TP and afterwards
for device deployment. Fusion imaging markers can be used to
depict the entrance orifice, landing area, and appendage depth.
Moreover, with echo image overlay, the operator can actually see
the deployment of the device without the need to use contrast,
enabling better manipulation of the device and optimal site im-
plantation (E Fig. 8.7) [10].

Fig. 8.6  Fusion imaging during transseptal

puncture. Left image, fluoro, and echo fusion image
showing superior vena cava, interatrial septum,
and the catheter pointing towards the interatrial
septum. In the right image, the echo view with the
bicaval plane is displayed.

MitraClip procedure
Fusion imaging during the MitraClip procedure is also useful to
monitor TP. Afterwards markers may be used to define a virtual
triangle between the septum, the left upper pulmonary vein, and
the mitral regurgitation, where the clip is going to make its way to
the mitral valve (E Fig. 8.8). Markers can also be used to define
the optimal implantation point along the mitral valve coaptation
line [11].
Paravalvular leak closure
This is probably the procedure where this kind of fusion image is
most important. With the system and using the markers tools, we
are able to locate the leak along the prostheses ring and display
this location for the interventionists in the X-​ray images. With the
reference point the operator is able to better approach the defect
I n tr aca rdiac echo ca rdi o g r a ph y 125
Fig. 8.7  Left atrial appendage closure procedure.
Fusion image on the left shows merging fluoro
with echo and catheter inside the left atrial
appendage. The right image corresponds to the
echo view focused on the left atrial appendage.
with the different wires and catheters, saving time and decreasing
X-​ray exposure and contrast. This is of paramount importance in
those prostheses with radionuclide rings, which make the pro-
cedure and the deployment of the device difficult if these types of
fusion imaging systems are not available (E Fig. 8.9).
Intracardiac echocardiography
Intracardiac ultrasound was first described more than 50 years
ago but it was not until 1991 when the possible application of
guiding interventional procedures was reported. From that time
IE has experienced an initial growth, mainly in the electrophysi-
ology (EP) lab to guide TP and in the cath lab to guide atrial septal
defect procedures. The exponential growth of TEE with techno-
logical developments and the learning curve needed with IE has
Fig. 8.8  MitraClip procedure. The septum, left
pulmonary vein ostium, and mitral regurgitant jet
have been marked and can be seen in the fusion
image (left). The echo view is displayed on the
right, showing a 3D image of the mitral valve with
the two 2D orthogonal planes below.
126 CHAPTER 8   Fusion imaging and u se of in tr aca rdiac echo ca rdi o g r a phy
Fig. 8.9  Paravalvular leak closure procedure. Left
image corresponds to X-​ray image with mitral
prostheses ring marked (ellipse). Leak position
is marked (circle point) as well to guide the
procedure, wire-​crossing through the defect and
device deployment. Right image corresponds to
the echo image (2D colour Doppler image), where
the prostheses annulus and leak position has been
marked.
limited its use in clinical practice [12–​14]. However, it is still an
alternative imaging modality that in experienced hands can be
enough to guide certain procedures. Moreover, interest in IE is
increasing due to the tremendous growth of percutaneous inter-
ventions for structural heart disease that could be guided with
this technology without the need of general anaesthesia.
Two different catheters are available for IE. Rotational catheters
are composed of a single piezoelectric crystal, are not steerable,
and allow only near-​field imaging (up to 5 cm). Phase-​array cath-
eters are composed of 64-​element transducer, are steerable, and
allow a deeper examination field. The catheter can be deflected in
four directions (anterior, posterior, right, and left) and produces
a wedge-​shaped image that is displayed on a conventional ultra-
sound workstation. Even though rotational catheters may be used
for TP in the EP lab with excellent image quality, more complex
structural heart disease interventions require a phase-​array trans-
ducer [12–​14]. No standard recommendations for performing IE
are available as there are with other imaging modalities, where
most cardiac structures involved in the different procedures can
be seen in one or more of the five catheter positions (mid-​right
atrium [RA], low RA, right ventricular inflow, right ventricle [RV]
Fig. 8.10  Intracardiac echocardiography images with the catheter
in the right ventricular inflow. Left atrium (LA), left ventricle (LV),
and septal (IVS) and posterior walls (PW) are seen.
Courtesy of Dr. J. Moreno.
outflow, and left atrium). From the mid-​RA position, an excellent
visualization of the tricuspid valve, RV, and interatrial septum
is achieved. The lower RA position enables visualization of the
aortic valve as well. If the catheter is advanced into the right ven-
tricle in the RV inflow position, the left ventricle, intraventricular
septum, mitral valve, and part of the left atrium can be evaluated.
The pulmonic valve, main pulmonary artery, and aortic valve
can be easily imaged from the right ventricular outflow position
(E Figs. 8.10 and 8.11). Finally, from the left atrial position the
left atrial appendage and mitral valve are visualized [13].
IE is able to guide almost any structural heart disease percu-
taneous intervention, however, established utility has been re-
ported for TP and atrial septal defect procedures [15]. Limited
data is available for other structural heart disease procedures, for
which feasibility and safety studies are underway. For years, TP
has been performed with IE guidance during electrophysiological
studies, long before the development of complex percutaneous
structural heart disease interventions. IE enables accurate assess-
ment of the atrial septum anatomy, guide a safe puncture, and
rules out possible complications. In the same way, several papers
have proved the usefulness and safety of IE during atrial septal

defects procedures. Moreover, in a recent US nationwide study,
more than 50% of atrial septal defect procedures were performed
with IE guidance, showing similar a success rate, adverse events,
and costs, but shorter hospital length compared to TEE guidance.
Avoidance of general anaesthesia along with interventionist
self-​performance and high-​resolution imaging supports the use
of IE to guide structural heart disease procedures. Some known
limitations of IE include the limited far-​field imaging, limited 3D
capabilities, and lack of biplane imaging—​but probably the most
relevant disadvantage that precludes its use in clinical practice is
the operator learning curve along with catheter price.
Future perspectives
We are facing an exponential growth in the number and com-
plexity of percutaneous structural heart disease interventions.
In parallel, new sophisticated devices are under development
to specifically treat and adapt to the different clinical scenarios.
Imaging plays a key role and technological development is gath-
ering pace to ensure successful and safe procedures. Taking into
account limitations of the different imaging modalities, fusion
Fig. 8.12  Fusion image of 3D echo with fluoroscopy. Delineation of the different cardiac structures is automatically performed.
C on c lusi on s 127
Fig. 8.11  Intracardiac echocardiography images with the catheter
positioned in the right ventricular outflow. The aortic valve (AV)
with an ablation catheter trough can be seen. The left atrium (LA)
and part of the pulmonary artery are also displayed.
Courtesy of Dr. J. Moreno.
systems are constantly evolving to give the best possible informa-
tion during an intervention. It is now possible through anatom-
ical intelligence to integrate fluoro with 3D echo volume imaging
of the heart in real time (E Fig. 8.12). Automatic analysis of the
different cardiac structures with measurements will be a reality, as
well as the possibility of automatic detection and visualization of
the different cardiac structures in a fused image.
Conclusions
Fusion imaging of echo and fluoro is a reality in the cath lab. It helps
the interventionalist during the procedure to better localize the dif-
ferent cardiac structures, increasing confidence, and enabling faster
and safer procedures. The different image displays possible with
the fusion systems offer an unique versatility to adapt the timing
of image capture to the type/​moment of the different procedures.
IE is able to accurately depict the different cardiac structures and
provide useful information to guide atrial septal procedures. It is
an alternative to TEE for structural heart disease interventions.
However, at the present time, and due to inherent limitations and
lack of data, it is a second line imaging modality in most cases.
128 CHAPTER 8   Fusion imaging and u se of in tr aca rdiac echo ca rdi o g r a phy
Further reading
Alkhouli M, Hijazi ZM, Holmes DR, et al. Intracardiac echocardiography
in structural heart disease interventions. J Am Coll Cardiol Intv 2018;
11: 2133–​47.
[Excellent review article on the basis and clinical utility of intracardiac
echocardiography with many schemes and figures to understand the
views and the way to perform this type of studies focused on structural
heart disease percutaneous interventions.]
References
1. Thaden J, Sanon S, Geske JB, et al. Echocardiographic and fluoro-
scopic fusion imaging for procedural guidance: an overview and early
clinical experience. J Am Soc Echocardiogr 2016; 29: 503–​12.
2. Veulemans V, Hellhammer K, Polzin A, Bönner F, Zeus T, Kelm M.
Current and future aspects of multimodal and fusion imaging in
structural and coronary heart disease. Clin Res Cardiol 2018; 107
(Suppl 2): S49–​S54.
3. Biaggi P, Fernández-​Golfín C, Hahn R, Corti R. Hybrid imaging
during transcatheter structural heart interventions. Curr Cardiovasc
Imaging Rep 2015; 8(9): 33.
4. Balzer J, Zeus T, Veulemans V, Kelm M. Hybrid imaging in the cath-
eter laboratory: real-​time fusion of echocardiography and fluoros-
copy during percutaneous structural heart disease interventions. Int
Cardiol Rev 2016; 11: 59–​64.
5. Wiley BW, Eleid MF, Thaden JJ. Fusion imaging for procedural guid-
ance. Rev Esp Cardiol 2018; 71(5): 373–​81.
6. Ternaclea J, Galleta R, Nguyena A, et al. Usefulness of
echocardiographic–​fluoroscopic fusion imaging in adult structural
heart disease. Arch Cardiovasc Dis 2018; 111: 441–​8.
7. Faletra FF, Biasco L, Pedrazzini G, et al. Echocardiographic–​
fluoroscopic fusion imaging in transseptal puncture: a new tech-
nology for an old procedure. J Am Soc Echocardiogr 2017; 30: 886–​95.
8. Gafoor S, Schulz P, Heuer L, et al. Use of EchoNavigator, a novel
echocardiography–​ fluoroscopy overlay system, for transseptal
Thaden J, Sanon S, Geske JB, et al. Echocardiographic and fluoroscopic
fusion imaging for procedural guidance: an overview and early clinical
experience. J Am Soc Echocardiogr 2016; 29: 503–​12.
[Review article that explains basic principles and clinical use of echo-​fluro
fusion imaging along with reporting initial clinical experience.]
puncture and left atrial appendage occlusion. J Interv Cardiol 2015;
28: 215–​17.
9. Afzal S, Veulemans V, Balzer J, et al. Safety and efficacy of transseptal
puncture guided by real-​time fusion of echocardiography and fluor-
oscopy. Neth Heart J 2017; 25: 131–​6.
10. Jungen C, Zeus T, Balzer J, et al. Left atrial appendage closure guided
by integrated echocardiography and fluoroscopy imaging reduces ra-
diation exposure. PLoS One 2015; 10: e0140386.
11. Sundermann SH, Biaggi P, Grunenfelder J, et al. Safety and feasibility
of novel technology fusing echocardiography and fluoroscopy images
during MitraClip interventions. EuroIntervention 2014; 9: 1210–​16.
12. Enriquez A, Saenz LC, Rosso R, et al. Use of intracardiac echocar-
diography in interventional cardiology working with the anatomy
rather than fighting it. Circulation 2018; 137: 2278–​94.
13. Alkhouli M, Hijazi ZM, Holmes DR, Rihal CS, Wiegers SE.
Intracardiac echocardiography in structural heart disease interven-
tions. J Am Coll Cardiol Intv 2018; 11: 2133–​47.
14. Neelankavil J, Jason Chua J, Kimberly Howard-​Quijano K, Aman
Mahajan A. Intracardiac echocardiography. J Cardiothorac Vasc
Anesth 2015; 29: 502–​5.
15. Korsholm K, Møller Jensen J, Nielsen-​ Kudsk JE. Intracardiac
echocardiography from the left atrium for procedural guidance of
transcatheter left atrial appendage occlusion. J Am Coll Cardiol Intv
2017; 10: 2198–​206.

Contents
Introduction  129
Cardiac hybrid imaging  129
Definition of cardiac hybrid imaging  129
Rationale for cardiac hybrid imaging  129
Hybrid scanners and image fusion
software  131
Imaging protocols for hybrid imaging  133
Radiation safety aspects of hybrid
imaging  134
Clinical impact of cardiac hybrid
imaging  135
Myocardial blood flow quantification  137
Dedicated cardiac-​only SPECT
scanners  137
Novel cardiac software  139
Future perspectives  139
Conclusion  140
CHAPTER 9
New technical developments
in nuclear cardiology and
hybrid imaging
Antti Saraste, Sharmila Dorbala, and
Juhani Knuuti
Introduction
Improvements in software and hardware have enabled the integration of dual imaging
modalities into hybrid systems, which allow combined acquisition of the different data
sets and fusion of images [1–​3]. Cardiac hybrid imaging offers the ability to combine
strengths of different imaging modalities in providing information on cardiac physiology
along with cardiac and coronary anatomy. Hybrid imaging has been mainly used for
combined anatomical and functional evaluation of coronary artery disease (CAD) [1, 3,
4], but it holds promise for many other applications in molecular imaging [1, 2, 3, 5]. In
addition to hybrid imaging, cardiac dedicated single photon emission computed tomog-
raphy (SPECT) scanners, novel software methods for low count image reconstruction,
and quantification of myocardial blood flow by positron emission tomography (PET)
have been introduced for evaluation of CAD. This chapter aims at describing currently
available clinical evidence from cardiac hybrid imaging, and briefly highlight some re-
cent developments in nuclear cardiology as well as discuss their future perspectives.
Cardiac hybrid imaging
Definition of cardiac hybrid imaging
The term cardiac hybrid imaging refers to combining two data sets into a fused image,
whereby both data sets are important in contributing to image information [1–​3]. This
can be achieved with a hybrid scanner or with separate imaging systems by software
based fusion. Hybrid scanners enable the use of X-​ray or magnetic resonance imaging
(MRI) based attenuation correction of perfusion imaging to improve image quality of
PET or SPECT images [1–​3]. However, we will focus on hybrid imaging as it relates to
any combination of structural and functional information beyond that offered by attenu-
ation correction or side-​by-​side analysis of images, by fusion of the separate data sets, for
example from coronary CT angiography (CTA) and from SPECT or PET into one image
(E Fig. 9.1).
Rationale for cardiac hybrid imaging
Non-​invasive diagnostic tests based on imaging have developed rapidly and now offer
alternatives for invasive tests of anatomical and functional evaluation of suspected ob-
structive CAD [6]‌. Due to different strengths and weaknesses of each test [6], addition
130 CHAPTER 9   N ew tech nical devel opments i n nu cl ea r ca rdi ol o g y a n d hy b ri d i m ag i n g

Fig. 9.1  Three-​dimensional cardiac hybrid SPECT/​CT image: a volume rendered coronary CTA image is fused with the stress perfusion SPECT. The left panel
shows a basal inferior ischaemic area (blue area, black arrow heads). The middle panel reveals a lesion in the right coronary artery (white arrow), with otherwise
unremarkable coronaries and normal perfusion. Invasive coronary angiography confirms a significant lesion in the right coronary artery (white arrow).

of a second diagnostic test after an inconclusive result with one
may increase diagnostic accuracy and assist in management of
the patient. It is this background which has paved the way for the
conceptual search of a non-​invasive technique to assess CAD in
which the detected perfusion abnormalities can be immediately
and accurately associated with the individual’s coronary anatomy.
Modern multidetector row CT systems allow robust imaging of
the coronary arteries [7]‌. Cardiac CT imaging can be performed
without contrast agent, and using electrocardiographic (ECG)
gating, to detect and quantify coronary artery calcium (CAC),
a measure of the extent of calcified coronary atherosclerosis.
Determination of CAC is supported by current guidelines and
large population studies for improving risk estimates of cardio-
vascular events in asymptomatic individuals [8]. Information of
coronary calcium also refines estimates of pretest probability of
CAD in symptomatic patients [9]. The extent or burden of cal-
cium, however, shows no reliable correlation to the presence and
severity of stenosis and therefore, cannot alone be used for diag-
nosing obstructive CAD [4].
Coronary CTA, an ECG-​ gated, contrast-​ enhanced study
during a breath hold, allows the detection of obstructive cor-
onary artery stenosis as well as non-​obstructive calcified and
non-​calcified atherosclerotic plaque after intravenous injection of
contrast agent [7]‌. Coronary CTA has become a valuable alter-
native to diagnostic invasive coronary angiography (ICA) for the
evaluation of many patients with suspected CAD. It shows very
high sensitivity (>95%) for the detection of coronary artery sten-
oses as compared with ICA [6, 10] and allows exclusion of ob-
structive CAD with high certainty. However, an overestimation
of stenosis by coronary CTA is often observed, particularly in the
presence of dense calcifications [11]. Furthermore, coronary CTA
is a morphologic imaging tool that does not provide information
on the haemodynamic relevance of a coronary artery stenosis.
The degree of coronary stenosis correlates poorly with the degree
of coronary flow reserve and stenoses estimated between 50% and
90% by visual inspection are not necessarily functionally signifi-
cant, i.e. they do not always induce myocardial ischaemia [12].
Accordingly, coronary CTA provides suboptimal specificity and
positive predictive value for the detection of flow limiting cor-
onary stenosis [6, 10, 11].
Myocardial perfusion imaging with SPECT, PET, or cardio-
vascular MRI (CMR) provides an integrated measure of different
factors influencing haemodynamic significance of a coronary
stenosis and accurate detection of flow limiting CAD [6, 12].
The presence, severity and extent of myocardial perfusion ab-
normalities are strong predictors of the risk of cardiac death and
non-​ fatal myocardial infarction [13, 14]. Professional guide-
lines recommend objective documentation of ischaemia prior to
elective PCI due to the evidence showing that ischaemia-​guided
revascularizations improve symptoms and event-​ free survival
when compared with coronary stenosis-​guided approach [4, 15].
Thus, hybrid imaging combining coronary CTA and myocardial
perfusion imaging may assist in differentiating haemodynam-
ically significant from non-​significant stenosis or artefacts. This
may help to reduce the false-​positive rate of coronary CTA and
optimize selection of patients who may ultimately benefit from
revascularization.
Normal or mildly abnormal myocardial perfusion study is gen-
erally associated with low risk of cardiac death or myocardial
infarction [13, 14]. However, perfusion imaging based on evalu-
ation of regional distribution of myocardial perfusion may under-
estimate the extent of multivessel CAD [16–​19]. This technique
often uncovers only the coronary territory supplied by the most
severe stenosis. In multivessel disease coronary flow reserve may
be abnormal in all territories thereby reducing the heterogeneity
of flow between ‘normal’ and ‘abnormal’ zones. Furthermore, a

normal myocardial perfusion study does not exclude the pres-
ence of subclinical, non-​obstructive coronary atherosclerosis that
is associated with increased event risk as compared to absence
of atherosclerosis [20–​24]. Therefore, assessment of obstructive
and non-​obstructive coronary atherosclerotic burden by cardiac
CT may improve the diagnostic and prognostic value of myo-
cardial perfusion imaging as well as help to optimize preventive
interventions [23].
In addition to combining CAC imaging, coronary CTA, and
myocardial perfusion imaging, clinical applications of hybrid
imaging include evaluation of myocardial viability, cardiac or vas-
cular inflammation, infection, and cardiac infiltration. The most
commonly used PET radiopharmaceutical for metabolic imaging
is glucose analogue 18F-​fluorodeoxyglucose (18F-​FDG) that can be
used to identify areas of viable myocardium, including hiberna-
ting myocardium with impaired contractile function. Indeed, 18F-​
FDG imaging is the reference standard for imaging myocardial
hibernation. CMR provides high contrast between blood pool
and myocardium together with excellent temporal resolution al-
lowing accurate evaluation of cardiac volumes, wall motion and
ejection fraction [2]‌. Furthermore, the late gadolinium enhance-
ment approach has high resolution to image scar including non-​
transmural myocardial scar and is the current reference standard
to image myocardial fibrosis. Regions of cardiac infiltration
and inflammation can also demonstrate expanded extracellular
volume and late gadolinium enhancement [2]. The new PET-​MR
scanners enable assessment of ventricular function and infarct/​
scar in combination with myocardial metabolism reflecting via-
bility [2] (E Fig. 9.2).
An alternative use of 18F-​FDG PET imaging is in the assessment
of inflammation. This is based on the high uptake of glucose by
macrophages and other inflammatory cells. In the heart, high-​fat-​
no carbohydrate dietary preparation can suppress physiological
uptake of 18F-​FDG by myocytes allowing regions of inflammation
to be observed. This method has been used to investigate inflam-
mation associated with atherosclerosis [25], cardiac sarcoidosis
[26], and infective endocarditis [27]. Both 18F-​FDG PET and
(a) (b)
Fig. 9.2  These images display apical five-​chamber views of CMR (a), 18F-​FDG PET (b), and fused PET/​CMR images (c) of a 76 year old man with history of recent
left anterior descending myocardial infarction. (a) Non-​transmural subendocardial late gadolinium enhancement (LGE) in the mid to apical septum and apex.
(b) 18F-​FDG image in the corresponding plane with non-​transmural scar and (c) a fusion of the two (software based fusion of sequential images).
Ca rdiac hy b ri d i m ag i n g 131
CMR are recommended by clinical guidelines for the investi-
gation of cardiac sarcoidosis (E Fig. 9.3) [26]. While 18F-​FDG
PET informs about myocardial and extra-​cardiac inflammation,
CMR informs about myocardial structure, function, and the pat-
tern of injury on late gadolinium enhanced images. Accurate co-​
registration of 18F-​FDG PET signal with an anatomical image in
hybrid images may facilitate discrimination of lesion location (to
the myocardium vs. mediastinal nodes) and pathological changes
compared with side-​by-​side evaluation (E Fig. 9.3).
Hybrid imaging is particularly helpful for the evaluation of pa-
tients with suspected prosthetic valve endocarditis. Indeed, one
study demonstrated that the addition of 18F-​FDG PET/​CT, as well
as 18F-​FDG PET with contrast enhanced CT substantially im-
proved the diagnostic accuracy of Duke criteria [28] (E Fig. 9.4).
Hybrid scanners and image fusion software
A hybrid scanner is an integrated device wherein the gantry in-
cludes SPECT, PET, or MRI and CT scanners. Hybrid scanners
combining PET or SPECT with multidetector CT which can
perform CT assessment of coronary anatomy are becoming the
standard for almost all commercially available nuclear imaging
systems [1]‌ . However, the most advanced CT technology is
not typically offered in hybrid configurations. The PET-​CT or
SPECT-​CT scanners offer sequential acquisition of both datasets
without moving the patient from bed. In addition to CT, the
newest generation of scanners offers combination of PET with
MRI [2]. The development of avalanche photodiode and silicon
photomultiplier detectors that are capable of working within the
MRI scanner has enabled combining MRI and PET into a single
scanner allowing truly simultaneous imaging [2].
Hybrid scanners allow an efficient and patient-​ friendly
image acquisition in only one visit to the imaging department.
Furthermore, it is possible to use CT or MRI images for attenu-
ation correction of the nuclear scan. A hybrid scanner facilitates
image co-​registration, because images are acquired simultan-
eously or sequentially within a short time with the patient’s pos-
ition fixed. However, software based fusion of images obtained
(c)
132 CHAPTER 9   N ew tech nical devel opments i n nu cl ea r ca rdi ol o g y a n d hy b ri d i m ag i n g

(a) (b) (e)

Suspected CS
Extracardiac sarcoidosis and
palpitations/syncope or abnormal
ECG/Holter or abnormal echo

CMR FDG PET/CT

preferred & MPI

(c) (d)

Abnormal/Unavailable/ FDG() & MPI (+)

Normal FDG (+)†
Contraindicated CMR LGE (+)

Clinical Immunosuppressive Rx‡

Consider ICD
Follow-up* Consider ICD

Fig. 9.3  Role of 18F-​FDG PET and CMR in the evaluation of cardiac sarcoidosis. This image demonstrates a hybrid PET-​CMR imaging of myocardial
inflammation with 18F-​FDG PET and gadolinium late enhancement in cardiac sarcoidosis after overnight fast to suppress physiological myocardial 18F-​FDG
uptake. (a) Cardiac PET, (c) late-​enhancement CMR approximately 5 minutes after intravenous injection of 0.15 mmol/​kg of Gd-​DTPA, and (b) shows PET/​
CMR fusion image. 18F-​FDG uptake consistent with inflammation co-​localizes with late gadolinium enhancement in the interventricular septum and inferior
walls (arrows). Granulomatous inflammation consistent with cardiac sarcoidosis was confirmed in histological analysis of an endomyocardial biopsy obtained
from the interventricular septum. In addition to myocardium, uptake of 18F-​FDG in mediastinal lymph nodes is typical of sarcoidosis (arrows in panel d). Panel
(e) demonstrates a multisocietal proposed algorithm for the use of 18F-​FDG PET/​CT and CMR imaging in the evaluation of cardiac sarcoidosis. CS = cardiac
sarcoidosis; CMR = cardiac MRI; ICD = implantable cardioverter defibrillator; MPI = myocardial perfusion imaging; LGE = late gadolinium enhancement;
ECG = electrocardiogram; FDG = fluoro deoxy glucose.
Reproduced from A joint procedural position statement on imaging in cardiac sarcoidosis: from the Cardiovascular and Inflammation & Infection Committees of the European
Association of Nuclear Medicine, the European Association of Cardiovascular Imaging, and the American Society of Nuclear Cardiology. Eur Heart J Cardiovasc Imaging.
2017;18:1073–​89 with permission from Oxford University Press.

Fig. 9.4  18F-​FDG PET/​CT in infective endocarditis. This image demonstrates images of a 80-​year-​old man with history of prior aortic valve replacement with a
bioprosthetic valve who presents with Staph aureus bacteraemia. Transoesophageal echocardiogram was unrevealing and an 18F-​FDG PET/​CT was performed for
evaluation of infective endocarditis. (a) An transaxial image with focal 18F-​FDG uptake in the chest. (b) The attenuation correction CT scan at the corresponding
plane. (c) The fusion of 18F-​FDG image with the CT and confirms the location of focal uptake to the aortic root (pseudoaneurysm). (d) The added value of
18
F-​FDG PET with or without contrast enhanced cardiac CT angiography (CTA) to Duke criteria (DC). Uncertainty of endocarditis diagnosis decreased with
the addition of 18F-​FDG PET to Duke Criteria (54% to 20%); addition of CTA further reduced uncertainty to 8%, P <0.001. Addition of contrast enhanced CT
(compared to non-​enhanced CT, NECT) to Duke criteria and 18F-​FDG PET reduced uncertainty of diagnosis from 22% to 12%.
Reproduced from Pizzi MN, Roque A, Fernández-​Hidalgo N, et al. Improving the Diagnosis of Infective Endocarditis in Prosthetic Valves and Intracardiac Devices With 18F-​
Fluordeoxyglucose Positron Emission Tomography/​Computed Tomography Angiography: Initial Results at an Infective Endocarditis Referral Center. Circulation. 2015;132:1113–​26
with permission from Wolters Kluwer.
 Ca rdiac hy b ri d i m ag i n g 133

in dedicated scanners remains a useful alternative to hybrid
scanners. Indeed, the dedicated scanner setting may appear fa-
vourable, because coronary CTA is acquired within seconds while
a perfusion study takes considerably longer [29]. Thus, in a hybrid
cardiac device, the high-​end CT facilities will be blocked during
long perfusion scan periods.
The added value of hybrid imaging originates from the spa-
tial correlation of structural and functional information on the
fused images which facilitates a comprehensive interpretation
of lesions and their pathophysiologic relevance. Fusion and co-​
registration of images from either hybrid scanner or dedicated
scanners can be achieved with the use of a software. Dedicated
cardiac fusion software packages are now commercially avail-
able allowing hybrid imaging with an excellent interobserver
reproducibility and short processing durations [30, 31]. These
software packages, following automated/​semi-​automated seg-
mentation, generate 3-​dimensional (3D) reconstructions of myo-
cardial perfusion data that are fused with 3D coronary anatomy
datasets resulting in a hybrid 3D visualization (E Fig. 9.5).
Verification of adequate co-​registration and possible manual
correction is needed to avoid misalignment, because of mis-
matches in the respiratory phases between the two data sets,
minor beat-​to-​beat variation in the heart’s position or different
ventricular size in ECG-​gated and non-​gated data sets [1, 3, 32].
For these reasons, software based co-​registration is currently
needed irrespective of whether images are acquired on a hybrid
scanner or dedicated scanners. Sophisticated approaches for
correcting motion artefacts on nuclear images based on direct
tracking of cardiac and respiratory motion have been developed
and have been shown to improve spatial resolution and signal-​
to-​noise ratio [33, 34].
Imaging protocols for hybrid imaging
Recommendations on how to perform, interpret and report car-
diac hybrid imaging can be found elsewhere [2, 3]. Patient prep-
aration and imaging protocols for coronary CTA, CAC imaging
and perfusion imaging are mainly the same as for the individual
scans [35, 36]. Proper indications and possible contraindications,
such as contrast allergy, should be reviewed separately for nuclear,
CT and CMR studies [3, 4, 15]. In hybrid imaging the stress study
is performed using pharmacologic stressors, such as adenosine,
dipyridamole, or dobutamine. To utilize the true power of hybrid
imaging, analysis system that is able to handle fused images and
data should be used in addition to independent analysis of ana-
tomic and functional images.
Hybrid imaging is a relatively novel technology and there
are no generally accepted indications for combined myocar-
dial perfusion imaging and coronary CTA or CAC imaging. A
hybrid imaging study can start with coronary CTA and only
those patients that have uncertain or equivocal findings by
CT will continue with sequential ischaemia-​testing by perfu-
sion imaging. The potential limitation of this strategy is that

(c)

(a)

(b) (d)

Fig. 9.5  Illustration of the main steps for creating a cardiac hybrid SPECT/​CT image from stand-​alone systems. The main steps include (a) image coregistration;
(b) epicardial contour detection; (c) coronary artery segmentation; and (d) MPI and CT image superposition. The same steps are also performed when hardware
based hybrid imaging (PET/​CT or SPECT/​CT) device were used.
Reproduced from Hansen CL, Goldstein RA, Berman DS, et al. Quality Assurance Committee of the American Society of Nuclear Cardiology. Myocardial perfusion and function
single photon emission computed tomography. J Nucl Cardiol. 2006;13:e97–​120 with permission from Springer.
134 CHAPTER 9   N ew tech nical devel opments i n nu cl ea r ca rdi ol o g y a n d hy b ri d i m ag i n g

the β-​blockers used as a premedication before CTA have been
shown to reduce the extent and severity of perfusion abnormal-
ities in some studies [37]. Another limitation of this protocol
is that information on microvascular dysfunction will not be
available unless perfusion imaging is performed. Vice versa,
hybrid imaging study can start with perfusion imaging and pa-
tients with uninterpretable or equivocal myocardial perfusion
images will continue with coronary CTA. However, analysis
of perfusion images is not fast enough to be used for imme-
diate decision whether to leave out coronary CTA in the case
of completely normal perfusion result. Thus, both studies are
often performed with this approach. In patients without pre-
vious myocardial infarction, low risk, and normal stress study,
stress-​only perfusion imaging may offer sufficient diagnostic
and prognostic information reducing the duration of hybrid
protocols [38, 39]. While coronary CTA is currently recom-
mended as the initial diagnostic test primarily in patients with
a lower range of pretest probability of CAD, it can be assumed
that patients at the higher range of pretest probability or with
known CAD are those that will most likely benefit from func-
tional evaluation of myocardial ischaemia [4]‌. E Table 9.1 lists
the diagnostic accuracy of several integrated myocardial perfu-
sion imaging and CT coronary angiogram studies.
Radiation safety aspects of hybrid imaging
Hybrid imaging will increase the patient radiation dose if the
‘additional’ imaging techniques utilize ionizing radiation. Thus, it
is important to follow procedures to keep patient exposure to ion-
izing radiation at the minimum dose consistent with obtaining a
diagnostic examination [40]. Using commonly available single-​
source 64-​slice CT scanners with a prospectively ECG-​triggered
step-​and-​shoot acquisition protocol, it is possible to consistently
perform a coronary CTA with an absorbed radiation dose of 2
and 5 mSv [40]. The radiation doses from single SPECT perfusion
imaging range from 2.5 to 8 mSv (99mTc-​based tracers) [41]. The
estimated radiation dose from a PET perfusion study is smaller,
e.g. 1.5 mSv with 15O-​water, 2.5 mSv with 82Rb and 2 mSv with
13
N-​ammonia [40]. Therefore, although the use of hybrid imaging
obviously causes increased radiation dose for the patient, the re-
cent technical development has improved the radiation safety
tremendously and a complete hybrid imaging can be performed
with radiation dose clearly below 10 mSv. Radiation exposure

Table 9.1  Diagnostic accuracy of integrated myocardial perfusion imaging and coronary CTA: vessel based analysis in identifying
obstructive CAD

First author/​Year N Gold standard (definition of Sensitivity Specificity PPV NPV Hybrid technique
significant CAD)
13
Namdar 25 Flow limiting coronary stenoses 90 98 82 99 N-​ammonia PET/​
2005 [43] requiring revascularization (ICA+PET) 4 slice CT
99m
Rispler 56 Flow limiting coronary stenoses 96 95 77 99 Tc SPECT/​
2007 [44] (>50% stenosis on ICA+SPECT+) 16 slice CT
82
Groves 33 >50% stenosis on ICA 88 100 97 99 Rb PET/​
2009 [49] 64 slice CT
99m
Sato 130 >50% stenosis on ICA 94 92 85 97 Tc SPECT/​
2010 [53] 64 slice CT¥
15
Kajander 107 Flow limiting coronary stenoses 93 99 96 99 O-​water PET/​
2010 [47] (>50% stenosis on ICA+FFR) 64 slice CT
15
Danad 120 Flow limiting coronary stenoses, CFR 72 89 69 90 O-​water PET/​
2013 [48] (>50% stenosis on ICA+FFR) 64 slice CT
15
Thomassen 44 ICA, QCA, 50%. stress MBF 88 97 85 97 O-​water PET/​
2013 [54] 64 slice CT
99m
Schaap 98 Flow limiting coronary stenoses 96 95 96 95 Tc SPECT/​
2013 [50]µ (>50% stenosis on ICA+FFR) 64 slice CT
99m
Dong 78 ICA/​CTA≥50% + SPECT defect 89 92 81 96 Tc SPECT/​
2014 [58] 16 slice CT
99m
Winther* 138 Flow limiting coronary stenoses 67 86 57 90 Tc SPECT/​
2015 [59] (>50% stenosis on ICA) Dual source CT
Liga 252 Flow limiting coronary stenoses [(>50% 83 68 NA NA SPECT/​PET/​CTA
2016 [66] stenosis on ICA) or (30–​50% stenosis on
ICA & FFR+) and perfusion defect]
*pre-​renal transplant patients, per patient analysis
¥ hybrid SPECT/​coronary CTA only applied for non-​evaluable arteries on coronary CTA
µ patient based analysis
CAD = Coronary artery disease, CTA = Computed tomography angiography, FFR = Fractional flow reserve, ICA = Invasive coronary angiography, MBF = Myocardial blood flow, N =
number, NPV = Negative predictive value, PET = Positron emission tomography, PPV = Positive predictive value, QCA = Quantitative coronary angiography, SPECT = Single photon
emission computed tomography
 Ca rdiac hy b ri d i m ag i n g 135

of hybrid PET-​MRI imaging is lower than that of PET-​CT or side-​by-​side analysis of images have shown that in almost one-​
SPECT-​CT, which might be particularly beneficial in younger pa- third of patients the fused SPECT-​CT or PET-​CT analysis pro-
tients who may need repeated scans [2]‌. vided added diagnostic information on pathophysiologic lesion
severity not obtained by side-​by-​side analysis [62–​66]. The most
Clinical impact of cardiac hybrid imaging pronounced incremental value has been found in patients with
As just mentioned, it is well established that a comprehensive multivessel disease (E Fig. 9.6) and lesions in distal coronary
assessment of CAD requires not only morphologic informa- segments, diagonal branches (E Fig. 9.7), the left circumflex,
tion about coronary artery stenosis location and degree but and right coronary arteries as well as in vessels with extensive
also functional information on pathophysiologic lesion severity. CAD or substantial calcification on CTA. Due to the variant
Eventually, many factors that cannot fully be assessed with cor- coronary anatomy in each individual and the complex disease
onary luminology determine whether a given lesion really in- pattern in these patients, hybrid images facilitate correct assign-
duces a myocardial perfusion defect. The goal of hybrid imaging ment of perfusion defect to a territory subtended by a haemo-
is to provide accurate spatial alignment of coronary angiography dynamically significant stenosis. As hybrid images offered
and myocardial perfusion data to improve co-​ localization of superior information with regard to identification of the culprit
myocardial perfusion abnormalities and subtending coronary vessel the diagnostic confidence for categorizing intermediate
arteries (E Fig. 9.1). The planar projections of coronary angio- lesions and equivocal perfusion defects was significantly im-
grams and axial slice-​by-​slice display of cardiac perfusion studies proved. Additional patient groups in which hybrid imaging
make a subjective integration of perfusion abnormalities with has been shown to provide complementary information on the
coronary anatomy difficult. This may lead to inaccurate allocation presence and localization of atherosclerotic lesions and myocar-
of the coronary lesion to its subtended myocardial territory, par- dial perfusion abnormalities are those with congenital coronary
ticularly in patients with multivessel disease and intermediate se- anomalies [67] and patients with recurrent chest pain after cor-
verity lesions. Hybrid imaging studies have shown that standard onary bypass surgery (E Fig. 9.8) [68]. Furthermore, hybrid
distribution of myocardial territories corresponds with the real imaging can identify patients with reduced coronary flow re-
anatomic coronary tree in only 50–​60% of cases which may cause serve due to microvascular dysfunction without obstructive
misleading interpretation [42]. CAD resulting in discordant findings in myocardial perfusion
Studies comparing cardiac hybrid imaging with stand-​alone images and coronary CTA [47, 69]. From these studies one can
perfusion imaging or coronary CTA have shown promising re- conclude that the greatest added value appears to be the exclu-
sults in the detection of obstructive CAD [43–​59]. A meta-​ sion of haemodynamic significance of coronary abnormalities
analysis of 12 diagnostic studies (951 patients in total) [60], found seen on coronary CTA, differentiation of epicardial and micro-
that pooled sensitivity of hybrid imaging for the detection of CAD vascular disease, as well as correct localization of the culprit le-
defined as luminal diameter reduction of at least 50% by ICA was sion causing ischaemia.
comparable to that of coronary CTA on per-​patient (91% vs. 90%) The independent prognostic value of coronary CTA and myo-
and per-​vessel (84% vs. 89%) basis. However, specificity of hybrid cardial perfusion imaging was demonstrated in a multicentre
imaging clearly outperformed that of coronary CTA alone on per-​ follow-​up study in more than 500 patients supporting the notion
patient (93% vs. 66%) and on a per-​vessel (95% vs. 83%) analyses. that both parameters need to be investigated in patients with CAD
There was also a modest improvement in overall diagnostic per- [70]. Another study using hybrid SPECT-​CT imaging showed
formance at per-​vessel level (area under the curve 0.97 vs. 0.92). that a matched finding of myocardial ischaemia in a territory
A limitation of the meta-​analysis and current studies is that in supplied by a stenotic coronary artery was associated with higher
most of them used angiographic stenosis diameter as the refer- risk of death or myocardial infarction than regionally unmatched
ence standard instead invasive fractional flow reserve (FFR) and ischaemia and stenosis [71]. Similarly, highest revascularization
thus, do not account for the potential discrepancy between sten- rates have been observed in the presence of perfusion abnor-
osis severity and functional significance of coronary lesions. A mality matched with a stenosis in the subtending coronary artery
recent single-​centre prospective study compared hybrid imaging [72]. In a recent study finding of myocardial ischaemia on was
with stand-​alone imaging in 208 patients who underwent cor- associated with five times higher risk of death, myocardial infarc-
onary CTA, SPECT perfusion imaging and 15O-​water PET per- tion, or unstable angina as compared with patients in whom sten-
fusion imaging and ICA combined with measurement of FFR in osis was suspected based on coronary CTA, but PET perfusion
all arteries [61]. In this study, the addition of functional imaging imaging did no show ischaemia [73]. These studies provide evi-
to coronary CTA improved specificity, but there was an increase dence that ischaemia at an anatomically appropriate location by
in false negative findings that resulted in no overall incremental hybrid imaging can provide incremental information about risk
diagnostic benefit as compared with stand-​alone imaging. of adverse events and have an impact on patient management in
Although the latter studies provide important clinical in- terms of revascularization decisions.
formation about the performance of different imaging modal- Several studies have shown that CAC imaging has incre-
ities, they do not directly show the incremental value of the mental diagnostic and prognostic value over myocardial
hybrid imaging. Studies comparing fused hybrid images with perfusion imaging, because of its ability to quantify overall
136 CHAPTER 9   N ew tech nical devel opments i n nu cl ea r ca rdi ol o g y a n d hy b ri d i m ag i n g

(b)

(a)

(d)
Fig. 9.6  Coronary CTA images (curved
multiplanar reconstructions) of a male patient
with effort angina. Images of the right anterior
descending artery (RCA) (a), left anterior
descending artery (LAD) (b), and left circumflex
artery (LCX) (c) show several calcified and
noncalcified plaques, which suggest significant
multivessel disease. Three-​dimensional cardiac
hybrid PET-​CT images of anterior (d) and right
lateral view (e) shows very different stress
perfusion patterns in each vessel region. The
perfusion in region supplied by the LCX was
normal (red and yellow colour), slightly reduced
in region supplied by the LAD (green colour) and
severely compromised in region supplied by the
(c) (e)
RCA (blue colour).

Fig. 9.7  Examples of two clinically similar

symptomatic patients who had also similar findings
in the LAD and the first diagonal branch (D1)
in CTA (left panels). The patient 1 (upper row)
showed in hybrid PET-​CT imaging (right panel)
only subtle reduction in territory supplied by D1.
The patient 2 (lower row) showed large poorly
perfused region covering whole anterior wall
supplied by both the LAD and D1.

atherosclerotic burden [74–​77]. High atherosclerotic burden
has been shown to increase the likelihood of obstructive CAD
in symptomatic patients [74, 75] and increasing CAC score is
associated with a stepwise increase in the risk of myocardial
infarction or death in patients with and without ischaemia on
perfusion imaging [76]. However, important to note that CAC
imaging does not assess the severity of stenosis. Although CAC
scan and perfusion images are usually interpreted separately,
their fusion is possible and patients with coronary calcifica-
tion and a matched perfusion abnormality in the territory sub-
tended by the calcified vessel were shown to be at highest risk
of cardiovascular events [77].
Myocardial blood flow quantification
Myocardial perfusion imaging with PET imaging offers possi-
bility to measure myocardial blood flow quantitatively (in ml/​
min/​g of myocardium) at rest and vasodilator-​stress that al-
lows for calculation of myocardial flow reserve (MFR, ratio
of stress over rest myocardial blood flow) [78–​79]. Accurate
and reproducible quantification of myocardial blood flow is
possible with the most commonly used PET perfusion tracers
15
O-​water, 13N-​ammonia 82Rb [79]. In addition to these, new
perfusion tracers labelled with 18F are currently investigated
and they may improve availability of PET myocardial perfu-
sion imaging, because due to long half-​life they could be dis-
tributed to centres without an on-​site cyclotron [80]. Due to
advances in scanner technology it has become possible to in-
clude quantification of myocardial blood in standard clinical
PET myocardial perfusion protocols [79]. Dynamic datasets
used for blood flow quantification can be reconstructed from
list-​
mode data, and compartmental modelling to calculate
myocardial blood flow is possible with many image analysis
software packages.
Dedi cated ca rdiac- on ly SPEC T sc a n n e r s 137
Fig. 9.8  In situations of complex CAD and after
bypass surgery hybrid cardiac imaging provides
added value. Coronary CTA may allow visualization
of patent bypass grafts but the evaluation of the
anastomoses and native arteries remains difficult. A
conclusion about haemodynamic relevant lesions
can only be reached in conjunction with perfusion.
The image documents ischaemia in the right
coronary artery territory (blue colour) due to a
stenosis at the distal graft anastomosis (red arrow).
Stress myocardial blood flow and MFR are consistently reduced
in the presence of high grade coronary stenosis associated with
abnormal FFR and can be used improve diagnostic accuracy of
PET myocardial perfusion imaging [16–​19, 61]. Quantification
of myocardial blood flow (MBF) is particularly useful in the de-
tection of multivessel CAD when relative assessment of myo-
cardial perfusion cannot uncover global reduction in perfusion
(E Fig. 9.9). Preserved global MFR of more than 2.0 has ex-
cellent negative predictive value exclusion of multivessel CAD
[16–​19]. In addition to obstructive CAD, abnormal coronary
flow reserve (CFR) can be caused by diffuse non-​obstructive
coronary atherosclerosis or coronary endothelial/​microvascular
dysfunction [81] and it has been shown to predict high coronary
risk independently incrementally to the presence and extent of
relative perfusion defects in patients evaluated for CAD [82].
Dedicated cardiac-​only SPECT
scanners
Dedicated cardiac SPECT cameras incorporate highly efficient
solid-​state cadmium zinc telluride (CZT) radiation detectors
with cardiofocal imaging that yield enhanced count sensitivity
[83]. Some of the dedicated cardiac SPECT CZT scanners offer
the option of hybrid imaging with CT. Compared to conven-
tional SPECT, these scanners combined with new reconstruc-
tion methods provide images with higher contrast and spatial
resolution, acquired in shorter time and with reduced radiation
dose to the patient [84]. Accumulated data show that diagnostic
performance of the new scanners compares favourably with
conventional SPECT scanners in the detection of obstructive
CAD [78]. High image quality may be particularly useful in the
detection of multivessel disease [83] and in obese patients [84].
Importantly, these scanners have been used successfully to per-
form low and very low radiation dose imaging.
138 CHAPTER 9   N ew tech nical devel opments i n nu cl ea r ca rdi ol o g y a n d hy b ri d i m ag i n g

(a) (b)

(c) (d)

Fig. 9.9  Hybrid images from stress PET-​CT study

in a patient with extensive CAD. The images (a and
b) scaled to relative scale where the best perfused
region is set to maximum and has the brightest
colour (in rainbow scale lowest = blue and highest
= red). The hybrid images of anterior (a) and
posterior (b) views suggested only minor perfusion
(e) (f)
abnormalities in the anterior wall. The images
scaled according to absolute scale (c and d) (0 ml/​
g/​min = blue and 3.5 ml/​g/​min = red) uncovered
global reduction of perfusion. The hybrid images
of anterior (c) and posterior (d) views showed
severely reduced stress perfusion in the anterior
wall but also abnormally low perfusion in other
myocardial territories (green colour).

(a) (c) Resolution Recovery Components

Pixel i Projection

An object close to the collimator will have An object farther from the collimator Collimator
less blur. will have more blur.
Solid angle
(b)
Voxel j

Fig. 9.10  Resolution Recovery Software for Low Count Density Image Reconstruction: (a) depicts depth dependent blurring of images with an object closer
to the collimator showing less blurring; (b) demonstrates that increasing collimator hole width, decreasing hole length, and increasing septal penetration result
in loss of resolution; (c) demonstrates how pixel weights are calculated mathematically, based on the solid angles subtended by the collimator between each
detector pixel and each body voxel to apply corrections and enhance image quality.
Reproduced from Dorbala S, Ananthasubramaniam K, Armstrong IS, et al. Single Photon Emission Computed Tomography (SPECT) Myocardial Perfusion Imaging Guidelines:
Instrumentation, Acquisition, Processing, and Interpretation. J Nucl Cardiol. 2018;25:1784–​846 with permission from Springer.

Novel cardiac software
In addition to novel hardware, several novel software approaches
have been developed for reconstruction of reduced count density
images (E Fig. 9.10) including iterative reconstruction, reso-
lution recovery, and noise reduction. Iterative reconstruction em-
ploys ordered subsets expectation maximization algorithms to
reduce image blurring in three dimensions and improve low count
density image quality. Resolution recovery methods apply correc-
tions for distance dependent blurring and correct for depth de-
pendent loss of resolution and improve spatial resolution with less
noise compared to conventional reconstruction methods. Noise
compensation, as opposed to conventional filtered back projection
techniques, improve signal-​to-​noise ratio. Enhancement in image
quality with the use of these three techniques allows personal-
ized protocols of reduced time imaging, reduced dose imaging, or
both. While majority of the novel SPECT scanners are equipped
with these software enhancements, a big advantage of these soft-
ware methods in that they can be applied to improve image quality
from old scanners with a much smaller capital investment.
Future perspectives
Hybrid imaging has been mainly used and implemented in guide-
lines for evaluation of CAD [1, 3, 4], In particular, guidelines
(a) (c)
(b) (d)
Fu tu re pe r spe c t i v e s 139
recommend that physicians ‘consider functional assessment’ in pa-
tients with coronary stenosis of uncertain severity by CTA [4, 85,
86]. However, there is still a need to clarify which patients can benefit
most from hybrid imaging, how to optimally combine different mo-
dalities, and what is the cost-​effectiveness of hybrid imaging.
The fusion of cardiac and coronary anatomy with molecular
imaging techniques holds potential for many research applications.
An example is hybrid PET-​CT imaging of atherosclerosis that
offers an opportunity to combine detailed morphology of athero-
sclerotic plaques with markers of disease activity, such as uptake of
18
F-​FDG in inflammatory cells (E Fig. 9.11) [25]. 18F-​FDG PET-​
CT has been used successfully to study biology of atherosclerosis
and anti-​inflammatory effects of novel atherosclerosis treatments
[25, 87]. This approach is possible only with localization of the PET
signal with high-​resolution morphological imaging of the coronary
arteries using hybrid imaging. In addition to 18F-​FDG, many new
PET radiotracers are in development and have been used to investi-
gate different aspects of cardiovascular disease, such as 18F-​fluoride
for detection of microcalcification and 68Ga-​DOTATATE targeting
somatostatin receptors for the detection of active macrophages in
coronary atherosclerotic lesions [88].
Hybrid imaging combining MR with PET is attractive for many
reasons, including lack of additional ionizing radiation, tissue char-
acterization properties of MRI and possibility to do simultaneous
acquisition with MRI and PET [2, 88]. Hybrid PET-​MRI scanners
have been available for short a relatively short period of time and
Fig. 9.11 Focal 18F-​FDG uptake in a patient
with high-​risk plaque morphology in the left
main coronary artery in orthogonal fused PET-​CT
images (a and b) and a corresponding maximum
intensity projection–​reconstructed CTA image of
the left main coronary artery non-​calcified plaque
(arrow; c), and axial CTA showing a cross-​sectional
view (d) of an additional plaque in the right
coronary artery manifesting positive remodelling
and low attenuation (arrow) in the same subject.
Reproduced from Singh P, Emami H, Subramanian
S, et al. Coronary Plaque Morphology and the Anti-​
Inflammatory Impact of Atorvastatin: A Multicenter
18F-​Fluorodeoxyglucose Positron Emission Tomographic/​
Computed Tomographic Study. Circ Cardiovasc Imaging.
2016 Dec;9(12) with permission from Wolters Kluwer.
140 CHAPTER 9   N ew tech nical devel opments i n nu cl ea r ca rdi ol o g y a n d hy b ri d i m ag i n g
there is still relatively little clinical data on their incremental value
in evaluation of myocardial viability and inflammatory cardiomy-
opathy [89]. However, development of new PET and MR tracers,
targeting different pathological processes, may expand our ability
to measure disease activity in the myocardium [88, 89].
Conclusion
The newest generation of the hybrid imaging devices have ma-
tured to the level that they can be successfully used for clinical
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Contents
Introduction  145
Historical development  145
Areas for improvement  146
Prospectively ECG-​triggered axial
acquisition  147
Single-​beat acquisition  147
Iterative reconstruction  148
Dual-​energy  CT  149
Functional assessment of coronary artery
lesions  150
CT myocardial perfusion imaging  150
FFRCT  151
Recent learnings  153
Future opportunities  153
Quantitative coronary plaque
evaluation  153
Radiomics and artificial intelligence in
cardiac CT  154
CHAPTER 10
New technical developments
in cardiac CT: Anatomy,
fractional flow reserve (FFR),
and machine learning
Stephan Achenbach, Jonathan Leipsic,
and James Min
Introduction
Computed tomography (CT), in the context of cardiac imaging, faces numerous chal-
lenges. The heart is a complex, three-​dimensional organ, which moves very rapidly and
has small dimensions. The coronary arteries, the main target of cardiac CT imaging, are
especially difficult to visualize by any non-​invasive technique. All the same, technology
progress has made the use of CT for cardiac and coronary diagnosis possible. For selected
applications, including ruling out coronary artery stenoses in low-​risk individuals, CT
has become a clinical tool [1, 2].
Historical development
In order to be useful for cardiac imaging, several prerequisites must be fulfilled (see
E Table 10.1). The first commercially available CT scanner that permitted visualization
of the heart with high temporal and spatial resolution was the ‘electron beam tomog-
raphy’ system introduced in the late 1980s. Instead of an X-​ray tube, which needs to
rotate mechanically around the patient, it used an electron beam that was deflected by
electromagnetic coils to sweep across semi-​circular targets arranged around the patient
where the X-​rays were created. The radiation passed through the patient and attenuation
was recorded by stationary detectors arranged on the opposite side. Temporal resolution
was 100 ms, but slice thickness was limited to 1.5 or 3.0 mm, images were relatively noisy,
and cost was high. The electron beam system is no longer available, but it demonstrated
the utility of CT imaging for coronary artery calcium assessment and even early CT cor-
onary angiography [3]‌. This prompted the development of cardiac applications for mech-
anical CT systems.
Around the year 2000, the first multidetector row spiral (or ‘helical’) CT systems were
introduced, permitting acquisition of up to four cross-​sections or slices with sub-​mm
thickness simultaneously along with electrocardiographic (ECG) synchronized image
reconstruction. A relatively low pitch (table feed) was used, so that every level of the
heart was covered during the entire cardiac cycle by at least one of the four detectors
(this acquisition mode is called ‘retrospectively ECG-​gated spiral acquisition’ and is still
in use today). It allows all data acquired in systole to be discarded and images to be
reconstructed based solely on X-​ray attenuation data acquired during phases of slow
cardiac motion in diastole. Multirow acquisition was necessary to cover the complete
146 CHAPTER 10   Anatomy, f ract ional f l ow reserve ( FFR ) , a n d m achi n e l ea rn i n g
Table 10.1  Prerequisites for cardiac imaging using CT
Prerequisite Achieved through
High spatial High-​resolution detector technology
resolution Thin slice thickness
Relatively high radiation exposure (to reduce noise)
High temporal High rotation speed
resolution Half-​scan reconstruction algorithms
Dual-​source  CT
Multicycle reconstruction algorithms
Synchronization Retrospectively ECG-​gated image reconstruction
to heartbeat Prospectively ECG-​triggered image acquisition
volume of the heart within one breath-​hold, and with four-​slice
systems, acquisition typically required 35 to 40 seconds. Imaging
the coronary arteries was cumbersome, but possible [4, 5]. It was
soon reported that low heart rates substantially improve image
quality (since the diastolic phase of slow motion is prolonged)
and short-​acting medication to control the heart rate has been
recommended for cardiac CT ever since [6]‌.
During subsequent years, the technology of CT evolved sub-
stantially. The main achievements were: faster rotation, which im-
mediately translates to better temporal resolution; thinner slices,
which improve spatial resolution; and stronger tubes, which are
necessary to limit image noise, and are a prerequisite to achieve
constant image quality while increasing temporal and spatial
resolution. Furthermore, wider detectors were constructed, ini-
tially from 4 to 16 and 64 detector rows. A further increase of the
number of simultaneously acquired slices was achieved through
tubes that have two focal points, so that by rapidly alternating X-​
ray emission between the two focal points, the number of cross-​
sectional slices that are acquired is twice as high as the number of
detector rows. Currently, the widest detectors have 320 rows. At a
slice thickness of 0.5 mm, a scan volume of 16 cm can be covered,
which is sufficient to cover the heart in ‘one sweep’, so that, un-
less a combination of data acquired during several cardiac cycles
is used to improve temporal resolution, the entire heart can be
imaged in one single diastolic phase [7]‌. This limits the potential
for artefacts, permits short breath-​holds, and through the shorter
data acquisition time, reduces the amount of contrast agent that
is required to achieve intravascular enhancement during the
acquisition.
Another major hardware achievement is dual-​source CT. It
combines two X-​ray tubes and two detectors arranged at an angle
of approximately 90° [8]‌. Since X-​ray attenuation data acquired
over an angle of approximately 180° are necessary to reconstruct
one cross-​sectional image, dual-​source CT permits collection of
the required data during a quarter rotation of the X-​ray gantry,
while single-​source CT requires one-​half rotation. Dual-​source
CT, therefore, improves temporal resolution by a factor of two.
With a gantry rotation time of 0.24 s, the temporal resolution of
each acquired slice is 66 ms (it does not exactly correspond to
one-​quarter rotation time because the two tubes and detectors are
not exactly aligned at a 90° angle). Another hardware innovation
that uses two X-​ray tubes, but instead of combining two tubes
Table 10.2  Hardware improvements in cardiac CT and their effect
on image quality
Hardware improvement Effect
Smaller detector elements Higher spatial resolution
Thinner detector rows Higher spatial resolution
More detector rows Faster coverage of the volume of the heart
(fewer heart beats), no influence on temporal
resolution or spatial resolution
Faster gantry rotation Higher temporal resolution
Dual-​source CT Higher temporal resolution
Stereo X-​ray tubes Smaller gantry size, improved spatial resolution
Stronger X-​ray tube Lower image noise. Necessary to offset
higher noise which would be introduced
through thinner slices and faster rotation
arranged at an 90° angle in the x-​y plane, it has a stereo tube de-
sign, combining the two tubes in the z-​axis (approximately 7 cm
apart). The stereo tube system allows for smaller gantry design,
improved spatial resolution (isotropic 0.28 mm) and whole-​heart
coverage of 14 cm. E Table 10.2 lists hardware advancements
and their influence on image quality.
Currently, four manufacturers provide high-​end CT systems
capable of cardiac imaging. Gantry rotation time is 0.24 to 0.35
s, the number of detector rows ranges from 64 to 320, minimum
slice thickness ranges from 0.5 to 0.625 mm, and X-​ray tube
output from 72 to 120 kW (see E Table 10.3).
Areas for improvement
At present, the main application of cardiac CT is coronary artery
imaging. Without contrast agent, coronary artery calcification
can be detected and quantified, an application that does not re-
quire technology to be stretched to its limits. After intravenous
injection of contrast, CT permits visualization of the coronary ar-
tery lumen. In this context, the spatial and temporal resolution
of current CT scanners is just about sufficient to achieve ad-
equate image quality. However, in order to achieve stable image
quality, the patient’s heart rate should be lowered to 60 beats/​min
or less, motion artefacts can still be present, and the limited spa-
tial resolution causes problems, e.g. with severely calcified cor-
onary arteries, in the presence of coronary artery stents and in
small vessels. Image noise can furthermore be a problem and in
the interplay of temporal resolution, spatial resolution, and image
noise, false-​positive findings can occur, which limit the specifi-
city of coronary CT angiography, especially in difficult-​to-​image
patients (patients with high heart rate, severe calcification, and
high body weight) [9, 10]. A further issue is radiation exposure.
Especially with spiral acquisition and retrospectively ECG-​gated
image reconstruction, radiation exposure can be high and unless
specific measures are taken to limit exposure, the effective dose
can reach 25 mSv or more [11]. Numerous measures have been
introduced to reduce dose, but they can increase image noise

Table 10.3  Comparison of technical properties of currently available high-​end cardiac CT systems
GE Healthcare Philips Healthcare iCT
Revolution
Gantry rotation time 0.28 s 0.27 s
Minimum reconstructed slice width 0.625 mm 0.625
Number of rows 256 128 (256 slices)
Detector width 160 mm 80 mm
X-​ray tube output 120 kW 120 kW
Gantry aperture 80 cm 70 cm
(such as the use of lower tube current and lower tube voltage), or
limit the options to obtain motion-​free images (such as the use
of prospectively ECG-​triggered axial acquisition). The use of low
and very low dose image acquisition protocols therefore need to
be carefully balanced against the need to maintain appropriate
image quality.
A completely different aspect is the fact that the limitations of
purely anatomic imaging of the coronary artery system are in-
creasingly realized. The extent of ischaemia that a lesion produces
is substantially more relevant than the mere anatomic degree of
luminal stenosis. Pure anatomic imaging—​as provided, for ex-
ample, by coronary CT angiography—​is therefore quite useful to
rule out haemodynamically relevant coronary artery disease, but
in order to identify lesions that require revascularization, infor-
mation on inducible ischaemia is often desired.
New technical developments—​both regarding hardware and
especially software—​in cardiac CT address the problems outlined
and it can be expected that they will increase the applicability of
coronary CT angiography and cardiac CT in general.
Prospectively ECG-​triggered axial
acquisition
The traditional image acquisition mode in coronary CT
angiograph has been retrospectively ECG-​gated spiral (or ‘helical’)
acquisition. X-​ray data are acquired continuously throughout the
cardiac cycle, and using the simultaneously recorded ECG, only
X-​ray data during a specified time interval—​usually diastole—​are
utilized for image reconstruction. Any desired time interval of
the cardiac cycle can be used for image reconstruction, so that
the ‘best time instant’ can systematically be searched to minimize
motion artefact. Also, dynamic datasets can be reconstructed,
which allow analysis of ventricular function. However, much of
the acquired X-​ray data are not used for image reconstruction
and hence, radiation exposure is relatively high.
For this reason, all CT manufacturers have implemented pro-
spectively ECG-​triggered axial acquisition modes. In this scan
mode, no ‘spiral’ or ‘helical’ acquisition is performed. Instead, X-​
ray data are acquired without table movement, at a prespecified
short time interval within the cardiac cycle, and then the X-​ray
tube is switched off and the table moved to the next position [6]‌.
Si n g l e- b eat ac qui si t i on 147
Siemens Healthcare Canon Aquilion One
Somatom FORCE
0.24 s 0.275 s
0.5 mm 0.5 mm
2 × 192 320
2 × 58 mm 160 mm
2 × 120 kW 100 kW
78 cm 78 cm
The possibility to perform this data acquisition mode hinges on
some hardware requirements: the detector must be of sufficient
width so that the complete volume of the heart can be covered
within a few steps. Typically, at least 64 slices must be acquired
simultaneously (approximately 3 cm), so that the 12–​15-​cm scan
range can be covered in 4 to 5 steps. Depending on heart rate,
this amounts to 4 to 10 heart beats (in higher heart rates, images
can only be acquired in every other cardiac cycle). Also, scanners
must have a sufficiently fast rotation time to guarantee motion-​
free images in the prespecified cardiac phase. Especially when
heart rate is well-​controlled (less than 60–​65 beats/​min), very high
image quality can robustly be achieved with prospectively ECG-​
triggered axial acquisition and the associated radiation exposure
is low (typically 1.0 to 3.5 mSv; see E Fig. 10.1). Prospectively
ECG-​triggered axial acquisition, often termed ‘step-​and-​shoot’
acquisition, has become the standard scan mode for coronary CT
angiography in many institutions.
Single-​beat acquisition
Acquisition of the entire cardiac data set in one single cardiac
cycle is attractive because it eliminates ‘misalignment’ artefacts
that can occur when the data set is pieced together from several
cardiac cycles—​as typically done in retrospectively ECG-​gated
spiral acquisition or prospectively ECG-​triggered axial acqui-
sition. There are two options to acquire a data set of the entire
heart within one cardiac cycle: If the detector is wide enough, a
single prospectively ECG-​triggered axial acquisition may provide
enough coverage to visualize the entire volume of the heart. This
is typically possible with 256 to 320-​slice scanners [7]‌. Another
option is high-​pitch spiral (or ‘helical’) acquisition, where the
table is moved with such a high speed that the entire volume of
the heart is covered during spiral acquisition in a period of about
200 ms [12]. This scan mode is well established and validated for
dual-​source CT and, providing that heart rate is low and very
stable, achieves good image quality at very low radiation exposure
(see E Fig. 10.2).
Single-​beat acquisitions are also attractive for myocardial per-
fusion studies since they provide a uniform data set of the com-
plete left ventricle, with all data acquired at the same time interval
after contrast injection.
148 CHAPTER 10   Anatomy, f ract ional f l ow reserve ( FFR ) , a n d m achi n e l ea rn i n g

(a) (b)

Fig. 10.1  Coronary CT angiography using

prospectively ECG-​triggered axial acquisition. In
patients with low heart rates, high image quality
can robustly be achieved. This example was
acquired using 100 kV tube voltage, at an effective
dose of 2.1 mSv, and shows a high-​grade stenosis
of the proximal segment of the left anterior
descending coronary artery, both in coronary CT
angiography (a) and invasive coronary angiography
(b). LCx: Left circumflex coronary artery, LAD: left
anterior descending coronary artery.

longer times for reconstruction when compared to filtered back

Iterative reconstruction projection. However, with modern computers, processing power
has increased so that iterative reconstruction methods can now
The conventional method of reconstructing images based on the
be used clinically. While they alter the visual impression of the re-
acquired X-​ray attenuation data is called ‘filtered back projection’.
constructed image data, their substantial advantage is lower image
This method does not make full use of the information in the X-​
noise (see E Fig. 10.3). Hence, they can be used in combination
ray data, but is computationally efficient, and therefore widely
with low-​dose tube settings in order to maintain an acceptable
used in order to keep image reconstruction time acceptable in
contrast-​to-​noise ratio while substantially reducing radiation ex-
clinical practice. ‘Iterative reconstruction’ is a more elaborate
posure [13, 14]. The potential of iterative reconstruction has not
image reconstruction method, which makes better use of the in-
been fully explored yet, but it can be expected to be disseminated
formation in the X-​ray attenuation data, but requires substantially

(a) (b)

Fig. 10.2  Single-​beat coronary CT angiography

using prospectively ECG-​triggered high-​pitch
acquisition. Visualization of the left anterior
descending coronary artery (a); left circumflex
coronary artery (b); right coronary artery (c); and a
three-​dimensional reconstruction of the heart and
coronary arteries (d). With 100 kV tube voltage, (c) (d)
the estimated effective dose was 0.84 mSv.
 Dua l -e n e rg y   C T 149

Fig. 10.3  Visualization of the right coronary

artery in a low-​dose coronary CT angiography data
set acquired at 80 kV (effective dose: 0.3 mSv).
Comparison of image noise in conventional filtered
back projection and iterative reconstruction.
Based on the same raw data set, iterative
reconstruction—​although at the cost of longer
reconstruction times and visually altered image
impression—​achieves lower image noise. It may
therefore be suited to preserve image quality in
low-​dose acquisitions.

widely very soon and to help keep radiation exposure of cardiac
CT in an acceptable range.
Dual-​energy  CT
The tissue-​specific absorption of X-​ray photons depends on their
energy. Therefore, tissue type (even when its concentration is un-
known) can be identified based on its relative absorption at dif-
ferent X-​ray energies. This effect is utilized in dual-​energy CT.
Dual-​energy CT image acquisition can be performed using two
different strategies, as energy separation can take place either at
the side of the X-​ray source or at the side of the detector. The most
useful approaches for dual-​energy scanning in cardiac imaging
are the ones with the lowest sensitivity to motion, which are fast
kV-​switching (also called single-​source rapid-​switching), dual-​
source, and dual-​layer detector scanners. Using these techniques
X-​ray photons with different peak energy levels are sent through
the tissue or X-​ray photons separated by two-​layered detectors.
Based on the differential absorption, specific materials—​such as
iodine—​can be recognized. In cardiac imaging, dual-​energy CT
is infrequently applied. Its use has been suggested to improve
the assessment of iodine concentration in the myocardium (see
Fig. 10.4), for example for perfusion imaging or late enhancement
[15]. In peripheral vascular CT, dual-​energy CT has been used
to improve the identification of iodine-​filled vessel lumen next
to severely calcified plaque [16]. In cardiac and coronary artery
imaging, this has not been fully explored, mainly since it would

(a) (b) (c)

Fig. 10.4  Colour-​coded dual-​energy imaging of the left ventricular myocardium. (a) Stress myocardial CT perfusion acquired by dual energy (100/​140 kV)
scanning. The iodine map indicates ischaemia with nearly zero iodine concentration (0.3 mg/​ml) in the basal septum (black arrow). The other myocardial
territories show normal iodine concentration (4–​6 mg/​ml). (b) Rest myocardial CT perfusion, dual energy (100/​140 kV). The iodine map indicates normal iodine
content (3–​4 mg/​ml). (c) Delayed scan, dual energy (100/​140 kV), monoenergetic image at 40 keV, with no apparent late enhancement.
Courtesy of Dr. Ákos Varga-​Szemes, Medical University of South Carolina, Charleston, SC.
150 CHAPTER 10   Anatomy, f ract ional f l ow reserve ( FFR ) , a n d m achi n e l ea rn i n g

not remove all negative effects that are created by calcium, such as
aggravated motion artefacts.
Functional assessment of coronary
artery lesions
Relevant coronary stenoses can be ruled out very reliably if a cor-
onary CT angiography data set shows a completely normal cor-
onary artery lumen or very slight deposition of plaque. However, if
luminal narrowing is present, CT does not provide for an accurate
assessment of lesion severity. It is even less accurate for identi-
fying lesions that cause ischaemia, since the degree of luminal
narrowing and the effects on blood flow at rest and exercise do
not correlate closely. All the same, ischaemia is the main reason to
treat a coronary artery lesion and the inability to separate ‘func-
tionally relevant’ (= ischaemia-​causing) lesions from stenoses that
do not cause ischaemia has been an area of critique. In order to
improve the ability of CT to identify ischaemia-​causing lesions,
and also to possibly make lesion assessment more independent
from image quality, several new developments are undertaken.
CT myocardial perfusion imaging
The same data used for coronary computed tomography angiog-
raphy (CCTA) acquisition can be reconstructed for visualization
of the myocardium and assessment of perfusion defects at rest
or stress. During the administration of a pharmacological stress,
CT myocardial perfusion images can be acquired using ‘static’
or ‘dynamic’ protocols which are compared with rest images to
examine the presence and extent of ischaemia or scar [17]. ‘Static’
protocols are based on the acquisition of one ‘snapshot’ during the
first-​pass inflow of iodine contrast, targeted at maximum myocar-
dial enhancement for the best visualization of hypoattenuated (is-
chaemic) myocardium (see E Fig. 10.5) [18].
Dynamic perfusion involves the acquisition of multiple images
during the myocardial contrast in and outflow and allows quan-
titative blood flow analysis. The benefit of myocardial blood flow
analysis can is to detect low flow states during stress without the
presence of relative perfusion defects, as may occur in balanced
or microvascular ischaemia. The multicentre CORE320 study
was the first and largest diagnostic accuracy study of combined
CCTA and static CT myocardial perfusion for the diagnosis of
ischaemia [19]. The gold standard was defined by ≥50% inva-
sive angiography quantified stenosis with corresponding perfu-
sion deficit on single photon emission computed tomography
(SPECT). CCTA quantitative stenosis assessment achieved a
C-​statistic of 0.84 on a per patient basis, which could be signifi-
cantly improved when CT perfusion data was added (C-​statistic
0.87, P = 0.02). A more recent study evaluated 100 patients pro-
spectively undergoing CCTA, static stress perfusion and invasive
fractional flow reserve of all vessels with intermediate coronary
stenoses using the newest generation CT scanners [20]. Binary

LAD

(a) (b) (c)

Stress

(d) (e) (f)

Rest

Fig. 10.5  The upper panel shows a left anterior descending artery (LAD) with a severe non-​calcified plaque. Images of CT perfusion during stress (a–​c)
and rest (d–​f ). During adenosine stress, 3D fusion (a), short-​axis reconstruction (b) and polar plot display (c) demonstrate anterolateral hypo-​enhancement
corresponding to the LAD lesion. (d–​f ) Rest CT perfusion, with same reconstructions as stress, demonstrate normal myocardial enhancement.
Reproduced from van Rosendael AR, Dimitriu-​Leen AC, Bax JJ, Kroft LJ, Scholte A. One-​stop-​shop cardiac CT: Calcium score, angiography, and myocardial perfusion. J Nucl Cardiol.
2016 Oct;23(5):1176–​9 ((http://​creativecommons.org/​licenses/​by/​4.0/​).

obstructive stenosis evaluation by CCTA yielded a sensitively of
98% and specificity of 54% for functionally significant coronary
artery disease (CAD). When obstructive vessels were considered
‘positive’ or ‘negative’ given the presence or absence of corres-
ponding downstream ischaemia, the sensitivity of the combined
anatomical/​ functional approach stayed high (98%) while the
specificity significantly improved to 83%. Similar results were
observed on a per-​vessel bases; the sensitivity and specificity of
CCTA were 98% and 76%, respectively, which was 91% and 94%
for CCTA combined with CT perfusion imaging, respectively. Of
importance, the mean effective dose was only 2.8 mSv for CCTA
and 2.5 mSv for CT perfusion. This approach enables rule-​out of
functional significant CAD with CCTA only, with selective rule-​
in of vessels with ischaemic obstructive stenosis by CT perfusion.
Based on the severity of coronary symptoms, presence or absence
of high-​risk anatomy, and extent of ischaemia this combined CT
protocol has the potential to select patients that may benefit from
revascularization, but this requires further prognostic study. A
further addition of CT perfusion to CCTA may be in patients
with prior revascularization, since coronary stents may cause
blooming artefacts. Assessment of downstream perfusion with
CT has been reported to significantly increase concordance rates
with invasive angiography detected in-​stent restenosis [21].
Multiple studies have confirmed the ability of CT perfusion to
diagnose functionally significant CAD. A meta-​analysis including
10 studies and approximately 750 patients of CCTA combined
with CT perfusion and invasive FFR as reference standard re-
ported the sensitivity ranging from 71 to 92% and specificity from
84% to 100% (1 study including 49 patients reported 47.8%) [22].
The CATCH-​2 (Cardiac CT in the treatment of acute chest pain
2 trail) evaluated the clinical utility of CT perfusion. Patient with
a recent admission for acute chest pain but acute coronary syn-
drome ruled out were randomized to either CCTA or CCTA with
CT perfusion. Following imaging, the patients within the CCTA +
CT perfusion arm underwent 50% less invasive angiograms and
revascularizations without increased major adverse events during
1.5 years of follow-​up [23]. Future studies should further define the
optimal role of CT perfusion, but cardiac CT is emerging as an op-
timal approach for patients with anginal symptoms. A challenge of
F F R CT 151
CT perfusion is the susceptibility to motion and beam hardening
artefacts that mimic true perfusion defects. Therefore, acquisition
with the newest generation CT scanners, most important with the
fastest gantry rotation times, gives the highest quality images and
further technological improvements are anticipated.
FFRCT
Fractional flow reserve CT (FFRCT) is a computationally derived
non-​invasive tool using computational fluid dynamics for the
derivation of a three-​dimensional pressure map (see E Fig. 10.6)
allowing for the determination of pressure at any point in the cor-
onary tree. Importantly, this model can be derived on the basis of
a resting coronary CT without the administration of adenosine or
a change in underlying CTA protocols [24–​28].
The methodology has been previously described extensively
but in short, FFRCT relies on fundamental scientific principles of
computational fluid dynamics enabled by an accurate anatomical
model of the coronary arteries and myocardium, microcirculatory
resistance and coronary branching, integration of physical laws that
govern flow, as well as simulated hyperaemia intended to model
the effects of adenosine. Finally, the Navier Stokes equations that
solve for velocity, pressure and resistance for all Newtonian fluids
can be applied to provide a three-​dimensional pressure map across
the coronary tree. In addition, centralized off-​site computational
analyses have created the potential to improve anatomical model-
ling through the developing of large data sets and the maturation
of deep and machine learning. The initial studies focused on the
diagnostic performance of FFRCT compared to the invasive gold
standard of FFR. The most contemporary data is a subanalysis of
the FFRCT AUC was 0.94, which was statistically higher than CT,
SPECT, and positron emission tomography (PET). The FFRCT
per-​vessel diagnostic accuracy was 87% with a sensitivity of 90%
and a specificity of 86% [28]. SPECT per-​vessel sensitivity was only
42%. Importantly there were 13% of subjects whose image quality
on CT was inadequate for FFRCT analysis highlighting the need to
adhere to best practice cardiac CT acquisition protocol and ensure
diagnostic quality coronary CT angiography.
Fig. 10.6  A 68-​year-​old male patient with
atypical chest pain underwent coronary CTA to
exclude coronary artery disease is found to have
a moderate (50–​69%) stenosis in the mid-​LAD.
The lesion was uploaded for FFRCT analysis which
documented borderline lesion-​specific ischaemia
with an FFRCT value of 0.78.
152 CHAPTER 10   Anatomy, f ract ional f l ow reserve ( FFR ) , a n d m achi n e l ea rn i n g
Regarding clinical utility, much of the initial investigations
were focused on the potential of CTA/​FFRCT to help serve as a
gate keeper to the invasive catheterization laboratory. This was
tested in the PLATFORM Study in which two non-​overlapping
cohorts of patients referred for invasive coronary angiography
(ICA) were assigned to either undergo ICA or CTA/​FFRCT ap-
proach only undergoing ICA based on the results of the CTA and
FFRCT. The CTA/​FFRCT arm resulted in significant enrichment
of the catheterization lab with the burden of non-​obstructive
disease reduced from 73 to 12% with stable obstructive disease
and no events in the 61% of subjects in whom ICA was deferred
through 12 months [29, 30]. The real-​world clinical utility of
FFRCT is becoming increasingly established. The initial experi-
ence in the Assessing Diagnostic Value of Non-​invasive FFRCT in
Coronary Care [30–​32] registry was recently published. In it the
data it was noted that FFRCT modified treatment recommenda-
tion in two-​thirds of subjects as compared to CCTA alone, was
associated with less negative ICA, predicted revascularization,
and identified subjects at low risk of adverse events through 90
days. Longer term prognostic data is also beginning to accrue as
well. Norgaard and colleagues recently presented data on nearly
700 subjects followed for a median of 2 years and highlighted
the safety of deferral from revascularization of subjects with
FFRCT>0.80, with equivalent risk of a >50% stenosis with FFRct
>0.80 as an individual with a more modest anatomical stenosis
[33]. As well, the investigators identified a heightened risk among
those with an abnormal FFRCT who were treated with medical
REFINEMENT
TECHNIQUE
Big data and machine learning
 automized anatomic segmentation
 improved physiologic modeling
 faster turn around time
 Cloud based processing
Standardized interpretation criteria
CLINICAL TRIALS
Procedural planning
 PCI and CABG
Fig. 10.7  The potential course for Randomized trials
ongoing technological development
 cost-efficiency, and safety relative to standard NI including CTP
 “physiologic” diffuse CAD
and scientific evaluation of FFRCT.
therapy compared to those that were revascularized. To build
on the initial experiences and to help fill the gap around ran-
domized data two randomized trials have begun, one in the UK
FORECAST and the other a larger international trial PRECISE,
which will evaluate FFRct among symptomatic patients being re-
ferred for non-​invasive testing.
Recently, there has been growing interest in using FFRCT to im-
prove the efficient use of the invasive catheterization lab through
increasing the PCI/​ICA ratio and providing guidance regarding
revascularization strategies before the invasive angiogram [34].
The PCI/​ICA ratio has been shown to increase across a variety
of healthcare systems with the greatest benefit being found in
patients considered to have a higher pretest likelihood. The re-
cently published SYNTAX III trial provided some insight into
the potential of a CTA/​FFRCT strategy to guide revascularization
decision-​making [34]. Heart teams were randomized to evaluate
patients with complex CAD using either a coronary CTA/​FFRCT
strategy or a conventional ICA strategy to guide revascularization
decision-​making. The primary endpoint was a Cohen’s Kappa of
0.60 which was surpassed with an actual Kappa of 0.82 (95% CI
0.73–​0.91). This along with the SYNTAX II [35] data highlighting
the strong correlation between non-​invasive functional syntax
(CTA/​FFRCT) and invasive functional syntax (ICA/​ iFR) have
helped solidify the hypothesis that a combined anatomical and
physiological roadmap may prove helpful to the interventionalist
in guiding and optimizing revascularization decision-​ making
(see E Fig. 10.7).
% Myocardium Plaque Intensity Planner
Map
More patient-specific physiological modeling
e.g. including information on:
 plaque burden and composition
 area at risk
 vessel volume to myocardial mass ratio
Improved CT image quality
 CT technology
 CT image quality control
 standardized CT acquisition
0.80
0.84
New patient categories
 a priori high risk?
 known CAD
Numerical risk models
 patient specific treatment

Recent learnings
The clinical integration of FFRCT and ongoing work looking at
atherosclerosis imaging with CT is introducing new opportunities
to learn more about mechanisms of ischaemia and clinical risk.
There is growing data linking previously described adverse plaque
features shown to be associated with an increased risk of myo-
cardial infarction (MI) with lesion-​specific ischaemia. Ahmadi et
al recently built on these findings by noting that adverse bulky
plaques with significant low attenuating components a feature
seen in optical coherence tomography (OCT) adjudicated thin-​
cap fibroatheroma (TCFA) were associated with an increased
likelihood of FFRCT positivity with the opposite also holding true
in that FFRCT negative lesions are exceptionally unlikely to have a
significant left atrial pressure (LAP) component [36].
Future opportunities
In 2014, a computational interactive PCI planning tool was intro-
duced aimed at idealizing the extracted lumen to allow for the recal-
culation of FFR simulating the post PCI state. A small prospective
analysis of 44 subjects and 8 lesions was performed with baseline
FFR and FFRct obtained prior to PCI in a fashion similar to other
FFRCT accuracy studies but in addition FFRct was modelled fol-
lowing ‘virtual stenting’ and compared with invasively measured
FFR post PCI. These data were highly provocative with an accuracy
of 96% (sensitivity: 100%, specificity: 96% positive predictive value:
50%, and negative predictive value: 100%) [37]. While these data are
very compelling there has been a lull in further scientific validation
with further advancements in computational processing needed
to enable its more routine evaluation. With the necessary compu-
tational capacity now available, a number of studies have begun
to both look at the diagnostic performance of the planner tool as
(a) (b)
Fig. 10.8  (a) A non-​calcified plaque in the mid-​RCA segment, which causes intermediate stenosis (white arrow). (b) A total vessel plaque quantification. The red
colour denotes low-​attenuation plaque burden. The corresponding invasive coronary angiography confirms the presence of plaque with intermediate stenosis (c).
Qua n ti tati ve c orona ry pl aqu e eva luat i on 153
compared with post PCI FFR (PREDICT—​PREDICTing Post-​PCI
in Substudy of NXT and PACIFIC Subjects) but also the extent to
which the availability of such a tool would impact revascularization
decision-​making and pressure wire usage (Benefits of Obtaining
information for planning With noninvasive FFRCT prior to Invasive
Evaluation: the BOWIE study).
Quantitative coronary plaque
evaluation
CCTA allows 3-​dimenstional high-​resolution visualization of the
coronary tree. Current CCTA reporting guidelines recommend
describing the most severe stenosis within the coronary tree com-
bined with the prevalence of high-​risk plaque (defined by a lesion
with ≥2 of low-​attenuation plaque, spotty calcification, or positive
remodelling) [38]. Classification of patients’ risk by most severe
stenosis provides good prognostic value and allows more intensive
treatment plans with for more severe stenosis, including lifestyle
intervention, medical therapy, or coronary revascularization [39].
However, the risk for future major cardiovascular events is more
closely related to the total atherosclerotic burden than necessarily
the most severe stenosis [40–​42]. Using multiple imaging modal-
ities, a clear stepwise relationship exists between plaque burden and
heightened event risk [40–​42]. A quantitative approach allows more
comprehensive and detailed evaluation of the whole-​heart athero-
sclerotic burden and has therefore potential to more precisely inform
a patient’s atherosclerotic risk. For instance, in addition to overall
atherosclerotic burden, plaque composition, morphology, location,
and volume have all shown prognostic value that cannot easily be in-
tegrated in a visual CCTA reports [43, 44]. Current semi-​automated
software packages with automated lumen and vessel wall detection
allow for plaque analysis of the entire coronary tree (see E Fig. 10.8)
and have shown to accurately quantify atherosclerosis [45].
(c)
154 CHAPTER 10   Anatomy, f ract ional f l ow reserve ( FFR ) , a n d m achi n e l ea rn i n g

The ICONIC (Incident COroNary Syndromes Identified by
Computed Tomography) evaluated the incremental role of quan-
titative plaque evaluation above visual stenosis assessment [46].
Independent from the volume of plaque, age, sex, and cardio-
vascular risk factors, plaque composed of fibro-​fatty or necrotic
cores, high diffuseness of disease, and high cross-​sectional plaque
burden, were among the atherosclerotic features independently
predictive for the occurrence of acute coronary syndromes after
CCTA. A further illustration of detailed plaque assessment is
provided in E Figure 10.9. Histopathological evaluation of pa-
tients who died from sudden coronary death has demonstrated
that ruptured coronary plaque had a large lipid-​laden core, with
a thin inflamed fibrous cap [47]. CCTA defines plaque compos-
ition on plaque attenuation differences, where lower attenuation
plaques correlate with ‘vulnerable’ lesions. There is an increasing
interest in the quantification of low-​attenuation plaque, since
multiple studies demonstrated that this type of plaque portents
higher risk for future major events than calcified plaque [46,
48, 49]. Similarly, this type of plaque seems to be most suscep-
tible to reduce in volume following statin therapy [50, 51]. As
current, quantification of plaque is time consuming due to the
semi-​automated nature of software packages. Future studies will
examine the exact role of automated plaque analysis for individu-
alized precise risk estimation.
For diagnostic purposes in patients with symptoms suspect for
myocardial ischaemia, a comprehensive atherosclerotic evalu-
ation has shown to be more accurate in diagnosing haemo-
dynamically significant CAD compared with stenosis assessment
[52, 53]. Atherosclerotic plaque increases vascular resistance and
reduces the capability of a vessel to dilate and increase flow fol-
lowing adenosine infusion, all limiting coronary pressure and
flow distal in the artery [54]. At a certain threshold, coronary
flow will be to too low to perfuse the myocardial and the patient
may experience anginal symptoms. The CREDENCE (Results
from the Computed TomogRaphic Evaluation of Atherosclerotic
DEtermiNants of Myocardial IsChEmia) will examine the diag-
nostic accuracy of a comprehensive quantitative coronary artery
evaluation with CCTA for the diagnosis of invasively diagnosed
ischaemia.
Radiomics and artificial intelligence
in cardiac CT
Beyond quantifying volumes of pathologies on radiological im-
ages, new analytic techniques such as radiomics try to enu-
merate the texture and shape of abnormalities [55]. Radiomics
is a feature generative technique which quantify concepts such as
heterogeneity with the use of mathematical formulas to numeric-
ally describe the composition and structure of pathologies [56].
Radiomics has been shown to identify napkin-​ring sign plaques
which are precursors of rupture prone plaque. Using radiomics it
is also possible to identify positron emission photography activity
from conventional CT images [57], see E Figure 10.10.
Radiomics has also be applied to the analysis of myocardium
on CT and on MRI [58, 59] and for the analysis of perivascular

(a) LAD (c)

Vessel wall
Lumen

LAP
(b)

SC

Fig. 10.9  (a) Quantitative analysis of high-​risk lesions before occurrence of STEMI. Multiplanar reconstruction of a left anterior descending artery
(LAD) lesion showing high risk atherosclerotic features. The cross-​sectional view demonstrated a large low-​attenuation area with a spotty calcification
(b). The next day the patient developed ST-​s egment elevation myocardial infarction for which he underwent successful percutaneous coronary
intervention.
Source data from van Rosendael AR, Al’Aref SJ, Dwivedi A, Kim TS, Pena JM, Dunham PC, et al. Quantitative Evaluation of High-​Risk Coronary Plaque by Coronary CTA and
Subsequent Acute Coronary Events. JACC Cardiovasc Imaging. 2019 Aug;12(8 Pt 1):1568–​71.
 Re f e re n c e s 155

Fig. 10.10  Representative curved multiplanar and volume rendered CT images of three coronary plaques corresponding to specific invasive and
radionuclide imaging markers of plaque vulnerability. (a) A coronary lesion showing attenuation on intravascular ultrasound. (b) Depicts a coronary
plaque which was positive for optical coherency tomography thin-​cap fibroatheroma. (c) A coronary lesion which showed positivity on NaF18-​positron
emission tomography. The corresponding best radiomics parameters from CT images all outperformed the best conventional parameters to identify these
pathologies [57].

fat tissue on CT [60]. The vast amount of information provided
by radiomics can also be inputs to machine learning models to
increase the capabilities of conventional CT imaging to identify
vulnerable plaques [61]. Machine learning is a field of artificial
intelligence gains new inferences by applying computer algo-
rithms with the ability to learn from data without being expli-
citly programmed [62]. These algorithms have the potential to
better model unique cases and therefore infer results specific
to each case rather than being generally true to the population.
However vast amounts of data are needed for these methods.
These methodologies—​ especially deep-​
learning—​ can also use
the raw images as inputs rather than defining parameters from
images beforehand as radiomic models do. These artificial intel-
ligence techniques have been shown to improve automatic seg-
mentation algorithms [63], and also to help clinical diagnosis of
significant CAD [64].

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 SECTION 3

Valvular heart disease

11 Aortic valve stenosis  161

Philippe Pibarot, Helmut Baumgartner, Marie-​Annick Clavel, Nancy Côté, and Stefan Orwat
12 Aortic valve regurgitation  181
Julien Magne and Patrizio Lancellotti
13 Mitral valve stenosis  191
Ferande Peters and Eric Brochet
14 Mitral valve regurgitation  199
Daniel Rodríguez Muñoz, Kyriakos Yiangou, and José Luis Zamorano
15 Tricuspid and pulmonary valve disease  211
Denisa Muraru and Elif Leyla Sade
16 Multiple and mixed valvular heart disease  223
Philippe Unger and Madalina Garbi
17 Intraoperative transoesophageal echocardiography for valvular surgery  233
Joseph F. Maalouf and Hector I. Michelena
18 Valvular prostheses  251
Luigi P. Badano and Denisa Muraru
19 Endocarditis 271
Daniel Rodríguez Muñoz and Álvaro Marco del Castillo

Contents
Introduction  161
Assessment of aortic valve
morphology  161
Aetiology of AS  161
Quantification of AS anatomic severity  163
Quantitation of AS haemodynamic
severity  164
Echocardiographic parameters of AS
haemodynamic severity  164
Transvalvular jet velocities and pressure
gradients  164
Discordant grading of AS severity and role of
multimodality imaging  170
Follow-​up interval and assessment of AS
progression  171
Assessment of cardiac damage associated
with AS  173
Left ventricular damage  173
Damage of other cardiac chambers  174
Integrative approach for the management
of AS  175
Asymptomatic severe AS  175
Conclusion  177
CHAPTER 11
Aortic valve stenosis
Philippe Pibarot, Helmut Baumgartner,
Marie-​Annick Clavel, Nancy Côté, and
Stefan Orwat
Introduction
Aortic valve stenosis (AS) is the most prevalent valvular heart disease and is increas-
ingly diagnosed in high-​income countries due to an ageing population but also to
more widely available diagnostic tools. The prevalence of AS is estimated at ~0.5% in
the general population, ~2–​3% in the population over 65 years old [1]‌. This disease
starts with mild fibrosis and calcification and thickening of the aortic valve leaflets
without obstruction of blood flow, which is termed aortic sclerosis, and evolves over
the years to severe calcification with impaired leaflet mobility and significant obstruc-
tion to blood flow, i.e. AS [2]. The clinical presentation includes the spectrum from
asymptomatic patients with different grades (mild, moderate, severe) of AS severity to
symptomatic patients with severe AS who may present with preserved or already de-
pressed LV function and/​or reduced transvalvular flow. Accurate assessment of the AS
anatomic and haemodynamic severity as well as the extent of cardiac damage associ-
ated with AS are crucial for the therapeutic management of patients with AS. Doppler-​
echocardiography is the method of choice providing a comprehensive non-​invasive
diagnostic work-​up of these patients [3]. E Table 11.1 describes the recommended
measures and findings to include in the standard echocardiography report. Other
imaging modalities may provide important incremental information in patients with
inconclusive results at echocardiography.
Assessment of aortic valve morphology
The morphological assessment of the aortic valve is best performed in a parasternal
short-​axis (PSAX) view. Additional information on aortic valve morphology and mo-
bility can be obtained from the parasternal long-​axis (PLAX), the apical three-​chamber
(A3C) and five-​chamber (A5C) views (E Table 11.1) [3]‌. Transoesophageal echocardi-
ography (TOE) is superior to transthoracic echo in assessing aortic valve morphology.
The assessment of aortic valve morphology is crucial and allows to identify the aetiology
of AS and to quantify its anatomic severity.
Aetiology of AS
Congenital AS
Congenital AS is typically encountered in the form of a bicuspid aortic valve (E Fig. 11.1),
although unicuspid, tricuspid, and quadricuspid forms are also encountered. Bicuspid
aortic valve (BAV) is the most common congenital cardiac defect, affecting 0.5–​2% of the
162 CHAPTER 11   Aortic valve st enosis

Table 11.1  Requirements for a standard echocardiographic report of a patient with aortic stenosis

Items to include in the standard echocardiographic report for a Image and signal acquisition check-​list
patient with AS
1. Aetiology of aortic stenosis 2D/​3D assessment of the valve morphology in PLAX, PSAX, and apical views.
TOE or MSCT if aetiology unclear with TTE
2. Morphology of the aortic valve and degree of valve calcification Degree of leaflet thickening and calcification and assessment of leaflet
mobility on 2D/​3D PLAX, PSAX, and apical views
3. Quantification of stenosis severity including the following measurements: Continuous wave Doppler performed from any imaging window that obtains
  Peak jet velocity across the aortic valve the highest velocity, with the densest, most uniform continuous wave
  and spectral profile
  Mean gradient across the aortic valve Pulsed-​wave Doppler of laminar flow just proximal to flow acceleration. The
  (Specify the echocardiographic window used to measure the velocity) modal velocity should be traced to measure the LVOT VTI
  Stroke volume index (flow state) LVOT diameter measured between aortic annulus and 5–​10 mm below
  Aortic valve area by continuity equation annulus on videoclip and image frame providing the largest diameter
4. Left ventricular size and function: AP4C and PA2C views optimized and focused on the LV for assessment of
  LVEF Biplane Simpson LV volumes.
  Diastolic dysfunction grade Pulsed-​wave Doppler of mitral flow at the tip of leaflets
  Left mass index and relative wall thickness Doppler-​tissue imaging of lateral and medial mitral annulus
Low PLAX view for measurement of LV dimensions
5. Concomitant valve diseases: Multiwindow, multiplane colour Doppler imaging
  Aortic regurgitation
  Mitral regurgitation
  Tricuspid regurgitation
6. Pulmonary artery pressure and right ventricular function Continuous wave Doppler of TR velocity
AP4C views optimized and focused on the RV
PLAX = parasternal long-​axis view; PSAX = parasternal short-​axis view, AP4C = apical 4-​chamber; AP2C = apical 2-​cahmber; RV = right ventricle; TR = tricuspid regurgitation;
VTI = velocity time integral.

population and can be associated with other congenital lesions the orifice has a characteristic ‘fish mouthed’ appearance. Colour
such as coarctation of the aorta [2, 4]. The most common variant Doppler may also be useful to identify the numbers of commis-
is the fusion between the right and left coronary cusps (approxi- sures (two in bicuspid versus three in tricuspid). Frequently BAV
mately 80%), which is also referred to as anterior-​posterior leaflet features cusps of different size. During diastole, the raphe, which
type (or Type 1), followed by a fusion of the right and the non-​ corresponds to an area of thickening at the site of the fused leaf-
coronary cusps (approximately 19%), the right-​left leaflet type lets, can make the valve appear tricuspid. The distinction between
(or Type 2). Fusion between the left and non-​coronary cusps is a tricuspid and a BAV with a raphe is not always easy and TOE
rare (approximately 1%, Type 3) [4]‌. To establish the diagnosis, may help to differentiate between both entities. A symmetrical
the valve must be visualized in the PSAX view in systole where bicuspid without raphe is often referred to as a true BAV and has
only two identifiable sinuses of Valsalva. Suggestive signs of a BAV
are doming of the cusps in the PLAX view or an eccentric diastolic
Bicuspid
closure line in the M-​mode. The most frequent associated finding
Normal Rheumatic Tricuspid True Bicuspid Calcific AS
aortic value (non-calcific) Calcific AS Calcific AS with raphe is a dilatation of the ascending aorta probably secondary to both
AS (Type 0) (Type 1) abnormalities of the aortic media as well as proximal aortic flow
and consequent wall stress. It can occur at the sinus level but also
be restricted to the tubular part. The ascending aorta can be con-
sidered as dilated if >40 mm or 21 mm/​m2.

Fig. 11.1  Aetiologies of AS transthoracic and transoesophageal
echocardiography. Transthoracic and transoesophageal 2D short-​axis views of
the aortic valve with different aetiologies of AS.
AS = aortic stenosis.
Rheumatic AS
Rheumatic AS is a major health issue in low income countries. The
valve is characterized by thickening predominantly at the edges of
the cusps and commissural fusion (E Fig. 11.1). Frequently, con-
comitant aortic regurgitation is present and in most cases also the
mitral valve is affected.
Calcific AS
Calcific AS is the most common form of AS observed in adult
patients and is characterized by thickened and calcified cusps

with reduced motion (E Fig. 11.1). Echocardiographically,
echodense zones may correspond to zones of calcification.
However, ultrasound is rather limited in differentiating between
severe fibrosis and calcification and is with this regard inferior
to other techniques such as multislice computed tomography
(MSCT). This entity was formerly called degenerative AS it was
thought to be a degenerative process [2]‌. However, it has been
demonstrated that the underlying disease process is active with
similarities to atherosclerosis and ultimately leads to valve calci-
fication: calcific AS is therefore the more appropriate term. BAVs
tend to calcify earlier than tricuspid valves. The distinction be-
tween bi-​and tricuspid valve may be difficult when extensive
calcification is present.
Quantification of AS anatomic severity
Calcification is the main culprit lesion of calcific AS although
valvular fibrosis also contributes to the stenosis severity. It is
thus important to quantitate the degree aortic valve calcifica-
tion, which in fact represents in calcific AS the anatomic se-
verity of AS and correlates strongly with the haemodynamic
severity of AS. This is not the case in young adults with con-
genital or rheumatic AS where valve area primarily represents
the severity of AS.
Semi-​quantitative assessment of aortic valve
calcification by echocardiography
Echocardiography can be used to semi-​quantitatively assess
aortic valve calcification by description of echodense areas
(E Table 11.1). For this purpose, the aortic valve is best viewed in
(a)
Aorta
(b)
Aorta
As ses sm en t of aorti c va lve morph ol o g y 163
a PSAX view, although the PLAX and the A3C and A5C views are
also helpful. The following classification has been proposed [5]‌:
◆ Mild calcification: isolated, small echodense spots
◆ Moderate calcification: multiple bigger spots
◆ Severe calcification: extensive thickening and calcification of
all cusps (E Fig. 11.1).
Although this classification has been shown to be of prognostic
value, MSCT is superior in quantifying the extent of aortic valve
calcification and has become the gold standard for this purpose
(E Fig. 11.2).
Quantitation of aortic valve calcification by MSCT
MSCT may be used to quantitate the amount of aortic valve calcifi-
cation and the anatomic severity of AS. Non-​contrast MSCT scan
with voltage of 120 mV and acquisition triggered at 70% to 80% of
the R-​to-​R-​wave interval on the electrocardiograph (ECG) allows
visualization of aortic valve calcification (AVC) and its quantita-
tion using the modified Agatston method (E Fig. 11.2) [6]‌. It
is the most frequently used method to calculate the AVC score.
Areas with ≥4 adjacent pixels having a density >130 Hounsfield
units are considered being calcification and are expressed as a
score in Arbitrary Units (AU) using a semi-​automated software.
Differentiating calcifications belonging to aortic valve versus to
the LV outflow tract or the aortic root may sometimes be difficult.
Nevertheless, MSCT quantitation of AVC allows correct identifi-
cation of haemodynamically severe AS with a positive predictive
value close to 90% in men and in women [7, 8]. Given that women
reach severe AS with relatively less amount of calcification than
LVOT
Fig. 11.2  Multislice non-​contrast CT to
quantitate aortic valve calcification in a
man showing very severe valve calcification
(a) and in a woman showing moderate
calcification (b).
AVC = aortic valve calcification; LVOT = LV
LVOT outflow tract.
164 CHAPTER 11   Aortic valve st enosis
men, sex-​specific thresholds must be used to identify severe AS:
AVC ≥1,200 AU in women and AVC≥2,000 AU in men. These
thresholds have been initially proposed by Clavel et al. [7] and
subsequently validated in the context of a multicentre study [8].
In patients with a small aortic annulus (e.g. women) or with
large aortic annulus (e.g. patients with bicuspid valve), the AVC
may not adequately reflect the AS haemodynamic severity and
the use of AVC density, i.e. AVC divided by the cross-​sectional
area of the aortic annulus measured by echocardiography, has
been proposed in these patients to identify severe AS with fol-
lowing sex-​specific thresholds: ≥300 AU/​cm2 in women and ≥500
AU/​cm2 in men.
Anatomically severe AS defined with the use of AVC or AVC
density thresholds presented here is strongly associated with the
presence of haemodynamically severe AS, with faster progres-
sion of AS, and with worse clinical outcomes, including mortality
and need for aortic valve replacement (AVR) [7, 9, 10]. The 2017
European Society of Cardiology (ESC) guidelines for the man-
agement of valvular heart disease recommend using the MSCT-​
derived AVC score for the evaluation of patients with low-​gradient
AS in an integrated approach [11]. Severe AS may be considered
very likely when AVC score ≥3,000 in men and ≥1,600 in women,
likely when ≥2,000 and ≥1,200, and unlikely when <1,600 and
<800, respectively (E Table 11.2).
Anatomic aortic valve area by planimetry
Planimetry of the anatomic orifice area of the valve, primarily
by 2-​D transthoracic echocardiogram (TTE) or TOE has also
been proposed. However, the orifice of a stenotic aortic valve fre-
quently represents a complex three-​dimensional structure that
cannot be reliably assessed with a planar 2D-​image. The presence
of valvular calcification further limits an accurate delineation of
the aortic valve orifice. Thus, this method has not been accepted
as a routine measurement. Nevertheless, it might be useful in
selected patients, particularly in patients with congenital AS and
less calcified valves. The anatomic aortic valve area (AVA) can
also be measured by contrast MSCT or cardiac magnetic reson-
ance (CMR) [12].
Quantitation of AS haemodynamic
severity
Echocardiographic parameters of AS
haemodynamic severity
The normal AVA is in the range of 3–​4 cm2. Under normal con-
ditions, the transvalvular flow is laminar with a peak transaortic
flow velocity typically less than 2 m/​s. With narrowing of the
aortic valve, the transvalvular jet velocities increase. As long as
normal flow rates are maintained, transvalvular velocity continu-
ously increases with reduction of the AVA and therefore provides
a relatively robust, although highly flow-​dependent, measure of
stenosis severity (E Tables 11.1 and 11.2).
Transvalvular jet velocities and pressure
gradients
Measurement of transvalvular velocity and gradients
Transvalvular jet velocities are measured by recording the max-
imal transvalvular flow signal using continuous wave (CW)
Doppler (E Figs. 11.3 and 11.4 and E Tables 11.1 and 11.2).
A peak jet velocity ≥4 m/​s is consistent with severe AS. With
increasing AS severity, the peak of the transaortic velocity oc-
curs later during systole and a ratio of time to peak velocity/​LV
ejection time >0.36 is suggestive of significant AS (E Fig. 11.4
and E Table 11.2). Transvalvular gradients can be derived from
transaortic velocities using the simplified Bernoulli equation (E
Table 11.2). The mean gradient can be determined by averaging
the instantaneous gradients over the entire systole and represents
one of the most frequently used parameters to quantitate AS se-
verity (E Fig. 11.4). A mean gradient of ≥40 mmHg is consistent
with severe AS (E Table 11.2).
When comparing Doppler derived gradients with invasively
measured catheter gradients it has to be kept in mind that dif-
ferent values may be provided by these two techniques. By the
invasive technique, the most easily provided measurement of the
peak-​to-​peak gradient represents the pressure difference between
peak systolic LV pressure and peak systolic aortic pressure. Since
the two pressure peaks do generally not occur at the same time
this pressure difference does actually not exist at any time and can
therefore not be calculated from Doppler velocities. In contrast,
the most easily provided measurement by Doppler is the peak in-
stantaneous gradient. Obtained from the peak velocity, this value
represents the highest instantaneously occurring pressure differ-
ence between the LV and the aorta in systole. The peak or mean
gradients obtained by Doppler echocardiography may be higher
than those obtained invasively because of the pressure recovery
phenomenon.
Pitfalls in the measurement of transvalvular velocity
Technical errors
For an accurate measurement of the transaortic jet velocity, the
Doppler beam needs to be aligned with the stenotic aortic jet
(E Fig. 11.3). Alignment errors lead to an underestimation of
the true velocity, and consequently of the calculated gradients
resulting in an underestimation of AS severity. Consequently, a
meticulous search of the highest transvalvular velocity using a
multi-​window interrogation with CW Doppler is mandatory (E
Fig. 11.3). This requires a comprehensive Doppler study that is
not only limited to the apical window but also includes right para-
sternal, suprasternal, and sometimes subcostal approaches using
a small, dedicated CW Doppler transducer (pencil probe or Ped-​
off transducer). Significantly higher aortic jet velocities can be re-
corded from non-​apical windows, and in particular from the right
parasternal window in up to 50% of the cases (E Fig. 11.3) [13].
Because all derived indices of AS rely on adequate measurements
of aortic jet velocity, it is crucial to ensure that the transvalvular
Doppler spectrogram is not underestimated.
 Qua n ti tati on of AS ha emody na m ic sev e ri t y 165

Table 11.2  Parameters for AS severity grading

AS severity parameter Imaging Formula/​method Concept/​limitations Mild AS Moderate Severe AS

modality criteria AS criteria criteria
Flow-​Dependent Parameters
Peak Aortic Jet Velocity TTE Direct measure Velocity increases with AS stenosis 2.0–​2.9 3.0–​3.9 ≥ 4
(m/​s) severity/​Highly flow dependent (≥ 5.5)*
Mean transvalvular TTE ΔP = 4×VAS2 Pressure gradient calculated from 10–​19 20–​39 ≥ 40
gradient (mmHg) velocity using the simplified (≥ 60)*
Bernoulli formula/​Highly flow
dependent
Less flow-​dependent parameters
Aortic valve area (cm2) TTE AVA = [CSALVOT × Effective AVA calculated by continuity 1.51–​2.0 1.01–​1.50 ≤1.0
VTILVOT] /​VTIAS equation/​Subject to measurement (≤0.60)*
errors
Aortic valve area Index TTE AVAi = AVA/​BSA Accounts for variability in body size by 0.91–​1.20 0.59–​0.90 ≤0.60
(cm2/​m2) indexing for BSA/​May overestimate AS ≤0.50†
severity in obese people
Doppler velocity index TTE DVI = VTILVOT/​VTIAS Simplification of the continuity ≥0.35 26–​0.350 ≤0.25
(velocity ratio) equation by eliminating LVOTAREA
from the continuity equation/​May
not provide accurate estimation of
AS severity in patients with small or
large LVOT
Energy loss coefficient& TTE ELC = (AVA × AA) /​ Accounts for pressure recovery by 1.51–​2.0 1.01–​1.50 ≤1.0
(cm2) (AA–​ AVA) correcting the AVA for the size of the
(Not used in clinical aorta/​Subject to measurement errors
practice)
Energy loss index& TTE ELI = ELC/​BSA Indexation of ELC for body size/​May 0.91–​1.20 0.59–​0.90 ≤0.60
(cm2/​  m2) overestimate AS severity in obese
(Not used in clinical people
practice)
LV per cent stroke work TTE %SWL = 100 [×ΔP /​ Proportion of LV pressure that is lost –​ –​ ≥25
loss& (%) (ΔP + SBP)] across the obstructed aortic valve/​Lack
(not used in clinical of clinical validation
practice)
Aortic valve resistance& TTE = 1333× [ΔP /​ Resistance to flow caused by AS –​ –​ ≥280
(dynes/​s/​cm2) (SV/​LVET)] assuming the hydrodynamics of a
(Not used in clinical tubular (non-​flat) stenosis/​Subject to
practice) measurement errors. No evidence of
superiority vs. AVA
Flow-​independent parameters
Projected aortic valve DSE AVAProj=AVARest + Estimates the AVA at normal flow 1.51–​2.0 1.01–​1.50 ≤1.0
area at normal flow rate§ [(AVAPeak-​AVARest)/​ rate using the AVA/​Q linear regression
(cm2) (QPeak-​Qrest)] × equation/​Subject to measurement
(250-​QRest) errors. Requires a minimum 15%
increase in Q to be calculated
Aortic valve calcification Non-​contrast Direct measure Quantitates valve calcification by –​ –​ Very likely:
(AU) MSCT counting areas of four adjacent pixels Women ≥1,600
with density >130 Hounsfield units/​ Men ≥3,000
Does not account valvular fibrosis Likely:
Women ≥1,200
Men ≥2,000
Unlikely:
Women <800
Men <1,600

(continued)
166 CHAPTER 11   Aortic valve st enosis

Table 11.2 Continued

AS severity parameter Imaging Formula/​Method Concept/​limitations Mild AS Moderate Severe AS

modality criteria AS criteria criteria
Aortic valve calcification Non-​contrast AVCd = AVC/​Aortic AVC score indexed to the cross-​ –​ –​ ≥300
density§ MSCT annulus area sectional aortic annulus area measured Women
(AU) by echocardiography/​Does not ≥500
account valvular fibrosis. Subject to Men
measurement errors
* Thresholds for the definition of very severe AS.
† Cut-​off used in setting of obesity (Body mass index<30 kg/​cm2).
¶
95% specific thresholds are: 1,700 AU women and 3400 AU in men and sensitive thresholds are 800 AU in women and 1700 AU in men.
§
Parameters that are not used in routine practice but that may provide incremental information for therapeutic management in some patients.
&
Parameters with limited clinical use.
AA = cross-​sectional area of the aorta measured 1 cm downstream of the sino-​tubular junction; AS = aortic stenosis; AVA = aortic valve area; AVARest AVA at rest; AVAPeak = AVA
at peak dobutamine stress; AVAProj = projected AVA at normal flow rate; AVC = aortic valve calcification; AVCd = AVC density; BSA = body surface area; CSA; cross-​sectional area;
ΔP = mean transaortic pressure gradient; DSE = dobutamine stress echocardiography; DVI = Doppler velocity index; ELC = energy loss coefficient; ELI = energy less index; LVET =
LV ejection time; LV = left ventricle; LVOT = LV outflow tract; MSCT = multislice computed tomography; Q = mean transvalvular flow rate; QRest = Q at rest; QPeak = Q at peak
dobutamine stress; SBP = systolic blood pressure; SV = stroke volume; TTE; transthoracic echocardiography; %SWL = percent stroke work loss; VAS = peak velocity of the AS jet;
VTIAS = velocity-​time integral of the AS jet; VLVOT = peak velocity in the LV outflow tract; VTILVOT = velocity-​time integral in the LV outflow tract.

Another reason for the inaccurate estimation of gradients is
neglecting proximal velocity when these are elevated or not sig-
nificantly lower than the distal one. The most simplified and gen-
erally used version of the Bernoulli equation neglects the velocity
proximal to the stenosis (E Table 11.2). This is appropriate in
most cases since this velocity commonly does not exceed 1 m/​s
and then does not significantly affect the calculation. However,
in settings with significantly higher proximal velocity such as pa-
tients with narrow LV outflow tract or patients with high flow
rates due to concomitant aortic regurgitation or other reasons,
neglecting this velocity may result in significant overestimation
of the transvalvular gradient.
Confusion with other signals
Another possible pitfall is to mistake the aortic jet CW Doppler
signal with an eccentric mitral regurgitation (MR) or even a tri-
cuspid regurgitation (TR) signal (E Fig. 11.4). When hyper-
trophic cardiomyopathy is coexisting, the differentiation of the

Suprasternal view

Right parasternal view

Apical view
Fig. 11.3  Multi-​window continuous wave
Doppler interrogation for recording of the highest
Subcostal view
transaortic velocity.
 Qua n ti tati on of AS ha emody na m ic sev e ri t y 167

two components of obstruction (subvalvular vs. valvular) leading
to increased outflow tract velocities may be difficult: the typical
shape of the signal in hypertrophic obstructive cardiomyopathy
(late-​peaking dagger-​shaped appearance) and the colour Doppler
view may be of help to distinguish the signals (E Fig. 11.4).
Arrhythmia
In the presence of arrhythmia, the gradients vary from beat to
beat. In particular, atrial fibrillation is not uncommonly encoun-
tered in patients with AS. In this setting, it is usually recom-
mended to average gradient and velocity measurements over
5–​10 consecutive beats. In case of premature beats, the following
beat will provide high non-​representative velocities and gradients
and these must be avoided.
Pressure recovery
Pressure recovery may explain some discordance between
echocardiographically and invasively determined transvalvular
gradients and AVA. From a haemodynamic perspective, flow ac-
celerates across the stenotic aortic valve to a maximum at the level
of maximal flow contraction, which is called the vena contracta.
This represents the zone of lowest pressure (potential energy) and
highest velocity (kinetic energy). After this point, flow decelerates
and part of the kinetic energy is reconverted into pressure down-
stream from the stenotic orifice in the ascending aorta. Since echo-
cardiography measures the peak velocity (occurring at the level of
the vena contracta), the Doppler gradient may be higher than the
actual net pressure drop across the stenosis, which is measured by
catheterization. While the phenomenon is of negligible magnitude
in many cases encountered in clinical practice since turbulences
followed by dissipation of kinetic energy into heat therefore pre-
cluding significant recovery of pressure, it may become relevant
in the presence of a moderate-​to-​severe AS and a small ascending
aorta that reduces the occurrence of turbulences [14]. In this latter
setting, significantly higher transaortic gradients may be recorded

(a) (b) (c) (d)

(e) (f) (g)

Fig. 11.4  Key measurements and pitfalls for quantitation of AS severity by echocardiography. (a) Measurement of LVOT diameter in the zoomed parasternal
long-​axis views. Several locations have proposed for performing this measurement in the LVOT (yellow arrows): ~10 mm below (1), ~5 mm below (2), just
(~ 2 mm) below (3), or at the level of (4) the aortic annulus. In this patient, the LVOT diameter measured 5–​100 mm below the annulus is smaller than the
diameter measured at—​or close to—​the annulus. (b) When extensive calcification is present in the LVOT, it is important to exclude these calcifications from
the measurement of LVOT diameter (yellow arrows) to avoid underestimation. (c) For the measurement of the LVOT velocity-​time integral by pulsed-​wave
Doppler, the objective is not to obtain the maximum velocity (as for aortic jet velocity by continuous wave Doppler) but rather the modal velocity. It is thus
recommended to trace the velocity (blue tracings) not on the top of the envelope (left panel) but somewhat inside the envelope with avoidance of the
spectral distribution at the top (right panel). (d) LVOT flow acceleration with dagger-​shaped envelope. In such case, the tracing of the velocity would lead to
major overestimation of SV and AVA. (e) For measurement of aortic valve velocity and gradients, the tracing should be performed at the top of the envelope
with optimal adjustment of Doppler gain and exclusion of the hairy signals. The ratio of the acceleration time (AT) to LV ejection time (LVET) may be used to
corroborate AS severity. (f) Mistaking the tricuspid regurgitation (left panel) or mitral regurgitation signal for the aortic velocity signal (right panel) may result in
important overestimation of transaortic velocity and gradient (20 versus 10 mmHg in this case). (g) Multiwindow interrogation by continuous wave Doppler
is key to obtain the maximum velocity and gradients. And in up to 50% of the cases, the maximum velocity is obtained at the right sternal border window.
However, with the signal obtained at the right sternal border, there is often an important background noise and attention should be paid not to include a
portion of the envelope that occurs after the valve closing (yellow arrow, left panel) click; this would indeed result in overestimation of aortic valve flow velocity-
time tegral. The tracing should be ended at the level of the click (right panel).
168 CHAPTER 11   Aortic valve st enosis

echocardiographically than invasively. In this case, the invasive
gradient rather reflects the burden to the left ventricle and is clin-
ically more relevant.
Flow dependence
Transaortic jet velocities and gradients are highly flow-​dependent.
In the presence of associated aortic regurgitation, high cardiac
output states such as anaemia, hyperthyroidism, or arterio-
venous shunts, transaortic flow velocities may be increased and
overestimate the actual AS severity. On the other hand, in the
presence of low-​flow state, the velocities and gradients may be
‘pseudonormalized’ and underestimate the AS severity [15].
Effective aortic valve area by continuity equation
Concept and calculation of the effective aortic valve area
AVA is a relatively—​although not entirely—​flow-​independent
variable that is calculated using the continuity equation (E Table
11.2 and E Fig. 11.5). It is based on the principle of the conser-
vation of mass: flows through the left ventricular outflow tract
(LVOT) and through the stenotic aortic valve are equal. Flow is
given by flow cross-​sectional area multiplied by velocity. By cal-
culating the flow in the LVOT and dividing it through the velocity
across the stenosis, the effective AVA can be estimated (E Table
11.2 and E Fig. 11.5). An AVA <1.0 cm2 suggests severe AS. In
patients with small or large body size, it is recommended to index
AVA for body surface area; an indexed AVA < 0.6 cm2/​m2 sug-
gests severe AS. It has to be kept in mind that the effective AVA,
which represents the cross-​sectional area of the vena contracta is
smaller than the anatomic AVA (area of the valve orifice) due to
flow contraction (E Fig. 11.6) [16]. Hence, if the anatomic AVA
is for e­ xample 1.1 cm2 the effective AVA may be 0.9 cm2.
The stroke volume (SV) at the level of the LVOT is calculated by
multiplying the cross-​sectional area (LVOTArea) by the velocity-​time
integral VTILVOT. SV should also be indexed to body surface area
(BSA) as SVi. Cardiac output (CO) is calculated by multiplying heart
rate (beats per minute) by SV. Similarly, the SV at the level of the
stenotic valve is defined as the product of AVA and VTIAS (E Fig.
11.3). The effective AVA is then obtained by dividing the SV meas-
ured in the LVOT by the VTIAS (E Table 11.2 and E Fig. 11.5).

(a)

Fig. 11.5  Aortic valve effective area by

continuity equation. (a) The standard (b)
continuity equation method to calculate the
effective AVA. (b) The use of the continuity
equation where the cross-​sectional area is
obtained by 3D echocardiography or contrast
MSCT instead of 2D echocardiography.
AVA = aortic valve area; CSA = cross-​sectional area;
LVOT = LV outflow tract; LVOTd = LVOT diameter;
VTIAS = velocity-​time integral of the AS jet; VTILVOT =
velocity-​time integral in LV outflow tract.

AA
AOA
EOA
LVOT
PLVOT
Pressure ∆Pmax ∆Pnet
PR
Fig. 11.6  Flow convergence and pressure recovery.
AA = cross-​sectional area of the aorta at 1 cm downstream of the sino-​tubular
junction; AOA = anatomic orifice area; ΔP = transaortic pressure gradient; ΔPmax =
maximum ΔP obtained at the level of the vena contracta; ΔPnet = net ΔP, i.e. ΔP
including pressure recovery; EOA = effective orifice area; PLVOT = blood pressure in
LVOT; PR = pressure recovery.
Adapted with permission from: Pibarot P and Dumesnil JG. The clinical significance of
pressure recovery in aortic stenosis. In: Cardiology 3rd Edition. Editors: Crawford MH,
DiMarco JP, Paulus WJ. (ISBN 978-0-7234-3485-6) Publisher: Elsevier; chapter 96C, section
6, pages 1308–11, 2010.
CSALVOT is determined after measurement of the LVOT diam-
eter (LVOTDiam), with the assumption of a circular shape of the
latter. LVOTDiam is measured in early to mid-​systole and is best
visualized in a PLAX zoomed view. VTILVOT is measured with
pulsed-​wave (PW) Doppler proximally to the aortic valve in
A5C and A3C views, and VTIAS is determined from the CW peak
transaortic velocity signal (E Tables 11.1 and 11.2, E Figs. 11.3
to 11.5) [3, 17]. Several cardiac cycles have to be averaged, espe-
cially in patients with arrhythmias.
Pitfalls in the assessment of the effective aortic valve area
The simplified assumptions of a circular outflow tract and of a lam-
inar flow profile as well as measurement errors of the different com-
ponents in the equation may result is inaccurate AVA calculations.
LVOT velocity
For measurement of LVOT velocity, the PW sample volume should
be placed 5–​10 mm proximal the aortic annulus plane to avoid
the zone of flow convergence. Any angle between the Doppler
beam and LVOT can result in underestimation of VTILVOT, and
therefore of SV and AVA. Ideally, a smooth velocity curve with
minimal spectral dispersion should be obtained. The VTILVOT
is measured by tracing the dense modal velocity (not the faint
higher velocity profile) throughout systole (E Fig. 11.4) [17].
Qua n ti tati on of AS ha emody na m ic sev e ri t y 169
LVOT diameter
Any discrepancy in the measurement of the LVOT diameter will
be squared, leading to errors in the calculation of the AVA. 2D
echocardiography may underestimate LVOT area and thus SV
and AVA. There are three main factors that may contribute to
this underestimation: (i) inadequate imaging plane not showing
the largest LVOT dimension; (ii) Measurement of LVOT diam-
eter at the level of the septal bulge; (iii) Oval-​shaped LVOT
cross-​section.
One should, first, aim to obtain the mid-​systolic image that
bisects the LVOT in its largest dimension: i.e. the plane that
bisects the right coronary cusp hingepoint anteriorly, and the
interleaflet triangle between the left and non-​coronary cusps
posteriorly (E Fig. 11.4) [17]. If two leaflets are well visual-
ized both anteriorly and posteriorly, this may not be the plane
providing the largest diameter and the LVOT diameter may be
underestimated from this view.
Although the guidelines allow measurements of the LVOT
diameter to be performed up to 1.0 cm apical to the annulus [3]‌,
historically the LVOT measurement has been taken at the annulus
[18–​20] and outcomes data upon which the guidelines are based,
use this measurement to calculate AVA [21–​23]. Some experts rec-
ommend measuring LVOT diameter 5 to 10 mm below the aortic
annulus because this is the location where the LVOT velocity is
measured by PW Doppler. Other experts suggest measuring more
closely to the annulus because the LVOT diameter varies less with
the cardiac cycle at this level and thus can be more accurately and
reproducibly measured [18, 24–​26] (E Fig. 11.4). In patients with
cylindrical shape LVOT, the two methods will provide similar
LVOT diameter measures, while in patients with a more funnel-​
shaped LVOT these methods will yield different results. In the set-
ting of ectopic calcification in the LVOT or annulus, the diameter
measurement should ignore this calcium and measure to the base
of the anterior mitral valve leaflet (E Fig. 11.4).
Even if carefully performed one limitation of the method re-
mains that the LVOT cross-​sectional area is often elliptical and
not circular and 2D echocardiography measures the antero-​
posterior diameter, which is the smaller diameter of the ellipse.
3D echocardiography (preferably TOE) or contrast MSCT may
prove to be useful in obtaining a more accurate estimation of the
LVOT cross-​section area. Using the LVOT area measured by these
imaging modalities in the continuity equation (E Fig. 11.5), pro-
vides on average larger (+0.20–​0.25 cm2) AVAs compared to the
AVA measured by 2D echocardiography [23, 27, 28]. This leads to
a reclassification of severe to moderate AS in a significant number
of patients primarily in the subset of low-​ gradient AS [27].
Whether this is therefore an important error in the traditional
use of the continuity equation leading to misclassification of AS
severity and urging to recommend the use of LVOT area by plan-
imetry or whether a larger cut-​off value (i.e. <1.2 cm2 vs. 1.0 cm2)
may be required to define severe AS when using such techniques
is a matter of controversy and deserves further study [23, 29].
In the rare cases when accurate estimation of SV and AVA
cannot be obtained by echocardiography or hybrid imaging
170 CHAPTER 11   Aortic valve st enosis
methods, CMR phase contrast imaging or cardiac catheterization
with thermodilution may be required to confirm AS severity [30].
Body size
It has been suggested to index AVA to body surface area (cut-​off
<0.6 cm2/​m2 for severe AS) to account for interindividual vari-
ability in body size, particularly in patients with either unusually
small or large body-​surface area (E Table 11.2). However, there
is no linear relation between body surface area and AVA and there
is particular distortion at the extremes of the spectrum. Some
studies suggest that an indexation of AVA to height may be su-
perior to an indexation to body surface area [31]. Furthermore,
the indexed AVA may overestimate AS severity in obese patients
and it has been suggested to use lower cut-​off value (<0.50 cm2/​
m2) in these patients (E Table 11.2).
Doppler velocity index or velocity ratio
Since the determination of LVOT area by 2D echocardiography is
prone to sources of error, another flow-​independent and dimen-
sionless variable, the velocity ratio, or Doppler velocity index, which
is defined as the ratio of velocities (VTIs or peak values) in the LVOT
and across the aortic valve may be used to corroborate AS severity,
particularly in patients with low-​gradient AS (E Table 11.2) [32,
33]. Severe stenosis is defined by velocity ratio <0.25. The finding of
an AVA <1.0 cm2 with a velocity ratio >0.25 should raise the suspi-
cion of error (underestimation) in the measurement of LVOT diam-
eter. This measurement, however, ignores variability in LVOT size
beyond variation in body size and has gained little acceptance.
Other measures of aortic stenosis severity
The energy loss index (ELI) is a measure that attempts to account
for pressure recovery and therefore provides a more accurate esti-
mate of the net energy loss between the LVOT and the ascending
aorta (E Fig. 11.6) [34]. The extent of the pressure recovery is es-
sentially determined by the ratio of the effective AVA to the cross-​
sectional area of ascending aorta area (AA). The ELI thus consists
in correcting the AVA for the AA measured 1 cm downstream of
the sino-​tubular junction to take into account pressure recovery
and is roughly equivalent to AVA measured by catheter (E Table
11.2 and E Fig. 11.6) [3, 35]. This parameter is not recommended
for routine clinical use but should be considered in patients with
AVA between 0.8 and 1.0 cm2 and small ascending aorta (<30 mm)
(i.e. patients susceptible to have significant pressure recovery). If
the ELI is >0.60 cm2/​m2, the stenosis would be reclassified from
severe to non-​severe (E Table 11.2) [35–​37]. Other parameters
such as aortic valve resistance and stroke work loss have been
proposed to quantify AS severity (E Table 11.2). However, these
parameters lack prognostic validation, they are still considered ex-
perimental and not recommended for routine clinical use.
Multiparameter grading of AS severity
AS severity encompasses a continuous spectrum of disease, ran-
ging from aortic sclerosis without haemodynamic obstruction to
very severe AS. The measures of disease severity therefore need
to be viewed in a continuous way. Definition of grades of se-
verity of AS is consequently to some extent arbitrary. In clinical
practice, peak transaortic jet velocities, mean gradients and AVA
should be estimated and the findings are ideally concordant (E
Table 11.2). The prognostic importance of peak aortic jet velocity
across the whole spectrum of AS and even beyond the threshold
of severe stenosis has been demonstrated. It should be recognized
that in clinical practice, a relatively large variability in AVA meas-
urements for a given peak aortic jet velocity has been reported.
E Table 11.2 shows the different quantitative parameters and cri-
teria of AS severity classified according to their flow dependence: (i)
flow-​dependent; (ii) less flow-​dependent; (iii) flow-​independent.
Since velocities and gradients are highly flow-​dependent, thresh-
olds for these variables refer to patients with normal flow rates
(e.g. SVi> 35 ml/​m2). In presence of low or high flow state, the
different echocardiographic parameters may become discordant
(see next section) and additional imaging modalities and param-
eters are needed to confirm AS severity.
Discordant grading of AS severity and role of
multimodality imaging
Classification of AS severity is easy and straightforward when
measurements of velocity, gradient, and AVA are concordant
(E Table 11.2) but becomes challenging when discordant values
of these indices are found.
Discordant grading with high gradient
AVA may be >1.0 cm2 despite a peak velocity >4 m/​s and mean
gradient >40 mmHg in the presence of high transvalvular flow.
This may be due to concomitant aortic regurgitation or shunt le-
sions. Although AVA may not indicate severe AS, velocity, and
gradients remain consistent with severe LV pressure overload and
therefore severe overall aortic valve disease (i.e. AS + aortic re-
gurgitation (AR)). For clinical decision-​making, reversible cause
of increased flow in case of high CO (fever, anaemia, hyperthy-
roidism, etc.) must be excluded.
Discordant grading with low gradient
More challenging is the discordant finding of an AVA ≤ 1.0 cm2
in the presence of a peak velocity <4 m/​s and mean gradient <40
mmHg [15, 38]. In this situation, measurement errors first need
to be carefully excluded, in particular the underestimation of
LVOT size and thus underestimation of SV and AVA. Also, careful
multiwindow CW Doppler interrogation should be performed
to avoid underestimation of aortic velocity and gradient (E Fig.
11.3). It also has to be emphasized that current cut-​offs for AVA
and velocity and gradient are not really consistent. Indeed, to gen-
erate a mean gradient of 40mmHg with a normal SV and mean
transvalvular flow rate, the AVA must be closer to 0.8 than to 1.0
cm2 [39]. Finally, a small AVA in a small body size patient may actu-
ally correspond to a moderate AS and thus generate a low gradient.
In such a patient, it is important to calculate the indexed AVA. After
exclusion of these reasons for discordant valve area/​gradient meas-
urements the following three ‘low-​gradient AS’ entities must be
considered.
Classical low flow—​low-​gradient AS with reduced LV function
One of the reasons for AVA-​gradient discordance is a reduced
flow due to LV systolic dysfunction (LVEF <50%). Low-​flow

state is defined as SV index <35 ml/​m2 in the current ESC guide-
lines [11]. This entity is often referred to ‘classical’ low-​flow, low-​
gradient AS with reduced LVEF. In these patients, a low-​dose
dobutamine stress echocardiography (DSE) protocol is used to
differentiate true versus pseudo-​severe AS (E Fig. 11.7) [15,
40]. This DSE protocol uses a starting dose of 2.5–​5.0 mcg/​kg/​
min followed by gradual increase of the dose by steps of 5 mcg/​
kg/​min every 5–​8 min to a maximum of 20 mcg/​kg/​min. During
DSE, a 12-​lead ECG has to be continuously monitored and
blood pressure is measured every 2 minutes. Echocardiographic
and Doppler data are assessed at each dose for measurement
of peak velocity, mean pressure gradient, AVA, and LV ejection
fraction.
DSE allows to assess the presence of flow reserve, which is
defined as a per cent increase in SV ≥20% with dobutamine. In
the French multicentre study, the absence of flow reserve was
associated with extremely poor prognosis in patients treated
conservatively and with very high operative mortality in pa-
tients with treated by surgical aortic valve replacement (SAVR)
[41, 42]. However, other studies including the True or Pseudo
Severe Aortic Stenosis (TOPAS) multicentre studies and some
recent transcatheter aortic valve replacement (TAVR) studies
did not find any association between flow reserve and outcomes
[43–​45].
If the patient has a significant increase in flow with DSE and
the mean gradient increases >40 mmHg with an AVA remaining
below 1.0 cm2, the stenosis is considered true severe (E Fig.
11.7). If the stress mean gradient is <40 mmHg and AVA increases
above 1.0 cm2, the stenosis is considered pseudo-​severe. However,
several patients show persistent discordant grading at DSE: e.g.
the gradient increases but remains <40 mmHg and the AVA in-
creases somewhat but remains <1.0 cm2. This situation typically
occurs in patients no flow reserve or with flow reserve but not suf-
ficient to reach a normal flow rate. In this case one can calculate
the projected AVA at normal flow rate (E Fig. 11.7) [43]. This is
a flow-​independent parameter that provides an estimate of what
would be the AVA had the mean flow rate (SV/​LV ejection time)
reached a normal flow rate of 250 ml/​s (E Table 11.2). The calcu-
lation of the projected AVA requires a minimum increase of mean
flow rate during DSE >15%, which occurs in the vast majority of
patients, including those with no flow reserve (i.e. the mean flow
rate may increase despite no or minimal increase in flow rate due
to acceleration of heart rate and shortening of LV ejection time
(LVET) during DSE). The projected AVA has been shown to be
superior to the stress mean gradient or AVA to predict actual AS
severity and outcomes in classical low-​flow, low-​gradient AS [43,
44]. A projected AVA <1.0 cm2 suggests true-​severe AS. If the per-
cent increase in mean flow rate is <15%, DSE is inconclusive and
aortic valve calcium scoring by MSCT should be considered to
confirm AS severity (E Table 11.2).
Paradoxical low-​flow, low-​gradient AS with preserved
LV function
The most challenging finding in clinical practice is an AVA <1.0 cm2
with a peak velocity <4 m/​s and mean gradient <40 mmHg
despite a normal LVEF. This new entity is named ‘paradoxical’
Qua n ti tati on of AS ha emody na m ic sev e ri t y 171
low-​flow, low-​gradient severe AS with preserved LVEF and re-
fers to patients with hypertrophied, small ventricles with often
advanced LV diastolic dysfunction and impaired longitudinal
function, resulting in reduced transvalvular flow (SV index <35
ml/​m2) despite normal LVEF [11, 46]. A particular attention
should be dedicated to rule out measurement errors in these pa-
tients. Patients with peak jet velocity <3 m/​s or mean gradient <20
mmHg are less likely to have severe AS. Also, concomitant hyper-
tension is frequent and may contribute to the low-​flow state and
to the symptoms. The first step is thus to optimize management
of hypertension if any, and re-​assess SV, AVA, and gradients and
symptomatic status after normalization of blood pressure [15, 38].
DSE is not an optimal approach to increase SV and differ-
entiate true-​severe vs. pseudo-​severe AS in the patients with
paradoxical low-​flow, low-​gradient AS. Quantitation of AVC by
non-​contrast MSCT is probably the best modality to confirm
stenosis in patients with paradoxical low-​flow, low-​gradient
AS. The sensitivity and specificity of the sex-​specific cut-​off
values of AVC are, however, ~80% and consideration of specific
threshold and sensitive threshold should be preferred to con-
firm or rule out true-​severe AS instead of using single cut-​off
values (E Table 11.2) [7, 8, 11, 15, 38].
Normal-​flow, low-​gradient  AS
An AVA <1.0 cm2 and a mean gradient <40 mmHg may be en-
countered even in the presence of normal flow. ESC guidelines
state that normal flow-​low-​gradient AS entity is unlikely to be
severe AS [11]. However, some studies suggest that up to 40% of
these patients may exhibit severe AS and benefit from AVR [15,
38, 47, 48]. Underestimation of transaortic velocity and gradient
and/​or overestimation of SV may lead to the false conclusion
that the patient has normal-​flow, low-​gradient AS. The counter-
intuitive occurrence of a low gradient in a patient with severe AS
and normal flow may be related to: i) The mis-​alignment of AVA
(1.0 cm2) and gradient (40 mmHg) thresholds: an AVA of 1.0 cm2
actually corresponds to a mean gradient of 30–​35 mmHg (rather
than 40 mmHg) in presence of normal flow; (ii) The presence
of a low mean flow rate (<200 ml/​s) despite a normal SV index
(≥35 ml/​m2): this may occur for example in patients with brady-
cardia and prolonged LVET; (iii) reduced arterial compliance
and systolic hypertension that may dampened the transvalvular
gradient, independently of AS severity and flow [47]. Hence, in
a symptomatic patient with normal-​flow, low-​gradient, the first
step is to rule out measurement errors and the second step is to
perform AVC quantitation by MSCT to further evaluate AS se-
verity (E Fig. 11.8).
Follow-​up interval and assessment of AS
progression
Intervals for follow-​up visits of asymptomatic patients with AS
can be scheduled based on the severity of AS. Generally patients
with severe stenosis should be seen every 6 months and patients
with moderate AS on a yearly basis. In addition, factors such as
the previous rate of haemodynamic progression and the degree
of valve calcification (important calcification is associated with
172 CHAPTER 11   Aortic valve st enosis

(a) (b)

(d)

(c)

Fig. 11.7  Dobutamine stress echocardiography to confirm stenosis severity in classical low-​flow, low-​gradient AS. (a) A patient with evidence of significant
flow reserve and true-​severe AS on DSE. (b) A patient with evidence of significant flow reserve and pseudo-​severe AS on DSE. (c) A patient with flow reserve but
persistent discordant grading at the end of DSE because of incomplete flow normalization. In this case, the projected AVA at normal flow rate was calculated.
The first step is to calculate the slope of the AVA/​Qmean regression line (or valve compliance): VC= ΔAVA/​ ΔQmean, where ΔAVA and ΔQmean are the absolute
increases in AVA and Qmean (SV /​LVET) during DSE. The VC was 0.0022 cm2/​ mls–​1. The projected AVA is then calculated using the formula: AVAProj = AVARest + VC ×
(250 –​QRest) = 1.08 cm2 in this case, which is consistent with pseudo-​severe AS. (d) A patient with no flow reserve and thus indeterminate AS severity with DSE.
In this case, AS severity was confirmed by aortic valve calcium scoring by CT that revealed a valve calcium score of 3682 AU. Adapted with permission from [15].
AVA = aortic valve area; DSE = dobutamine stress echocardiography; LVEF = LV ejection fraction; MG = mean transvalvular gradient; Qmean = mean transvalvular flow rate; SV = stroke volume.
 As ses sm en t of ca rdiac da m ag e as s o ciat e d w i t h   AS 173

Fig. 11.8  Stepwise integrated approach for the assessment of AS severity.

AVA = aortic valve area; AVC = aortic valve calcification; MSCT = multislice computed tomography; ΔP = mean transaortic pressure gradient; LVEF = LV ejection fraction;
TTE = transthoracic echocardiography; SV = stroke volume; Svi = SV index; VAS = peak velocity of the AS jet.

more rapid disease progression) help to optimize the timing of >0.3 m/​s/​year is associated with a high event rate in asymptom-
follow-​up visits. atic severe AS [3, 11].
AS progression should be routinely assessed and reported
in clinical practice [3, 11]. Changes in peak aortic jet velocity,
mean gradient, and AVA can be determined between two exams.
Haemodynamic progression can be expressed as an annualized
Assessment of cardiac damage
progression rate. It is advisable to use examinations that are associated with AS
separated by 6–​12 months. AS progression is most sensitively
Besides the grading of AS severity, it is also essential to assess the
recorded by changes in peak aortic jet velocity, while AVA is
extent of LV and other cardiac chamber damage in order to deter-
less sensitive to detect small changes in AS severity due to im-
mine the timing and indication of AVR (E Tables 11.1 and 11.3).
precision involved in its calculation. The assessment of changes
in aortic jet velocity is more reliable when the velocity measure-
ments are performed from the same echocardiographic window,
Left ventricular damage
which should therefore be mentioned in the echocardiographic Left ventricular remodelling and hypertrophy
report. Furthermore, a change in ventricular function needs Chronic pressure overload in AS leads to concentric LV hyper-
to be excluded when using flow-​dependent measures to assess trophy, which is an adaptive mechanism to the increased LV
haemodynamic progression. Rapid haemodynamic progression pressure. It is a compensatory mechanism permitting the main-
defined as an annualized increase in peak aortic jet velocity of tenance of a normal wall stress. Phenotypically, the extent and
174 CHAPTER 11   Aortic valve st enosis
type of LV hypertrophy is variable between individuals. While
some patients with severe AS may present with extensive hyper-
trophy, others may only have mild hypertrophy or even a normal
LV mass. These later patients however often have LV concentric
remodelling (increased LV wall thickness ratio but with normal
LV mass). The impact of left ventricular hypertrophy on out-
come has been studied for a long time with inconclusive results.
LV concentric hypertrophy is associated with worse outcomes in
women but not in men [49]. Excessive hypertrophy is associated
with a significantly higher event rate in asymptomatic patients
[50]. The concomitant presence of a hypertrophic cardiomyop-
athy, of a hypertensive cardiomyopathy, or of an infiltrative myo-
cardial disease (i.e. cardiac amyloidosis) should be considered
when hypertrophy is excessive. Up to 15% of patients with para-
doxical low-​flow, low-​gradient AS may have transthyretin cardiac
amyloidosis [51]. In case of clinical and/​or echocardiographic
suspicion of amyloidosis, bone scintigraphy coupled with analysis
of monoclonal proteins should be considered. Cardiac amyloid-
osis is associated with high risk of AVR futility. However, encour-
aging results have been published on pharmacotherapy of cardiac
amyloidosis [52].
Left ventricular dysfunction
Grade I LV diastolic dysfunction with abnormal LV relaxation
and impaired LV filling are already present early in the disease
course. Progression to more advanced LV diastolic dysfunction
(≥ Grade 2) with elevated LV filling pressures is frequent in pa-
tients with severe AS and is the main cause of onset of symptoms
in these patients [53]. Grade 3 diastolic dysfunction (restrictive
physiology pattern) is associated with higher risk of treatment fu-
tility with AVR.
Deterioration of LV ejection fraction generally occurs late in
the course of the disease. AVR is recommended (Class I) in pa-
tients with severe AS and reduced LV systolic function defined
as LVEF <50%. Reduced LVEF (<50%) is extremely rare (~1%)
in asymptomatic patients with severe AS and is associated with
worse outcomes [54]. Patients with reduced LVEF and high gra-
dients (mean ≥40 mmHg) generally benefit from AVR and an
improvement in LV function and symptoms can be expected.
Nevertheless, poor LV function is known to be associated with a
worse outcome.
LVEF underestimates the extent of myocardial systolic dys-
function in the presence of LV concentric remodelling or hyper-
trophy. Several recent studies suggest applying a higher cut-​off
value of LVEF (<55 or 60%) to identify subclinical LV systolic
dysfunction and eventually trigger intervention in asymptom-
atic patients with severe AS but still require validation [55–​57].
Parameters of LV longitudinal systolic function, including mi-
tral annulus displacement or global longitudinal strain, are a
surrogate marker of the severity of myocardial fibrosis. These
parameters appear superior to LVEF in quantifying the extent
of myocardial impairment and to predict outcome in patients
with all major types of AS, asymptomatic severe AS with normal
flow and high gradient, classical or paradoxical low-​ flow,
low-​gradient AS, severe AS prior to AVR [58–​62]. A recent
meta-​analysis report that a global longitudinal strain <16% is
associated with rapid progression to symptoms and worse out-
comes in asymptomatic patients with severe AS [62]. However,
intervendor differences in strain measurements and afterload
dependence remain limitations.
Left ventricular myocardial fibrosis
In patients with severe AS, AVR should be performed before the
development of irreversible myocardial fibrosis. Several studies
have reported an association between extent of myocardial fi-
brosis and adverse outcomes in AS [63, 64]. Focal fibrosis is quan-
titated by CMR with the use of late gadolinium enhancement.
Focal fibrosis located in the subendocardial layer is generally re-
lated to ischaemic cardiomyopathy, whereas focal fibrosis located
in the mid-​endocardial layer is more related to LV hypertrophy,
pressure overload, and is thus considered being more specific to
AS [64]. Regardless of the location, focal fibrosis is irreversible
following AVR.
T1 mapping is used to quantitate myocardial extracellular
volume, which is a surrogate marker of diffuse fibrosis [65].
Extracellular volume includes focal and diffuse fibrosis and thus
represents total fibrosis. Further studies are needed to further val-
idate the use of CMR-​derived myocardial fibrosis.
Unfortunately, CMR will not be available for all asymptom-
atic patients with AS and surrogate markers for fibrosis need to
be used such as global longitudinal strain, as discussed before,
or blood biomarkers that can be provided in all patients (strain
is not always feasible), and are fast and not expensive. The more
useful biomarkers seem to be high-​sensitivity troponin and brain
natriuretic peptide [66–​68].
Damage of other cardiac chambers
Pulmonary hypertension, tricuspid regurgitation, and
right ventricular dysfunction
Assessment of pulmonary artery pressure and TR provides
information on the stage of disease and may have important
prognostic implications. Systolic pulmonary arterial pressure
is obtained for the TR peak velocity and adding estimated right
atrial pressure. Systolic pulmonary hypertension at rest (>50
mmHg) and with exercise (>60 mmHg) has been shown to
predict rapid progression to symptoms development in asymp-
tomatic patients with severe AS [69]. Pulmonary hypertension
is also associated with increased risk of mortality following
AVR [70]. Right ventricular dysfunction represents a more
advanced stage of the AS disease and associated heart failure.
The presence of moderate-​severe right ventricular (RV) dys-
function is associated with poor prognosis following AVR.
Généreux et al. have recently proposed a classification for sta-
ging the extent of cardiac damage and heart failure associated
with AS. This classification integrates the different parameters
of LV hypertrophy and dysfunction (Stage 1), left atrial dila-
tion, fibrillation, and significant MR (Stage 2), pulmonary

arterial hypertension, and TR (Stage 3), and RV dysfunction
(Stage 4) [71].
Concomitant valvular disease
Aortic regurgitation
AR often coexists with AS. In patients with mixed aortic valve
disease, an echocardiographic multiparameter approach, often
associated with multimodality imaging (DSE, MSCT, and CMR)
should be implemented to assess: (i) the individual haemodynamic
severity of each lesion: i) AS, which is best quantitated by AVA and
AVC, and AR, which is quantitated by vena contracta width, ef-
fective regurgitant orifice area, and regurgitant volume and frac-
tion; (ii) the overall haemodynamic severity of the aortic valve
disease, which is best estimated by the mean transaortic gradient
(which increases with both AS and AR severity). A mean gradient
≥ 40 mmHg is consistent with severe mixed aortic valve disease
and indication for AVR in presence of symptoms. The combin-
ation of a moderate AS and a moderate AR is also considered se-
vere aortic valve disease even the gradient may be <40 mmHg.
Mitral regurgitation
When MR is significant (≥ moderate) it may lead to a reduction
in transaortic flow and thus in the peak aortic jet velocity and
gradient. In low-​flow, low-​gradient AS related to MR, DSE may
not be able to achieve significant increase in transaortic flow rate
and thus distinction between true versus pseudo-​severe AS. AVC
measured by MSCT may be useful to confirm AS severity in this
context. When MR is present, it is important to assess the mech-
anism. When an organic lesion is present, correction of significant
MR at the moment of aortic valve surgery should be considered.
However, controversy exists with regard to concomitant mitral
valve surgery in the setting of secondary MR. Without mitral
valve surgery an improvement of MR has been reported in half to
two-​thirds of the patients after SAVR [72]. In patients with severe
AS and concomitant ≥moderate MR, secondary MR is more likely
to regress than primary MR. In the case of significant residual
MR and persisting symptoms following TAVR, transcatheter mi-
tral edge-​to-​edge repair may be considered in a staged approach.
Dilation of ascending aorta
The ascending aorta should be routinely assessed in patients with
AS since a dilation of the ascending aorta is frequently observed.
In particular, patients with bicuspid valves tend to have associ-
ated aortic aneurysms. The assessment is performed in a PLAX
view and includes measurements at the levels of the aortic an-
nulus, the sinuses of Valsalva, the sino-​tubular junction, and the
ascending aorta. While the aortic annulus is measured as an inner
diameter, the other measures of the ascending aorta are measured
from leading edge to leading edge. When an aortic aneurysm is
detected by echocardiography or when the echocardiographic
visualization is insufficient, additional imaging modalities, such
as MSCT or CMR may be required. When surgery is primarily
indicated for the aortic valve, replacement of the aortic root or
tubular ascending aorta should be considered when ≥45 mm,
particularly in the presence of a bicuspid valve.
Asym p to m ati c sev e re   AS 175
Integrative approach for the
management of AS
Patients with AS may present with high-​ gradient severe AS;
classical (low LVEF) low-​ flow, low-​ gradient AS, paradoxical
(preserved LVEF) low-​ flow, low-​gradient AS, or normal-​ flow,
low-​gradient AS with low LVEF; or low-​gradient AS with normal
LVEF. Considering all these different entities of AS, the definition
of severe AS has become more and more challenging over recent
years and current guidelines emphasize that diagnosis in clin-
ical practice must be based on an integrated approach including
transvalvular velocity/​gradient, AVA, valve morphology and calci-
fication, flow rate, LV morphology and function, blood pressure,
and symptoms (ETables 11.1 and 11.2; E Fig. 11.8). The recom-
mendations for AVR in patients presenting with AS rely mainly
on the demonstration of severe stenosis and the presence of symp-
toms (dyspnoea, heart failure, angina, or syncope) related to AS
(E Table 11.3) [3, 11, 73]. E Figure 11.8 summarizes the algo-
rithm proposed in the ESC guidelines for the management of AS.
The first step is to measure peak aortic velocity and mean gradient.
If the mean gradient is ≥40 mmHg and reversible causes of high
flow status are excluded AS can be considered severe. If mean gra-
dient is <40 mmHg but AVA is <1.0 cm2 careful further evaluation
is required to confirm severe AS. In patients with high-​gradient
severe AS and symptoms or LVEF <50%, there is a strong indi-
cation (Class I) for AVR. If the mean gradient is ≥40 mmHg and
AVA is ≥1.0 cm2, additional imaging is needed to exclude meas-
urement errors, identify presence of high flow state, and confirm
stenosis severity. The next step (Step 2) is to rule out measurement
errors that may result in underestimation of flow, AVA, and/​or
gradient (E Fig. 11.8 and E Table 11.4). The following step (Step
3) is to determine the LVEF and flow to identify the subtype of
low-​gradient AS. Step 4 consists in confirming stenosis severity
with the use of low-​dose DSE in patients with classical low-​flow,
low-​gradient AS or with the use of an integrated approach (E
Table 11.4) including AVC scoring by MSCT in patients with para-
doxical low-​flow, low-​gradient AS as well as patients with classical
low-​flow, low-​gradient AS, and inconclusive DSE. E Table 11.4
presents the parameters and criteria. AS is unlikely to be severe
with normal-​flow, low-​gradient AS. However, if the patient is
symptomatic and measurements errors have been ruled-​out, fur-
ther evaluation with non-​contrast computed tomography (CT) is
reasonable to confirm AS severity (E Table 11.4).
Asymptomatic severe AS
In patients with high-​gradient severe AS presenting themselves
as asymptomatic exercise stress test is recommended. Earlier
elective AVR should be considered in selected patients with high-​
gradient severe AS who are still asymptomatic as confirmed by
exercise testing (E Table 11.3). In this decision-​making process,
pros (e.g. lower operative risk for less symptomatic patients) and
176 CHAPTER 11   Aortic valve st enosis

Table 11.3  Indication for aortic valve intervention and choice of intervention in the European guidelines

Recommendation Class of indication

A) Indication for aortic valve intervention
Intervention is indicated in symptomatic patients with severe, high-​gradient AS (mean gradient ≥40mmHg or peak I
velocity ≥4.0 m/​s)
SAVR is indicated in asymptomatic patients with severe AS and systolic LV dysfunction (LVEF <50%) not due to I
another cause
SAVR is indicated in patients with severe aortic stenosis undergoing other cardiac surgery I
Intervention is indicated in symptomatic patients with severe low-​flow, low-​gradient (<40 mmHg) AS with reduced LVEF and I
evidence of flow reserve excluding pseudo-​severe AS
Intervention should be considered in symptomatic patients with low-​flow, low-​gradient AS, and reduced LVEF without flow IIa
reserve, particularly when MSCT calcium scoring confirms severe AS
Intervention should be considered in symptomatic patients with low-​flow, low-​gradient (<40 mmHg) AS with normal LVEF IIa
after careful confirmation of severe aortic stenosis
SAVR is indicated in asymptomatic patients with severe AS and an abnormal exercise test showing symptoms on exercise I
clearly related to AS
AVR is reasonable in asymptomatic patients with severe AS and decreased exercise tolerance or an exercise fall in blood IIa
pressure
SAVR should be considered in asymptomatic patients with normal LVEF and none of the aforementioned exercise test IIa
abnormalities if the surgical risk is low and one of the following findings is present:
Very severe AS defined by a peak aortic velocity >5.5 m/​s
◆
Severe valve calcification and a rate of peak aortic velocity progression ≥0.3 m/​s/​year
◆
Markedly elevated BNP levels (> 3-​fold age-​and sex-​corrected normal range) confirmed by repeated measurements without
◆
other explanations
Severe pulmonary hypertension (systolic pulmonary artery pressure at rest >60mmHg confirmed by invasive measurement)
◆
without other explanation
Intervention should not be performed in patients with severe comorbidities when the intervention is unlikely to improve III
quality of life or survival
B) Choice of intervention in symptomatic aortic stenosis
Aortic valve interventions should only be performed in centres with both departments of cardiology and cardiac surgery on site I
and with structured collaboration between the two, including a Heart Team (heart valve centres)
The choice for intervention must be based on careful individual evaluation of technical suitability and weighing of risks and I
benefits of each modality. In addition, the local expertise and outcomes data for the given intervention must be taken into
account
SAVR is recommended in patients at low surgical risk (STS or EuroSCORE II < 4% or logistic EuroSCORE I < 10% and no other I
risk factors not included in these scores, such as frailty, porcelain aorta, sequelae of chest radiation)
TAVI is recommended in patients who are not suitable for SAVR as assessed by the Heart Team I
In patients who are at increased surgical risk (STS or EuroSCORE II ≥4% or logistic EuroSCORE I ≥10% or other risk factors not I
included in these scores such as frailty, porcelain aorta, sequelae of chest radiation), the decision between SAVR and TAVI
should be made by the Heart Team according to the individual patient characteristics, with TAVI being favoured in elderly
patients suitable for transfemoral access
Balloon aortic valvotomy may be considered as a bridge to SAVR or TAVI in haemodynamically unstable patients or in patients IIb
with symptomatic severe aortic stenosis who require urgent major non-​cardiac surgery
Balloon aortic valvotomy may be considered as a diagnostic means in patients with severe aortic stenosis or other IIb
potential causes for symptoms (i.e. lung disease) and in patients with severe myocardial dysfunction, pre-​renal
insufficiency or other organ dysfunction that may be reversible with balloon aortic valvotomy when performed in
centres that can escalate to TAVI
AS = aortic stenosis; AVR = aortic valve replacement; BNP = B-​type natriuretic peptide; SAVR = surgical AVR; STS = Society of Thoracic Surgeons; TAVI = transcatheter aortic valve
implantation.
Reproduced from Baumgartner H, Falk V, Bax JJ, De Bonis M, Hamm C, Holm PJ, Iung B, Lancellotti P, Lansac E, Muñoz DR, Rosenhek R, Sjögren J, Tornos Mas P, Vahanian A, Walther
T, Wendler O, Windecker S, Zamorano JL. 2017 ESC/​EACTS guidelines for the management of valvular heart disease: The Task Force for the management of valvular heart disease
of the European Society of Cardiology (ESC) and the European Association for Cardio-​Thoracic Surgery (EACTS). Eur Heart J 2017;38(36):2739–​91. with permission from Oxford
University Press.

Table 11.4  Criteria that increase the likelihood of severe AS in
patients with AVA <1.0 cms and mean gradient <40 mmHg in the
presence of preserved LVEF
Criteria
Clinical criteria Typical symptoms without other explanations
Elderly patient (> 70 y.o.)
Qualitative LV hypertrophy (additional hypertension to be
imaging data considered)
Reduced LV longitudinal function without other
explanation
Quantitative Mean gradient 30–​39 mmHg
imaging data
AVA ≤ 0.8 cm2
Low flow (SVi<35 ml/​m2) confirmed by techniques
other than standard Doppler technique
(LVOT measurement by 3D TOE or contrast MSCT;
CMR, invasive data)
Calcium score by non-​contrast MSCT:
Severe AS very likely: women: ≥1,600, Men ≥3,000
Severe AS likely: women: ≥1,200, Men ≥2,000
AVA = aortic valve area; CMR = cardiac magnetic resonance; LVOT = LV outflow
tract; MSCT = multislice computed tomography; SVi = stroke volume index; TOE =
transoesophageal echocardiography.
Source data from Baumgartner H, Hung J, Bermejo J, Chambers JB, Edvardsen T,
Goldstein S, Lancellotti P, LeFevre M, Miller F, Jr., Otto CM. Recommendations on
the echocardiographic assessment of aortic valve stenosis: A focused update from
the European Association of Cardiovascular Imaging and the American Society of
Echocardiography. J Am Soc Echocardiogr 2017;30(4):372–​92; Baumgartner H, Falk V, Bax
JJ, De Bonis M, Hamm C, Holm PJ, Iung B, Lancellotti P, Lansac E, Muñoz DR, Rosenhek
R, Sjögren J, Tornos Mas P, Vahanian A, Walther T, Wendler O, Windecker S, Zamorano
JL. 2017 ESC/​EACTS guidelines for the management of valvular heart disease: The
Task Force for the management of valvular heart disease of the European Society of
Cardiology (ESC) and the European Association for Cardio-​Thoracic Surgery (EACTS).
Eur Heart J 2017;38(36):2739–​91.
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Contents
Anatomy and function of the aortic
valve  181
Aetiology and mechanisms of AR  181
Aetiology  182
Degenerative calcific AR  182
Rheumatic AR  182
Unicuspid, bicuspid, or quadricuspid AR  182
Mechanisms of AR  182
Assessment of AR severity  183
Qualitative parameters  183
Colour flow Doppler  183
Continuous wave Doppler of
the AR jet  183
Diastolic flow reversal in the descending
aorta (or peripheral arteries)  183
Semi-​quantitative parameters  184
Continuous wave Doppler: pressure
half-time 184
Vena contracta width  184
AR Jet width and jet area  184
Quantitative parameters  185
Proximal isovelocity surface area (PISA): the
flow convergence method  185
Doppler volumetric method  185
Other 2D/​M-​mode findings in AR  186
Consequences of AR  186
LV size and function  186
Integrating indices of severity  186
Cardiac magnetic resonance (CMR)  187
Computed tomography (CT)  189
Recommended follow-​up  189
CHAPTER 12
Aortic valve regurgitation
Julien Magne and Patrizio Lancellotti
Anatomy and function of the aortic valve
The aortic valve (AV) consists of a complex of structures surrounding the aortic orifice
along the outflow tract of the left ventricle (LV) and allowing blood transfer, through the
valve, to the ascending aorta and systemic circulation [1]‌. Typically, three semi-​lunar
leaflets composed AV. The cups are inserted into a fibrous connective tissue sleeve, which
is attached to the aorta media above. Below, the cusps are attached to the myocardium
of the LV outflow tract and to the anterior mitral leaflet. Each cusp is attached along
its curves edge, and the cusps meet at three commissures that are equally spaced along
the circumference of the sleeve at the supra-​aortic ridge. The area of the cusps is ap-
proximately 40% greater than the cross-​sectional area of the aortic root. In normal AV,
the cups are symmetrical, mobile, and free to the commissures, with equal overlap on
closure. The sinuses of Valsalva are located between the valve sleeve and cusps.
Transthoracic echocardiography (TTE) is the first-​line imaging tool to assess AV,
aorta, and subsequent aortic regurgitation (AR). The parasternal long-​axis view is clas-
sically used to measure the left outflow tract, the aortic annulus, and the aortic sinuses.
Leaflet thickening and morphology can be visualized from this window as well as from
the parasternal short-​axis view and the apical five-​chamber view. Nevertheless, 2D TTE
may be limited and not enabling correct identification of the anatomy and causes of AR.
In this situation, 3D echocardiography and cardiac magnetic resonance (CMR) could
provide better delineation of the AV morphology. In some cases, Transoesophageal echo-
cardiography (TOE) could be required, more particularly for assessing the aortic root
dimensions.
Aetiology and mechanisms of AR
The AR results from disease of either the aortic leaflets or the aortic root that distorts
the leaflets to prevent their coaptation [2]‌. Common causes of leaflet abnormalities may
be (1) congenital, such as non-​tricuspid AV or ventricular septal defect, or (2) acquired
and result from senile leaflet calcifications, infective endocarditis, rheumatic fever, or
radiation-​or toxin-​induced. Aortic causes of AR include annulo-​aortic ectasia, idio-
pathic root dilatation, systemic hypertension, connective tissue disease (i.e. Marfan’s
syndrome, Ehlers–​Danlos, Loeys–​Deitz, or osteogenesis imperfect), trauma, aortic dis-
section, autoimmune disease, collagen vascular disease, and syphilis.
182 CHAPTER 12   Aortic valve regu rgitat ion
Aetiology
Degenerative calcific AR
Calcification of a tricuspid AV is most prominent in the cen-
tral part of each cusp. There is no commissural fusion. A
stellate-​shaped systolic orifice is observed on the parasternal
short-​axis  view.
Rheumatic AR
Rheumatic AR is characterized by commissural fusion, calcifica-
tions, and variable thickening of the leaflets especially at the level
of their free edge. The resulting retraction of aortic leaflets usually
induces central regurgitation.
Unicuspid, bicuspid, or quadricuspid AR
A small proportion of the adult population has bicuspid AV, and
more rarely unicuspid or quadricuspid AV. These valves lead to
stenosis, regurgitation, or both, owing to abnormal leaflet archi-
tecture and coaptation. Bicuspid aortic valves may be associated
Fig. 12.1  Mechanisms of aortic regurgitation
according to the Carpentier’s functional
classification. Type I: aortic annulus dilatation;
Type IIa: prolapse of the left coronary cusp (red
arrow); Type III: rheumatic aortic valve disease with
restricted cusp motion.
with dilatation of the aorta. A congenitally abnormal valve is
strongly suspected whenever markedly eccentric leaflet coapta-
tion is seen in parasternal views. The long-​axis view may reveal an
asymmetric closure line, a systolic doming, or a diastolic prolapse
of the leaflets. The short-​axis view is more specific. The diagnosis
is confirmed when only two leaflets are seen in systole with two
commissures framing an elliptical systolic orifice. Diastolic image
may mimic a tri-​leaflet valve when a raphe is present. The fusion
of the right and left coronary cusps (large anterior and small pos-
terior cusp with both coronary arteries arising from the anterior
cusp) is the more frequent.
Mechanisms of AR
The Carpentier’s classification is the most common functional
classification currently used to describe mechanisms involved
in AR (E Fig. 12.1). Type I mechanism relates to normal leaflet
motion, whereas Type II and III correspond to excessive leaflet
motion and restrictive leaflet motion, respectively. Specifically
 As ses sm en t of A R sev e ri t y 183

Table 12.1  Functional classification of AR lesions

Dysfunction Echocardiographic findings

I: enlargement of the aortic root with normal
cusps
IIA: cusp prolapse with eccentric AR jet
◆​  cusp  flail
◆​  partial cusps prolapse
◆​  whole cusp prolapse
IIB: free edge fenestration with eccentric AR jet
III: Poor cusps quality or quantity
◆​ Dilatation of any components of the aortic root (aortic annulus, sinuses of Valsalva, sinotubular
junction)
​ Complete eversion of a cusp into the LVOT in long-​axis views
◆
​ Distal part of a cusp prolapsing into the LVOT (clear bending of the cusp body on long-​axis views and
◆
presence of a small circular structure near the cusp free edge on short-​axis views)
​ Free edge of a cusp overriding the plane of aortic annulus with billowing of the entire cusp body into the
◆
LVOT (presence of a large circular or oval structure immediately beneath the valve on short-​axis views)
◆​  Presence of an eccentric AR jet without definite evidence of cusp prolapse
​ Thickened and rigid valves with reduced motion
◆
​ Tissue destruction (endocarditis)
◆
​ Large calcification spots/​extensive calcifications of all cusps interfering with cusp motion
◆

for AR, Type I is leaflet perforation, type II, prolapse of one or
more cusps and type III, restricted motion as the consequence
of rheumatic disease or secondary to significant calcifications.
However, 2D TTE does not always show the lesion responsible
for leaflet malcoaptation. In this situation, transoesophageal
echocardiography (TEE) provides useful information regarding
the cusp pathology (redundancy, restriction, cusp height to indi-
cate likely adequacy of coaptation, mobility/​pliability, thickness,
integrity), commissure variations (fusion, splaying, attachment
site, and alignment), and root morphology (septal hypertrophy,
annular size, sinus, and sino-​tubular junction dimension, and as-
cending aorta dimension). Recently, the diagnostic value of TEE
in defining the mechanisms of AR has been highlighted (E Table
12.1). Three functional mechanisms have been described: Type
1: enlargement of the any components of the aortic root (aortic
annulus, sinuses of Valsalva, sinotubular junction) with normal
cusps; Type 2: cusps prolapse or free edge fenestration with an ec-
centric regurgitant jet; Type 3: poor cusps tissue quality (cusp re-
traction, extensive cusp calcifications (≥ grade 3), endocarditis).
Cusps prolapse are further categorized in three groups: cusps
flail (eversion of the cusps into the LV outflow tract), partial cusp
prolapse, and whole cusp prolapse (free edge of aortic cusp over-
riding the plane of aortic annulus).
The degree of leaflet calcification of the AV is scored as follows:
grade1: no calcification, grade 2: isolated small calcification spots,
grade 3: bigger calcification spots interfering with cusp motion,
grade 4: extensive calcifications of all cusps with restricted cusp
motion. The incidence of valve sparing or repair decreases with
the severity of dysfunction and is less than 50% in type 3 dys-
function. The 3D echocardiographic observation of the AV may
provide unique additional information in the diagnosis of various
types of AV disease.
Assessment of AR severity
Qualitative parameters
Morphology and structure of the AV may provide indirect in-
dices regarding the presence of significant AR. Abnormal leaflet
motion suggesting Type II or III of the Carpentier’s classification
may indicate the presence of AR. Flail leaflet or large coaptation
defect may be a sign of severe AR.
Colour flow Doppler
The regurgitant jet into the LV in diastole can be visualized by
using multiple views, parasternal views remaining the preferred
because of better axial resolution. The colour jet area and length
are weakly correlated to the degree of AR but may serve for visual
assessment of AR and are not currently recommended. Central
jets are highly suggestive of rheumatic disease while eccentric jets
are associated with AV prolapse or perforation.
Colour-​coded M-​mode is suitable for time-​dependency of flow
signals during the heart cycle.
Continuous wave Doppler of the AR jet
CW Doppler of the AR jet reflects the pressure difference between
the aorta and the LV during diastole. It is classically best obtained
from the apical 5-​chamber view. For eccentric jets, better sig-
nals may be obtained from the second right parasternal window.
While faint spectral display is compatible with trace or mild AR,
significant overlap between moderate and severe regurgitation
exists in more dense jet tracings.
Diastolic flow reversal in the descending aorta
(or peripheral arteries)
AR can lead to diastolic flow reversal in the aorta. The flow re-
versal is best imaged in the upper descending aorta at the aortic
isthmus level using a suprasternal view by using pulsed-​wave
Doppler. The sample volume is placed just distal to the origin
of the left subclavian artery and it is aligned as much as pos-
sible along the major axis of the aorta. The Doppler filter is de-
creased to its lowest setting to allow detection of low velocities
(<10 cm/​s). With milder degrees of regurgitation, there is a brief
reversal of flow early in diastole. As the degree of the regurgita-
tion increases, the duration, and the velocity of the reversal flow
increase. It becomes sustained throughout diastole at velocities
exceeding 18 cm/​s in severe AR (end-​diastolic velocity meas-
ured at peak R wave). Significant holodiastolic reversal in the
184 CHAPTER 12   Aortic valve regu rgitat ion
abdominal aorta is also a sensitive sign of severe AR. However,
in case of reduced aortic compliance (advancing age, porcelain
aorta) or in the presence of increased heart rate, the duration
and velocity of flow reversal may be increased and overestimate
AR. In severe acute AR, diastolic velocity decreases quickly with
no end-​diastolic velocity due to equalization of aortic and LV
diastolic pressures.
Semi-​quantitative parameters
Continuous wave Doppler: pressure half-​time
Accurate measurement of pressure half-​time is dependent of
adequate spectral envelope of the regurgitant jet. The rate of de-
celeration of the diastolic AR jet and the derived pressure half-​
time reflect both the degree of regurgitation and the ventricular
end-​diastolic pressures. As the degree of AR increases, the aortic
diastolic pressure decreases and the LV end-​diastolic pressure in-
creases [3, 4]. The late diastolic jet velocity is thus reduced and
the pressure half-​time shortened. A pressure half-​time of <200
ms is consistent with severe AR, whereas a value >500 ms sug-
gests mild AR. The pressure half-​time is however influenced by
chamber compliance in addition to chamber pressures. For a
given severity of AR, pressure half-​time may be further reduced
by elevated LV diastolic pressures or prolonged in patients with
increase in peripheral resistance or who have a dilated aorta with
increased aortic compliance. It tends to normalize with chronic
LV adaptation to AR.
Vena contracta width
For AR, imaging of the vena contracta—​the regurgitant jet as
it traverses the aortic orifice or the effective regurgitant area—​
is obtained from the parasternal long-​axis view (E Fig. 12.2)
[5, 6]. A narrow sector scan coupled with the zoom mode is
recommended to improve measurement accuracy. Practically,
the vena contracta represents the smallest flow diameter at the
level of the AV in the LV outflow tract, immediately below the
flow convergence region. It provides thus an estimate of the size
Fig. 12.2  Semi-​quantitative assessment of
aortic regurgitation severity using the vena
contracta width (VC). The three components of
the regurgitant jet (flow convergence zone, vena
contracta and jet turbulence) are obtained. The
ratio of the VC and left ventricular outflow tract
(LVOT) can be calculated as estimate of aortic
regurgitation severity.
of the effective regurgitant orifice area (EROA) and is smaller
than the regurgitant jet width in the LV outflow tract (expan-
sion of the jet immediately after the vena contracta). Using a
Nyquist limit of 50–​60 cm/​s a vena contracta <0.3 cm indicates
mild, 0.3–​0.6 cm indicates moderate, and >0.6 cm indicates se-
vere AR [7]‌.
The measurement of the vena contracta is affected by several
factors as the presence of multiple jets. In this situation, the
respective widths of the vena contracta are not additive. The
concept of vena contracta is indeed based on the assumption
that the regurgitant orifice is almost circular. The orifice is
however often elliptic or irregular, which changes the width of
the vena contracta in different views. The 3D colour Doppler
echocardiography has been shown to be a useful tool in the
visualization of the actual shape of the regurgitant orifice and
could be used to measure the vena contracta in experienced
hands  [6]‌.
AR Jet width and jet area
The width and the cross-​sectional area of the jet at its origin are
good colour Doppler indexes of AR severity.
The maximum colour jet diameter (width) is measured in
diastole immediately below the AV (at the junction of the LV
outflow tract and aortic annulus) in the parasternal long-​axis
view. The jet width is proportional to the size of the AV de-
fect. However, if the orifice is irregular, as in bicuspid valve, the
colour jet width is less related to the degree of AR. Its accuracy
can thus be improved by dividing the jet width by the LV out-
flow tract diameter.
The cross-​sectional areas of the jet from the parasternal short-​
axis view and its ratio to the LV outflow tract area are also in-
dicators of AR severity. A ratio of AR jet width/​left ventricular
outflow tract (LVOT) diameter <25% generally indicates mild
AR, 25–​64% indicates moderate AR, and ≥65% indicates se-
vere AR [8]‌. Similarly, a ratio of jet cross-​sectional area/​LVOT
cross-​sectional area <5% indicates mild AR, 5–​60% indicates
moderate AR and ≥60% indicates severe AR [9]. However, these
measurements suffer from a high interobserver variability.
Parasternal long axis view
 Qua n ti tati ve pa r a m et e r s 185

either the anterior mitral leaflet or the interventricular septum).

Quantitative parameters
Proximal isovelocity surface area (PISA): the
flow convergence method
The assessment of the flow convergence zone has been less exten-
sively performed in AR. Imaging of the flow convergence zone
is obtained from the apical five-​chamber or parasternal long-​axis
or upper right-​sternal views (E Fig. 12.3). The area of interest is
expanded by using the zoom mode, the sector size is reduced as
narrow as possible to maximize frame rate, and the Nyquist limit
is adjusted to obtain a clearly visible, round, and measurable PISA
radius [10]. The colour-​flow velocity scale is shifted towards the
direction of the jet (downward or upward in the left parasternal
view depending on the jet orientation and upward in the apical
view). The PISA radius is measured from a stop frame as the dis-
tance between the regurgitant orifice and the first aliasing in early
diastole (closest to the peak of regurgitant velocity). The con-
tinuous wave Doppler recording of the regurgitant peak velocity
and velocity time integral allows calculation of the EROA and
regurgitant volume (Rvol). When imaged from the apical window,
the PISA method significantly underestimates AR severity in the
presence of eccentric AR jets [11]. In this situation, imaging the
flow convergence zone from the parasternal long axis improves
the accuracy of the PISA method (if the jet is directed towards
For central AR jets, the apical view remains suggested. The PISA
method for quantification of AR suffers from similar limitations
than for mitral regurgitation (MR) quantification. Briefly, non-​
planar or confined flow convergence zones that invalidate the
hemispheric assumption are potential causes of either under-​or
overestimation of AR severity by the PISA method. Accordingly,
caution should be applied when using the PISA method in pa-
tients with obtuse flow convergence angles, such as those with
aneurismal dilation of the ascending aorta or those with con-
fined flow convergence zone such as could occur in patients with
cuspal perforation or commissural leaks. Imaging from the right
parasternal window may be helpful for PISA assessment [12]. An
EROA >30 mm2 or a Rvol >60 ml indicates severe AR, EROA be-
tween 10 and 30 mm2 and Rvol between 30 and 60 ml indicates
moderate AR.
Doppler volumetric method
The pulsed-​wave Doppler method can also be used as an alter-
native method to quantify the AR severity, similarly than in MR.
In the absence of significant MR, the mitral inflow is used to cal-
culate the systemic stroke volume. The mitral inflow volume can
be substracted to the LV outflow tract stroke volume to obtain
the Rvol. The pulmonic site can be used in patient with signifi-
cant MR. This approach is time-​consuming and is associated with

(a) (b) (e)

(c) (d) (f )

Fig. 12.3  Quantitative assessment of aortic regurgitation severity using the proximal isovelocity surface area (PISA) method. Stepwise analysis of aortic
regurgitation: (a) parasternal long-​axis view (PT-​LAX); (b) colour-​flow display; (c) zoom of the selected zone; (d) downward shift of zero baseline to obtain
a hemispheric PISA; (e) measure of the PISA radius using the first aliasing; (f) continuous wave Doppler of aortic regurgitation jet allowing calculation the
effective regurgitant orifice area (EROA) and regurgitant volume (R Vol). TVI indicates time-​velocity integral.
186 CHAPTER 12   Aortic valve regu rgitat ion

several drawbacks. The threshold for Rvol and EROA are similar haemodynamic consequences of the presence of AR, mainly on
than with the flow convergence method. the LV, should be carefully assessed.

LV size and function

Other 2D/​M-​mode findings in AR
In addition to the anatomic evaluation of the AV, several 2D and
M-​mode echocardiographic findings can be observed in AR. If
the regurgitant jet impinges on the anterior mitral valve leaflet,
a reverse doming (concavity towards the ventricular septum) of
the anterior leaflet can be observed on the parasternal long-​axis
view. As a result, the leaflet presents a high frequency fluttering
during diastole and its opening can be compromised. The M-​
mode echocardiography can confirm the fluttering motion
of the anterior leaflet. It can also appear on the mitral valve
chordae or the interventricular septum. Its absence (i.e. in case
of mitral valve stenosis) cannot rule out the diagnosis of AR and
a pseudo-​fluttering can be observed in atrial fibrillation and in
cardiac hyperkinesia. The M-​mode echocardiography is also
helpful in demonstrating the premature mitral valve closure as a
sign of severe, usually acute, AR and marked increase in LV dia-
stolic pressure. Rarely, a premature diastolic opening of the AV
may appear if LV pressure exceeds aortic pressure. In chronic
AR, if the regurgitant jet is eccentric towards the septum, a fi-
brotic reaction could occur and a local rise in echogenicity can
be seen.
Consequences of AR
Grading AR using cardiovascular imaging cannot be reduced
to AR severity assessment. Similarly than the morphology of
the AV and the size of each section of the ascending aorta, the
The AR is a volume overload imposed to LV. In acute AR, the
LV is classically not enlarged, while in the chronic situation,
the LV progressively dilates and irreversible LV myocardial
damage may occur. In the current guidelines, surgery is recom-
mended in asymptomatic patients with severe AR when the LV
ejection fraction is ≤50% and/​or when the end-​systolic diam-
eter (less preload dependent) is >50 mm (>25 mm/​m2), or LV
end-​diastolic diameter is >70 mm. A end-​systolic volume index
≥45 ml/​m2 has been shown to be predictive of outcome and
can thus be used for referring patients for surgery. New param-
eters, mainly derived from speckle-​tracking echocardiography,
are currently available for a better assessment of LV function.
In patients with chronic AR and preserved LV ejection fraction,
LV global longitudinal strain could be an important marker of
poor prognosis [13, 14]. A cut-​off value of –​19% has been iden-
tified and patients with reduced LV global longitudinal strain
despite preserved LV ejection fraction have reduced post-
operative survival. In addition, the absence of postoperative
recovery in terms of LV longitudinal function seems also asso-
ciated with increased mortality [15].
Integrating indices of severity
Echocardiographic assessment of AR includes integration of data
from 2D/​3D imaging of the aortic root, AV, and ventricle as well
as Doppler measures of regurgitant severity (E Table 12.2 and
E Fig. 12.4). The measurement of the proximal jet width (in case
of central jet), the vena contracta width, the rate of deceleration

Table 12.2  Grading the severity of AR

Parameters Mild Moderate Severe

Qualitative
Aortic valve morphology Normal/​Abnormal Normal/​Abnormal Abnormal/​Flail/​Large coaptation  defect
Colour flow AR jet width $ Small in central jets Intermediate Large in central jet, variable in eccentric jets
CW signal of AR jet Incomplete/​Faint Dense Dense
Diastolic flow reversal in descending aorta Brief, protodiastolic flow reversal Intermediate Holodiastolic flow reversal (end-​diastolic
Semi-​quantitative velocity >18 cm/​s)
VC width (mm) <3 Intermediate ≥ 6
Pressure half-​time (ms) £ >500 intermediate <200
AR Jet width/​LVOT width (%) <25 25–​45;  46–​64 ≥65
AR Jet area/​LVOT area (%) <5 5–​20;  21–​59 ≥60
Quantitative
EROA (mm2) <10 10–​19;  20–​29 ≥30
R Vol (ml) <30 30–​44; 45–​59 ≥60
+ LV size §
AR = aortic regurgitation; CW = continuous wave; LA = left atrium, EROA = effective regurgitant orifice area; LV = left ventricle; R Vol = regurgitant volume; VC = vena contracta.
$ At a Nyquist limit of 50–​60 cm/​s. £ PHT is shortened with increasing LV diastolic pressure, vasodilator therapy, and in patients with a dilated compliant aorta or lengthened in
chronic AR.
§ Unless for other reasons, the LV size is usually normal in patients with mild AR. In acute severe AR, the LV size is often normal. Normal values: LV end-​diastolic diameter <56 mm,
LV end-​diastolic volume <82 ml/​m2, LV end-​systolic diameter <40 mm, LV end-​systolic volume <30 ml/​m2.
 Ca rdiac m ag n eti c res ona n c e   (C M R ) 187

Fig. 12.4  Three examples of aortic regurgitation are provided, all taken from the parasternal long-​axis view using colour Doppler (top) and from the apical five-​
chamber view using continuous wave Doppler (mid). The vena contracta (VC) increases with the severity of aortic regurgitation. The pressure half-​time (PHT)
decreases with more severe aortic regurgitation, whereas the left ventricular outflow time-​velocity (LVOT TVI) integral increases.

of the diastolic regurgitant jet, the diastolic flow reversal in the
descending aorta, and the EROA by the PISA method are recom-
mended, whenever possible. These parameters should be inter-
preted according the chronicity of AR and the LV remodelling.
Advantages and limitations of the various echocardiographic and
Doppler parameters used in assessing AR severity are detailed in
E Table 12.3.
Cardiac magnetic resonance (CMR)
The AR grading may be performed using CMR and CMR remains
the gold standard for assessment of LV size and function. CMR
can also be used for valve analysis using steady-​state free preces-
sion sequences, which precisely discriminate blood from tissue.
The CMR could be indicated in patients with AR in case of [9]‌:
(1) suboptimal echocardiographic images for evaluation of any
components of the AV or aorta; (2) discordance between grading
parameters; (3) discordance between echocardiographic find-
ings and LV consequences, clinical status, or symptoms; (4) or
in case of multiple valvular lesions. Steady-​state free precession
(SSFP) acquisitions with ECG gating can be used to evaluate the
AV morphology and orifice area. AR results in turbulent flow,
generating signal voids, which appear as dark ‘jets’ emanating
from the AV. As its magnitude depends on a number of factors
(the echo time, flip angle, imaging plane), the qualitative assess-
ment of regurgitant jet signal void of AR has significant limita-
tions and should be interpreted with caution. Quantification of
AR at CMR can be done either by through-​plane phase-​contrast
velocity mapping, or by stroke volume method. However, these
methods are not as widely used or standardized as Doppler flow
measurements. CMR flow mapping allows the measurement of
forward flow (FF) and regurgitant flow (RF) across the AV, and
the calculation of the regurgitant fraction as 100 × RF/​FF (%)
(E Fig. 12.5). A cut-​off value of regurgitant fraction of 33% by
CMR, associated with LV end-​diastolic volume >246 ml, pre-
dicts the development of indication for surgery within 3 years
[16]. The stroke volume method is applicable only in AR pa-
tients without other valve insufficiency or shunt lesions, and is
based on the calculation of the regurgitant volume as the dif-
ference between LV stroke volume and right ventricular stroke
volume.
188 CHAPTER 12   Aortic valve regu rgitat ion

Table 12.3  Echocardiographic parameters used to quantify AR severity: recordings, advantages, and limitations

Parameters Recordings Usefulness/​Advantages Limitations

Aortic valve Visual assessment
◆ ◆  Flail valve is specific for significant AR ◆ Other abnormalities are non-​specific of
morphology Multiple views
◆ significant AR
Colour flow AR Optimize colour gain/​scale
◆ Ease of use
◆ ◆ Influenced by technical and
jet width and Parasternal long and short-​axis views
◆ Evaluates the spatial orientation
◆ haemodynamic factors
area of AR jet Inaccurate for eccentric jet
◆
Quick screen for AR
◆ Expands unpredictably below the
◆
orifice
VC width ◆ PT-​LAX is preferred (AP-​4chamber if not Relatively quick and easy
◆ Not valid for multiple jets
◆
available) Relatively independent of
◆ Small values; small measurement errors
◆
Optimize colour gain/​scale
◆ haemodynamic and instrumentation lead to large % error
Identify the three components of the
◆ factors Intermediate values need confirmation
◆
regurgitant jet (VC, PISA, Jet into LV) Not affected by other valve leak
◆ Affected by systolic changes in
◆
Reduce the colour sector size and imaging
◆ Good for extremes AR: mild vs severe
◆ regurgitant flow
depth to maximize frame rate
Expand the selected zone (Zoom)
◆
Use the cine-​loop to find the best frame for
◆
measurement
Measure the smallest VC (immediately distal
◆
to the regurgitant orifice, perpendicular to the
direction of the jet)
PISA method ◆ Apical 5-​chamber for central jets (PT-​LAX for Can be used in eccentric jet
◆ ◆ PISA shape affected
eccentric jets) Quantitative: estimate lesion severity
◆ ●​  by the aliasing velocity

Optimize colour flow imaging of AR

◆ (EROA) and volume overload (R Vol) ●​ in case of non-​circular orifice

Zoom the image of the regurgitant aortic valve

◆ ●​ by systolic changes in regurgitant

Increase the Nyquist limit in apical views/​

◆ flow
decrease or increase in PT-​LAX ●​ by adjacent structures (flow

With the cine mode select the best PISA

◆ constrainment)
Display the colour off and on to visualize the
◆ PISA radius is more a hemi-​ellipse
◆
AR orifice Errors in PISA radius measurement are
◆
Measure the PISA radius at diastole using the
◆ squared
first aliasing and along the direction of the Interobserver variability
◆
ultrasound beam Not valid for multiple jets
◆
Measure AR peak velocity and TVI (CW)
◆ Feasibility limited by aortic valve
◆
Calculate flow rate, EROA, R Vol
◆ calcifications
Flow at two Flow across the mitral valve ◆ Quantitative: estimate lesion severity Time-​consuming
◆
sites-​PW Measure the mitral inflow by placing the PW
◆ (ERO) and volume overload (R Vol) Requires multiple measurements:
◆
sample volume at the mitral annulus (AP-​4CV) Valid in multiple jets
◆ source of errors
Measure the mitral annulus diameter (AP-​4CV)
◆ Not applicable in case of significant
◆
at the maximal opening of the mitral valve MR (use the pulmonic site)
(2–​3 frames after the end-​systole).
Flow across the aortic valve
Measure the LV outflow tract flow by placing
◆
the PW sample volume 5 mm below the aortic
cusps (AP-​5CV)
Measure the LV outflow tract diameter
◆
(parasternal long-​axis view)
CW AR jet ◆  Apical five-​chamber ◆  Simple, easily available Qualitative, Complementary finding
◆
profile Complete signal difficult to obtain in
◆
eccentric jet
Pressure Apical five-​chamber
◆ ◆ Simple ◆ Affected by LV compliance, blood
half-​time CW AR jet
◆ pressure, acuity
Diastolic flow PW Doppler
◆ ◆ Simple Affected by sample volume location
◆
reversal in Proximal descending aorta/​Abdominal aorta
◆ Affected by aortic compliance.
◆
descending Brief velocity reversal is normal
◆
aorta Cut-​off validated for distal aortic arch
◆

LV size ◆  Use preferably the Simpson method ◆ Dilatation sensitive for chronic ◆ Dilatation observed in other
significant AR conditions (non-​specific)
Normal size almost excludes significant
◆ May be normal in acute severe AR
◆
chronic AR
AR = aortic regurgitation; CW = continuous wave; EROA = effective regurgitant orifice area; LV = left ventricle; PW = pulse wave; R Vol = regurgitant volume; VC = vena contracta.

Computed tomography (CT)
Common indications for CT include: (1) dilated aorta in patients
with unsatisfactory acoustic window; (2) comprehensive assess-
ment of entire aorta for quantifying aortic dilation or coarctation
in patients with bicuspid AV; (3) rapid rule out of aortic dissec-
tion; (4) assess valve morphology, aortic calcifications, and ather-
omatous plaques; (5) rule out significant coronary artery disease
in patients with indication for surgery for severe AR and low
probability of coronary atherosclerosis. Cardiac CT allows a re-
liable quantification of AV calcifications and its excellent spatial
resolution enables the measurement of regurgitant valve orifice
area by planimetry. However, there is no current clinically valid-
ated method for measuring flow velocity or flow volume using CT.
References
1. Muraru D, Badano LP, Vannan M, Iliceto S. Assessment of aortic
valve complex by three-​dimensional echocardiography: a framework
for its effective application in clinical practice. Eur Heart J Cardiovasc
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2. Lancellotti P, Tribouilloy C, Hagendorff A, et al. Recommendations for
the echocardiographic assessment of native valvular regurgitation: an
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RE F E RE N C E S 189
Fig. 12.5  Phase-​contrast velocity mapping
for aortic regurgitation quantification. The slice
location for through-​plane measurement is shown
on a three-​chamber still image with a jet of aortic
regurgitation visible (white arrow). Through-​
plane images are shown in systole depicting
magnitude (top left) and flow (top middle) and
diastole showing regurgitation in black (top right).
Regurgitant volume and fraction can then be
calculated from a time-​flow curve (bottom).
Recommended follow-​up
Echocardiography is a tool of choice for repeating AR assessment,
but also for the management and the risk stratification and also
to refine the timing of surgery. After initial diagnosis of signifi-
cant AR or if LV size or LV ejection fraction are close to guide-
lines recommended threshold, evaluation should be repeated
every 3–​6 months, even in the absence of surgical indications. In
asymptomatic patients with mild AR, little or no LV dilatation
and normal LV ejection fraction at rest, echocardiograms can be
done every 2–​3 years. Serial echocardiograms are also required
when symptoms occur or when worsening AR or increasing LV
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invasive evaluation of native valvular regurgitation: a report from the
American Society of Echocardiography developed in collaboration
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with the Society for Cardiovascular Magnetic Resonance. J Am Soc
Echocardiogr 2017; 30: 303–​71.
10. Tribouilloy CM, Enriquez-​Sarano M, Fett SL, Bailey KR, Seward JB,
Tajik AJ. Application of the proximal flow convergence method to
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the flow convergence method for quantification of aortic regurgita-
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102: 475–​80.
12. Shiota T, Jones M, Agler DA, et al. New echocardiographic windows
for quantitative determination of aortic regurgitation volume using
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1999; 83: 1064–​68.
13. Verseckaite R, Mizariene V, Montvilaite A, et al. The predictive
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ventricular ejection fraction. A long-​term speckle-​tracking echocar-
diographic study. Echocardiography 2018; 35: 1277–​88.
14. Alashi A, Mentias A, Abdallah A, et al. Incremental prognostic
utility of left ventricular global longitudinal strain in asymptomatic
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left ventricular ejection fraction. JACC Cardiovasc Imaging 2018; 11:
673–​82.
15. Alashi A, Khullar T, Mentias A, et al. Long-​term outcomes after
aortic valve surgery in patients with asymptomatic chronic aortic
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global longitudinal strain. JACC Cardiovasc Imaging 2020; 13(1 Pt
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16. Myerson SG, d’Arcy J, Mohiaddin R, et al. Aortic regurgitation quan-
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Contents
Introduction  191
Defining valve morphology  191
Quantification of mitral stenosis—​how to
do it?  191
2D, 3D echocardiography  191
Exercise echocardiography  193
Cardiac magnetic resonance imaging
(CMR)  193
Multislice computed tomography
(MSCT)  193
Imaging in the decision-​making  193
The role of echocardiography during and
after PMC  194
Detection of complications
during PMC  195
Echocardiography after the procedure  196
The new challenge—​degenerative MS  196
Conclusion  197
CHAPTER 13
Mitral valve stenosis
Ferande Peters and Eric Brochet
Introduction
Chronic rheumatic heart disease is the predominant aetiology of mitral stenosis (MS).
Less often it can be degenerative, congenital, or the result of inflammatory or drug-​
induced valve diseases [1]‌. Echocardiography, using M-​mode, two-​dimensional echo-
cardiography (2DE) and 3DE, is the main method to diagnose and assess the severity and
consequences of MS and guides selection of therapy [2].
Defining valve morphology
2DE is utilized initially to detect the limited motion and opening of the mitral valve and
to evaluate the morphology of the valve apparatus. The leaflets are often thickened and
may have superimposed calcification accompanied by varying degrees of chordal short-
ening and fusion. The hallmark of rheumatic MS is commissural fusion which can be
directly observed on short axis and inferred by the hockey stick appearance of the an-
terior leaflet (E Fig. 13.1). The posterior leaflet is usually restricted and immobile. A key
concept is that morphological abnormality, especially calcification noted in the annulus
and at the base of the leaflet but sparing the leaflet tips without commissural abnormality
involvement usually infers non-​rheumatic pathology.
2DE evaluation provides the best assessment of the leaflets’ mobility and calcifica-
tion. 3DE, particularly transoesophageal echocardiography (TEE) improves the visu-
alization of the leaflet motion, submitral apparatus involvement and commissural
abnormality [3, 4] (see E Fig. 13.1). Commissural assessment is also critical in patients
presenting with restenosis after previous surgical commissurotomy or percutaneous mi-
tral commisurotomy (PMC), allowing restenosis to be differentiated due to commissural
fusion from restenosis due to valve rigidity in which there is no commissural fusion [5]‌.
Quantification of mitral stenosis—​how to do it?
2D, 3D echocardiography
Mitral valve area (MVA) is the main parameter, assessed through direct valve planimetry
or by Doppler-​derived methods, such as pressure half-​time (PHT), the continuity equa-
tion, or the proximal isovelocity surface area (PISA) method.
MVA by planimetry is performed using 2DE, by direct tracing of the mitral orifice,
including opened commissures, in the parasternal short-​axis mid-​diastole view. It has
192 CHAPTER 13   Mitr a l valve stenosis
(a)
Fig. 13.1  An example of rheumatic mitral stenosis
with bicommissural fusion viewed in short-​axis
view using 2D TTE (a) and real-​time 3D TTE (b).
the advantage of being a direct anatomic measurement of MVA
independently of flow conditions; consequently it is considered
the reference measurement [6]‌. The major disadvantage is that
correct alignment at the leaflet tips, perpendicular to the mitral
orifice is often technically challenging leading to frequent over-
estimation of valve area. Using 3DE, any orientation of the car-
diac structures can be obtained, independently of the stenotic
valve opening angle, assessing the optimal plane of the smallest
mitral valve orifice (E Fig. 13.2). This methodology shows the
best agreement with the mitral orifice area calculations, derived
from the Gorlin formula, and it is currently suggested as the
new standard for MVA quantification [3]. Accurate planimetry
Fig. 13.2  Real-​time 3D TEE multiplane
reconstruction allowing correct alignment of the
plane to perform planimetry of the mitral valve
orifice.
(b)
measurements require optimal gain settings for the visualization
of the whole contour of the mitral orifice, and may be challenging
in calcific degeneration of the valve. Moreover, either 2DE or 3DE
MVA planimetry require technical expertise.
The determination of the MVA by PHT method, uses the equa-
tion: MVA= 220/​PHT. PHT is defined as the time interval in
milliseconds between the maximum mitral gradient in early dia-
stole and the time point where the gradient is half the maximum
initial value. It is measured by tracing the deceleration slope of
the E-​wave on Doppler spectral display of transmitral flow using
the same Doppler signal used for the measurement of mitral gra-
dient. The deceleration slope can be bimodal; in these cases it is

recommended to measure in mid-​diastole, instead of the early
deceleration slope. This equation should not be used immedi-
ately after balloon valvuloplasty or for patients who have severe
aortic regurgitation or high filling pressures by decreased left
ventricle (LV) compliance, as in these cases MS severity might be
underestimated.
MVA can also be estimated using the continuity equation:
MVA= LVOTD2 × 0.785 (LVOT VTI/​MV VTI), where D is the
diameter of the LV outflow tract (LVOT) in cm and velocity time
integral (VTI) is in cm. However, this method is less often used,
hampered by the risk of error from the multiple measurements
needed. Moreover, this equation cannot be used in cases of atrial
fibrillation or if there is marked aortic or mitral valve regurgi-
tation, as aortic regurgitation can cause underestimation of MS
severity while mitral regurgitation can cause its overestimation.
The PISA method uses the colour doppler hemispherical shape
of the convergence of diastolic mitral flow on the atrial side of the
mitral valve to estimate MVA, according to the following formula:
MVA = 0.785 × R2 (V aliasing ) / peak V mitral × α /180 degrees
R the radius of the convergence hemisphere (in cm), V aliasing,
aliasing velocity (in cm/​s), peak V mitral, peak continuous wave
Doppler (CWD) velocity of mitral inflow (in cm/​s), and α, the
opening angle of mitral leaflets relative to flow direction.
This method is rarely used in daily practice, as it is technically
demanding, particularly at the measurement of the radius of the
convergence hemisphere. Angle correction maybe needed to cor-
rect the equation. Additionally, it can be used in the presence of
significant mitral regurgitation [7]‌.
The mean mitral gradient is assessed by the apical window
using colour Doppler to identify the best orientation of diastolic
mitral inflow jet, followed by CWD, to ensure maximal veloci-
ties and parallel alignment of the ultrasound beam. The mean
gradient is dependent on MVA, heart rate, and cardiac output.
It is important to note that patients with low cardiac output or
bradycardia may have a low mean gradient, even in the presence
of severe MS and vice versa. In patients with atrial fibrillation, the
mean gradient should be calculated as the average of five cycles
with the least R–​R variation.
Finally, comprehensive evaluation of concomitant valve dis-
ease and pulmonary artery pressures disease is mandatory. The
presence of severe aortic valve disease, moderate or severe mitral
regurgitation (MR), or severe/​organic or functional tricuspid re-
gurgitation (TR) is a contraindication to PMC.
Exercise echocardiography
Exercise echocardiography can be utilized in patients whose
symptoms are discordant with the severity of MS or in asymp-
tomatic patients with significant MS–​ MVA<1.5 cm. Exercise
echocardiography is useful in the subgroup of patients with only
mild MS–​MVA >1.5 cm, who describe limiting symptoms such
as dyspnoea. PMC can be proposed in patients during exercise,
I m ag i n g i n the deci sion -m a k i n g 193
who exhibit a transmitral mean gradient >15 mmHg or sPAP
>60 mmHg (class IIb, level of evidence C, according to the ACC/​
AHA guidelines) [8]‌. Dobutamine stress echocardiography may
be useful in patients who cannot exercise [9, 10]. An absolute in-
crease in the mean transmitral gradient >18 mmHg, during the
test has been shown to predict clinical deterioration or the need
to operate [10].
Cardiac magnetic resonance
imaging (CMR)
CMR may be helpful for patients with MS, if echocardiography
data are insufficient or are inconsistent, Its large spatial reso-
lution with no acoustic window constrains allows evaluation of
mitral valve morphology, LA size, and the eventual presence of
thrombus, right ventricle size, left and right ventricle systolic
function, and the coexisting MR or aortic valve disease. The
thickening of the subvalvular apparatus and leaflet calcification
is frequently suboptimal when compared to echocardiography
[11]. Direct planimetry of the MS orifice area can be performed
by placing an imaging plane at the mitral valve tips during dia-
stole. This method has good agreement with echocardiography
(E Fig. 13. 4; z Video 13.1).
Phase-​contrast pulse sequences (velocity-​ encoded cine, Q
flow, or velocity mapping) are used for velocity measurements.
Similar to echocardiography, peak and mean transvalvular gra-
dients are obtained from the same series [12]. The major limita-
tion is that the lower temporal resolution of MRI may lead to
inaccurate assessment.
Multislice computed
tomography (MSCT)
The assessment of the MVA in patients with MS can also be
performed by MSCT. MSCT allows 3D acquisition of the entire
heart throughout the cardiac cycle and using multiple plane re-
constructions and it can provide an accurate MVA evaluation
[13]. MSCT also reliably detects MV calcification in patients
with MS [13, 14]. Therefore, CT may be useful in the decision-​
making process in selected cases, especially in patients with
poor echocardiographic windows. The main constraint can be
the presence of atrial fibrillation, which may significantly limit
image quality.
Imaging in the decision-​making
The management of MS has been described comprehensively in
the recently updated European Society of Cardiology (ESC) 2017
guidelines [15]. Echocardiography is utilized to confirm the se-
verity of MS, as intervention is considered only in patients with
significant MS (moderate to severe MS with an MVA<1.5 cm2)
194 CHAPTER 13   Mitr a l valve stenosis
Fig. 13.3  Calcifications of the anterolateral
commissure (arrow) viewed in short-​axis view
using 2D TTE (a) Severe thickening and fusion of
the subvalvular apparatus (arrows) viewed in the
parasternal long-​axis view using TTE (b).
[8]‌. Thereafter assessment of valve anatomy is essential for the se-
lection of candidates for PMC [8, 16].
The assessment of commissural fusion is the most important
parameter to report, and it is best evaluated in short-​ axis
transthoracic echocardiogram (TTE) view [17, 18] (E Fig. 13.1).
Commissural assessment is also critical in patients presenting
with restenosis after previous surgical commissurotomy or PMC,
allowing restenosis to be differentiated due to commissural fusion
from restenosis due to valve rigidity in which there is no commis-
sural fusion [18]. The main anatomic features of MS to be assessed
are leaflet thickening, mobility and pliability, presence and loca-
tion of calcifications, and impairment of the subvalvular appar-
atus (E Fig. 13.3 a and b). Different scoring systems have been
developed in order to predict immediate and long-​term results of
PMC. The most widely used is the Wilkins’ score (see E Table
13.1) [16] in which anatomic components are graded from 1 to 4.
Summation of these grades provides a score between 4 and 16, a
score of ≤8 being considered favourable for PMC. A simpler score
is the Cormier score [19], which relies on a global assessment of
mitral valve anatomy. Other scores have been described including
using 3D TTE but are more rarely used (see E Table 13.2).
TEE may be useful to assess valve anatomy, but its main indi-
cation is to exclude LA thrombus before performing PMC [2]‌,
which is a main contraindication for the procedure (E Box 13.1).
LA thrombi are usually, but not exclusively, located in the LA ap-
pendage, which must be excluded by the systematic performance
(a)
Fig. 13.4  Cardiac magnetic resonance imaging
view of mitral orifice (a) and measurement by
direct planimetry of the MS orifice area (b).
Courtesy of Dr P. Ou, Bichat Hospital.
of TEE immediately before PMC [18, 20]. Dense LA spontaneous
contrast is an important thromboembolic risk-​factor but is not a
contraindication to PMC.
PMC is the preferred treatment in patients with favourable
valve anatomy, i.e. with a Wilkins’ score of ≤8 or a Cormier class
1 and no contraindications to the procedure. In patients with less
favourable valve anatomy (Wilkins score >8 or Cormier class 2 or
3), the decision should be individualized [16, 21]. PMC should be
considered as an initial treatment for selected patients with mild-​
to-​moderate leaflet calcification or unfavourable subvalvular ap-
paratus, who have otherwise favourable clinical characteristics,
especially young patients in whom it allows the deference of valve
replacement [22]. PMC may be also performed in selected pa-
tients with unfavourable anatomy but with high risk for surgery,
or as a bridge to surgery in critically ill patients, or to avoid re-​
intervention in patients with previous surgery (i.e. previous sur-
gical commissurotomy or aortic valve.
The role of echocardiography during
and after PMC
Echocardiography plays a key role during PMC to monitor com-
missural opening and to detect the presence of complications.
In many centres PMC is performed under local anaesthesia and
TTE guidance [23]. Advantages of TTE are wide availability and
(b)
 Detecti on of c o m pl i cati on s duri n g   P MC 195

Table 13.1  Wilkins’ score

Grade Mobility Subvalvular thickening Thickening Calcification

1 Highly mobile value with only leaflet
tips restricted
2 Leaflets mid and base portions have
normal mobility
3 Valve continues to move forward in
diastole mainly from the base
4 No or minimal forward movements
of the leaflets in diastole
Minimal thickening just below the
mitral leaflets
Thickening of chordal structures
extending up to one-​third of the
chordal length
Thickening extending to the distal
third of the chords
Extensive thickening and shortening
of all chordal structures extending
down to the papillary muscles
Leaflets near normal in thickness
(4–​5 mm)
Mid-​leaflets normal, considerable
thickening of margins (5–​8 mm)
Thickening extending through
the entire leaflet (5–​8 mm)
Considerable thickening of all
leaflet tissues (>8–​10 mm)
A single area of increased
echo brightness
Scattered areas of brightness
confines to leaflet margins
Brightness extending into the
mid-​portions of the leaflets
Extensive brightness
throughout much of the
leaflet tissue

that it can better formed in conscious patients. According to this
strategy, TEE may be restricted to cases of difficult trans-​septal
puncture, or during pregnancy to avoid radiation exposure [24].
In some centres TEE guidance under general anaesthesia is pre-
ferred [24]. It offers the potential to enhance safety during trans-​
septal puncture, offers good visualization of the balloon position
as it is advanced into the mitral orifice, and allows a rapid as-
sessment of the severity and mechanism of MR [25]. Real-​time
3D TEE further improves the quality of guidance, allowing better
visualization of the positioning of the balloon relative to the mi-
tral valve orifice (z Video 13.2) and facilitates the assessment of
commissural splitting immediately after balloon inflation [26,
27]. The main limitation of TEE is that it generally requires gen-
eral anaesthesia during long procedures.
During PMC, echocardiography is performed after each bal-
loon inflation to assess commissural splitting, appearance or
increment of MR [28] and presence of complications, such as peri-
cardial effusion or severe MR. The symmetry and completeness
of commissural opening is assessed in the parasternal short-​axis
view during TTE (E Fig. 13.5). RT 3D TTE using parasternal
short-​axis views and RT 3D TEE en face views of the mitral valve
further improve assessment of commissural splitting from the left
atrial or the left ventricular perspective (E Fig. 13.6) [26, 27].
Changes in the degree of MR should be assessed carefully with
colour Doppler, paying attention to the mechanism and loca-
tion of the MR jet. If mitral valve opening is insufficient and MR
has not increased, inflation should be repeated with the balloon
diameter increased by 1–​2 mm, according to the symmetry or
not of commissural splitting [3]‌. Planimetry of MVA performed
in short-​axis view using 2D TTE is the method of choice to as-
sess the result. Opened commissural areas should be included
in the planimetry area in order to avoid underestimation of the
result. Planimetry can also be performed using 3D TEE using
multiplane reconstruction [29] (E Fig. 13.2). Due to changes in
the heart rate or cardiac output the use of the mitral gradient is
less reliable to assess outcome post PMC. The desired endpoints
of the procedure are (a) MVA >1 cm/​m2 of body surface area; (b)
complete opening of at least one commissure; or(c) appearance or
increase of MR >¼ [29, 30].
Detection of complications
during PMC
Procedural complications are rare with the Inoue technique [30–​
32] but the availability echocardiography in the cath lab allows
for immediate assessment when a complication is suspected [30].
Haemopericardium may be related to trans-​septal catheterization
or, more rarely, to LV perforation by the guidewire or the balloon.
Immediate pericardiocentesis is ideally performed under echo-
cardiographic guidance.
Severe MR is relatively rare ranging from 2 to 19% and is
mostly related to non-​commissural leaflet tearing but occasion-
ally chordal or more rarely papillary muscle rupture may occur

Table 13.2  Cormier score Box 13.1  Contraindications to PMC

Echocardiographic Mitral valve anatomy Contraindications for percutaneous mitral commissurotomy

group
Group 1 Pliable non-​calcified anterior mitral leaflet and mid-​
subvalvular disease (i.e. thin chordae ≥10 mm long)
Group 2 Pliable non-​calcified anterior mitral leaflet and severe
subvalvular disease (i.e. thin chordae <10 mm long)
Group 3 Calcification of mitral valve of any extent, as
assessed by fluoroscopy, whatever the state of
subvalvular apparatus
Left atrial thrombus
More than mild mitral regurgitation
Absence of commissural fusion
Severe or bicommissural calcification
Combined severe aortic valve disease and severe tricuspid sten-
osis and regurgitation
Coronary disease requiring bypass.
196 CHAPTER 13   Mitr a l valve stenosis
(a) (b)
Fig. 13.5  Monitoring of commissural opening during PMC in short-​axis 2D TTE view. Before PMC (a), opening of the postero-​medial commissure (arrow) (b),
opening of both commissures (arrows) (c).
[31, 32]. Although anatomic factors are important, these compli-
cation remains largely unpredictable in any given patient [33, 34].
Immediate TTE and/​or TEE should assess the mechanism and
severity of MR (E Fig. 13.7) [25].
Echocardiography after the
procedure
TTE examination should be performed early after PMC, generally
the day after the procedure. The most accurate evaluation of the re-
sult is valve area, measured by planimetry, using 2D or RT 3D TTE
[35]. In difficult cases, RT 3D TTE has been shown to increase the
ability to perform an accurate MVA planimetry immediately after
PMC [35]. In addition to the valve area, the completeness and sym-
metry of the commissural opening should be systematically reported
after PMC. As previously explained, the PHT method is not reliable
in this acute setting, due to changes in atrioventricular compliance
[36]. The final echo report should document the mean mitral gra-
dient, severity, and mechanism of residual MR and the pulmonary
artery pressure. If mitral regurgitation is more than moderate, TEE
should be utilized to delineate the exact mechanism of MR. Left to
right interatrial shunts are often small and usually disappear in the
majority of cases at follow-​up. Pericardial effusion is rare.
(a)
Fig. 13.6  Real-​time 3D TEE ‘en face’ view of the
mitral valve showing opening of the commissure
(arrow) from the left atrial perspective (a) and
from the left ventricular perspective (b).
(c)
The prediction of long-​term outcome and event-​free survival
following PMC is based not only on morphological characteristics
of the valve, but also on a number of clinical variables, including
age and New York Heart Association (NYHA) functional class
[21, 28]. The degree of valve opening, post-​procedural MVA, and
a small mean mitral gradient have been shown to have an im-
pact on late functional outcome. Both the degree of commissural
opening and MVA have been shown to be independent predictors
of good late functional results [28, 37].
The new challenge—​degenerative MS
In the Euro heart study, degenerative MS accounted for 12.5%
of all cases of MS [38]. As expected the frequency of this ab-
normality increases with age such that it accounts for 60% of
all cases of MS identified in those over 80 years of age. In up
to 24% of cases of degenerative aortic stenosis the MVA is less
than 1.5 cm2 [39]. Recent data reveals that in patient under-
going transcatheter aortic valve implantation (TAVI) the pres-
ence of coexisting MS was an independent poor prognostic
factor [40]. Hence the accurate differentiation of degenerative
MS from purely mitral annular calcification is crucial in elderly
individuals.
(b)

(a) (b)
Fig. 13.7  Severe mitral regurgitation (MR) due to anterior leaflet tear during PMC. Note the eccentric posteriorly directed MR jet in long-​axis 2D TTE view (a)
and the identification of the anterior tear in short-​axis 2D TTE view (b) even better assessed with 3D TTE (c).
The key echocardiographic findings in degenerative MS in-
clude prominent calcification at the base of the leaflets asso-
ciated with valve thickening and diminished leaflet opening.
Importantly no commissural fusion is noted and thus PMC or
surgical commisurotomy are not therapeutic options. The echo-
cardiographic assessment of MVA is particularly challenging
since both 2D and 3D TEE planimetry may not be feasible due
to either poor image quality or distorted valve anatomy and cal-
cification. The latter may prevent the accurate delineation of the
orifice geometry. Furthermore, the transmitral gradient is often
unreliable due to the association of hypertensive heart disease or
coronary disease with diastolic dysfunction.
Transoesophageal echocardiography may offer greater anatom-
ical delineation and allow for more accurate assessment of vale
area by planimetry. Cardiac CT may also be utilized and allows
for accurate assessment of the mitral annulus anatomy. In cases of
uncertainly or discrepancy between imaging data and the clinical
presentation calculation of MVA by invasive catheterization may
be required.
When medical therapy fails, surgery may be considered and
is often challenging due to the risk associated with medical
comorbidity and technical difficulties related to valve implant-
ation within highly calcified annuli. The latter has been associ-
ated with a greater incidence of postoperative perivalvular leaks.
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(c)
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Contents
Introduction  199
Anatomy and function of the mitral
valve  199
Valvular leaflets  199
Mitral annulus  200
Chordae tendinae and papillary muscles  200
Pathophysiology of MR  200
Echocardiographic evaluation  201
Assessment of MR severity  202
Consequences of MR  205
Assessment of repairability and results of
mitral valve repair  207
Beyond echocardiography: evaluation of
mitral regurgitation  207
Exercise echocardiography  207
Cardiac magnetic resonance  208
Cardiac multislice computed tomography
(MSCT)  209
CHAPTER 14
Mitral valve regurgitation
Daniel Rodríguez Muñoz, Kyriakos Yiangou,
and José Luis Zamorano
Introduction
The prevalence of mitral regurgitation (MR) is increasing in Western countries, which re-
sults in making it the second most frequent valvular heart disease requiring surgery [1]‌.
MR can be classified as primary (organic) or secondary (functional). Causes of primary
MR consist of leaflet lesions, either degenerative changes (Barlow’s disease, fibroelastic
degeneration and annular calcification), rheumatic disease, or infective endocarditis.
Causes of secondary MR consist of those that produce geometrical distortion of the
subvalvular apparatus due to dilatation and remodelling of the left ventricle such as is-
chaemic heart disease and cardiomyopathies.
The implementation of mitral valve repair as well as the rise of new transcatheter tech-
niques, provided that are performed in experienced, high volume centres with the contri-
bution of a valvular heart team, have impressively changed the prognosis of patients with
severe MR [2]‌. This has set new frontiers in the management of MR and has upgraded
the role of imaging, creating new responsibilities, since its presence in every step of the
procedure either preoperatively (quantification of MR, determination of the underlying
mechanisms, investigation of reparability, determination of prognosis) or intra-​and
postoperatively, has been declared as fundamental.
Anatomy and function of the mitral valve
The mitral valve apparatus should be considered as a unity and the normal function of
the mitral valve is based upon the perfect function of a complex of structures which con-
sists of the mitral valve leaflets, the mitral annulus, the subvalvular apparatus (papillary
muscles and chordae tendinae) as well as the left ventricle (E Fig. 14.1).
Valvular leaflets
The normal mitral valve has two leaflets (anterior and posterior) attached to the
fibromuscular annulus at their bases and by their free edges to the subvalvular appar-
atus. They have two zones which are the membranous part (base) and the coaptation
zone where the chordae tendinae fuse. The posterior leaflet covers approximately the
two-​thirds of the annular circumference and the anterior leaflet the remaining one-​third.
The posterior leaflet is crescent in shape, is smaller, and more flexible than the anterior
leaflet and has two distinct indentations, which divide it into three scallops named as P1,
P2, and P3. The anterior leaflet has trapezoid or dome-​shape, and is thicker than the pos-
terior leaflet. It is usually continuous but is literally divided into three portions A1, A2,
200 CHAPTER 14   Mitr a l valve regu rgitat ion
Fig. 14.1  Anatomy and morphology
of the mitral valve anatomy using
a three-​dimensional transthoracic
echocardiographic model.
Courtesy of Lancellotti P and Magne J.
and A3 mirroring the posterior scallops P1, P2, and P3. The com-
missures define a distinct area where both leaflets come together
at their insertion into the annulus.
Mitral annulus
The mitral annulus is part of the fibrous heart skeleton and con-
sists of a fibromuscular ring situated between the left atrium
(LA) and the left ventricle (LV). Mitral valve leaflets attach to
this annulus. The normal annulus is elliptical in shape and had
a saddle-​shaped configuration with an annular area of between
5 and 11 cm2. It can be divided into anterior and posterior seg-
ments based on the insertion of the anterior and posterior leaflets.
The anterior leaflet is relative immobile compared to the posterior
one and therefore haemodynamic changes can affect mainly the
latter. Pathological annular dilatation arises predominantly by the
increase of the posterior segment annular circumference which
leads to increase of the anteroposterior diameter and therefore
compromise leaflet apposition.
Chordae tendinae and papillary muscles
Chordae tendinae can be divided into three categories: (1) pri-
mary or marginal chordae tendinae which are attached to the
leaflet’s free edges, they are thin with limited extensibility and
they prevent leaflets from prolapsing and they are aligning the
coaptation zone. (2) Secondary or intermediate chordae tendinae
which are thicker and insert to the ventricular face of the leaflets.
They relieve excess tension and maintain the LV shape and func-
tion. (3) The basal or third order chordae tendinae which, can be
found on the posterior leaflet only and connect its base and the
posterior mitral annulus to the papillary muscles.
Papillary muscles are named as the anterolateral and the
posteromedial. Anterolateral papillary muscle is the larger of the
two and has a single body with two heads (anterior and posterior)
and has dual blood supply from the left circumflex (LCx) and left
anterior descending artery (LAD). The posteromedial papillary
muscle is smaller, has two bodies and three heads (anterior, inter-
mediate, posterior) and has a single artery supply (LCx or right
coronary artery, RCA) making it more vulnerable to ischaemic
conditions.
The subvalvular apparatus analysis includes the measurement
of chordal characteristics such as length, calcification, fusion, and
rupture. The possible displacement of the papillary muscles needs
to be described. Normally, but not routinely, two measurements
are performed: (a) apical displacement of the posterior papil-
lary muscle (distance between the papillary muscle head and the
interventricular fibrosa), and (b) interpapillary distance meas-
ured in the short-​axis parasternal view.
Pathophysiology of MR
MR is the systolic retrograde flow, as a result of the incomplete mitral
valve closure and from the pressure gradient between the LV and the
LA. It may occur when dysfunction of one or more of the compo-
nents of the mitral apparatus takes place. The precise determination
of the mechanism of MR is a fundamental part of the imaging ap-
proach especially when mitral valve repair is contemplated. For this
purpose, the Carpentier’s classification is often used, which has sub-
divided the mechanisms of MR according to leaflet motion.
◆ Type I: The leaflet motion is normal. The MR is produced by
leaflet perforation/​destruction (as i.e. in infective endocarditis)
or, more frequently, by annular dilatation.
◆ Type II: Excessive and increased leaflet mobility accompanied by
displacement of the free edge of one or both leaflets beyond the
mitral annular plane (i.e. in mitral valve prolapse).
◆ Type III: Reduced mobility in one or both leaflets. The type III
subdivides further in type IIIa (restricted leaflet motion during
both diastole and systole due to shortening of the chordae and/​
or leaflet thickening as i.e. in rheumatic disease) and type IIIb
when leaflet motion is restricted only during diastole (as i.e. in
ischaemic or non-​ischaemic cardiomyopathy).
However, mixed mechanisms may occur and both primary and
secondary MR can be generated by ischaemic or non-​ischaemic
pathological conditions.

Fig. 14.2  On the left, primary lesion of the mitral valve involving also mitral stenosis. The leaflets are affected, causing mitral regurgitation observed on the
right-​hand  panel.
By definition, primary MR is a result of the structural damage
of one or more components of the mitral apparatus (E Fig.
14.2). On the contrary, secondary MR results from the geomet-
rical alterations of LV after myocardial infarction or in cases of
cardiomyopathies (E Fig. 14.3). In those cases, the changes in
LV geometry and the contractility impairment may cause a dis-
placement and repositioning of the papillary muscles, which may
generate an imbalance between tethering and closing forces and
thus an incomplete coaptation.
Different haemodynamic impact exists in significant MR of
acute or chronic regurgitation. Acute MR mainly results from
chordae rupture, leaflet perforation and leads to rapid decrease in
LV afterload and consequently to a decrease in LV forward stroke
volume. In chronic MR, LV volume overload is generated and
thus LV forward stroke volume is preserved. This volume over-
load progressively produces LV eccentric dilatation and at the
same time LA enlargement which ‘absorbs’ the increased LA and
pulmonary pressures and thus remaining in the normal range.
When this compensated phase is overcome, symptoms, atrial
Fig. 14.3  Left-​side panel shows how left ventricular remodelling has affected mitral valve function with tethering observed. Incomplete coaptation leads to
mitral regurgitation, shown in right-​side panel.
Echo ca rdi o g r a phi c eva luat i on 201
fibrillation, pulmonary hypertension, LV systolic, and diastolic
dysfunction may occur.
Echocardiographic evaluation
Echocardiography remains the cornerstone for the evaluation
of MR. It allows comprehensive evaluation from aetiology and
underlying mechanisms, to severity assessment, and impact on
cardiac morphology and function. The initial echocardiographic
modality of choice to assess MR and to evaluate its haemo-
dynamic consequences is transthoracic echocardiography (TTE).
However, transoesophageal echocardiography (TOE) has a piv-
otal role in cases in which TTE is non-​diagnostic, when more de-
tailed information regarding MR aetiology is required or when
mitral valve surgery is scheduled.
Short-​axis views in both TTE and TOE allow identification of
the origin of the regurgitant jet (E Fig. 14.4). Additional planes
allow a more detailed evaluation of the integrity and function of
202 CHAPTER 14   Mitr a l valve regu rgitat ion
A2
P2
0
Fig. 14.4 Transoesophageal
echocardiographic segmental
analysis of the mitral valve. Anterior
leaflet (A1, A2, A3), posterior leaflet
(P1, P2, P3).
Courtesy of Lancellotti P and Magne J.
each leaflet (E Fig. 14.5). Additionally, three-​dimensional (3D)
echocardiography can provide additional information in patients
with complex valve lesions or when surgery is contemplated, and
can aide surgeons by providing the possibility to observe images
similar to the ones they will encounter when performing the
intervention (E Fig. 14.6).
Assessment of MR severity
Multiple echocardiographic approaches are utilized in order to
assess the severity of MR. An integrative approach and a combin-
ation of many of them should be encouraged [3]‌.
Qualitative assessment
Colour flow imaging
Colour Doppler is an initial starting tool for MR evaluation (E
Fig. 14.7). It is not recommended to use it as a method for quan-
tifying the MR severity since the jet size is affected by several
haemodynamic and technical factors that could potentially lead
to over-​or underestimation of the MR severity.
However, it allows a fast screening and justifies the need for fur-
ther MR quantification. Even so, a central jet with jet area <4 cm2
or <10% of the MR jet/​LA area ratio, with no obvious valvular
abnormality is highly suggestive of a mild MR. A flow jet directed
against the atrial wall appears to be smaller than a free jet of the
same regurgitant volume (Coanda effect), so the size of the jet
should be interpreted in the context of its geometry and the sur-
rounding solid boundaries [4]‌.
Continuous wave (CW) Doppler
The signal intensity (jet density) of the CW Doppler envelope
can be a qualitative guide to MR severity, since a dense signal
LAA
Ao A1
P1
A2
P2
A3
P3
135
45
90 A2
P2
P3 A2 P1
with a full envelope indicates more severe MR than a faint signal
(E Fig. 14.8). In eccentric MR it may be difficult to obtain the
full CW envelope because of the jet eccentricity, irrespective of
its dense features. Sometimes, the CW Doppler envelope may
be truncated (notched) with a triangular contour and an early
peak velocity. This implies elevated LA pressure or a prominent
regurgitant pressure wave due to severe MR.
Semi-​quantitative assessment
Anterograde velocity of mitral inflow
Pulsed wave (PW) Doppler mitral inflow pattern can be a sup-
portive sign to evaluate the MR severity. In the absence of mitral
stenosis, an E-​wave velocity >1.5 m/​s suggests severe MR while
on the contrary, a dominant A wave (atrial contraction) basically
excludes severe MR. The PW Doppler mitral to aortic velocity
time (VT) ratio is also used as an index for the quantification of
isolated primary MR. Tracings are obtained at the mitral valve
tips and aortic annulus in the apical 3-​or 5-​chamber views. A
velocity-​time integral (VTI) ratio >1.4 strongly indicates severe
MR while a VTI ratio <1 is in favour of mild MR. Moderate MR
cannot be accurately distinguished by using these parameters.
Pulmonary venous flow
Pulsed Doppler evaluation of pulmonary venous flow pattern is
an adjunct for grading the MR severity. Normally, the pulmonary
flow tracing gives a systolic wave (S) followed by a smaller dia-
stolic wave (D) and a reverse negative wave following atrial con-
traction (Ar). When severe MR occurs, the systolic component
(S) becomes reversed if the regurgitant jet enters the sampled
vein. Atrial fibrillation and elevated LA pressure can weaken the
systolic pulmonary vein flow however, the finding of systolic flow
 Echo ca rdi o g r a phi c eva luat i on 203

(a) (b)

Fig. 14.5  Mitral valvular

segmentation: (a) parasternal long-​axis
view, (b) short-​axis view, (c) apical
4-​chamber view, and (d) apical 2-​
chamber view. Anterior leaflet (A1, A2,
(c) (d) A3), posterior leaflet (P1, P2, P3).
Courtesy of Lancellotti P and Magne J.

reversal in more than one pulmonary vein is specific but not sen-
sitive indicator of severe MR.
Vena contracta width
The vena contracta, the narrowest and highest velocity segment
of the regurgitant jet as it traverses the mitral orifice, is obtained
from the parasternal long axis or the four-​chamber apical view. A
vena contracta width <3 mm correlates with mild MR whereas a
width ≥7 mm indicates severe MR. Since there is large overlap re-
garding the severity of the intermediate values, the use of another
method is required. It is reliable for both central and eccentric
jets and it is independent of flow rate; however, it is affected by
the cyclic changes of the regurgitant orifice and geometrical as-
sumptions regarding the circularity of the orifice may alter the
true amount of the regurgitation.

(a) (b) (c)

Fig. 14.6  Real-​time 3D transoesophageal echocardiography volume rendering of the mitral valve. (a) Surgical ‘en-​face’ view. (b) Mitral valve prolapse of P2. (c)
Flail (ruptured chordae) of P3. A1, A2, A3, anterior mitral valve scallops; P1, P2, P3, posterior mitral valve scallops; ANT COM, anterolateral commissure; POST
COM, posteromedial commissure.
Courtesy of Lancellotti P and Magne J.
204 CHAPTER 14   Mitr a l valve regu rgitat ion

Fig. 14.7  Colour Doppler is affected by several

factors. One of them is the direction of the jet,
which can be directed towards the atrial wall. In
these cases of eccentric jets, assessment of the
severity of mitral regurgitation based on colour
area is extremely misleading, since colour area may
be relatively small even in severe lesions.

Quantitative assessment
The flow convergence method—​proximal isovelocity surface area
(PISA) method
The flow convergence method is the most recommended quan-
titative method to evaluate the degree of MR. Most commonly,
the apical four-​chamber view or the parasternal long-​axis views
are used. To properly use the flow convergence method, the zoom
mode is used in order to reduce the area of interest. The sector
size is reduced as narrow as possible to maximize the frame rate
and the Nyquist limit is also reduced in order to have a clearly
rounded shaped PISA radius (15–​40 cm/​s) (E Fig. 14.9). The
measurement of the radius should begin from the mitral valve

Fig. 14.8  Continuous wave Doppler signal

density can be useful as an initial approach to
mitral regurgitation severity. It must, however, be
limited to such initial assessment and should be
complemented with further measurements.

EROA = Flow/Peak velocity
EROA = (2πr2 × Va)/Peak velocity
EROA = (2 × 3.14 × 1 × 33)/531
EROA = 207/531 = 0.39 cm2
R Vol = EROA × TVI
R Vol = 0.39 cm2 × 159 cm = 61mL
tips to the first aliased velocity, which occurs to mid-​to-​late sys-
tole. The flow convergence method has as advantages the fact that
is not affected by haemodynamic or instrumental factors and also
the aetiology of the regurgitation or the presence of concomitant
valvular disease does not affect the calculations. It can be used
also in cases of eccentric jets. On the other hand there are some
limitations. The shape of the PISA changes as the aliasing velocity
changes. Moreover, there is regurgitant orifice variation during
the cardiac cycle, which can make the calculation challenging es-
pecially in cases where the regurgitation is not holosystolic (i.e. as
in mitral valve prolapse).
Several studies have, however, showed the potential of three-​
dimensional PISA and its accuracy in overcoming some of the
limitations of the two-​dimensional method (E Fig. 14.10 and
Fig. 14.11).
Doppler volumetric method
In the absence of significant aortic regurgitation, mitral
regurgitant volume (mitral RVol) it can be derived from the for-
mula RVol = LV stroke volume—​LV forward stroke volume thus
Fig. 14.10  PISA method calculated in two-​dimensions is most reliable when the jet is centrally directed and the orifice is circular-​shaped (left-​side panel).
However, it has several limitations mainly concerning regurgitations with more than one jet or elliptical shaped orifices (central panel) and can be challenging in
eccentric jets (right-​side panel).
Echo ca rdi o g r a phi c eva luat i on 205
Fig. 14.9  Method of calculation of the EROA
and of the regurgitant volume (R vol) using the
PISA method.
Courtesy of Lancellotti P and Magne J.
the difference between the mitral valve antegrade stroke volume
and the LV outflow tract stroke volume. This method can be
used as an additive or alternative method, especially when other
methods are not applicable, although it is time-​consuming and
holds several drawbacks.
Consequences of MR
The presence of severe MR has significant haemodynamic effects,
mainly on the LV, LA, and pulmonary pressures (E Fig. 14.12).
LV size and function
MR imposes additional volume load on the LV. While in acute
MR, the LV is not enlarged, in the chronic situation, the LV pro-
gressively dilates since end-​diastolic volume increases in order to
maintain forward stroke volume. Eccentric hypertrophy and ir-
reversible LV dysfunction may occur. A systolic tissue Doppler
velocity at the lateral annulus of <10.5 cm/​s has been shown to
identify subclinical LV dysfunction and similarly a global longi-
tudinal strain <18% has been associated with postoperative LV
dysfunction.
206 CHAPTER 14   Mitr a l valve regu rgitat ion

Fig. 14.11  Real-​time 3D

transthoracic echocardiography for
the 3-​dimensional assessment of the
flow convergence zone of the mitral
regurgitation and the calculation of
the effective regurgitant orifice area
(EROA) using the 3D PISA method.
Courtesy of Lancellotti P and Magne J.

Fig. 14.12  Echocardiographic evaluation of a patient with ‘moderate to severe’ mitral regurgitation. Upper panels show the consequences of mitral regurgitation
on left ventricular dilatation and dysfunction. Middle panels report the haemodynamic consequences of mitral regurgitation, mainly with elevated mitral E-​wave
velocity and markedly increased transtricuspid pressure gradient (TTPG). Lower panels show an eccentric jet, the classical pattern of convergence zone of primary
mitral regurgitation using colour M-​mode, and the effective regurgitant orifice area (EROA) and regurgitant volume (R vol) calculation.
Courtesy of Lancellotti P and Magne J.
 Beyond echo ca rdi o g r a phy: eva luati on of m i tr a l reg urg i tat i on
Left atrial size and function
The LA dilates in response to chronic volume and pressure over-
load. LA remodelling may predict onset of atrial fibrillation while
conversely mitral valve repair leads to LA reverse remodelling. A
normal size LA is not normally associated with severe MR unless
it is acute.
Systolic pulmonary artery pressure
The excess regurgitant blood that enters the LA may induce a pro-
gressive rise in pulmonary pressures. Pulmonary hypertension
(PH) (PSAP >50 mmHg) is associated with adverse outcomes,
however it is not common to have asymptomatic patients with
preserved ejection fraction and PH.
Assessment of repairability and results of
mitral valve repair
Valve analysis through echocardiography is essential in the evalu-
ation of the possibilities of successful repair of a regurgitant mi-
tral valve, as well as intraoperatively to guide the surgeon through
the evaluation of immediate results.
Assessment of repairability
Assessment of repairability comprises several aspects, previously
mentioned, but must mainly be focused in the evaluation and
thorough description of the valve anatomy and function. The first
issue that needs to be clearly reported by the echocardiographist
is whether leaflet motion is normal, excessive, or restrictive.
Secondly, the segments responsible for valvular dysfunction must
be clearly reported and specified. 2D TTE is useful to that end,
but 2D and specially 3D TOE is extremely useful in clarifying
both the mechanism and extent of segments involved. This is
particularly important when commissural prolapse is present, as
it can frequently be misdiagnosed through 2D TTE. Two other
parameters must be a part of a report assessing repairability of
mitral regurgitation: the height of A2 and the diastolic diameter
of the tricuspid annulus, which will determine the need for add-
itional tricuspid repair [5]‌.
It is also important to assume that echocardiography is limited
in the evaluation of chordal lesions, such as elongation and even
(a) (b)
Fig. 14.13  Repairability can be assessed at different stages. The initial definition of the mechanism behind mitral regurgitation is usually carried out through
TTE (left-​side panel showing prolapse of the posterior leaflet). TOE provides higher definition in the assessment of the specific segments involved, which directly
affects repairability. Finally, 3D-​TOE provides excellent information regarding the extent of the lesions and potential involvement of other mechanisms.
207
rupture. These can occasionally be observed, but one should keep
in mind that they cannot be ruled out by echocardiographic as-
sessment, as they can frequently go unnoticed. This limitation
should be acknowledged by both the echocardiographist and the
surgeon when planning repair, as the surgeon must keep in mind
the need for direct visual evaluation during surgery [6]‌.
Intraoperative evaluation
During surgery, the surgeon expects and needs guidance from the
echocardiographist with regards to the result of mitral valve repair
(E Fig. 14.13). The first aspect to pay attention to is the result
in terms of residual regurgitation. Assessment must include the
presence and extent of residual regurgitation, but also the mech-
anism behind it. This is essential when further repair is needed,
as the surgeon needs guidance on which leaflet and segment are
involved. Both 2D and 3D TOE are essential tools for this [7]‌.
Other factors, such as the presence of factors predicting the
need for reoperation, systolic anterior motion, or the presence of
signs suggesting complications—​atrial septal defect, alterations in
segmental contractility suggesting potential injury to the circum-
flex artery or aortic cusp stitching are among the potential com-
plications that need to be kept in mind.
Beyond echocardiography: evaluation
of mitral regurgitation
Both TTE and TOE are the cornerstone of the diagnosis and
decision-​making regarding timing of intervention and treatment
options for mitral regurgitation. But these tools also have some
limitations that can be overcome by additional exams. Among
these, exercise echocardiography and, lately, cardiac magnetic
resonance have emerged to resolve some of the pitfalls in conven-
tional echocardiographic assessment.
Exercise echocardiography
When a patient with mitral regurgitation sits in front of us we typ-
ically ask about symptoms during exertion. Resting echocardiog-
raphy informs us of the underlying characteristics of mitral valve
(c)
208 CHAPTER 14   Mitr a l valve regu rgitat ion
disease. However, there is an essential discrepancy between the
conditions in which imaging evaluation is obtained and the infor-
mation we ask the patient to provide us with regarding functional
status. This can be misleading when the patient minimizes his/​her
functional repercussion and resting echocardiography does not
yield severity criteria. Exercise echocardiography is an extremely
valuable tool in patients who claim to be asymptomatic or mildly
symptomatic, or in those in whom we may attribute symptoms to
other concurrent cardiac or extracardiac conditions.
Exercise echocardiography can typically be performed during
or after peak exertion. When exercise is performed in a tread-
mill, the quality of echocardiographic exam is compromised or,
at times, directly not feasible. In these cases, it is essential that
the exam is performed immediately following peak exercise,
ideally in the first minute, since recovery to resting status, with
a decrease in MR severity and pulmonary pressures can be very
rapid [8]‌. If available, ergometers that allow the patient to exercise
in a left lateral decubitus position are ideal for continuous echo-
cardiographic evaluation during exercise. This is, still, far from
easy, given the challenging conditions in which images must be
obtained, especially tachycardia and tachypnoea.
It is important to keep in mind that dobutamine stress echo-
cardiography does not accurately reproduce exercise conditions,
alters the patient’s haemodynamic status and may underestimate
the severity of MR. Its role is limited to patients not suitable for
exercise echocardiogaphy in whom an ischaemic mechanism of
MR is suspected, or in whom the presence of viable myocardium
may alter therapeutic management [9]‌.
Several parameters identify patients who may benefit from early
surgery despite a mildly symptomatic status [10]. These include:
◆ exercise-​induced worsening of MR severity with an increase in
effective regurgitant orifice area (EROA): ≥10 mm2, regurgitant
volume ≥15 ml or pulmonary arterial pressure ≥60 mmHg;
(a)
Fig. 14.14  Quantification of mitral regurgitation
using cardiac magnetic resonance. (a) Total
stroke volume derived from left ventricular
volumes assessment. (b) Forward stroke volume
derived from velocity-​encoded cardiac magnetic
resonance flow quantification of aortic flow. (c)
Left ventricular outflow tract velocity measured
throughout the cardiac cycle. (d) Planimetry of the
anatomical regurgitant orifice area on a slice parallel
to the valvular plane obtained by cardiac magnetic
resonance. EROA indicates effective regurgitant
orifice area and R Vol, regurgitant volume.
Courtesy of Lancellotti P and Magne J.
◆ impaired contractile reserve, with markedly reduced increases in
LVEF (≤4%) or longitudinal strain (≤2%).
Cardiac magnetic resonance
Cardiac magnetic resonance adds important advantages to the
assessment of mitral regurgitation. This becomes particularly
relevant when the possibilities for echocardiographic evaluation
are limited or data obtained are inconclusive. In this regard, it is
important to understand the technique and know what we can
expect from it.
Cardiac magnetic resonance is an excellent tool to determine
chamber size and function. It can also provide useful anatomic
information regarding valve lesions and the nature of its dys-
function, using steady-​state free-​precession (SSFP) sequences,
which improve discrimination between valve tissue and blood.
Subvalvular apparatus is hard to define correctly due to limited
temporal resolution [11].
Evaluation of MR severity can be performed through planim-
etry and both direct and indirect calculation of regurgitant volume
(E Fig. 14.14). This analysis must, however, be performed by ex-
perienced operators and appropriate software, as it poses several
challenges. Planimetry is not easy since the regurgitant orifice
often varies throughout systole, as does the mitral valve plane.
This requires appropriate alignment throughout the full systolic
period. It is important to keep in mind that planimetry and PISA
can yield different results given that the first provides anatomic
and the second functional data. Planimetry defines the anatomic
regurgitant orifice, while PISA defines the EROA, that is, the area
of the narrowest regurgitant flow stream, which is usually smaller
(E Fig. 14.15). Regurgitant volume can be calculated directly, by
direct quantification of the regurgitant blood flow identified by
phase-​contrast sequences, or indirectly from the difference be-
tween LV total and forward stroke volume.
(b) (c)
(d)

Cardiac multislice computed tomography
(MSCT)
As in other cardiac conditions, cardiac computed tomography
(CT) allows excellent visualization of calcifications, which is par-
ticularly important in the evaluation of the annulus, leaflets, and
subvalvular apparatus. This, added to the possibility of providing
References
1. Iung B, Baron G, Butchart EG, et al. A prospective survey of patients
with valvular heart disease in Europe: the Euro Heart Survey on
Valvular Heart Disease. Eur Heart J 2003; 24: 1231–​43.
2. Braunberger E, Deloche A, Berrebi A, et al. Very long-​term results
(more than 20 years) of valve repair with Carpentier’s techniques in
nonrheumatic mitral valve insufficiency. Circulation 2001; 104(12
Suppl 1): I8–​I11.
3. Baumgartner H, Falk V, Bax JJ, et al. 2017 ESC/​EACTS Guidelines for
the management of valvular heart disease. Eur Heart J 2017; 2739–​91.
4. Monin JL, Dehant P, Roiron C, et al. Functional assessment of mitral
regurgitation by transthoracic echocardiography using standardized
imaging planes: diagnostic accuracy and outcome implications. J Am
Coll Cardiol 2005; 46: 302–​9.
5. Bolling SF, Li S, O’Brien SM, Brennan JM, Prager RL, Gammie JS.
Predictors of mitral valve repair: clinical and surgeon factors. Ann
Thorac Surg 2010; 90: 1904–​11.
6. Omran AS, Woo A, David TE, Feindel CM, Rakowski H, Siu SC.
Intraoperative transesophageal echocardiography accurately predicts
RE F E RE N C E S 209
Fig. 14.15  Cardiac magnetic
resonance imaging showing tethering
of the mitral valve (a) and the
regurgitant jet (red arrow, b). Mitral
valve P2 prolapse (c). Eccentric
regurgitant jet (d).
Courtesy of Lancellotti P and Magne J.
information on the absence of coronary artery disease, consti-
tutes its main strength. Additionally, it has shown to provide an
accurate estimation of MR severity by EROA and regurgitant
volume [12]. Although it is not recommended as a first choice
in the evaluation of MR, it constitutes a reasonable alternative,
especially in patients in whom other diagnostic tools may not
be suitable.
mitral valve anatomy and suitability for repair. J Am Soc Echocardiogr
2002; 15: 950–​7.
7. Feneck R, Kneeshaw J, Fox K, et al. Recommendations for reporting
perioperative transoesophageal echo studies. Eur J Echocardiogr
2010; 11: 387–​93.
8. Magne J, Lancellotti P, Piérard LA. Exercise-​induced changes in de-
generative mitral regurgitation. J Am Coll Cardiol 2010; 56; 300–​9.
9. Magne J, O’Connor K, Mahjoub H, et al. Evaluation and impact on
outcome of left ventricular contractile reserve in asymptomatic de-
generative mitral regurgitation. Eur Heart J 2014; 35: 1608–​16.
10. Lancellotti P, Magne J. Stress testing for the evaluation of patients
with mitral regurgitation. Curr Opin Cardiol 2012; 27: 492–​8.
11. Christiansen JP, Karamitsos TD, Myerson SG. Assessment of valvular
heart disease by cardiovascular magnetic resonance imaging: a re-
view. Heart Lung Circ 2011; 20: 73–​82.
12. Guo YK, Yang ZG, Ning G, et al. Isolated mitral regurgitation: quanti-
tative assessment with 64-​section multidetector CT—​comparison with
MR imaging and echocardiography. Radiology 2009; 252: 369–​76.
 CHAPTER 15

Tricuspid and pulmonary

valve disease
Denisa Muraru and Elif Leyla Sade

Contents Introduction
Introduction  211
Tricuspid valve  211 Right heart valves have gained significant interest in the context of a plethora of new
TV anatomy  211 emerging percutaneous transcatheter interventions for treating tricuspid (TV) and pul-
TV pathology  212
monary valve (PV) diseases. Multimodality imaging is pivotal for patient diagnosis,
Imaging  213
Pulmonary valve  216
management, and prognosis, as well as for planning interventional and surgical valve
Anatomy  216 procedures. This chapter highlights the current use of various imaging modalities for the
Imaging  216 state-​of-​the-​art assessment of right-​sided valvular heart diseases, with emphasis on the
PV pathology  216
main clinical indications, as well as on the strengths and limitations of each modality.
Conclusion  219

Tricuspid valve
Despite formerly neglected, TV has recently gained more consideration and scientific
interest, as physicians have become aware of the detrimental consequences of severe tri-
cuspid regurgitation (TR) on patient prognosis, functional capacity, and surgical risk [1]‌.
TR has been shown to negatively impact on patient outcome after surgery for acquired
and congenital heart disease [2–​4] or transcatheter structural aortic and mitral proced-
ures [5, 6].
Accurate anatomic characterization of the TV and evaluation of the underlying cause
of dysfunction are the first steps in the assessment of patients with TV pathology.

TV anatomy
In the normal heart, TV is the largest valve among all cardiac valves, with a normal orifice
area between 7 and 9 cm2. TV apparatus includes leaflets, annulus (TA) and subvalvular
apparatus (chordae tendineae, papillary muscles), and is closely linked anatomically and
functionally with the right atrium (RA) and the right ventricle (RV) myocardium in
the so-​called valve-​ventricular complex [7]‌. Effective TV competence depends on the
structural integrity and functional coordination of all components of TV apparatus [8].
Although TV is classically described as having three leaflets (described as septal anterior
and posterior), a great variability in the number of leaflets (from to 2 to 6) has been de-
scribed in autopsy studies [9, 10] (E Figs. 15.1a–​c, z Videos 15.1a–​c).
TA is a three-​dimensional, saddle-​shaped structure (E Fig. 15.2), which changes sig-
nificantly during the cardiac cycle (by 30–​35%) and with loading conditions. As opposed
to the mitral valve, the TA is more difficult to identify as a distinct structure on surgical
212 CHAPTER 15   Tric uspid and pu lmonary va lve di sease

(a) (b) (c)

Fig. 15.1  Anatomy and spatial

relationships of tricuspid valve by
three-​dimensional echocardiography
(a). Tricuspid leaflets are commonly
identified as anterior (Ant), posterior
(Post) and septal (Sep) (ventricular
view). Occasionally, anatomic variants
can be revealed by three-​dimensional (d) (e) (f)
en face rendering, that are impossible to
identify in conventional 2D longitudinal
views of the valve: bicuspid (b) and
quadricuspid (c) morphology; (d)
Functional tricuspid regurgitation;
(e) Organic rheumatic tricuspid valve
steno-​insufficiency; (f) Organic tricuspid
regurgitation due to anterior leaflet flail
(atrial view). Abbreviations: AML =
anterior mitral leaflet; PV = pulmonary
valve; RVOT = right ventricular
outflow tract.

or anatomical specimens, as it contains very little fibrous tissue or
collagen, suggesting that the term ‘annulus’ is a misnomer. With
functional TR, the TA dilates toward the postero-​lateral free wall
and becomes more spherical and planar [11].
TV pathology
The aetiology of TV diseases is generally divided into functional
(no structural abnormalities of leaflets) and organic (with intrinsic
structural changes of leaflets) (E Figs. 15.1d–​f ). Trivial or mild
functional TR without any detectable abnormality of the TV is
seen in 65–​75% of healthy subjects and is considered benign.
Only a minority of severe TR (10–​15%) is organic, and includes
various aetiologies, such as prolapse (myxomatous disease), endo-
carditis, rheumatic, congenital, carcinoid, traumatic, tumours,
induced by leads/​catheters or drugs, etc. [12]. In most cases,
functional TR develops as a consequence of deformation of the
TV apparatus, such as dilation and abnormal shape of TA, leaflet
tenting and RV dilatation with papillary muscle displacement, in

(a) (b) (e)

(c) (d) (f)

Fig. 15.2  Quantification of tricuspid annulus geometry by three-​dimensional echocardiography. From a transthoracic 3D data set (a), by multiplanar
reconstruction (Flexi-​slice), the septal-​lateral, (b) and anteroposterior (c) diameters, as well as the projected 2D annular area can be measured (d). Using a
dedicated prototype software, the reconstruction of non-​planar tricuspid annulus (e) or anulus and leaflets (f) can be obtained for quantification purposes.
Image Courtesy of Federico Veronesi, University of Bologna, Italy.

the context of left-​sided heart valve diseases, pulmonary hyper-
tension, ischaemic heart disease, congenital heart defects, and
cardiomyopathies [13].
Imaging
2D Echocardiography. Two-​dimensional echocardiography (2DE)
is the current imaging gold standard for assessing TV disease and
is often sufficient for diagnosis. Doppler echocardiography de-
tects the presence of regurgitation, and enables to understand the
mechanisms of TR and quantitate its severity and consequences
[14]. In comparison to other imaging modalities, echocardiog-
raphy has significant advantages: low cost, immediate access,
safety, excellent temporal resolution, and portability.
Because of its complex anatomy, several views are required to
assess TV during a transthoracic echocardiography (TTE) study,
including a combination of parasternal long-​and short-​axis,
apical RV-​focused 4-​chamber, subcostal 4-​chamber, and short-​
axis, modified apical 4-​chamber, etc. for a clear visualization of
TV apparatus and optimal alignment of Doppler measurements.
Identification of TV leaflets in standard 2D longitudinal views
remains a controversial issue, difficult to predict due to the ana-
tomic variability of the leaflets and the variable orientation of
imaging 2D planes.
Quantification of TR severity is challenging and can be per-
formed by many methods. The use of traditional quantitative
parameters (proximal isovelocity surface area (PISA), vena
contracts, etc.) is based on multiple—​and often erroneous—​
geometrical assumptions about the shape of the regurgitant
orifice and proximal convergence zone of the jet (E Fig. 15.3,
z Video 15.3) [14, 15].
Poor acoustic windows and suboptimal patient body ha-
bitus can compromise TTE image quality. Transoesophageal
(a)
Fig. 15.3  Geometric features of functional tricuspid regurgitation jet that limit the accuracy of conventional quantification of regurgitation severity by 2D
Doppler methods. (a) elliptical shape of vena contracta, displaying the smaller dimension in 4-​chamber view and larger dimension in the orthogonal view,
making single plane vena contracta diameter not suitable for adequately evaluating the severity of regurgitation; (b) flat proximal convergence zone (rather than
hemispheric), thus limiting the accuracy of PISA method.
I m ag i n g 213
echocardiography (TEE) is commonly performed when further
diagnostic refinement is required. Mid-​oesophageal, and particu-
larly low oesophageal and transgastric views allow a comprehen-
sive evaluation of TV morphology and function, including by
3DTEE [16].
3D Echocardiography. Three-​ dimensional echocardiography
(3DE) provides realistic anatomic images of TV apparatus, im-
portant functional insights, and more accurate quantitation op-
portunities for a better understanding of TV pathophysiology.
The identification of individual leaflets is more reliable by 3DE
than by 2DE, as well as the leaflet prolapse/​flail is better delin-
eated from TV ‘surgical’ view than by 2DE (E Fig.15.1f) [16].
Although current guidelines recommend 2DE to size the TA
[17, 18] (a cut-​off value of 40 mm or 21 mm/​m2 for the TA diam-
eter measured in apical 4-​chamber view in diastole indicating the
need of TV annuloplasty in case of surgery for left-​sided heart
valve diseases), it is well known that routine 2DE assessment
of TA diameter in 4-​chamber view underestimates the true TA
size [19]. In healthy subjects, TA diameter is correlated to age,
gender, RA, and RV volume [20]. 3DE brings unique opportun-
ities for a sound quantitation of the complex shape of TA and
leaflets (E Fig. 15.2).
3DE planimetry of the area of the vena contracta has been pro-
posed as a method to overcome the problems related to the asym-
metric shape of the regurgitant orifice in patients with FTR (E
Fig. 15.3, z Video 15.3). However, a validated cut-​off for the diag-
nosis of severe TR using 3DE planimetry of the vena contracta is
still lacking. 3DE is more accurate and reproducible than 2DE
for quantitating the haemodynamic consequences of the TR on
RV volumes and function. Poor acoustic window and irregular
rhythms are challenges for the clinical application of 3DE for TV
assessment in routine patients.
Cardiac magnetic resonance. The ability to dynamically visu-
alize the heart without any limitations related to body habitus
(b)
214 CHAPTER 15   Tric uspid and pu lmonary va lve di sease
or need for ionizing radiation makes cardiac magnetic reson-
ance (CMR) ideally suited to assess TV pathology and right heart
chamber remodelling. Cine SSPF imaging may reveal anatomic
leaflet abnormalities, such as Ebstein anomaly, leaflet thickening
(e.g. in rheumatic or carcinoid disease), abnormal movement
(e.g. flail) or loss of coaptation. Objects with highly irregular or
random motion (ruptured chordae, small mobile vegetations, or
masses, etc.) may not be well visualized by CMR.
TR jet can be qualitatively evaluated in a long-​axis RV view by
in-​plane velocity mapping. The ‘signal void’ phenomenon (cor-
responding to the turbulent regurgitant flow) and its extension
into the RA can be used as a semi-​quantitative parameter of TR
severity by CMR. However, similarly to colour Doppler jet area,
this method is also influenced by RA pressure and by imaging
parameters. In case of isolated TR, TV regurgitation volume can
be calculated as the difference between the RV and left ventricular
stroke volumes. Phase-​contrast imaging of the TV presents chal-
lenges as with the mitral valve, due to the active annular motion
during the cardiac cycle. Through-​plane phase-​contrast velocity
mapping in the pulmonary artery is undertaken to calculate for-
ward flow volumes. This is subtracted from the total RV stroke
volume to provide a TR regurgitant volume [21]. The conse-
quences of TV disease on RV volumes and systolic function can
be accurately evaluated by cine SSFP CMR imaging [22] and rep-
resent the current gold standard for RV assessment.
Finally, CMR has the unique capability of enabling in vivo
tissue characterization (i.e. fibrosis, fatty infiltration, etc.) (E Fig.
15.4). Due to the thin wall of RV and limited spatial resolution
of late-​gadolinium sequences, partial volume effects may create
difficulty to assess non-​transmural RV fibrosis. However, when
RV thickness is increased (amyloidosis, pulmonary hypertension,
etc.) or in case of transmural infarction, the late-​gadolinium en-
hancement can be more easily appreciated (E Fig. 15.5). Patients
(a) (b)
Fig. 15.4  Cardiac magnetic resonance imaging of a patient with functional tricuspid regurgitation in the setting of arrhythmogenic cardiomyopathy. The right
ventricle is severely dilated and dysfunctional in comparison with the left ventricle (a) with signs of diffuse fibrosis by late-​gadolinium enhancement (b) and fatty
infiltration by T1 mapping (c).
Courtesy of Dr. Camilla Torlasco from Istituto Auxologico Italiano, IRCCS, S. Luca Hospital, Milan, Italy.
with very irregular heart rhythms (e.g. uncontrolled atrial fibril-
lation, frequent ventricular ectopy), can present a challenge for
CMR due to motion artefacts. In these patients, real-​time cine
imaging with free breathing produces dynamic images similar to
those obtained by echocardiography, albeit with lower temporal
and spatial resolution.
Computerized tomography. Multidetector row cardiac com-
puted tomography (CT) imaging (MDCT) may demonstrate
clinical usefulness in TV disease—​especially when echocardiog-
raphy and CMR are either suboptimal or contraindicated—​with
information about TV morphology, TR mechanisms, and right
chambers size and function (E Fig. 15.6). MDCT is faster and
less hampered by metal artefacts than CMR, and can be an im-
portant alternative imaging modality for assessing patients with
pacemakers/​defibrillators which have not been considered safe
for CMR scanning. However, visualization of right-​sided valves
is less reliable than for the left-​sided valves, due to their complex
thinner structure and the fact that contrast injection protocols are
not timed to enable visualization of the right heart [23]. In order
to avoid streak artefacts, triphasic contrast injection protocols
(contrast, contrast/​saline, then saline) for right heart enhance-
ment should be used. Heart rate control is required to avoid mo-
tion and misregistration artefacts [24].
MDCT allows an excellent anatomic evaluation of TA and RV
cavity, and of their spatial relationships (E Fig. 15.6). The distance
between the TA and the right coronary artery is of particular im-
portance to avoid the risk of coronary injury from transcatheter
annuloplasty devices. Retrograde contrast opacification of the
inferior vena cava or hepatic veins seen on contrast-​enhanced
MDCT is a highly specific, but insensitive sign of right heart path-
ology (TR, pulmonary hypertension, or RV systolic dysfunction)
[25]. Radiation exposure, the lower temporal resolution (particu-
larly for older generation MDCT scanners) and the inability to
(c)
 I m ag i n g 215

(a) (b) (c)

(d) (e) (f)

Fig. 15.5  Use of multimodality imaging to evaluate the anatomy and function of tricuspid valve and the cause of regurgitation in a patient with
heart failure and severe functional tricuspid insufficiency. (a) and (b) show a severe, free tricuspid regurgitation jet due to right chamber and annular
dilation, and tethering of leaflets. (c) 3DE (ventricular view, systolic frame) illustrates the lack of any structural abnormalities of tricuspid leaflets,
which present a huge coaptation gap. (d) and (e) CMR imaging confirms the right chamber dilation, severe RV dysfunction with presence of
transmural scar at the inferior wall of the RV and LV, and inferior septum. (f) Coronary angiography confirmed an chronic occlusion of the right
coronary artery with collaterals.

(a) (b)

Fig. 15.6  (a) Cardiac computed tomography in a patient with functional tricuspid regurgitation due to dilation of right heart chambers, revealing a sinus
venosus type atrial septal defect. (b) Severe tricuspid annular enlargement (53 mm) due to right chamber remodelling as the prevalent mechanism of
functional tricuspid regurgitation.
Image Courtesy of Dr. Camilla Torlasco from Istituto Auxologico Italiano, IRCCS, S. Luca Hospital, Milan, Italy.
216 CHAPTER 15   Tric uspid and pu lmonary va lve di sease

assess transvalvular flow and pressure gradients, as well as the
challenges of assessing TV leaflet morphology are important
drawbacks, which favour the use of echocardiography or CMR
for the routine TV workup.
Pulmonary valve
Anatomy
PV is located anterior, superior, and lies perpendicular to the
aortic valve. The cusps of the PV are very thin and defined by their
relationship to aortic valve as anterior, right, and left. Sinuses and
sinotubular junction of the pulmonary root are less prominent
than the aortic root. Semilunar attachments of the leaflets form
the functional annulus which is located above the interventricular
muscular septum; in between is situated the infundibular segment
so-​called the right ventricular outflow tract (RVOT). There is no
fibrous continuity between the PV and the TV leaflets [26, 27].
Imaging
2D Echocardiography. The PV is typically seen in its longitudinal
axis by TTE. TTE views allowing visualization of PV are illus-
trated in E Figure 15.7. Assessment of RV and RVOT morph-
ology and function is an integral part of the evaluation of PV
[28]. Occasionally, TEE provides additional information about
the PV which is located at the far field of the scan line. Only the
longitudinal axis of the PV can be obtained. TEE views used for
visualization of the PV are illustrated in E Figure 15.7.
3D Echocardiography. 3DE enables en face view of PV leaflets
and commissures (E Fig. 15.8a, z Video 15.8a) which is best
obtained from an acquisition plane perpendicular to the PV plane
in a zoomed mode. This is achieved either from mid-​oesophageal
ascending aorta short-​axis view, or upper oesophageal aortic arch
short-​axis view by transoesophageal echocardiogram (TOE), and
from the parasternal short-​axis view by TTE.
PV pathology
Structural or functional abnormalities of the PV, annular dila-
tation, associated abnormalities of the RVOT, main pulmonary
artery (PA), and proximal PA branches should be examined to
elucidate the full spectrum of PV disease. Although TTE is the
first line imaging modality to assess the morphology of the PV
and associated abnormalities, multimodality imaging is the
standard of patient care [29, 30].
Pulmonary stenosis (PS) is mostly congenital. Isolated con-
genital PS can be observed with unicuspid, bicuspid, or dys-
plastic valves (E Figs. 15.8b–​d, z Videos 15.8b–​d). PS can
also be associated with cyanotic congenital defects like the tet-
ralogy of Fallot (TOF). Acquired causes are rare, may result from
rheumatic or carcinoid diseases. In both conditions, PS coexists
with pulmonary regurgitation (PR) and tricuspid valve involve-
ment. PS can be valvular, subvalvular (infundibular as in TOF,

(a) (b) (c) (d)

(e) (f) (g) (h)

Fig. 15.7  Tomographic views of pulmonary valve (arrows) by transthoracic (a–d) and transoesophageal echocardiography (e–h): (a) Parasternal long-axis view of
the right ventricular outflow (by tilting the probe infero-laterally and rotating it counter-clockwise), (b) Parasternal short-axis view, (c) Apical 4-chamber view with
extreme anterior angulation, (d) Subcostal short-axis view; (e) Mid-oesophageal short-axis view (70°, clockwise rotation), (f) Transgastric right ventricular outflow
tract view (120°, anteflexion and clockwise rotation), (g) Mid-oesophageal ascending aorta short-axis view (0°), (h) Upper oesophageal aortic arch short-axis view
(70-90°). Abbreviations: Ao = aorta; LA = left atrium; LV = left ventricle; RA = right atrium; RVOT = right ventricular outflow tract; TV = tricuspid valve.

(a) (b)
Fig. 15.8  En face views of the pulmonary valve cusps from the pulmonary artery perspective by 3D TEE. (a) Normal tricuspid; (b) Unicuspid*; (c) Bicuspid*;
(d) Rudimentary. Arrows indicate pulmonary valve. Abbreviations: A = anterior; L = left; R = right cusp; Ao = aorta.
*Image courtesy of Dr Tugba Kemaloglu Oz
subinfundibular as in double chambered RV), supravalvular, or
sometimes in series at more than one level (E Figs. 15.9 and​
15.10, z Videos 15.10a, b). Infundibular hypertrophy secondary
to PS may cause dynamic RVOT obstruction (E Fig. 15.9).
Thickened and calcified leaflets, systolic doming, infundibular,
and RV hypertrophy are relevant to stenosis severity. Flow con-
vergence zone by colour Doppler helps to define the level and to
estimate the severity of obstruction. Mean and peak gradients >40
and >64 mm Hg (peak velocity >4 m/​sec), respectively, by colour
wave Doppler (CWD) across the valve are evidence for severe PS
and the main decision making criteria required for intervention
[29, 31]. The mean PS gradient appears to correlate better with
catheter-​derived peak-​to-​peak gradient than the peak instantan-
eous gradient [32]. Of note, Doppler gradients may be overesti-
mated in patients with tubular stenosis, with stenoses in series or
with concomitant severe PR. Whereas, concomitant TR, depressed
RV function or PA branch stenosis may cause underestimation
of PS severity. Another useful index of PS severity is the RV sys-
tolic pressure estimated from the TR jet velocity and RA pressure
Pu l mona ry   va lv e 217
(c) (d)
[29, 31]. Echocardiographic estimation of PV area is not recom-
mended due to difficulties in the measurement of RVOT diameter.
Post-​stenotic dilatation of the PA can be observed. However, the
degree of dilatation does not correlate with the degree of PS.
Assessment of PS severity is important for timing of inter-
vention while morphological properties are important for the
choice of intervention. Percutaneous balloon valvuloplasty is
the first choice intervention to relieve PS. Effective commissural
splitting with balloon valvuloplasty is the main determinant of
procedural success. Therefore, patients with dysplastic PV may
have suboptimal results [33]. Balloon valvuloplasty is not suit-
able for carcinoid because of concomitant PR, and not suitable for
fixed subvalvular or supravalvular PS or hypoplastic pulmonary
annulus which are best approached surgically. Infundibular
hypertrophy may cause transient worsening of the RVOT ob-
struction and haemodynamic deterioration immediately fol-
lowing valvulotomy that regresses gradually [34].
PR is most often acquired. It develops secondary to pul-
monary trunk dilatation due to pulmonary hypertension, after
Fig. 15.9  Infundibular hypertrophy
secondary to pulmonary stenosis due
to bicuspid pulmonary valve. Note
the dynamic obstruction of right
ventricular outflow tract (arrow in end
systolic frame).
Courtesy of Dr. Omac Tufekcioglu.
PV = pulmonary valve; RVOT = right
ventricular outflow tract.
218 CHAPTER 15   Tric uspid and pu lmonary va lve di sease
(a)
Fig. 15.10  Supravalvular pulmonary
stenosis (PS). (a) Parasternal short-
axis view showing proximal left
pulmonary artery (LPA) branch
stenosis in a patient with tetralogy of
Fallot (arrowheads), (b) Alising and
color flow convergence in systole
indicating proximal LPA stenosis (c)
(arrow), (c) PW Doppler showing
mildly stenotic PV with severe PR,
(d) CW Doppler showing higher
velocity forward flow suggesting
more important stenosis, (e) PW
Doppler sample volume at the
level of proximal LPA showing flow
acceleration with aliasing indicating
the level of second stenosis.
transannular patch repair in TOF or valvuloplasty for an isolated
PS (E Fig. 15.11, z Videos 15.11a–​c) [35–​37]. Primary PR is
encountered with absent or rudimentary PV, usually in asso-
ciation with TOF, less commonly with PV prolapse, bicuspid,
quadricuspid valves, carcinoid syndrome, endocarditis, or trau-
matic injury. PR and PS may coexist in dysplastic valves, de-
generated bioprosthetic PV, or pulmonary homografts and after
balloon valvulotomy. In PR secondary to pulmonary arterial
hypertension, PV has a characteristic systolic notching W-shaped
that can be observed on M-​mode. TTE reveals thickened, re-
stricted leaflets, lack of coaptation, rudimentary leaflets, annular,
or pulmonary trunk dilatation. While PR can be secondary to
pulmonary trunk dilatation, severe PR may also cause PA an-
eurysm by flow augmentation and acceleration [38].
Abnormal valve morphology with lack of coaptation, as de-
scribed earlier, is a sign of severe PR (E Figs. 15.11a, b, z Videos
15.11 a, b). Mild PR has faint colour wave (CW) Doppler signal
with slow diastolic decay. A dense holodiastolic Doppler signal
indicates pathological PR, whereas a steep deceleration slope is
consistent with severe PR indicating early equalization of PA and
RV diastolic pressures. A pressure half-​time <100 msec (or decel-
eration time of <260 msec) usually indicates severe PR [39, 40].
Rapid deceleration may leave a no-​flow period in end-​diastole.
The ratio of the PR duration to the duration of diastole (PR index)
has been found to correlate with PR severity [41]. However, not
all instances of rapid deceleration indicate severe PR, as it may
occur in patients with low PA diastolic pressure and/​or elevated
RV diastolic pressure despite no severe PR. Importantly, PR with
laminar retrograde flow may be due to unrestrictive, very large
regurgitant orifice. Care should be taken not to miss severe PR
because of laminar colour flow appearance and short duration
[42]. Diastolic flow reversal in branch PAs is indicative of severe
(b)
(d) (e)
PR. The ratio of vena contracta width of the PR jet to the annulus
diameter >0.7 suggests significant PR [40, 43]. Although less com-
monly observed, premature opening of the PV at end-​diastole (by
transient rise in RV pressure above PA pressure during atrial con-
traction) (E Figs. 15.11c–​e), very low peak velocity of the PR jet,
and premature TV closure also suggest severe PR [44]. Of note,
these parameters are influenced by heart rate, RV compliance,
and other factors.
Nonparallel intercept angle with the PR jet and unequal distri-
bution of distal flow within the PA complicate the quantification
of antegrade and retrograde flow volumes by echocardiography.
In addition, precise measurement of pulmonary annulus is dif-
ficult and RVOT diameter has a dynamic nature. All these fac-
tors are potential sources of error in PR volume quantification by
echocardiography and cut-​offs are not validated. Multiparametric
approach is essential and concordance between more than one
parameter improves the accuracy and reproducibility of the as-
sessment. Because quantification of PR is not well standardized
the decision for surgery is mainly based on RV dysfunction and
dilatation that result from longstanding PR. However, RV dilata-
tion is not specific for PR.
Cardiac magnetic resonance. CMR is superior to echocardiog-
raphy to evaluate the RVOT obstruction or dysfunction, to quan-
tify RV mass and volumes. CMR is the gold standard non-​invasive
quantification tool for PR volume by phase-​encoded contrast vel-
ocity imaging that allows direct measurement of total pulmonary
forward and backward flow volume [45]. Regurgitant fraction
>40% indicates severe PR, whereas <20% indicates mild PR [46].
Flow can be assessed perpendicular (through-​plane) or parallel
(in plane) to the flow jet. The latter is particularly useful in the
presence of stenoses at multiple levels where information on the
area of maximum flow acceleration is needed. Other methods
 C on c lusi on 219

(a) (b)

(c) (d) (e)

Fig. 15.11  Pulmonary regurgitation (PR) after repair of tetralogy of Fallot. (a) Noncoapting PV leaflets in diastole, enlarged right ventricular outflow tract
(RVOT), transannular patch (arrowheads); (b) En face view of PV by 3D echo from above showing noncoapting leaflets and noncontracting transannular RVOT
patch in diastole and systole, interfering with the leaflets; (c) Diastolic flow reversal from pulmonary artery branch (arrow); (d) Pre-systolic forward flow across PV
(arrow); (e) PW Doppler showing rapid deceleration, early cessation (arrowheads) of the regurgitant flow yielding a PR index (A/B)=0.67, and pre-systolic forward
flow (arrows). Ao = aorta.

include the use of difference in RV and left ventricle (LV) stroke
volumes by quantification ventricular volumes with endocardial
contouring with or without additional phase-​contrast imaging
[45]. CMR is the recommended reference technique for serial as-
sessment of PR, RV volume and function after TOF repair [29,
30, 47]. Several studies suggested that RV end-​diastolic volume
<160 ml/​m2 or end-​systolic volume <80 ml/​m2 indicates the op-
timal timing for PV intervention [48–​50]. CMR can also define
the location and the severity of PS including sub-​or supravalvular
stenosis post-​stenotic dilatation, asymmetric dilatation of the
branch PAs. A diameter stenosis ≥50% is usually considered as
significant. PV area can also be measured by direct planimetry
from cine images perpendicular to the valve tips. Good temporal
resolution, excellent functional assessment and lack of radiation
are the advantages of CMR for serial follow-​up (E Fig. 15.12).
Computed tomography. High spatial resolution of MDCT can
provide valuable information about the PV anatomy. It is su-
perior to CMR for the assessment of PA and its branches. MDCT
is best used in patients with pre-​existing stents, calcified homo-
grafts, supravalvular or distal graft stenosis, and PV prostheses
[51, 52]. MDCT offers the advantages of fast acquisition, excellent
anatomical definition. MDCT is particularly useful in the pres-
ence of multiple obstructions in series and CMR non-​compatible
implants [53]. Excellent anatomic assessment of the coronary ar-
teries is an added advantage. Yet, the temporal resolution is not
enough for functional assessment. Radiation exposure and in-
ability to obtain haemodynamic information are the main limi-
tations of MDCT. This technique is used when the information
needed cannot be obtained by echocardiography or CMR.
Conclusion
TTE is the first line imaging modality to assess TV and PV. An
integrative approach with multiparametric and multimodality
imaging is standard of care for initial and follow-​up evaluation,
for preprocedural planning and for postoperative surveillance.
The full spectrum of TV and PV disease necessitates integrated
evaluation of entire valve complex, including RA, RV, and RVOT
remodelling, main, and branch PAs. CMR is the standard refer-
ence for the assessment of RV remodelling, tissue characteriza-
tion, and quantification of PR, while MDCT is the best modality
to assess supravalvular (particularly branch PA) stenosis, distance
between TA and right coronary artery, and cardiac anatomy and
function in patients with intracardiac devices or in situ corrective
implants.
220 CHAPTER 15   Tric uspid and pu lmonary va lve di sease

(a) (b) (e)

Fig. 15.12  Assessment of pulmonary

regurgitation (PR) by CMR. (a)
PR jet (arrow) in diastolic cine-
frame (balanced steady-state free
precession sequence). (b) In plane
and (c) through plane phase contrast
velocity mapping images showing
the regurgitant flow (arrow). (d)
Velocity-time curve derived from the
through plane phase contrast images (f)
(d)
allowing quantification of forward and (c)
backward flows. Regurgitant volume
is 46 mL, regurgitant fraction is 44% in
this patient. (e) Cine frames from the
right ventricular (RV) outflow images
in two patients with repaired tetralogy
of Fallot showing aneurysm of the RV
outflow tract (arrow). (f) Subvalvular
stenosis due to infundibular
hypertrophy (arrow).
Courtesy of Cemil Izgi.

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Contents
Introduction  223
Haemodynamic interactions  224
Imaging modalities  224
Multiple valve disease  225
Mixed valve disease  227
Role of imaging in the management
strategy  229
Conclusions  230
CHAPTER 16
Multiple and mixed
valvular heart disease
Philippe Unger and Madalina Garbi
Introduction
Multiple valvular heart disease (VHD) is the combination of stenotic and/​or regurgitant
lesions occurring on two or more cardiac valves. Mixed VHD is the combination of sten-
otic and regurgitant lesions on the same valve.
Both multiple and mixed VHD are highly prevalent. In the Euro Heart Survey, 20%
of the included patients with native VHD had multiple VHD, defined by at least mod-
erate VHD of two or more valves; 17% of the patients undergoing intervention had mul-
tiple VHD [1]‌. In the American Society of Thoracic Surgeons Database which included
290,000 patients undergoing surgery between 2003 and 2007, 11% had undergone double
valve procedures (replacement or repair) [2], whereas triple valve surgery accounted for
1% of cases. Based on hospital discharge codes without quantification of valvular dys-
function, multiple VHD accounted for 11% of patients in a Swedish nationwide study
[3]; multiple VHD comprised most frequently of aortic stenosis (AS) with associated
aortic regurgitation (AR), AS with associated mitral regurgitation (MR) and AR with
associated MR.
Multiple and mixed VHD encompass heterogeneous clinical situations, including nu-
merous possible combinations and different aetiology, severity, surgical risk, reparability,
and suitability for transcatheter therapies; this large variability contributes to the scarcity
of literature and limits the availability of evidence-​based management strategies.
Multiple VHD is most often acquired [4]‌. In the Euro Heart Survey [5], rheumatic
fever and degenerative VHD were the predominant aetiologies (51% and 41%, respect-
ively). Other acquired aetiologies, albeit less frequent, include infective endocarditis, ra-
diation therapy, drug-​induced VHD, and inflammatory diseases. Ageing and an overall
decrease in incidence of rheumatic fever explain the shift from rheumatic towards degen-
erative aetiologies observed in industrialized countries. Degenerative AS in the elderly
frequently coexists with mitral annulus calcification that can extend within the mitral
valve leaflets and cause calcific mitral stenosis (MS). The combination of calcific AS and
MS may impact the prognosis and may pose specific therapeutic challenges [6]; calcific
MS is not suitable for mitral balloon commissurotomy and surgical mitral valve replace-
ment has high morbidity and mortality in these cases. Secondary upstream MR and
tricuspid regurgitation (TR) may develop in patients with aortic VHD, and in patients
with right ventricular volume and/​or pressure overload due to left-​sided or pulmonary
VHD. Acquired pulmonary regurgitation, although unusual, usually results from endo-
carditis or carcinoid disease. Elderly patients with VHD frequently have coexistent cor-
onary artery disease and previous myocardial infarction, making associated ischaemic
MR not uncommon in this setting [7]. Congenital aetiologies are far less frequent causes
of multiple VHD.
224 CHAPTER 16   Multiple and mixed valvu l a r hea rt di sease

Among patients undergoing aortic valve replacement, con- Therefore, an integrative diagnostic approach is particularly im-
genital (mainly bicuspid aortic valve) and degenerative VHD are portant in the setting of multiple/​mixed VHD.
currently the most frequent aetiologies of mixed aortic VHD in When conventional echocardiography is inconclusive, other
industrialized countries, whereas rheumatic disease and endocar- imaging modalities can be used for the determination of the se-
ditis are less frequent [4, 5]. Mixed mitral VHD mainly results verity of stenotic lesions, particularly in the setting of low-​flow
from rheumatic disease in young patients, whereas calcified de- situations, but there is currently limited data in patients with
generative processes are mainly found in the elderly. multiple VHD.
There is increasing evidence that three-​dimensional echocardi-
ography improves the assessment of AS severity, (1) by allowing
Haemodynamic interactions direct measurement of left ventricular (LV) outflow tract area,
which is usually not circular, and, thereby, a more accurate calcu-
Concomitant stenotic and/​or regurgitant lesion on the same or lation of the aortic valve area; and, (2) by allowing direct planim-
on another valve may modulate the haemodynamic and clin- etry of the orifice [9]‌. Three-​dimensional echocardiography may
ical consequences of any given valvular lesion, depending on also be used to measure mitral valve area in MS [10] and, in MR,
several factors, including the specific combination of VHD, to assess its mechanism and severity [11].
the severity and timing of onset of each individual lesion, the In patients with low-​flow, low-​gradient AS, and depressed LV
loading conditions, and the ventricular systolic or diastolic per- ejection fraction, low-​dose dobutamine stress echocardiography
formance. The resulting haemodynamic interactions that may allows distinguishing severe from pseudo-​severe AS. However,
impact on the diagnosis of multiple and mixed VHD are sum- there is no evidence for the use of low-​dose dobutamine stress
marized in E Box 16.1 [8]‌. echocardiography in the case of low-​flow low-​gradient AS due to
multiple VHD.
Exercise testing may unmask symptoms, abnormal blood
Imaging modalities pressure response, and/​or exercise-​induced ST-​segment abnor-
malities or arrhythmias [12, 13–​15]. Despite the lack of spe-
As for single valve stenosis or regurgitation, Doppler-​ cific data on multiple and mixed VHD, stress echocardiography
echocardiography is the key diagnostic method in multiple/​ might be considered to elucidate the cause of disproportionate
mixed VHD. However, it may be affected by the haemodynamic symptoms in relation to the resting haemodynamics, which may
consequences of multiple and mixed VHD on blood flow, ven- include a higher than expected transvalvular pressure gradient,
tricular size, and ventricular function; furthermore, various abnormal response of the LV and/​or pulmonary arterial pres-
methods routinely used to assess VHD have not been valid- sure increase.
ated in this setting, and may be misleading if not correctly in- The assessment of calcium score by multidetector computed
terpreted. E Table 16.1 lists the main diagnostic caveats [4]‌. tomography is increasingly used to distinguish severe from
pseudo-​severe AS in low-​flow, low-​gradient AS with both re-
duced and preserved LV ejection fraction. High calcium scores
Box 16.1  Haemodynamic interactions that may impact on the (>1,200 and >2,000 Agatston Units for women and men, respect-
diagnosis of multiple and mixed valvular heart disease ively), are consistent with likelihood of severe AS [9, 16].
◆ In multiple valvular heart disease, valve stenosis can be Cardiac magnetic resonance (CMR) can be used to assess
low-​flow low-​gradient regurgitant lesions when echocardiographic image quality is in-
In mixed valvular heart disease there is typically high-​flow
◆
adequate, in patients with discordance between echo parameters
high-​gradient valve stenosis, because of the addition of the and in patients with discordance between clinical assessment
regurgitant volume to the forward flow and echocardiography, through the calculation of regurgitant
◆ The continuity equation is inherently inapplicable when volume and of regurgitant fraction [17, 18]. However, volumetric
transvalvular flows are unequal methods can be inaccurate in the presence of multiple regurgitant
◆ Severe stenotic, regurgitant, or mixed valvular lesions may lesions, as these methods assume that only one valve is affected
induce or aggravate upstream valve regurgitation [19]. In this setting, phase-​contrast velocity mapping can directly
measure antegrade and retrograde flow volume in semilunar
◆ Pressure half-​time-​derived methods may be invalid in the
presence of altered left ventricular compliance/​relaxation valves, but for the assessment of MR severity is more challenging
and/​or abnormal left ventricular filling induced by another due to the movement of the mitral valve annulus during systole,
valvular lesion and to the high velocity and turbulence of the regurgitant jet
[19]. Quantification and serial changes in ventricular volumes,
Source data from Unger P, Pibarot P, Tribouilloy C, Lancellotti P, Maisano F,
Iung B, Piérard L, On Behalf of the European Society of Cardiology Council mass, and function, reflecting the global burden of the VHD
on Valvular Heart Disease. Multiple and mixed valvular heart diseases: can be accurately assessed by CMR, and may contribute deter-
pathophysiology, imaging, and management. Circulation Cardiovascular mining the optimal timing for surgical or transcatheter valvular
Imaging 2018;11:e007862.
intervention [17].
 M u lti pl e va lv e di se ase 225

Table 16.1  Main diagnostic caveats in the assessment of multiple and mixed valvular heart disease

Combination of Aortic stenosis Aortic regurgitation Mitral stenosis Mitral regurgitation

valve lesions
Aortic stenosis AR pressure half-​time method MS pressure half-​time method Increased mitral
unreliable unreliable regurgitant volume
Peak aortic velocity and mean Low-​flow, low-​gradient Increased MR jet area on
gradient reflect the severity of stenosis colour-​flow mapping.
both AR and AS; they reflect the Mitral effective regurgitant
severity of the combined disease orifice less affected than MR
rather than purely the severity volume and colour-​flow
of AS mapping parameters
Aortic Simplified Bernoulli equation for Aortic regurgitant jet can be Doppler volumetric method
regurgitation gradient determination might not mistaken for mitral stenosis jet using left-​sided assessment of
be applicable if left ventricular Continuity equation is net forward flow invalid
outflow tract velocity is elevated unreliable to calculate mitral Mitral to aortic Velocity Time
due to high-​flow valve area Integral ratio unreliable
Gorlin formula using MS pressure half-​time method
thermodilution/​Fick method are unreliable
invalid
Continuity equation remains
applicable to assess AVA
Mitral stenosis Low-​flow, low-​gradient aortic MS can blunt the increase in Mitral to aortic Velocity Time
stenosis pulse pressure and the LV dilation Integral ratio unreliable
associated with AR
MS may decrease the AR
regurgitant volume
Mitral Mitral regurgitant spectral Doppler Volumetric methods Continuity equation
regurgitation signal should not be mistaken Pressure half-​time method can unreliable
for the aortic stenosis spectral be unreliable Pressure half-​time method
Doppler signal unreliable
Low-​flow, low-​gradient aortic Gorlin formula using
stenosis thermodilution invalid
This table presents the caveats in the echocardiographic assessment of a given valvular lesion (horizontal rows) in the presence of concomitant valvular lesion (vertical columns).
AVA = aortic valve area; AS = aortic stenosis; AR = aortic regurgitation; MR = mitral regurgitation; MS = mitral stenosis.
Reproduced from Unger P, Rosenhek R, Dedobbeleer C, Berrebi A, Lancellotti P. Management of multiple valve disease. Heart 2011;97:272–​7 with permission from BMJ.

When non-​invasive evaluation is inconclusive or discordant
with clinical findings, cardiac catheterization remains currently
recommended and commonly performed in multiple VHD [1, 9].
However, severe TR and very low cardiac output, which are both
frequent in multiple and mixed VHD may alter cardiac output
measurements by the thermodilution and by the Fick methods,
and therefore preclude the use of Gorlin formula for the calcula-
tion of aortic or mitral valve area. Moreover, the Gorlin formula
is inherently inaccurate in patients with mixed aortic or mixed
mitral valve disease.
Multiple valve disease
Aortic stenosis and mitral regurgitation. AS increases afterload,
thereby promoting LV concentric hypertrophy. LV hypertrophy
can result in diastolic dysfunction, dilatation of the left atrium,
and, hence, atrial-​secondary MR. As a result of high afterload,
the LV systolic function can drop with or without associated
LV dilatation; in this case, mitral annular dilatation with or
without leaflet tethering may induce ventricular-​secondary MR.
Ischaemic MR, as a result of the high prevalence of coronary
artery disease and primary MR, due to mitral annular calcifi-
cation are also highly prevalent in the elderly population [20].
Mitral valve chordal rupture can rarely occur in patients with
severe AS [21].
In order to avoid overestimating AS severity, differentiation of
the AS and MR spectral Doppler signal envelope is mandatory.
This is usually achieved based on flow timing-​related difference
in envelope morphology: the AS envelope has shorter duration,
as the transaortic valve flow starts late, after the isovolumic con-
traction time and ends early, when the isovolumic relaxation
time begins; on the contrary, the MR envelope starts early, during
the isovolumic contraction time, as the transmitral regurgitant
flow begins as soon as the LV contracts and persists within the
isovolumic relaxation time (E Fig. 16.1). In the presence of
AS with the resulting increased afterload, MR is characterized
by an increased transmitral systolic velocity and pressure gra-
dient, and, hence, by a higher regurgitant volume and by a higher
colour-​flow jet area for any given effective regurgitant orifice
area. Significant MR may decrease the forward flow across the
aortic valve (E Fig. 16.2), and, thereby, the transaortic pressure
226 CHAPTER 16   Multiple and mixed valvu l a r hea rt di sease
Fig. 16.1  Continuous wave Doppler tracings recorded from the apical
window in a patient with both mixed aortic valve disease and mixed mitral
valve disease. Unlike mitral regurgitation (MR), aortic stenosis (AS) flow does
begin after isovolumic contraction and ends when isovolumic relaxation
begins (yellow and red *, respectively); similarly, unlike aortic regurgitation
(AR), mitral stenosis (MS) flow does not include the isovolumic contraction
and relaxation periods. As shown in this example where flows are recorded
with similar velocity scales, AR, and MR invariably present higher flow
velocities than MS and AS, respectively.
gradient, a situation commonly referred to as ‘low-​flow low-​
gradient AS’, similar with the low-​flow low-​gradient AS that oc-
curs in the presence of reduced (classical low-​flow low-​gradient
AS) or preserved (paradoxical low-​flow low-​gradient AS) LV
ejection fraction [22]. Dobutamine stress echocardiography is
used to increase forward flow, and, thereby, to confirm AS se-
verity in classical low-​flow low-​gradient AS. However, in the pres-
ence of MR, it may fail to increase forward stroke volume, and,
therefore, to allow confirmation of AS severity. Quantification
of aortic valve calcium score by multidetector computed tomog-
raphy may be useful to differentiate true versus pseudo-​severe
AS in patients with concomitant MR (E Fig. 16.2).
Aortic stenosis and mitral stenosis. Approximately one-​tenth
of patients undergoing transcatheter aortic valve replacement
(TAVR) have concomitant MS, usually of calcific aetiology.
Severe MS is infrequent in this setting, but it is an independent
predictor of adverse clinical outcomes following transcatheter
aortic valve replacement [23]. In these patients, the reduction in
cardiac output is usually more pronounced than in isolated AS
or MS, and the resulting lower than expected aortic and mitral
pressure gradients may lead to underestimation of the severity of
both stenoses (E Fig. 16.3, z Video 16.1a). This situation usu-
ally requires a careful quantification of stenosis severity using
an integrative approach including aortic valve calcium quanti-
fication by multidetector computed tomography. The pressure
half-​time method to assess mitral valve area should not be used
because of the impaired LV filling in patients with AS. In rheum-
atic MS, planimetry of the mitral valve orifice should be pre-
ferred; three-​dimensional (3D) echocardiography allows accurate
measurement of the mitral valve anatomic orifice area based on
3D-​guided two-​dimensional planimetry, aligned with the valve
orifice, and precisely positioned at the mitral valve leaflet tips. In
the absence of AR, the continuity equation using the LV outflow
tract flow velocity is the preferred method in calcific MS.
Aortic regurgitation and mitral stenosis. The higher velocity
and earlier onset of the AR spectral Doppler signal allow differ-
entiation from the MS spectral Doppler signal (E Fig. 16.1). The
decrease in LV preload due to the associated MS may result in
lower LV volumes in these cases, compared to isolated AR [24].
Therefore, the typical signs of AR including increased pulse pres-
sure may be blunted in the presence of MS [25]. In addition, both
continuity equation (using the LV outflow tract flow velocity as
reference) and pressure half-​time methods are invalid for the cal-
culation of the mitral valve orifice area, in case of concomitant
significant (≥ moderate) AR. In this setting, the assessment of
mitral valve area, preferably with 3D echocardiography in case
of rheumatic aetiology, should be used to confirm the MS se-
verity (E Fig. 16.4). CMR imaging can be used to quantitate AR
volume and fraction.
Aortic regurgitation and mitral regurgitation. The combin-
ation of AR and MR is characterized by a marked increase in LV
preload and, mainly as a result of AR, by an increase in afterload
[26]. Therefore, severe LV dilatation may occur, together with LV
hypertrophy, usually eccentric hypertrophy with wall thickness
to cavity ratio typically below 0.45, and with increased sphericity
[27]. In addition, not infrequently, there is reduced LV ejection
fraction on presentation with symptoms, more pronounced than
in the case of isolated AR or MR [27, 28]. As a consequence, both
LV relaxation and compliance may be impaired, both known to
influence AR pressure half-​time [29]. In addition, chronic MR
may lead to LV dilation and altered LV compliance [30]. Hence,
the pressure half-​time method to assess AR severity should be in-
terpreted cautiously in the presence of MR, as in any condition
altering LV relaxation/​compliance. Volumetric methods, whether
derived from CMR or Doppler imaging are inherently invalid
to quantifying MR and/​or AR. The proximal isovelocity surface
area (PISA) method remains accurate to quantify the regurgita-
tion. CMR imaging using phase-​contrast velocity mapping may
be useful to quantify AR. When acute severe AR develops in pa-
tients with MR, the marked increase in LV end-​diastolic pressure
may be transmitted backwards, because the incompetent mitral
 M i x ed va lv e di se ase 227

(a) (b) (c)

(d) (e) (f)

Fig. 16.2  Patient with calcified aortic stenosis, mitral regurgitation, and tricuspid regurgitation. Left ventricular ejection fraction is preserved. The mean pressure
gradient across the aortic valve is 21 mmHg, maximal velocity is 280 cm/​s, and VTI 69.4 cm (a). The velocity time integral (b) and diameter of the left ventricular
outflow tract are 15.8 and 2.3 cm, respectively, allowing calculating an aortic valve area of 0.94 cm2. Using transesophageal echocardiography, the aortic valve area
is 0.83 cm2 by planimetry (c). There is concomitant moderate-​to-​severe mitral regurgitation associated with posterior mitral leaflet restriction (mitral effective
regurgitant orifice 28 mm2; regurgitant volume 48 ml) (d) and moderate tricuspid regurgitation (e). The calcium score of the aortic valve is 2736 AU (f). When
combined with other valvular lesions, aortic stenosis presents frequently with low flow and low gradient. High calcium scores are consistent with likelihood of
severe aortic stenosis in this setting.

valve fails to limit reversal of flow into the left atrium and the pul-
monary veins (E Fig. 16.5, z Video 16.1b and 16.1c). Mixed valve disease
MR associated with AR may be primary or it may be secondary
Mixed aortic valve disease. AS results in pressure overload with
to LV remodelling as a consequence of AR. The primary or sec-
consequent LV hypertrophy and reduced LV compliance. In
ondary MR aetiology should be determined, as it impacts the
this setting, the volume overload due to associated AR dispro-
likelihood of spontaneous MR severity reduction after isolated
portionately increases the LV diastolic pressure, resulting in a
aortic valve surgery [31].
greater LV wall stress and a poorer clinical tolerance than iso-
Tricuspid regurgitation and left-​sided VHD. Several factors
lated AS or AR [37, 38]. Due to impaired LV relaxation and/​or
may contribute to the occurrence and severity of secondary TR
to raised LV filling pressure, AR pressure half-​time is unreli-
in the setting of downstream VHD, including pulmonary hyper-
able [39]. The LV is usually not dilated, despite the volume over-
tension, atrial fibrillation, right ventricular dilatation and dys-
load, because of the AS-​related LV concentric hypertrophy [38,
function, tricuspid valve leaflet tethering, annular dilatation, and/​
40–​41]. In addition, the increased stroke volume resulting from
or right atrial enlargement,. Secondary TR is highly prevalent
AR may further increase the pressure gradient and overload
among patients presenting with left-​sided VHD, and may even
even when AS is moderate (>1.0 cm2). However, the simplified
worsen after the treatment of the mitral and/​or aortic valve dis-
Bernoulli equation may be not applicable for calculation of the
ease [32, 33]. Secondary TR is associated with reduced long-​term
aortic valve pressure gradient if the LV outflow tract velocities
functional capacity and survival [34]. TR is highly sensitive to
are elevated. Neither the calculated aortic valve area nor the ef-
changes in loading conditions; it has therefore been proposed that
fective regurgitant orifice area or regurgitant volume adequately
annular dilatation and leaflet coaptation, rather than TR severity
reflect the overall haemodynamic burden associated with mixed
itself predict future TR development and may serve as a thera-
aortic valve disease. As peak aortic valve velocity and mean
peutic guide [35]. When TR is severe, thermodilution-​derived
gradient both increase with the severity of AS but also of AR,
cardiac output may be erroneously low, and left-​sided valve area
these parameters are useful to assess the overall severity of the
may be underestimated by the Gorlin equation [36].
228 CHAPTER 16   Multiple and mixed valvu l a r hea rt di sease

(a) (b) (c)

(c) (d) (e)

Fig. 16.3  Transthoracic echocardiography in a patient with rheumatic mitral and aortic stenosis. Diastolic and systolic still frames recorded in the parasternal
long-​axis view (a and b, respectively), and moderate primary tricuspid regurgitation by colour Doppler in apical four-​chamber view (c). By continuous wave
Doppler, the mean transaortic pressure gradient is 22 mmHg and the maximal velocity is 325 cm/​s (d); the mean transmitral pressure gradient is 8 mmHg (e).
Although mitral and aortic pressure gradients are only moderately elevated, mitral valve area is 0.82 cm2 by planimetry (f), and aortic valve area is 0.90 cm2 by
the continuity equation, thus consistent with severe aortic and mitral stenosis. The calculated stroke volume is 28 ml/​m2. Multiple valve disease is frequently
associated with low flow, and, hence, low gradient through stenotic valves.

(a) (b)

(c) (d)

Fig. 16.4  Transthoracic echocardiography in a

patient with rheumatic mitral stenosis and mixed
aortic valve disease. Continuous wave Doppler
consistent with mixed aortic valve disease (a).
The mitral valve area obtained using the pressure
half-​time method is 1.7 cm2 (b). Mitral valve area
obtained with 3D-​guided 2D planimetry is 1.14
cm2 (c and d). The pressure half-​time method
is inaccurate to calculate mitral valve area in
the setting of concomitant aortic valve disease.
Planimetry of the mitral valve orifice should be the
preferred method in this setting.
 Rol e of i m ag i n g i n the m a nag em en t st r at e g y
(a)
Fig. 16.5  Patient with acute onset of severe aortic regurgitation as a result of infective endocarditis. Diastolic still-​frame showing the simultaneous occurrence
of aortic and mitral regurgitation (white and yellow arrow, respectively, a). M-​mode tracing demonstrates the early diastolic closure of the mitral valve
(arrowhead, b), followed by the occurrence of diastolic mitral regurgitation.
mixed aortic valve disease and predict outcome [37, 38, 40].
Intervention should be considered in case of a peak velocity ≥4
m/​s and a mean gradient ≥40 mmHg in a symptomatic patient
with moderate AS and moderate AR (E Fig. 16.6).
Mixed mitral valve disease. Due to concomitant MR, the
flow rate, and hence, the pressure gradient across the stenotic
mitral valve increase, resulting in an increase in left atrial pres-
sure, and contributing to exercise intolerance by increasing
pulmonary venous and capillary pressure. Therefore, mixed
moderate MR and MS may be haemodynamically significant
and result in dyspnoea or fatigue [42]. Due to the loading ef-
fect of MR, LV size is usually larger than in isolated MS. MR
may alter LV and left atrial compliances [43]; therefore, the as-
sessment of mitral valve area by the pressure half-​time method
may be unreliable [44]. Mitral valve area assessed by the con-
tinuity equation with the stroke volume obtained from the LV
outflow tract is underestimated in the presence of concomitant
MR. In this setting, the assessment of mitral valve area using
three-​dimensional echocardiography should be considered in
case of rheumatic aetiology. Similarly to mixed aortic VHD, the
transmitral peak velocity, mean gradient, or velocity time inte-
gral may provide assessment measure of the overall severity of
the mixed mitral VHD.
Role of imaging in the management
strategy
Imaging allows assessment of aetiology, mechanisms, severity,
progression, and consequences of the valvular abnormalities. It is
crucial for determining the indication and timing of intervention,
229
(b)
(c)
and for assessing the feasibility of valve repair or of transcatheter
therapies.
There is currently only limited evidence in the literature regarding
the medical, surgical, and interventional management of multiple
VHD, as emphasized by the C level of evidence given in most recom-
mendations made by the American Heart Association/​American
College of Cardiology and European Society of Cardiology/​
European Association for Cardio-​Thoracic Surgery guidelines on
the management of VHD [9, 13, 14]. In addition, the numerous
combinations of valve lesions do not allow a standardized approach,
applicable to each clinical situation. Three main clinical scenarios
may present in the setting of multiple valve disease, based on the
severity of each individual lesion as well as on their overall conse-
quences [45], making the management strategy highly dependent
on cardiac imaging. Due to the haemodynamic interactions and
the resulting diagnostic caveats, multimodality imaging is often re-
quired to ascertain the severity of each individual lesion.
i) When two or more severe lesions are present, severe func-
tional intolerance will likely persist if one of these lesions re-
mains untreated, and surgical management usually requires
addressing all these lesions during the intervention [9, 13, 14].
ii) When a severe valvular lesion is associated with one or more
non-​severe lesion(s), the severe lesion should be addressed
according to current guidelines; the interventional manage-
ment of the less-​than-​severe lesion(s) is (are) less straightfor-
ward and has (have) received a class II recommendation for
most combinations [9, 13, 14].
iii) When two or more moderate lesions are present, the assess-
ment of the overall haemodynamic burden induced by these
lesions is of critical importance. Besides symptoms, this
230 CHAPTER 16   Multiple and mixed valvu l a r hea rt di sease

(a) (b) (c)

Fig. 16.6  Patient with mixed aortic valve disease. (d) (e)
(a) Systolic frame in apical five chambers showing
residual opening of the aortic valve. However, the
continuous wave Doppler of the aortic valve (b)
shows a 4.02 m/​s maximal velocity, consistent with
severe AS. (c) There is moderate aortic regurgitation
(vena contracta 5 mm). (d) Pulsed wave Doppler
of the left ventricular outflow tract is 34 cm, and
3D-​guided 2D planimetry of the left ventricular
outflow tract is 4 cm2 (e), giving a calculated stroke
volume of 136 ml, and an aortic valve area of 1.49
cm2. Although both aortic stenosis and aortic
regurgitation are moderate, increased aortic forward
velocity, which provides an overall assessment of
aortic valve disease, is consistent with severe mixed
aortic valve disease.

assessment should include the overall consequences on ven-
tricular volume and pulmonary pressure, and may require the
assessment of natriuretic peptides, of functional capacity, of
maximal oxygen consumption and of pulmonary pressure
during exercise. Despite the absence of a severe lesion, sur-
gical or transcatheter valve intervention might be considered
in selected cases. However, this scenario, whose exact preva-
lence is unknown, is not covered by current guidelines, and
literature is particularly scarce [46].
Mixed VHD may also present as different scenarios, according
to the respective severity of stenosis and regurgitation. Severe
stenosis combined with severe regurgitation, or severe stenosis
(or regurgitation) combined with non-​severe regurgitation (or
stenosis) should be managed according to current guidelines re-
commendations applicable to severe lesions. However, the com-
bination of moderate stenosis and moderate regurgitation is also
not uncommon. This scenario may be associated with symp-
toms, reduced exercise tolerance, LV consequences, pulmonary
hypertension, and poor prognosis. It may therefore require con-
sideration of intervention, although not addressed in current
guidelines.
Importantly, decision-​making in multiple and mixed VHD
disease requires a collaborative approach between cardiologists
and cardiac surgeons in the setting of the Heart Team multi-
disciplinary meeting as recommended by current guidelines [9,
13, 14], thereby allowing an individually tailored management
strategy. The decision-​ making requires integration of nu-
merous factors, including natural history of native heart valve
disease (HVD), potential progression in MR or TR severity
after the treatment of a downstream valvular lesion, life ex-
pectancy, comorbidities, individual surgical risk profile, likeli-
hood of repair, increased risk of redo surgery, and feasibility of
transcatheter approaches [8]‌.
Conclusions
In multiple and/​or mixed VHD, several haemodynamic inter-
actions may impact the clinical expression of each singular valve
lesion and the clinician should be aware of these interactions
as well as of the resulting diagnosis pitfalls. Accurate quantifi-
cation of the valve lesions requires the use of methods that are
less dependent on loading conditions, such as the assessment of
the effective regurgitant orifice area and of the vena contracta for
regurgitant lesions, and planimetry for stenotic lesions. The clin-
ical decision-​making in these patients not only requires the as-
sessment of the severity of each singular valve lesion but also of
the overall consequences resulting from the combination of all
lesions. Echocardiography remains the cornerstone for diagnosis
in multiple and mixed VHD, however it should use an integrative
approach, including 3D echocardiography, stress echocardiog-
raphy, and other imaging modalities, like multidetector computed
tomography and magnetic resonance imaging.

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Contents
Introduction  233
General considerations  233
Mitral valve surgery  236
Mitral valve repair  236
Mitral valve replacement  241
Aortic valve surgery  243
Tricuspid regurgitation  249
Conclusion  249
CHAPTER 17
Intraoperative
transoesophageal
echocardiography for
valvular surgery
Joseph F. Maalouf and Hector I. Michelena
Introduction
Intraoperative transoesophageal echocardiography (IOTEE) is widely used to guide
valvular heart disease (VHD) surgery [1, 2]. The critical role of IOTEE is to aid the sur-
geon in tailoring the surgical approach to the specific mechanism(s) of valve dysfunction
in patients with mitral or aortic regurgitation undergoing valve repair surgery, identify all
valvular abnormalities that may warrant intervention, and to assess in a timely manner
the results of the operative intervention upon coming off cardiopulmonary bypass
(pump) thus allowing immediate correction of less-​than-​satisfactory results before the
patient leaves the operating room (OR). IOTEE is also useful to monitor results of con-
current interventions such as coronary artery bypass graft surgery and aorta aneurysm
repair, and to evaluate post –​bypass biventricular function
General considerations
The haemodynamic severity of VHD in need of surgical intervention should be estab-
lished preoperatively, and in the majority of cases by transthoracic echocardiography
(TTE). Pre-​pump IOTEE confirms targeted valve disease severity and severity of poten-
tially associated valvular (e.g. mitral and tricuspid regurgitation in patients undergoing
aortic valve replacement, AVR) or non-​valvular (e.g. dilated aortic root or ascending
aorta in patients with bicuspid aortic valve dysfunction) [1]‌. Pre-​pump IOTEE is also
critical to confirm and refine the mechanism and aetiology of regurgitant lesions, and
establishes baseline right and left ventricular function [1]. A thorough understanding
of valvular anatomy and pathology is a prerequisite for performing IOTEE in patients
undergoing valve surgery in general, and mitral and aortic valve repair in particular.
The four cardiac valves are anchored to their annuli, or valve ‘rings’. These fibrous rings
join to form the fibrous skeleton of the heart. The centrally located aortic valve forms the
cornerstone of the cardiac skeleton, and its fibrous extensions abut each of the other three
valves. The direct fibrous continuity between the mitral and aortic valves means that sur-
gical repair of one valve could significantly alter the geometry and function of the other
[3] (E Fig. 17.1, panels 1–​3 and E Fig. 17.2a).
Multiple simultaneous OR start times are typical of busy cardiac surgery practices.
Thus, the time available to complete a pre-​pump IOTEE exam on one patient before
being called to perform another IOTEE or prior to use of cautery which interferes with
234 CHAPTER 17   In traoperative transoesophag ea l echo ca rdi o g r a phy for va lvu l a r su rg e ry

image acquisition, is limited, and must be used wisely. This is best
achieved by adopting a focused goal-​oriented approach to IOTEE
that is tailored to the planned operation. When the anticipated
time available for pre-​pump imaging is not sufficient to obtain
a diagnostic study (e.g. assessment of mechanism and severity
of mitral regurgitation (MR) or complex valve evaluations), a
strategy of performing a diagnostic transoesophageal echocardio-
gram, when necessary, prior to date of surgery, is recommended.
At the time of pre-​pump evaluation, alerting the surgeon to the
presence of more than mild aortic regurgitation is critical to aid

(a) (b) (c)

LA LA
*
RV

Ao
LV LV

(d) (e) (f)

AV

LA LA
L M
*

LV LV

(a) (b) (c)

Ao
NC
C

M L LCC
RCC

Fig. 17.1  Panels 1 and 2 illustrate the potential impact of AVR on MV function (z Videos 17.1–17.4). (a)-(c):Pre-​bypass images in a patient undergoing
redo AVR. (a) TG view of aortic bioprosthesis showing severe prosthesis AR (orange arrows). The mitral valve annuus is calcified (red arrows)with calcification
extending into the anterior mitral leaflet (yellow arrow); (b) mid-​oesophageal view of mitral valve showing moderate regurgitation (arrow) and leaflet coaptation.
(c) MR CWD showing a peak velocity of 7 m/​sec. Blood pressure 106/​34 mmHg. (d–​f ) Post-​bypass images in same patient after AVR show worsening of MR due
to interference of AVR with mitral annulus/​coaptation. (d) Mid-​oesophageal view of mitral valve showing lack of leaflet coaptation in systole (yellow arrow) and
severe MR with eccentric jet (blue arrow); (e) 3D LA view of mitral valve showing large coaptation gap (*) in systole (arrow). (f) Characteristic ‘dagger-​shaped’
MR CWD signal with early low peak (3 m/​sec) and rapid decline due to rapid equilibration of systolic LV and LA pressures. The signal is dense because of severe
MR. Panel 3 (z Videos 17.5–17.7): Pre-​bypass 3D images from a patient with severe AR following MVR. (a) Ventricular view of mitral bioprosthesis stents (red
arrows) shows a large perforation (blue arrows) in the non-​coronary cusp of the AV, due to inadvertent AV damage while replacing the mitral valve, possibly with
suture needle. (b) The perforation (arrows) as viewed from the ascending aorta. (c) Colour flow Doppler showing convergence of mitral inflow (yellow arrow)
with the AR jet (red arrow) in diastole. Panel 4 (z Videos 17.8, 17.9): Pre-​bypass assessment of functional MR severity. (a) Trivial functional MR (arrow) at a SBP
of 100 mmHg. (b) Severe MR in same patient (arrow) 4 minutes later after increasing SBP with phenylephrine to 140 mmHg. Panel 5 (z Videos 17.10-17.12):
Post-​bypass intracardiac air pre and post adequate deairing of LAA (a, black arrows) and LV apex (b, white arrows).
Ao = ascending aorta; AR = aortic regurgitation; AV = aortic valve; AVR = aortic valve replacement; CWD = continuous wave Doppler; L = lateral; LA = left atrium; LAA = left atrial
appendage; LCC = left coronary cusp; LV = left ventricle; M = medial; MR = mitral regurgitation; MV = mitral valve; MVR = mitral valve replacement; NCC = non-​coronary cusp;
RCC = right coronary cusp; RV = right ventricle; SBP = systolic blood pressure; TG = transgastric.

(a)
LA
LV
(a)
Fig. 17.1 Continued
the surgeon with the decision to consider a left ventricular vent
to prevent overdistension of the left ventricle during antegrade
administration of cardioplegia or to proceed with retrograde
cardioplegia through the coronary sinus [1]‌. Mobile or complex
atheromas, as well as calcification, particularly in the ascending
aorta should be brought to the surgeon’s attention before can-
nulation because of increased likelihood of atheromatous debris
embolization or damage to the vessel. In the rare event when ad-
equate imaging of the ascending aorta and arch with IOTEE is
not possible, intraoperative (IO) epicardial echo may be useful,
although rarely used. Echocardiography has a limited role in the
assessment of porcelain aorta; X-​ray-​based modalities such as
computed tomography and fluoroscopy are more accurate.
Post-​pump IOTEE provides timely goal-​directed assessment
of surgical results allowing immediate correction of less-​than-​
satisfactory valve intervention results (via subsequent pump
runs). Indeed, patients leaving the OR with moderate or more
residual valvular regurgitation incur higher complication rates
and mortality than those with a satisfactory surgical result [1]‌.
Consequently, more than mild residual valvular regurgitation
should generally be corrected before the patient leaves the OR. In
G en er a l c on si de r at i on s 235
(b)
LV
(b)
the post-​pump period, IOTEE may also identify cardiovascular
factors responsible for haemodynamic instability in the OR such
as transient ventricular dysfunction, regional wall motion abnor-
malities, underfilled ventricles, functional left ventricular outflow
(LVOT) obstruction, etc. [1].
Regardless of type of surgery performed, it is important to
make sure that the cardiac chambers are satisfactorily de-​aired
prior to removal of the aortic vent. Common sites of entrapped
intracardiac air in patients undergoing valve surgery include the
left atrial appendage, left ventricular apex, and pulmonary veins
[1]‌ (see E Fig. 17.1, panel 5). Due to its anterior position, the
right coronary artery is more susceptible to air embolism than the
left coronary artery. And myocardial ischaemia secondary to air
embolism (most commonly inferior wall) is an important cause
of left and right ventricular systolic dysfunction in the immediate
post-​bypass period [1]. It is also important to confirm that there
is no injury to the ascending aorta after arterial decannulation
and removal of aortic vent, in particular aortic dissection or intra-
mural haematoma. A pseudoaneurysm may rarely form at the
aortotomy suture line or at site of graft anastomosis, needle punc-
ture or cannulation [4].
236 CHAPTER 17   In traoperative transoesophag ea l echo ca rdi o g r a phy for va lvu l a r su rg e ry
Special care must be taken in interpreting the severity of mitral
or tricuspid regurgitation pre or post-​pump because of the altered
and dynamic haemodynamic milieu (due to general anaesthesia,
use of vasodilators or vasopressors, fluctuating intravascular vol-
umes, changes in cardiac rhythm, and impact of cardioplegia on
myocardial contractility) that is characteristic of the operating
theatre, and reflects the dependence of MR and in particular
functional MR and tricuspid regurgitation (TR) on loading con-
ditions (see E Fig. 17.1 panel 4 a and b) [1]‌.
With exception of MR due to flail leaflet, MR due to other
causes and TR may, therefore, appear much less severe than ex-
pected, highlighting the importance of establishing a definitive
severity diagnosis before the patient reaches the OR. Pulmonary
vein systolic reversals can corroborate the presence of severe MR
but sensitivity is limited [1]‌. All valvular haemodynamic measure-
ments should include the heart rate and blood pressure at the time
the measurements were obtained. Administration of intravenous
phenylephrine to restore left ventricular afterload and volume in-
fusion to restore preload, are often required for adequate assess-
ment of MR particularly when the aetiology is functional (see E
Fig. 17.1 panel 4 a and b), but also to effectively corroborate the
presence of ≤ mild residual MR after repair or replacement [1].
Mitral valve surgery
Anatomically important structures during mitral valve surgery
include the left circumflex coronary artery, which courses within
Fig. 17.2  Schematic diagrams illustrating (a) MV in relation to surrounding anatomy, and (b) schematic illustration of MR mechanisms based on MR aetiology.
the left atrioventricular groove near the anterolateral commis-
sure, and the coronary sinus, which courses within the left atrio-
ventricular groove adjacent to the annulus of the posterior mitral
leaflet (Fig. 17.2a).
Because of their close anatomic proximity to the mitral valve,
the non and left coronary aortic valve cusps (see E Fig. 17.2a)
are prone to injury during mitral valve surgery which may result
in cusp perforation during placement of annuloplasty sutures (see
E Fig. 17.1 panel 3) or cusp retraction from pull on the adjacent
aorto-​mitral curtain (see E Fig. 17.2a), with secondary severe
aortic regurgitation (AR) [3, 5]. Other rare complications of mi-
tral valve surgery include left ventricle to coronary sinus, right
atrium, or right ventricle fistula(s), and ischaemia or infarction in
territory of the left circumflex if the artery is injured [3]‌. Surgical
ligation of the left atrial appendage (LAA), common during mi-
tral valve surgery and/​or maze procedure, is frequently incom-
plete. Evidence of residual flow between the LAA and body of
left atrium can be detected on post-​pump imaging and must be
reported.
Mitral valve repair
Degenerative mitral valve regurgitation is a common indica-
tion for IOTEE because mitral valve repair is feasible in the
majority of patients. The posterior mitral leaflet is usually ana-
tomically divided by minor commissures into three scallops
(lateral P1 scallop, middle P2 scallop, and medial P3 scallop)
 M i tr a l va lv e   re pa i r 237

with the middle P2 scallop being the largest of the three (see
E Fig. 17.2a). The anterior leaflet is arbitrarily divided into
corresponding A1, A2, and A3 scallops (see E Fig. 17.2a) and
there may be two additional commissural (anterolateral and
posteromedial) scallops. Occasionally, the only pathology is
commissural scallop prolapse or flail. Because the goal of mi-
tral valve repair is to restore normal valve function, the mech-
anism of dysfunction must be identified. Surgical mechanisms
of MR are based on whether the aetiology is annular dilatation
or leaflet perforation with otherwise normal leaflet mobility
(Type 1; see E Fig. 17.2b), excessive leaflet mobility due to flail
or prolapse (Type 2, degenerative or organic MR; see E Fig.
17.2b) or restricted leaflet mobility due to post-​inflammatory
disease or papillary muscle displacement in patients with func-
tional MR (Type 3; see E Fig. 17.2b).
IOTEE can accurately diagnose the mechanism of MR in the
vast majority of cases based on leaflet mobility and jet direction
(E Figs. 17.3 and 17.4).
The jet of MR is eccentric and directed away from a flail or pro-
lapsed leaflet segment. In contrast, the jet of MR is also eccentric
but directed toward the affected leaflet when the mechanism of
MR is leaflet tethering as in functional MR or leaflet retraction
as in post-​inflammatory MR (see E Fig. 17.3). The jet of MR
is generally central in MR due to annular dilatation (see E Fig.
17.1). For identification of a flail leaflet, the presence of a ruptured
chord (rapid systolic movement of the leaflet/​chord tip within the
left atrium) and eccentric jet have a 100% accuracy. A complete
two-​dimensional transoesophageal (TEE) assessment of the mi-
tral valve can be obtained from the mid-​oesophageal position
starting at 0 degrees and dialling different angles combined with

(a) (b) (c) (d)

LA
AV LA
LA
Ao

Ao
LV LV
LV

(a) (b) (c) (d)

LA LA LA
LA
LA

Ao
P1
LV
A2
P3 LV
LV LV
LV

(a) (b) (c)

LA

LV

Fig. 17.3  Top panel: (a) and (b) (z Videos 17.13, 17.14) 2D and corresponding 3D TEE of a flail AML (red arrows, Type 2), blue arrow points to ostium of LAA;
(c) and (d) (z Videos 17.15, 17.16): mid-​oesophageal views of flail P1 segment (red arrows); brown arrow points to AML. Note that on CFD, the regurgitant
jet is directed medially away from the flail segment. Yellow arrow in A and C points to AV. Middle panel: (a) and (b) (z Videos 17.17, 17.18): mid-​oesophageal
commissural views; (a): Prolapsing flail P2 segment (arrow) is seen above the A2 segment; (b): MR originating at P3 segment (arrow). (c) and (d) (z Videos
17.19, 17.20): mid-​oesophageal TEE long-​axis AV views showing a tethered PML (yellow arrow) and AML override (brown arrow) with secondary posteriorly
directed MR (d). Bottom panel (z Videos 17.21, 17.22): (a) Pre bypass 3D enface LA view of the MV in a patient with mycotic aneurysms showing a large AML
perforation involving the A3 segment (black arrow) with adjacent unruptured smaller mycotic aneurysm (asterisk) and corresponding surgical pathology (b,
white arrow and asterisk) (c) 2D TEE commissural view of mitral annular disjunction in a patient with bileaflet MVP. Red arrow points to basal myocardium and
yellow arrow to mitral annular separation in systole. Note the LAA (asterisk).
Ao = ascending aorta; AML = anterior mitral leaflet; AV = aortic valve; CFD = colour flow Doppler; LA = left atrium; LAA = left atrial appendage; LV = left ventricle; MR = mitral
regurgitation; MV = mitral valve; MVP = mitral valve prolapse; PML = posterior mitral leaflet.
238 CHAPTER 17   In traoperative transoesophag ea l echo ca rdi o g r a phy for va lvu l a r su rg e ry
probe manipulation (see E Fig. 17.3). The transgastric short-​
axis views, analogous to the transthoracic short-​axis views can be
invaluable for identifying the scallop affected, and in particular
commissural MR. And the transgastric long-​axis plane provides
a good view of the submitral chordal apparatus and papillary
muscles [1]‌. With 3D echocardiography (3DE), enface views of
the mitral valve leaflets, analogous to the surgeon’s view of the
mitral valve from the left atrium, can be readily obtained (see E
Fig. 17.3). Real time or live and multibeat acquisition 3DE of the
mitral valve including colour 3D, provide a very quick and con-
venient way of assessing the spectrum of mitral valve pathology
and the mechanism (s) of MR (E Figs. 17.3 and 17.4).
Prominent posterior leaflet interscallop indentations at site of
minor commissures may be seen in myxomatous mitral valve dis-
ease and are commonly referred to as cleft-​like indentations [6]‌.
These are not to be confused with congenital clefts that divide the
body of a leaflet into two [6]. Accurate characterization of these deep
cleft-​like indentations is best achieved with 3D TEE, and is critical
prior to mitral valve repair because they may be associated with sig-
nificant MR (E Fig. 17.4). Gaps are abnormal spaces between two
leaflets, often at the usual site of a major commissure [7], thus a cause
of commissural MR (E Fig. 17.4). They are also best appreciated on
3D TEE. Mitral annular disjunction (MAD) is characterized by de-
tachment of the mitral annulus from the ventricular myocardium
to which it would normally be attached, and is a common anatomic
abnormality in patients with severe myxomatous mitral valve dis-
ease [8] (E Fig. 17.3 bottom panel c). Recognition of MAD is im-
portant because it may alter the surgical approach to mitral valve
repair [8]. In certain patients with MR secondary to endocarditis,
repair is possible, particularly of the anterior leaflet.
The enface 3D colour flow Doppler left ventricular (LV) views
are particularly helpful in localizing the site and extent of MR (see
E Fig. 17.4). With 3D TEE, prioritizing the origin of the predom-
inant jet(s) of MR in patients with Barlow’s disease(prolapsing
myxomatous disease affecting multiple or all mitral scallops) can
be readily achieved (see E Fig. 17.4). This is important for the
surgeon to tailor the repair to address the anatomic pathology
directly responsible for the MR.
IOTEE is therefore, critical to establishing the pathoanatomic
mechanism of degenerative ‘organic’ MR in order to guide mi-
tral valve repair [1]‌. Any degree of mitral annular calcification
including leaflet involvement should be communicated to the
surgeon because it may impact mitral valve repair. Severe mitral
annular calcification, usually best appreciated on the preoperative
TTE, may preclude successful mitral valve repair.
Minimally invasive surgeries such as robotic-​assisted mitral
valve repair are usually performed using femoral–​femoral bypass.
IOTEE is useful in such operations to guide positioning of the
guidewire and venous cannula in the superior and inferior vena
cava and to verify position of the arterial guidewire in the lumen
of the descending thoracic aorta, prior to initiation of cardiopul-
monary bypass.
Pre-​pump IOTEE can also help identify patients at high risk for
post mitral valve (MV) repair systolic anterior motion of the mi-
tral valve (SAM) which may prompt surgical techniques directed
at its prevention [9]‌. A long redundant anterior leaflet, an acute
angle between the mitral and aortic annular planes (usual angle
is approximately 135°), leaflet coaptation point to septal distance
≤2.5 cm, ratio of co-​apted systolic lengths of the anterior and pos-
terior leaflets ≤1.3, and presence of a subaortic septal bulge or
pre-​pump SAM have all been associated with post-​repair systolic
anterior motion [1, 9] (E Fig. 17.5).
In patients with hypertrophic obstructive cardiomyopathy
undergoing myectomy, the severity and mechanism of associated
MR is ascertained [i.e. predominately functional and posteriorly
directed MR secondary to SAM, or in association with a primary
mitral valve pathology such as mitral valve prolapse or flail seg-
ment]. Central or anteriorly directed MR should alert the IOTEE
operator to a primary mitral valve pathology [1]‌(E Fig. 17.6).
Unless a flail segment or other clearly defined primary mitral
valve pathology is identified, and even in atypical non-​posteriorly
directed jets, it is recommended to reassess the MR post-​bypass
after myectomy at physiologic haemodynamic conditions of
preload and afterload and without residual SAM because even
atypical including multidirectional MR jets in the setting of struc-
tural mitral valve anomalies may improve or even resolve after
myectomy  [1]‌.
MV repair pre-​pump check list
✓ Confirm severity of MR
✓ Assess severity of associated TR
✓ MV pathology and mechanism of degenerative MR
Prolapsed segment and scallop (s) involved. In Barlow’s dis-
●
ease, prioritize scallops associated with major jets of MR
Flail segment and scallop (s) involved
●
Presence of annular disjunction
●
Restricted leaflet/​scallop mobility
●
Commissural MR and commissural gaps
●
Leaflet perforation
●
Leaflet aneurysm
●
Leaflet vegetation(s)
●
Mitral leaflet cleft-​like indentations associated with MR
●
Other congenital mitral valve abnormalities
●
Extent of mitral annular calcification
●
Ruptured papillary muscle
●
Predictors of post-​
● repair SAM (leaflet length, septal-​
to-​
coaptation length, and basal septal thickness)
In mitral valve repair, the presence of ‘less than echo-​perfect’
results from repair (>1+ residual MR) increases the risk of
reoperation, and in our practice, mandates a second pump run
for correction [1]‌. The surgeon needs to understand the mech-
anism of residual MR (e.g. residual prolapse or leaflet gaps) and
its anatomic location in a timely fashion
Other potential causes of unacceptable post MV repair MR in-
clude residual ‘leaking’ clefts and suture and/​or annuloplasty de-
hiscence which may be best appreciated on 3D TEE. Markedly
restricted/​stenotic mitral repairs may result from rigid leaflets,
constricting annular calcification, undersized annuloplasty rings
or Alfieri edge-​to-​edge mitral valve repair that involves suturing
 M i tr a l va lv e   re pa i r 239

(a) (b) (c)

AV

M L M L

(a) (b) (c)

AV
AV

L M
M L

(a) (b) (c)

LVOT
LVOT

M L M L
M L

(a) (b) (c)

AV
AV A
A A L M
L
M L M P

IAS
P P
IAS

LAA

Fig. 17.4  Panel 1 (z Videos 17.23–17.25): (a) 3D MV LA view showing large anterolateral commissural scallop prolapse (red arrows; blue arrow points to ostium of
LAA). (b) and (c) Different patient, 3D MV LV views of commissural gap (arrow) with flow through the gap (c). Panel 2 (z Videos 17.26–17.28) (a) 3D CFD showing
medial paracommissural regurgitation (red arrow). (b) and (c) 3D MV in a patient with Barlow’s disease prior to MV repair; (b) LA view showing myxomatous bileaflet
prolapse (yellow and brown arrowheads point to AML and PML, respectively, and red arrow points to ostium of LAA). (c) 3D CFD LV view showing two distinct origins
of MR (arrows). Panel 3 (z Videos 17.29–17.31): 3D mitral valve as viewed from LV; (a) deep posterior leaflet cleft (arrows). (b) CFD showing MR through cleft (arrows).
(c) Different patient, LV 3D CFD. Two posterior leaflet clefts (arrows) but only one (red arrow) is associated with MR. Panel 4 (z Videos 17.32–17.34) (a) Enface LA 3D
CFD of a mechanical bileaflet mitral prosthesis. Blue arrows point to washing volume MR jets. Red arrow points to an anteromedial PPL and yellow arrow points to an
anterolateral PPL. (b) Enface LA 3D CFD of another mechanical bileaflet mitral prosthesis. Red arrow points to a lateral PPL. The black arrows point to normal MR jets at
the occluder hinge points. (c) Enface LA 3D of the same prosthesis. Blue arrowheads point to the PPL and red arrows point to the hinge points of the leaflet occluders.
The spatial coordinates of the PPL are determined using three fixed anatomic landmarks: the anterior AV, anterolateral LAA, and medial IAS.
A = anterior; Ao = ascending aorta; AML = anterior mitral leaflet; AV = aortic valve; CFD = colour flow Doppler; IAS = interatrial septum; L = lateral; LA = left atrium; LAA = left
atrial appendage; LV = left ventricle; LVOT = left ventricular outflow tract; M = medial; MR = mitral regurgitation; MV = mitral valve; P = posterior; PML = posterior mitral leaflet;
PPL = periprosthetic leak.
240 CHAPTER 17   In traoperative transoesophag ea l echo ca rdi o g r a phy for va lvu l a r su rg e ry

(a) (b)

LA AL PL

PL α

AL
Ao
CS

VS
LV

(a) (b)

LA
AL PL
LA

VS
* *VS
LV LV

Fig. 17.5  Top panel: 2D TEE five-​chamber mid-​oesophageal view in a patient with bileaflet MVP and schematic diagram illustrating the recommended pre-​
pump measurements used to predict post MV repair SAM. Bottom panel (z Videos 17.35, 17.36): IOTEE during MV repair of MR secondary to PL prolapse. (a)
Pre-​bypass four-​chamber view. The CS distance measured 1.9 cm. (b) Same view post-​bypass showing SAM (arrow).
Ao = ascending aorta; AL = anterior mitral leaflet; AV = aortic valve; CFD = colour flow Doppler; CS = mitral leaflet coaptation to septal distance; LA = left atrium; LV = left ventricle;
* = left ventricular outflow tract; MR = mitral regurgitation; MV = mitral valve; MVP = mitral valve prolapse; PL = posterior mitral leaflet; SAM = systolic anterior motion of the MV;
VS = ventricular septum.

of the A2 and P2 segments of the mitral valve, resulting in a char-
acteristic double-​orifice mitral valve.
Post mitral valve repair systolic anterior motion (SAM) may
be associated with significant MR [1, 9] (see E Figs. 17.5 and
17.6). The mechanism of SAM in this setting is anterior displace-
ment of redundant valve tissue that gets ‘sucked’ into the left ven-
tricular outflow tract during systole causing various degrees of
outflow obstruction and a characteristic posteriorly directed MR
jet. The usual causes include hypovolemia, increased left ven-
tricular contractility (from increased sympathetic tone or use of
inotropic agents) or decreased afterload (from use of vasodilators
or anaesthetic agents) with usual resolution of SAM after volume
expansion, beta-​blocker therapy, increased afterload, or any com-
bination thereof [1]‌(see E Fig. 17.6).
Mild SAM tends to improve spontaneously over time in the
vast majority of patients. If SAM-​related MR persists or LVOT
gradient remains significant, a second pump run may be con-
sidered. When the cause of post MV repair SAM, is a large redun-
dant anterior leaflet, revision of the repair may involve insertion
of a neochord to the anterior mitral leaflet or an Alfieri repair.
The mean gradient across the mitral valve and heart rate should
always be recorded post-​repair with the continuous wave (CW)
Doppler cursor aligned parallel to the mitral diastolic flow.
MV repair post-​pump check list
✓ Severity of residual MR under physiologic haemodynamic con-
ditions; more than mild residual MR should prompt a second
pump run for correction, effective and timely communication
of residual defect mechanism and anatomic location
✓ If MR is moderate or severe and posteriorly directed, exclude
SAM as underlying mechanism
✓ Measure mean gradient across MV with parallel cursor alignment
 M i tr a l va lve re pl ac e m e n t 241

(a) (b) (c) (d)

V V

LA LA LA
LA
LA LA
Ao Ao

AV
Ao
VS
* VS
VS VS
* LV LV LV
VS LV LV
LV

(a) (b) (c) (d)

LA LA LA
LA

VS
LV LV
LV VS
LV

(a) (b) (c) (d)

AV AV

L * M L
* * * M
* * *

Fig. 17.6  Top panel (z Videos 17.37–17.40): (a) and (b) Pre and post-​bypass MR in a patient with HOCM: Baseline severe posteriorly directed jet of MR
secondary to SAM (arrows); (b) Trivial residual MR (arrow) post myectomy and resolution of SAM. (c) Different patient, post MV repair SAM (yellow arrow)
with secondary severe MR (arrows). (d) No residual MR after resolution of SAM with medical treatment (beta-​blockers, volume expansion) in the OR. Middle
panel (z Videos 17.41–17.44): (a) Pre-​bypass severe posteriorly directed jet of MR in a patient with HOCM and SAM (arrow); (b) Persistent severe posteriorly
directed jet of MR post myectomy (arrows). Patient required a second pump run, excision of AML and MVR; AML pathology showed post-​inflammatory
changes consistent with clinical history of healed endocarditis. (c and (d) Central severe MR in a patient with HOCM consistent with primary mitral valve
pathology (arrows). On inspection of the MV, the leaflets were very thickened and the posterior leaflet was calcified—​patient required MVR. Bottom panel
(z Video 17.45): (a) Enface 3D LA view of MV post-​surgical repair and corresponding surgical view (b). There is residual A3 prolapse (asterisk; arrows point to
adjacent portion of annuloplasty band). (c): Enface 3D LA view of MV from another patient post MV repair. The annuloplasty band is marked by black asterisks.
Note areas of leaflet malcoaptation at medial commissure (yellow arrow) and at A2-​P2 (red arrows). There is also dehiscence at lateral margin of the annuloplasty
band (black arrow). MR at all three sites was documented by CFD (d).
Ao = ascending aorta; AML = anterior mitral leaflet; AV = aortic valve; CFD = colour flow Doppler; HOCM = hypertrophic obstructive cardiomyopathy; LA = left atrium; LV = left
ventricle; MR = mitral regurgitation; MV = mitral valve; MVR = mitral valve replacement; OR = operating room; PL = posterior mitral leaflet; SAM = systolic anterior motion of the
MV; VS = ventricular septum.

✓ Exclude left circumflex coronary artery injury/​occlusion) (i.e.
new lateral-​posterior wall regional wall motion abnormality, ar-
rhythmias, difficulty coming off bypass)
Mitral valve replacement
Post-​pump IOTEE evaluation of mitral valve prostheses includes
verifying normal mechanical prosthesis leaflet occluder motion
(submitral chordae or rarely papillary muscle may interfere with
prosthesis occluder motion), excluding periprosthetic regurgitation
or rarely left ventricular outflow tract (LVOT) obstruction by the
prosthesis [10] or retained anterior mitral leaflet that is displaced
into the left ventricle [11] (the current practice is to preserve the
posterior mitral leaflet and submitral chordal apparatus and to ex-
cise the anterior mitral leaflet). Oversizing of any mitral prosthesis
can potentially result in LVOT obstruction. Post-​pump evaluation
also includes baseline assessment of prosthesis haemodynamics
(measurement of peak mitral prosthesis inflow velocity and mean
gradient), and colour Doppler imaging of the normal built-​in regur-
gitation unique to each type of mechanical prostheses referred to as
‘washing jets’, and which serve as its ‘fingerprint’(see E Fig. 17.4
242 CHAPTER 17   In traoperative transoesophag ea l echo ca rdi o g r a phy for va lvu l a r su rg e ry

panel 4 a and b). For St Jude and Carbomedics bileaflet prostheses,
the most commonly used mechanical prostheses, normal ‘washing
jets’ consist of a small central jet (from regurgitation between the
two occluder disc leaflets) and two or more small peripheral jets
(from regurgitation that occurs between the occluder disc leaflets
and adjacent sewing ring). Additional trivial to mild regurgitation
can occur at the hinges of the occluder [12]. Mild prosthetic re-
gurgitation can be observed with some bioprostheses. Pathologic
prosthetic regurgitation or obstruction can result from a mechan-
ical prosthesis leaflet being entangled to residual native subvalvular
support apparatus (E Fig. 17.7) [13, 14]. Unless recognized by
IOTEE, a patient with a mechanical bileaflet prosthesis may not
have problems coming off pump if one of its two leaflets/​disc
occluders is stuck in a closed position.
The most common complication after mitral valve replace-
ment is periprosthetic regurgitation commonly referred to as
periprosthetic leak (PPL) especially when the mitral annulus is
severely calcified, due to the difficulty in suturing the sewing ring
to a calcified surface. PPLs are found more commonly after mi-
tral valve replacement than AVR and are usually mild; decreasing
by up to 50% after protamine anticoagulation reversal has been
administered [1]‌. More than mild PPL usually requires a second
pump run for closure. Despite excellent correlation between PPL
described by TEE and direct surgical observation, communi-
cating its location to the surgeon can be confusing. Localizing
the PPL in reference to anatomic landmarks is critical. This is
best appreciated with 3D (see E Fig. 17.4 panel 4 b and c), but
may also be achieved with 2D TEE by careful scanning of the
entire sewing ring in the mid-​oesophageal window by gradually
rotating the transducer array from 0 to 150 degrees and when
feasible, by obtaining a short-​axis view of the sewing ring from
the transgastric window. PPL location should be reported in re-
lation to the aortic valve (adjacent to it = anterior), left atrial
appendage (adjacent to it = anterolateral), interatrial septum (ad-
jacent to it = medial), opposite to the aortic valve(posterior) [1],
see E Fig. 17.4 panel 4 c.

(a) (b) (c)

LA LA
LA

* Ao
LV
LV

(d) (e) (f)

LA
LA
LA

RA
Ao
Ao

Fig. 17.7  Top panel (z Videos 17.46, 17.47) (a) and (b): Post-​bypass images following MVR with a 27 mm mechanical Carbomedics bileaflet prosthesis. (a)
Impaired opening in diastole (yellow arrow) of one of the prosthesis leaflets (disc occluder) when compared to the normal opening excursion of the other leaflet
(white arrows) but normal leaflet closure in systole (b). Note that leaflet coaptation in systole is intra-​annular for the standard Carbomedics mechanical bileaflet
prosthesis as opposed to supra-​annular for mitral St. Jude mechanical bileaflet prostheses. Annulus is marked by the solid line; * points to leaflet coaptation in
systole. Patient was placed again on CPB and the prosthesis was rotated. Repeat imaging showed normal prosthesis leaflet excursion in diastole (yellow arrows).
Bottom panel (z Videos 17.48–17.50) (d–​f ): Several minutes later, imaging showed intermittent impaired opening (white arrow) of the anterior prosthesis leaflet;
Yellow arrow points to normal diastolic excursion of the posterior prosthesis leaflet. (d) and secondary severe MR (e, white arrows). Eventually the affected leaflet
failed completely to open, and patient was placed back on CPB. Repeat imaging after excising the subvalvular apparatus, and replacing the mitral prosthesis by a
29 mm mechanical Carbomedics bileaflet prosthesis showed normal diastolic bileaflet excursion (f, arrows)
Ao = ascending aorta; AV = aortic valve; CPB = cardiopulmonary bypass; LA = left atrium; LV = left ventricle; MR = mitral regurgitation; MV = mitral valve; MVR = mitral valve
replacement; RA = right atrium.

Rarely reported complications of mitral valve replacement or
repair, particularly when dealing with significantly calcified mitral
annuli, include dissecting intramyocardial haematoma, myocar-
dial rupture, and left ventricular posterior wall pseudoaneurysm
formation. Posterior aortic root haematoma/​wall oedema fol-
lowing mitral valve surgery may indicate disruption of the mitral-​
aortic continuity.
Aortic valve surgery
The vast majority of patients with haemodynamically signifi-
cant aortic stenosis (AS) or AR or both undergo AVR, and pre-
operative TTE determination of AR and AS severity is critical.
In addition to confirming the severity of aortic valve disease,
pre-​pump IOTEE specific to AVR includes measurement of the
aortic annular diameter from the mid-​oesophageal aortic valve
long-​axis window, and assessing severity of concomitant mitral
or tricuspid valve disease. IOTEE is highly accurate in predicting
annular size compared to surgical obturator and may reduce
pump time by 10 to 30 minutes of thaw time when allografts or
homografts are used [1]‌. Post-​inflammatory AS is characterized
by commissural fusion, cusp retraction, and free-​edge involve-
ment. In degenerative calcific AS, calcification is mainly limited
to the belly of the cusps without significant involvement of the
free edges or commissures.
Recently, attention has been focused on the impact of moderate
and severe patient–​prosthesis mismatch in the aortic position on
long-​term morbidity and mortality [15]. Thus, attention to an-
nular size and body surface area of the patient during pre-​pump
IOTEE is warranted before valve replacement, and specific mis-
match prevention algorithms have been published [15]. A calci-
fied, small annulus (<2 cm) should be brought to the surgeon’s
attention because annular debridement with posterior annular
enlargement with pericardial patch (or less commonly widening
of the LVOT with a Konno procedure)may be required. A hyper-
trophied subvalvular anteroseptum with or without SAM may re-
sult in LVOT obstruction after valve replacement, and thus must
be communicated to the surgeon as it may require concomitant
myectomy. Measurements of the aortic root and ascending aorta
should also be obtained in all patients, particularly if they appear
enlarged or if a sutureless aortic valve prosthesis is being con-
sidered (e.g. Perceval valve). It is generally accepted that a root
or ascending aorta ≥45 mm should be concomitantly repaired if
the aortic valve is bicuspid. Repair of a dilated root or ascending
aorta, and annuloplasty of a dilated annulus are important for
regurgitant bicuspid aortic valve repair, since stabilization of
the annulus, root, and sinotubular junction will improve repair
durability.
Post-​pump imaging objectives include evaluation of pros-
thesis function including mechanical prosthesis occluder
motion, presence, and severity of prosthetic or periprosthetic
regurgitation, and measurement of the systolic gradient across
the aortic prosthesis [1]‌. The transgastric window (short-​axis
view with the TEE probe anteflexed or long-​a xis view with
Aorti c va lv e surg e ry 243
clockwise rotation and anteflexion of the TEE probe) lends
itself best for measurement of the LV outflow flow veloci-
ties and aortic valve gradients because the Doppler signal
can be aligned parallel to flow (E Fig. 17.8). When unable
to determine mechanical aortic prosthesis occluder mo-
tion and the gradient across the prosthesis is inexplicably
high, suspect interference with occluder motion by annular
calcification.
As with mitral prostheses, trivial or mild PPLs are not un-
common and may resolve after anticoagulation reversal with
protamine. More than mild PPL should prompt consideration
of a second pump run for correction, however. Also, similar to
imaging of mitral PPLs, exclusion of aortic PPLs requires scan-
ning in multiple planes, with the colour scale ≥60 cm/​sec, and
under physiologic haemodynamic conditions. A clue to presence
of aortic PPL is an AR jet with very eccentric trajectory. The spa-
tial location of the PPL (e.g. anterior or posterior or in relation
to native coronary cusps) should be clearly communicated to the
surgeon. 3D may be of help but is not as useful as in imaging of
mitral PPL.
Rare complications of aortic valve surgery include extension of
an aortic pseudoaneurysm into the interventricular septum with
rupture into the right ventricle (aorto-​right ventricular fistula),
and aorto or LVOT to right or left atrium fistula (see E Fig. 17.8)
[1]‌. In patients with severe calcific aortic valve stenosis, aortic an-
nular calcification may extend into the mitral valve annulus and
base of anterior mitral leaflet. In the process of debridement of
the aortic annular calcifications, the mitral valve annulus or base
of anterior mitral leaflet may be disrupted resulting in significant
MR. Rarely, the alteration to the mitral-​aortic curtain associ-
ated with AVR can affect the shape or angulation of the mitral
valve and its annulus and result in severe MR (see E Figs. 17.1
and 17.2a) [3].
Aortic valve repair: Selected patients with aortic regurgitation
are considered for aortic valve repair. Analogous to the aforemen-
tioned mechanisms of MR, AR can be caused by dilatation of the
aortoventricular junction (annulus) and/​or sinuses of Valsalva
and/​or sinotubular junction that collectively comprise the func-
tional aortic root complex, or primary disease of the aortic valve
leaflets, and not infrequently in combination with each other [1]‌
(E Fig. 17.9). The pre-​pump IOTEE provides invaluable infor-
mation on the anatomic pathology of the aortic valve and aortic
root complex, and the mechanism of aortic regurgitation, hence
the feasibility of aortic valve repair either as an isolated procedure
or as part of aorta surgery for aneurysm or dissection. Pre-​pump
IOTEE assessment includes number of aortic valve cusps [usu-
ally tricuspid or bicuspid], cusp thickening or calcification, cusp
perforation, prolapse or flail, and tethering due to chronic aortic
root dilation with secondary mal-​coaptation of the valve cusps
[1]. The mid-​oesophageal short ​and long-​axis views of the aortic
valve with and without colour Doppler are needed to determine
the origin of the AR jet and presence of cusp prolapse or retrac-
tion (E Fig. 17.9).
For communication with the surgeon, it is recommended using
a classification of aortic valve and/​or aortic root pathologies
244 CHAPTER 17   In traoperative transoesophag ea l echo ca rdi o g r a phy for va lvu l a r su rg e ry

(a) (b) (c)

I I

A
* P A LV P

S S

(a) (b) (c)

LA LA
LA

RA
RA RA

RVOT

(a) (b) (c) (d)

LA LA LA LA
AL PL LA
RA
* AVP
LV *
LV LV

Fig. 17.8  Top panel (z Video 17.51): Post-​bypass images of an On-​X aortic valve mechanical bileaflet prosthesis. (a) and (b) TG images of the prosthesis disc
occluders (arrows) in diastole (a) and systole (b), asterisk marks MV orifice in diastole. (c) Parallel alignment allows for accurate CW gradient measurement
across the prosthesis; Middle panel (z Videos 17.52–17.54): mid-​oesophageal short-​axis views of aortic valve. (a) Normal parallel systolic excursion of bileaflet
mechanical occluders (red arrows). Note the small posterior aortic root haematoma (yellow arrows). (b) Post AVR bioprosthesis PPL(arrow), originates posterior
to sewing ring from region of the non-​coronary sinus. The patient was placed back on bypass and the PPL was suture closed. No residual PPL is seen after the
second pump run (c, arrow heads point to bioprosthesis leaflets). Bottom panel (z Videos 17.55–17.58) (a–​c) IO transapical TAVR; (a) pre TAVR, (b and c)
during TAVR: AL perforation (white arrow) with secondary severe MR (yellow arrows). LVOT is marked by asterisk. (d) Mid-​oesophageal AV views from a patient
who underwent AVR showing development of LV to RA fistula (Gerbode type defect; arrows).
A = anterior; AL = anterior leaflet; Ao = ascending aorta; AV = aortic valve; AVP = aortic valve prosthesis; AVR = aortic valve replacement; CWD = continuous wave Doppler; I =
inferior; IO = intraoperative; L = lateral; LA = left atrium; LV = left ventricle; LVOT = left ventricular outflow tract; M = medial; MR = mitral regurgitation; MV = mitral valve; MVR =
mitral valve replacement; P = posterior; PL = posterior leaflet; PPL = periprosthetic leak; RA = right atrium; RVOT = right ventricular outflow tract; S = superior; TAVR = transcatheter
aortic valve replacement; TG = transgastric.

similar to the functional and anatomic classification used for the
mitral valve because such a classification links the various causes
of regurgitation to a specific surgical technique [1]‌(see E Fig.
17.9). Accordingly, in Type I AR cusp mobility is normal, but
there is either cusp separation due to outward displacement of
the commissures (caused by dilatation of one or all three com-
ponents of the functional aortic root complex) or cusp perfor-
ation. The resulting AR is usually central but can be eccentric
if the aortic root dilatation is asymmetric or the cause is cusp
perforation. In Type II AR, leaflet mobility is excessive due to
aortic valve cusp prolapse (e.g. conjoined cusps of a bicuspid
aortic valve (BAV) or less commonly the non-​conjoined cusp)
or flail leaflet. The subsequent regurgitant jet is eccentric and
in opposite direction to the prolapsing or flail cusp (see E Fig.
17.9). Cusp prolapse may be amenable to surgical cusp plication
or re-​suspension [16]. In Type III AR, there is restricted cusp
mobility or commissural fusion from fibrosis or calcification
caused by rheumatic or degenerative calcific disease resulting in
 Aorti c va lv e surg e ry 245

inadequate cusp coaptation (see E Fig. 17.9). The AR jet here
is either central or eccentric. BAVs are generally more amenable
to repair than tricuspid valves because there is only one line of
coaptation to work on.
In BAVs there is usually a combined mechanism for AR which
includes cusp prolapse, some retraction of the conjoined free
edge, and annular/​ST-​junction dilatation. This is why contem-
porary BAV repair includes some form of annuloplasty (ring or
suture), particularly with large annuli (i.e. >27–​28 mm); thus the
importance of accurate pre-​bypass annular measurement [16,
17] (E Fig. 17.10). This is also why a dilated aortic root (i.e. ≥45
mm) should be stabilized with root remodelling or replacement
techniques as part of the valve repair [16, 17]. In addition, esti-
mation of the angle formed by the non-​fused cusp commissures
is important, as best repair results are obtained with angles >150
degrees [17] (the closer the angle is to 180 degrees, the better the
outcome; see E Fig. 17.10).
Surgical repair considerations for both bicuspid and tri-
cuspid aortic valves include coaptation length (length of leaflet
apposition) and effective cusp height (distance between the
aortic annulus and the tip of leaflet coaptation), which are
best evaluated from the mid-​oesophageal long-​axis view of the

(b)

B
(a)

Type I Type II Type III

C

Fig. 17.9  Panel 1 (a) General mechanisms of AR (adapted from Boodhwani et al) [18] type I normal cusp mobility with dilated functional root complex or
cusp perforation, type II excessive cusp mobility with prolapse and jet directed away from the affected cusp; and type III retraction or restriction (see text);
(b) Mechanisms of AR in aortic dissection [19] (a) Normal, (b) root/​ascending aorta dilatation, corresponds to mechanism type I, (c) intimal dissection flap
reaches the root and causes ipsilateral cusp prolapse, corresponds to mechanism type II, (d) prolapse of the intimal dissection flap through the aortic valve
is diastole renders it incompetent. Panel 2 (z Videos 17.59, 17.60) (a) mid-​oesophageal SAX colour-​compare view shows three normal-​mobility aortic valve
cusps with a central coaptation defect due to separation of the cusps from root dilatation and large colour flow regurgitant defect(type I mechanism); (b)
mid-​oesophageal LAX view of a bicuspid aortic valve shows prominent prolapse of the anterior cusp(R-​L conjoined cusp) generating a posteriorly directed
jet of AR (type II mechanism) with a large VC (arrows). Panel 3 (z Videos 17.61, 17.62) (a) mid-​oesophageal SAX view in diastole of a post-​inflammatory
valve with thickened free edges, fused commissures and severe three-​cusp retraction with (b) large regurgitant orifice by colour flow (type III mechanism).
(c) intraoperative photograph of the valve, note severe thickening, retraction, and fusion of the three cusps. Panel 4 (z Videos 17.63, 17.64) (a) Mid-​
oesophageal LAX view of the aortic valve shows a dissection flap (red arrow) reaching the posterior sinus of Valsalva and causing the non-​coronary cusp
to prolapse (yellow arrow), generating an eccentric anteriorly directed jet of AR (b). (c) A diastolic zoomed image of the jet is required to measure the VC
(the smallest diameter between the flow convergence and the rest of the jet). The VC in AR should be measured early in diastole and perpendicular to the
jet, such that the flow convergence appears as the union of a blue half and a red half. The smallest diameter measurable after the convergence of these two
components (red and blue) and before the expansion of the rest of the jet; is the VC, which was 0.65 cm in this case(measurements callipers), consistent
with severe AR. Panel 5 (z Videos 17.65, 17.66) (a) Mid-​oesophageal LAX view of the aortic valve shows extensive prolapse of a dissection flap through the
aortic valve orifice in diastole, causing severe AR that is partially contained within the prolapsing flap (b).
Ao = ascending aorta; AR = aortic regurgitation; L = left coronary cusp; LA = left atrium; LAX = long-​axis view; LV = left ventricle; LVOT = left ventricular outflow tract; N =non-​
coronary cusp R =right coronary cusp; SAX = short-​axis; VC = vena contracta.
246 CHAPTER 17   In traoperative transoesophag ea l echo ca rdi o g r a phy for va lvu l a r su rg e ry

(a) (b)

(a) (b) (c)

(a) (b) (c)

(a) (b)

Fig. 17.9 Continued
 Aorti c va lv e surg e ry 247

aortic valve [16, 17] (see E Fig. 17.10). Finally, the presence
of calcification (whether affecting a cusp or a raphe)is critical
to evaluate since best repair results occur in valves with min-
imal or no calcification. The functional anatomy of AR lesions
as defined by IOTEE has been shown to be strongly predictive
of valve reparability and postoperative outcome, particularly in
BAVs [16, 17].
In the setting of type A aortic dissection, pre-​pump IOTEE
evaluation of the AR mechanism can assist the surgeon in iden-
tifying patients likely to benefit from aortic valve repair [1]‌.
Incomplete leaflet coaptation (central AR), leaflet prolapse (ec-
centric AR) and dissection flap prolapse through the aortic valve
are the main mechanisms [1] E Fig. 17.9). A simple and reli-
able measurement of AR severity on IOTEE is the vena contracta
(E Fig. 17.9). Holo-​diastolic flow reversal in the aortic arch /​
proximal descending aorta suggests severe AR.
The post-​pump IOTEE must evaluate the aortic repair result
with physiologic cardiac preload and blood pressure, which may
require volume and/​or pressor administration. Coaptation tips lo-
cated below the annular plane, residual regurgitation that is more
than mild, coaptation length <4 mm, and effective height <9 mm,
have all been shown to be predictors of recurrent 3+ AR within 2
years [16, 17]. Evidence of more than mild residual regurgitation
(VC >0.3 cm) should therefore, prompt consideration of a second
pump run for correction or AVR [18]. Any residual eccentric jet
after valve repair and/​or valve-​sparing surgery suggests residual
cusp prolapse. As with pre-​pump IOTEE, orthogonal views of the
aortic valve from the mid-​oesophageal window are best to show
origin of AR [19].
Complications of aortic valve repair include aortic cusp perfor-
ation following removal of a fibrotic raphe or a piece of leaflet cal-
cium, and perforation of the base of the anterior mitral leaflet [20].

(a) (b)
Normal Prolapse

Annulus

eH

(a) (b) (c)

Fig. 17.10  Panel 1 (a, left) Schematic of a normal valve to aortic effective height (eH) measured from the annulus plane to the tip of valve coaptation, normal
eH value is 9–​10 mm. Right:, double headed blue arrow shows decreased coaptation length, and red arrow shows extent of cusp prolapse (adapted from le Polain
de Waroux et al.) [16]. (b) (z Video 17.67) Mid-​oesophageal LAX colour-​compare diastolic view of a bicuspid aortic valve shows both leaflets prolapsing but the
conjoined one (R–​L fusion) prolapses more generating a posteriorly directed jet. The valve opens well in systole and does not have calcification (panel 2a),
(z Video 17.68) and the angle of the non-​fused cusp (non-​coronary = N) commissures is estimated at 160 degrees (panel 2b and c), making it a good candidate
valve for repair. Pre-​pump measurements demonstrate a dilated annulus of 27 mm with eH of only 4 mm (panel 3a, measurement callipers), with no dilatation
of the root or ascending aorta (Panel 3b, mid-​ascending aorta measurement callipers). The repair consisted of plication of the prolapsing cusps and annuloplasty
suture. Post-​pump measurements show a decreased annulus of 20 mm and eH of 9 mm (measurement callipers), as well as no residual AR (z Video 17.69).
Panels 4 and 5 (z Videos 17.70-17.73): IOTEE in a patient with myxomatous mitral and tricuspid valve disease and complex AR. Panel 4: mid-​oesophageal SAX
views in systole (a) and diastole (b and c). Note the linear structure (arrow) on the right coronary cusp consistent with a fibrous band commonly seen in patients
with partial cusp prolapse. Panel 5: mid-​oesophageal LAX views of the AV in diastole (a) and with colour Doppler (b). Note that there is a gap between the free
edge of the right coronary cusp (anterior cusp, a) and fibrous band, representing the free edge prolapse of the right cusp. The right cusp is the most commonly
prolapsing in tricuspid valves while the fused cusp is the most commonly prolapsing in bicuspid valves. The eccentric posteriorly directed jet of AR in the LAX
view is shown in (b). The three commissures were resuspended and the gap was suture closed. Post-​bypass showed no more than mild residual AR (Panel 5c).
AR = aortic regurgitation; AV =aortic valve; L = left coronary cusp; LAX = long-​axis; R = right coronary cusp; SAX = short-​axis.
248 CHAPTER 17   In traoperative transoesophag ea l echo ca rdi o g r a phy for va lvu l a r su rg e ry
(a) (b)
(a) (b)
(a) (b)
Fig. 17.10 Continued
Complications of aortic root aneurysm repair include fistula [20]
or pseudoaneurysm formation if the aortic wall tissue is abnor-
mally fragile. Aortic cusp retraction with secondary severe AR is
a reported complication of coronary reimplantation during valve-​
sparing aortic root surgery [20]. Valve repair can reduce the effective
opening of the leaflets and as such peak and mean transvalvular gra-
dients should be assessed to ensure there is no significant stenosis.
For patients undergoing the Ross procedure, new post-​pump
regional wall motion abnormalities in the left anterior descending
(LAD) distribution may be due to septal perforator injury in-
curred during harvesting of the pulmonary autograft. Thickening
of the posterior aortic root secondary to wall oedema or haema-
toma is common after aortic valve surgery and should be docu-
mented so that it is not mistaken for an early aortic root abscess
on subsequent follow-​up echocardiograms (see E Fig. 17.8a
(c)
(c)
(c)
middle panel). Potential post myectomy associated complications
include aortic regurgitation secondary to blade-​induced leaflet
perforation or cusp retraction.
Valve replacement post-​pump check list
✓ Verify normal occluder motion (mechanical prostheses) and
ample leaflet excursion and coaptation (bioprostheses)
✓ Exclude periprosthetic regurgitation
✓ Measure gradient across the prosthesis
✓ Colour flow Doppler documentation of normal physiologic pros-
thesis regurgitation (mechanical prostheses)
✓ Exclude LVOT obstruction (mitral prostheses)
✓ Exclude left circumflex coronary artery injury/​occlusion (MV
replacement)
✓ Rule out iatrogenic fistula
 C on c lusi on 249

(a) (b) (c)

(a) (b)

Fig. 17.11  Panel 1 (z Videos 17.74, 17.75) (a) Pre-​pump mid-​oesophageal four-​chamber diastolic measurement of the tricuspid annulus demonstrates
dilatation at 4. 6 cm. (b) Pre-​pump mid-​oesophageal four-​chamber systolic view reveals prolapse not only of the mitral valve (primary surgical indication) but
of the tricuspid valve as well, with a laterally directed jet of severe TR (c). Panel 2 (z Videos 17.76, 17.77) (a) Post-​pump mid-​oesophageal four-​chamber systolic
view shows tricuspid and mitral repairs with prolapse correction and no residual leaks (b). RA = right atrium, RV = right ventricle.

✓ Rule out intramyocardial haemorrhage (mitral valve repair or
replacement)
Tricuspid regurgitation
Tricuspid regurgitation should not be overlooked, especially in the
setting of left-​sided cardiac disease. As emphasized earlier, IOTTE
estimated severity of TR may be downgraded due to anaesthesia-​
related haemodynamic changes, thus, evaluation of preoperative
TTE images is indicated. Annular dilatation may be a predictor of
future severe TR even if no significant regurgitation is present at
baseline [1]‌. Thus, observing prominent tricuspid annular dilata-
tion regardless of the degree of regurgitation should be communi-
cated to the surgeon because it could warrant surgical exploration
and potential annuloplasty repair. In the four-​ chamber mid-​
oesophageal view, the normal diastolic tricuspid annular meas-
urement between the base of the anterolateral and septal leaflets is
2.8 ± 0.5 cm, and should not exceed 3.5 cm or 2.1 cm/​m2 (E Fig.
17.11) [1]. Tricuspid valve repair is a Class IIa recommendation
in the 2021 ACC/​AHA and 2017 ESC guidelines in patients with
mild or moderate secondary TR with a dilated annulus (>40 mm
or >21 mm/​m2 by 2D echocardiography) undergoing left-​sided
valve surgery. CW Doppler mean gradient across the tricuspid
valve should be assessed post-​bypass and reported together with
the heart rate.
Instrumentation of the right heart with wires, catheters, or
cannulas during cardiac surgery may rarely cause de novo post-​
pump severe TR secondary to traumatic papillary muscle injury
or rupture, or flail tricuspid valve leaflet (usually septal). The non-​
coronary cusp of the aortic valve may be injured during tricuspid
valve surgery.
Conclusion
IOTEE is a mature, indispensable tool to guide heart valve surgical
procedures and as a safety net to check the surgical results and
minimize cardiovascular complications. The impact of IOTEE
is greatest for valvular interventions. For each surgical indica-
tion, specific imaging strategies and a critical knowledge-​based
tailored to the nature of the procedure and its potential compli-
cations are warranted. Post-​pump goal-​directed assessment of
surgical results under appropriate haemodynamic conditions, fol-
lowed by effective communication of detected abnormalities and
their mechanisms to the surgeon, is critical.
250 CHAPTER 17   In traoperative transoesophag ea l echo ca rdi o g r a phy for va lvu l a r su rg e ry
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Committee, Cardiac Imaging Committee of the American Heart
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a registered branch of the European Society of Cardiology, the
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 CHAPTER 18

Valvular prostheses
Luigi P. Badano and Denisa Muraru

Contents Introduction
Introduction  251
Heart valve prostheses specifications and Prosthetic heart valves may be mechanical or bioprosthetic. Mechanical valves, which are
functional parameters  251 composed primarily of metal or carbon alloys, are classified according to their design as
Assessment of prosthetic valve ball-​caged, single-​tilting-​disc, or bileaflet-​tilting-​disc valves (E Fig. 18.1). In ball-​cage
function  252
Valve prosthesis normal function and valves, the occluder is a sphere which is contained by a metal ‘cage’ when the valve is in
dysfunction  259 its open position, and fills the orifice when the valve is in its closed position. In single-​
tilting-​valves, the occluder is a single circular disc which is constrained in its motion by
a cage, a central strut, or a slanted slot in the valve ring, therefore it opens at an angle less
than 90° to the sewing ring plane. In bileaflet-​tilting-​disc valves there two occluders, two
semicircular discs that open forming three orifices, a central one and two lateral ones.
Biological tissue valves prostheses may be heterografts, which are composed of por-
cine, bovine, or equine tissue (valvular or pericardial), or homografts, which are pre-
served human aortic valves. Heterografts include stented and stentless bioprostheses
(E Fig. 18.2). In stented valves, the biological tissue of the valve is mounted on a rigid
stent (plastic or metallic) covered with fabric. Conversely stentless bioprostheses use the
patient’s native aortic root as the valve stent. The absence of a stent and sewing ring cuff
make it possible to implant a larger valve for a given native annulus size, resulting in a
larger effective orifice area (EOA).

Heart valve prostheses specifications and

functional parameters
The size of mechanical and stented biological valve prostheses can be described using geo-
metrical and functional parameters. Geometrical parameters are measurements obtained
by manufacturers and usually reported in product brochure. The sewing ring diameter
(measured in mm) is the largest diameter of the sewing cuff (E Fig. 18.3). The internal
orifice diameter (IOD, in mm) is the internal diameter of the stent. From the IOD, the
geometric orifice area of the prosthesis (the internal valve area theoretically available
for the bloodstream to pass through) can be calculated using the geometric formula
π·(IOD/​2)2. The external diameter (ED, in mm) is the diameter of the stent plus fabric.
From the ED, the mounting area of the prosthesis (the area that the prosthesis will oc-
cupy within the patient’s native annulus) may be calculated using the geometric formula
π·(ED/​2)2. The latter is rarely reported in product brochure, but it is needed in order to
calculate the ratio between geometric orifice area and mounting area. This ratio depends
on the prosthesis design and gives an indication of the space subtracted from the native
252 CHAPTER 18   Valv ul ar prosth eses

Fig. 18.1  Different types of

mechanical valve prostheses. (a)
Starr–​Edwards ball-​caged valve; (b)
all carbon tilting-​disc-​valve; (c) fit-​line
aortic bileaflet-​tilting-​disc  valve.
Courtesy of Edwards Lifesciences, Irvine,
CA and Sorin Biomedica Cardio S.p.A.,
Saluggia, IT.

annulus ‘flow area’ by the fixed structures (stent and cuff) of the pr recommended that labelled prosthesis size should represent the
osthesis. This ratio also depends on the implant technique used. G tissue annulus (TAD) of the patient into whom the valve is in-
enerally, for a totally intra-​annular prosthesis, this ratio is 40–​70% tended to be implanted.
[1], it increases to 80–​85% for partially supra-​annular prostheses,
and reaches 100% (resulting in a maximization of blood flow) for
totally supra-​annular prostheses. Assessment of prosthetic valve
Functional parameters of prosthesis size include both in-​vitro
and in-​vivo EOA. In-​vitro EOA can be measured under static function
hydrodynamic conditions at a variety of flow rates, or under dy- Several imaging techniques can be used to assess valve prosthesis
namic conditions with variable pulsatile waveforms and flow function
rates. Estimates of static EOA for bioprostheses vary by as much Echocardiography. Echocardiography remains the imaging
as 100% as the steady flow rate increases. Dynamic pulsatile in-​ technique of choice for the assessment of prostheses function.
vitro EOA data are non-​standardized, unreproducible, and un- Two-​dimensional transthoracic echocardiography can be used to
available. Therefore, in-​vitro EOA is generally unsuitable for assess sewing-​ring stability and occluder motion (E Fig. 18.4).
assessment of the clinical effect of prosthesis size [2]‌. In-​vivo EOA The mechanical valves have a specific pattern of echoes that can
is always smaller than the geometric orifice area and corresponds
to the smallest area of the jet passing true the prosthesis as it exits
the valve (vena contracta). Both the shape of the inlet and the size SRD
of the orifice affect the ratio between the geometric and EOA (co-
efficient of orifice contraction) [3].
For clinical purposes, the size of prostheses is reported as la-
belled prosthesis size (i.e. 19 mm, 21 mm, etc.). However, labelled
size is often the approximation of an integer number (i.e. labelled IOD ED
size = Bicarbon 21 mm; actual size = 21.2 mm). International
Organization for Standardization (ISO) specification concerning
the valve size labelling of heart valve prostheses (ISO/​CD 5840) AORTA

GOA LVOT
MA
TAD

Fig. 18.2  Biological tissue valves. (a) Stented Soprano pericardial valve; (b)
Stentless Solo pericardial valve.
Courtesy of Sorin Biomedica Cardio S.p.A., Saluggia, IT.
Fig. 18.3  Geometrical valve size specifications. The sewing ring diameter
(SRD) is the maximum diameter of the sewing cuff. The external diameter
(ED) is the diameter of the housing or housing plus fabric. From ED the area
that the prosthesis will occupy within the patient annulus (mounting area,
MA) is calculated (see text for details). The internal orifice diameter (IOD)
is the internal diameter of the housing. From IOD, the internal valve area
theoretically available for bloodstream to pass through (geometric orifice area,
GOA) is calculated (see text for details). LVOT, left ventricular outflow tract;
TAD, native tissue annulus diameter.

help identify the type of prosthesis. A ball-​caged valve will display
a cage and the moving echo of the ball on the ventricular side. A
single echo moving up and down on the ventricular side can be
seen with tilting-​disc valve (E Fig. 18.4), and the two leaflets of
the bileaflet valve can be visualized separately (E Fig. 18.4). The
transthoracic echocardiography has a higher sensitivity for dem-
onstrating the motion of the two leaflets of a bileaflet-​tilting disc
valve in mitral position than for the aortic position. The hetero-
graft bioprosthesis (porcine or pericardial) are trileaflet structures.
The two-​dimensional and M-​Mode appearance of the leaflets of
these valves is similar to those of the native aortic valve, which is
a box like opening in systole, if implanted in aortic position (E
Fig. 18.5), or diastole, if implanted in mitral position). However,
similar to what happens with mechanical prosthesis the sewing
ring and the struts may limit the visualization of the leaflets. The
stentless bioprosthetic aortic valves have an appearance similar to
Fig. 18.5  Two-dimensional echocardiographic characteristics of bioprostheses: stented bioprosthesis (mosaic 23 mm) in aortic position visualized from
parasternal approach (a); stentless bioprosthesis (Freedom 21-mm) in aortic position visualized from parasternal approach (b)..
As ses sm en t of pro stheti c va lve f un c t i on 253
Fig. 18.4  Two-​dimensional
echocardiographic characteristic
features of mechanical heart valve:
(a) bileaflet tilting-​disc valve in aortic
position visualized from parasternal
approach; (b) single tilting-​disc valve
in mitral position visualized from
parasternal approach; (c) bileaflet
tilting-​disc valve in mitral position
visualized from apical approach;
(d) single tilting-​disc valve in mitral
position visualized from apical
approach.
that of native aortic valve except for increased echogenicity in the
aortic root (E Fig. 18.5). An aortic homograft appears similar to
a native aortic valve except for an increased thickness in the left
ventricular outflow tract (LVOT) and the ascending aorta.
However, mechanical valve prostheses and stented bioprostheses
are often difficult to visualize (prosthesis in aortic position more
difficult than in mitral position) due to the presence of artificial
components with far different acoustic properties that the sur-
rounding cardiac tissue that creates reverberations, artefacts, and
acoustic shadowing. The latter can be overcome with the use of
the transoesophageal (TOE) approach and casting the shadowing
in the opposite direction [4]‌(E Fig. 18.6). In addition, since all
echo systems are calibrated to measure distance on the velocity of
ultrasound in the human body tissue, the presence of prosthetic
material may alter the displayed size and location of the pros-
thesis and can distort the appearance of its components.
254 CHAPTER 18   Valv ul ar prosth eses

gradients by Doppler in the prosthetic valves [5, 6]. There are

Fig. 18.6  Transoesophageal echocardiographic visualization of a
normofunctioning bileaflet tilting-​disc prosthesis in the mitral position. The
metallic leaflet is visualized in systole in the closing position. An intense
acoustic shadowing due to the highly reflective metallic leaflets can be
appreciated on the left ventricular side.
Transthoracic Doppler echocardiography by providing a com-
plete haemodynamic assessment is pivotal in assessing a valve
prosthesis function. The Bernoulli equation is used to calculate
the peak and mean pressure gradients from the Doppler veloci-
ties. Although many assumptions are made in derivation of the
Bernoulli equation, an excellent correlation has been obtained be-
tween. The continuity equation is used to calculate the aortic EOA.
In general, the same principles used in native aortic valves are
applicable to assess valve prosthesis function using echocardiog-
raphy. However, the fluidodynamic characteristics of prosthetic
valves are not exactly the same as those of native valves and proper
formulae should be used to calculate reliable transprosthetic gra-
dients and EOA. Although good agreement between Doppler
derived and catheter derived pressure gradients for a variety of
different valve prostheses has been reported (ETable 18.1), some
investigators have found significant overestimation of pressure
several reasons that may explain these apparent discrepancies be-
tween Doppler and catheter gradients. The presence of pressure
recovery downstream from the prosthesis has been suggested as
one potential cause [5]‌. Localized pressure gradients that may be
recorded by selectively sampling velocity in the narrow ‘slit-​like’
central orifice of some bileaflet-​tilting-​disc prostheses [5], but not
in all [7]. However, the most important cause of transprosthetic
gradient overestimation using Doppler echocardiography is a
methodological one.
Routine echocardiographic assessment of gradients through
stenotic native or prosthetic valves in the aortic position is usually
performed using the ‘simplified’ (4V22), instead of the ‘modified’
[4 (V22 –​V12)] Bernoulli equation (the former does not take into
account the velocity (V1) in the LVOT). However, the simplified
Bernoulli equation ignores the viscous friction and the energy re-
quired to overcome the initial forces caused by flow acceleration
found in a pulsatile system and is only reliable for flow that is [8]‌:
(1) through a restrictive orifice (negligible inertial component);
and
(2) with V2 much greater than V1.
Since new normofunctioning prosthetic valves (especially
stentless and stented supra-​annular bioprostheses) do not have a re-
strictive orifice and they show very low V2 values (usually less than
2 m/​s), the use of the simplified Bernoulli equation causes a sig-
nificant overestimation of transprosthetic gradients also in patients
with V1 < 1 m/​s. This overestimation may be negligible in stenotic
native valves with a restrictive orifice and high V2 values (from
+3 to +5%), but it is clinically significant in normofunctioning
bioprosthetic stentless valves (from +13 to +19%) [9]‌.
In-​vivo EOA for prosthesis in aortic position is calculated
from the continuity equation. The continuity equation assumes

Table 18.1  Studies which have validated transprosthetic gradients measured by Doppler echocardiography with cardiac catheterization data

Author, reference Valve type/​Position Type of study r SEE (mm Hg)

(patients)
Sagar, J Am Coll Cardiol 1986; 7: 681 Hancock, Bjork, Shiley/​Mitral In vivo (19) 0.93 2.5
Hancock, Bjork, Shiley/​Aortic In vivo (11) 0.94 7.4
Wilkins, Circulation 1986; 74: 786 Starr–​Edwards, Bjork–​Shiley, porcine/​mitral In vivo (11) 0.96
Burstow, Circulation 1989; 80:504 Not specified/​aortic In vivo (20) 0.94 3
Not specified/​mitral In vivo (20) 0.97 1.2
Baumgartner, Circulation 1990; 82:1467 St Jude In vitro 0.98 1.9
Hancock In vitro 0.98 1.4
Stewart, J Am Coll Cardiol 1991; 18: 769 Bioprostheses In vitro 0.78–​0.98
Baumgartner, J Am Coll Cardiol 1992; 19:324 St Jude In vitro 0.98 2.0
Medtronic–​Hall In vitro 0.99 0.5
Starr–​Edwards In vitro 0.97 2.0
Hancock In vitro 0.99 1.5

that flow coming into the narrowed orifice has a flat profile. The
actual flow profile varies between prostheses, with mechanical
tilting-​disc prostheses having the greatest variance from a flat
profile, and bioprosthetic valves showing a nearly flat profile of
transprosthetic flow [1]‌.
Similar to stenotic native valves, the main source of error in
calculating prosthesis EOA with the continuity equation is the
measurement of the LVOT diameter. Due to the potential errors
(inner-​edge-​to-​inner-​edge measurement, foreshortening of
LVOT) and limitations (interference of prosthesis shadowing) it
was suggested that the nominal size of the replacement heart valve
should be substituted for the direct measurement of the LVOT
when applying the continuity equation [10, 11]. The assumption
is that, regardless of manufacturer or model, all valves of a cer-
tain nominal size are interchangeable for a given patient tissue
annulus diameter. However, this is not true. Studies attempting to
assess the size of a valve by echocardiography show good agree-
ment between LVOT diameter and valve size for stentless valves
[12]. Conversely, as much as 2 mm difference was shown in one
study on mechanical and stented biological valves [13]. Another
study found a 95% confidence interval from –​8.5 to +5.1 mm be-
tween LVOT measured by transthoracic echocardiography and
nominal valve size [14]. Therefore, the ED of the prosthesis (if
known), but not the labelled size can be used as a surrogate for
LVOT diameter. However, the ED of the prosthesis is rarely avail-
able so the most convenient way is still to measure LVOT diam-
eter during the baseline echocardiographic assessment of a given
valve and then to use this constant value during follow-​up echo-
cardiographic controls.
Although the Hatle’s method has been proposed to calculate
the EOA for prosthetic valves in mitral position, and it should be
theoretically applicable to such valves since pressure half-​time is a
physiologic measure of obstruction and does not require assump-
tions about inlet geometry and flow rate [15], there is now good
evidence that the Hatle’s method is not valid in normofunctioning
prosthetic valves in mitral position [7, 16]. In such valves, with
relatively large orifice areas, the pressure half-​time is more de-
pendent on other factors such as heart rate, transmitral pressure
gradient at onset of diastole, stroke volume, and left atrial and
ventricular compliance, than on prosthetic orifice area.
A complete echocardiographic study should include estima-
tion of pressure peak and mean gradients, valve area, and mean
transprosthetic flow rate. However, there are some peculiarities
that should be taken into account to correctly interpret echocar-
diographic results.
First, prostheses are not all equal. Different types (i.e. mech-
anical bileaflet, mechanical tilting-​ disc, stented bioprosthesis,
stentless bioprosthesis) show markedly different haemodynamics.
For example, an EOA of 1.1 cm2 may be normal in a 21-​mm single-​
tilting-​disc prosthesis [16], but it will be a pathologic finding in
a 21-​mm stentless bioprosthesis (ETable 18.2). Different models
of the same type show markedly different haemodynamics des-
pite having the same labelled size and being made of the same
tissue (i.e. bovine pericardium) [17]. The 21-​mm Hancock II
As ses sm en t of pro stheti c va lve f un c t i on 255
stented bioprosthesis shows a mean EOA (1.2 ± 0.7 cm2) [18] that
is significantly lower than or the Pericarbon (1.5 ± 0.4 cm2) [19].
Different sizes of the same valve model and type show different
haemodynamics (ETable 18.2) [17]. Therefore, the important
message to the echocardiographer is the need to know the model,
type, and size of the implanted valve in order to interpret echocar-
diographic haemodynamic data correctly.
Second, reference values reported in the literature about the
haemodynamic performance of different valve prostheses repre-
sent a poor reference for the individual patient. This is particularly
true for biological prostheses. Estimates of bioprosthesis in-​vivo
EOA are particularly sensitive to cardiac output and blood pres-
sure [20]. In addition, in-​vivo EOA of stentless bioprostheses has
been observed to increase during the first year after implantation
as haemodynamic data change and perivalvular haematoma and
oedema resolve. Transprosthetic gradients are particularly sen-
sitive to transprosthetic flow rate and change significantly with
the haemodynamic state of the patient. Therefore, the second
important message to the echocardiographer is to obtain a base-
line full haemodynamic assessment of that prosthesis in a given
patient together with his/​her haemodynamic status (i.e. body
surface area, cardiac rhythm, heart rate, blood pressure, haemo-
globin level, and LV function) to use as a reference for interpreting
follow-​up studies.
The timing of baseline assessment of valve prosthesis haemo-
dynamics is crucial. Ideally, it should be performed as soon as
possible after the operation to make sure that the valve is actu-
ally normofunctioning (i.e. no tissue degeneration for biological
valves or pannus formation for mechanical valves), but not too
soon, in order to avoid misleading data. In patients undergoing
aortic valve replacement there is a relative high output state im-
mediately after the operation due to relative anaemia and sudden
reduction of LV afterload, which affects transprosthetic gradi-
ents. Moreover, perivalvular oedema and haematoma may reduce
prosthetic EOA. Finally, LV function will change significantly
soon after aortic valve replacement due to regression of hyper-
trophy, and adaptation to the changed pre and afterload condi-
tions. Therefore, the optimal timing of the baseline assessment of
valve prosthesis haemodynamics should be placed between the
third and the sixth month (not later than 1 year) after surgery.
The predischarge study should be used to assess postoperative LV
function, exclude complications or early malfunction of the pros-
thesis, but not to assess normal function parameters of a certain
valve in a given patient.
Follow-​up examinations in asymptomatic patients without
complications and with a ‘normal’ initial echocardiogram can
be performed at yearly intervals and should consist of a detailed
history and physical examination. Echocardiography should be
performed whenever there is evidence of a new heart murmur,
when there are doubts of prosthetic valve integrity or function,
or there are concerns about ventricular or other valve function.
There is no support in the literature for the strategy of performing
an annual ‘routine’ Doppler echocardiogram in patients without
complications [21].
256 CHAPTER 18   Valv ul ar prosth eses

Table 18.2  Published data about Doppler haemodynamic parameters of normofunctioning prosthetic valves in aortic position

Type Doppler Size (mm)

parameter
19 20 21 22 23 24 25 26 27 29
Single tilting-​disc valves
Starr–​Edwards GOA 1.41 1.67 1.79 1.94 2.16 2.57
(n = 79) EOA 1.3 1.45 1.44 1.53 1.53 1.53
Mean gr. 34 ± 6 29 ± 11 27 ± 9 23 ± 8 23 ± 1
Bjork–​Shiley* GOA 1.5 2 2.5 3.1 3.8 4.6
(n = 106) EOA 0.7 ± 0.2 1.1 ± 0.1 1.6 ± 0.3 2.0 ± 0.4 2.6 ± 0.4
Mean gr. 16 ± 4 13 ± 5 13 ± 3 11 ± 4 8±4
Medtronic​ GOA
Hall (n = 108) EOA 1.2 ± 0.5 1.1 ± 0.2 1.4 ± 0.4 1.9 ± 0.4 1.9 ± 0.5
Mean gr. 14 ± 6 14 ± 5 10 ± 4 9±6
Omnicarbon GOA 1.63 2.11 2.55 3.14 3.80 3.80
(n = 49) EOA 1.4 ± 0.1 1.5 ± 0.2 1.8 ± 0.4 1.9 ± 0.4 2.2 ± 0.2
Mean gr. 21 ± 7 13 ± 3 11 ± 4 13 ± 3 9±2
Allcarbon GOA 1.5 2.0 2.5 3.1 3.8 4.5
(n = 83) EOA 0.9 ± 0.1 1.1 ± 0.2 1.4 ± 0.2 2.1 ± 0.8 2.8 ± 0.6 4.1 ± 0.7
Mean gr. 29 ± 8 22 ± 7 20 ± 6 15 ± 4 11 ± 4 8±2
Bileaflet-​tilting-​disc valves
St Jude Medical GOA 1.63 2.06 2.55 3.09 3.67 4.52
(n = 67) EOA 1.0 ± 0.2 1.3 ± 0.2 1.3 ± 0.3 1.8 ± 0.4 2.4 ± 0.6 2.7 ± 0.3
Mean gr. 17 ± 7 14 ± 5 16 ± 6 13 ± 6 11 ± 5 7±1
St Jude Medical EOA 1.7 ± 0.2 2.2 ± 0.3
HP (n = 49) Mean gr. 16 ± 4 10 ± 3
Carbomedics GOA 1.06 1.41 1.75 2.19 2.63 3.07
(n = 96) EOA 1.0 ± 0.4 1.5 ± 0.3 1.6 ± 0.3 2.0 ± 0.4 2.4 ± 0.5 2.6 ± 0.4
Mean gr. 19 ± 6 12 ± 4 10 ± 4 8±4 9±3 6±3
Carbomedics Top–​Hat GOA
(n = 65) EOA 1 ± 0.2 1.2 ± 0.3 1.4 ± 0.4
Mean gr. 20 ± 2 17 ± 6 13 ± 4 11
Duromedics Tekna GOA 1.53 2.02 2.36 2.94 3.58
(n = 90) Mean gr. 8±5 7±2 5±2 6±3
Bicarbon GOA 1.76 2.27 2.83 3.45 4.14 5
(n = 166) EOA 1.0 ± 0.3 1.6 ± 0.3 2.1 ± 0.4 2.5 ± 0.6 3.6 ± 0.8 3.5 ± 0.3
Mean gr. 13 ± 1 14 ± 5 11 ± 4 11 ± 3 7±2 5±1
ATS Open Pivot EOA 1 ± 0.2 1.6 ± 0.4 1.8 ± 0.2 2.2 ± 0.4 2.5 ± 0.3 3.1 ± 0.3
(n = 59) Mean gr. 26 ± 8 14 ± 4 12 ± 4 11 ± 4 9±2 8±2
On X EOA 1.5 ± 0.2 1.7 ± 0.4 2 ± 0.6 2.4 ± 0.8 3.2 ± 0.6
(n = 60) Mean gr. 12 ± 3 10 ± 4 9±3 9±5 6±3
Jyros (n = 23) EOA 1.5 1.5 1.7
Mean gr. 11 11 8
Stented bioprostheses
Hancock I EOA
(n = 64) Mean gr. 12 ± 4 11 ± 2 10 ± 3
 As ses sm en t of pro stheti c va lve f un c t i on 257

Table 18.2 Continued

Type Doppler Size (mm)

parameter
19 20 21 22 23 24 25 26 27 29
Hancock II EOA 1.2 ± 0.3 1.4 ± 0.2 1.5 ± 0.2 1.6 ± 0.2 1.6 ± 0.2
(n = 376) Mean gr. 15 ± 4 17 ± 7 3 –​ –​
17 ± 7
Bio Medical ° EOA 1.3 ± 0.4 1.6 ± 0.6 2.1 ± 0.7 3.2
Mean gr. 9±4 8±2 7±5 6
Carpentier-​Edwards EOA 0.9 ± 0.2 1.5 ± 0.3 1.7 ± 0.5 1.9 ± 0.5 2.3 ± 0.5 2.8 ± 0.5
porcine (n = 419) Mean gr. 26 ± 8 17 ± 6 16 ± 6 13 ± 4 12 ± 6 10 ± 3
Carpentier-​Edwards EOA 1.2 ± 0.1 1.5 ± 0.4 1.8 ± 0.3 –​ –​
Pericardial (n = 75) Mean gr. 24 ± 9 20 ± 9 2.3 ± 0.5 9±2 6
Carpentier-​Edwards EOA 1.1 ± 0.1 1.1 ± 0.2
Supra-​annular (n = 23) Mean gr. 14 ± 5
Medtronic Intact EOA 1.6 ± 0.4 1.7 ± 0.4 1.9 ± 0.3 2.2 ± 0.2 2.4 ± 0.5
(n = 243) Mean gr. 24 ± 9 19 ± 8 19 ± 6 16 ± 6 15 ± 4 16 ± 2
Medtronic Mosaic EOA 1.6 ± 0.7 2.1 ± 0.8 2.1 ± 1.6
(n = 279) Mean gr. 12 ± 7 12 ± 7 10 ± 5 9
Mitroflow EOA 1.1 ± 0.2
(n = 21) Mean gr. 10 ± 3 15 8±3 11 ± 7 7±2
Pericarbon More EOA 1.2 ± 0.3 1.5 ± 0.4 1.8 ± 0.5
(n = 22) Mean gr. 23 ± 9 18 ± 8 16 ± 5
Soprano EOA 1.9 ± 0.5 2.1 ± 0.5
(n = 77) Mean gr. 7±4 7±4
Ionescu–​Shiley EOA 1.2 ± 0.2
(n = 95) Mean gr. 20 ± 9 15 ± 2 10 ± 3 9±6
Stentless bioprostheses
Toronto SPV EOA 1.3 ± 0.38 1.2 ± 0.7 1.2 1.6 ± 0.8 1.6 ± 0.4 2.0 ± 0.4
(n = 554) Mean gr. 8±4 5 8±4 7±4 6±4 5±2
Medtronic Freestyle EOA 1.6 ± 0.3 1.9 ± 0.5 2.0 ± 0.4 2.5 ± 0.5
(n = 369) Mean gr. 13 8±3 7±3 5±2 5±2
O’Brien Angell EOA 1.2 ± 0.1 1.1 ± 0.3 1.6 ± 0.2 2.1 ± 1.2
(n = 50 Mean gr. 15 ± 8 19 ± 13 18 ± 13 12 ± 7
O’Brien Angell 1.6 ± 0.6 2.4 ± 0.2 2.9 ± 0.9
Supra-​annular (n = 50) 9±1 8±1 9±1 7 ± 1.4
Cryolige O’Brien EOA 1.3 ± 0.1 1.6 ± 0.6 2.2 2.3 2.7
(n = 329) Mean gr. 12 ± 5 10 ± 2 9 8 7
Edwards Prima EOA 1 ± 0.3 1.3 ± 0.3 1.5 ± 0.5 1.7 ± 0.6 2 ± 0.6 2.5 ± 0.5
(n = 253) Mean gr. 15 ± 7 16 ± 11 12 ± 5 11 ± 9 7±4 5±5
Biocor EOA 1.4 ± 0.5 1.6 ± 0.4 1.9 ± 0.5
(n = 331) Mean gr. 18 ± 4 19 ± 7 18 ± 7 18 ± 2
Biocor Extended EOA 1.3 ± 0.4 1.6 ± 0.3 1.8 ± 0.3
(n = 50) Mean gr. 10 ± 4 8±3 8±2
Homograft EOA 2.1 ± 1.3 3.6 2.4 ± 0.7 2.6 ± 1
(n = 27) Mean gr. 13 ± 1 10 8±2 12 ± 1
*monostrut.
GOA = geometric orifice area provided by the manufacturer in cm2; EOA = effective orifice area (continuity equation) in cm2; Mean gr. = mean transprosthetic gradient in mm Hg;
n = examined patients
258 CHAPTER 18   Valv ul ar prosth eses

Fig. 18.7  Cinefluoroscopic side

view of an Allcarbon single tilting-​
disc (a) and a St Jude Medical
bileaflet tilting-​disc (b) valve in open
position. The disc of the Allcarbon
valve forms an angle of 60° with the
housing plane. The two hemidisks of
the St Jude Medical form a 10° angle.
See text for details.

Cinefluoroscopy. Cinefluoroscopy is a simple, rapid, in- Cardiac catheterization. Since cardiac catheterization is
expensive, and accurate technique to assess valve prosthesis an invasive technique, it is indicated only when the infor-
function. The main indications for cinefluoroscopy are in pa- mation obtained by non-​invasive techniques is inconclusive.
tients with abnormally high aortic or mitral gradients or un- With cardiac catheterization, the transprosthetic pressure
usual regurgitant flow patterns observed with colour Doppler gradients and flow can be measured and EOA calculated.
echocardiography. A catheter can be passed safely through the orifice of a
The cinefluoroscopic exam usually begins by determining the bioprosthesis without adverse effects. However, the catheter
valve’s rotational orientation with a view perpendicular to the may become entrapped in the orifice of a single-​tilting-​disc,
valve plane. By positioning the image intensifier in the right an- sometimes requiring immediate surgical removal, or cause
terior oblique cranial position, the view is roughly perpendicular substantial valvular regurgitation if placed through the orifice
to either the aortic or mitral valve plane. Occasionally, a left an- of ball-​caged-​valve.
terior oblique caudal view is required to image the mitral valve. Cardiac magnetic resonance. The low cost, wide availability
As an example, in a normally functioning bileaflet-​tilting disc of echocardiography makes it the primary clinical tool for the
valve, two parallel lines appear and disappear intermittently
(E Fig. 18.7b). If only one or if neither of the lines fails to appear
Table 18.3  Cinefluoroscopic opening and closing angles of
or disappear, valve leaflet motion may be restricted or one leaflet commonly used normofunctioning mechanical heart valves (see text
as escaped. Then we should obtain a side view to assess leaflet for details on how to measure angles)
opening and closing angles. To obtain this view the image intensi-
fier is moved longitudinally 90°, usually caudally and transversely Heart valve prosthesis Specification Opening Closing
angle (°) angle (°)
to a position in line with the valve leaflet axis of rotation. Opening
and closing angles are defined as the distance between the valve Bileaflet-​tilting-​disc valves
housing and the disc at its full opening and closing in single-​disc St Jude Medical 19–​25 mm 10 120
valves (E Fig. 18.7a) and as the distance between leaflets in the 27–​33 mm 10 130
fully open and closed positions for bileaflet valves (E Fig. 18.7b). Carbomedics 12 118
ETable 18.3 lists the approximate normal opening and closing
Bicarbon 22 138
angles several heart valve prostheses. Deviation from the listed
angles or differences between the open or closed angle of one Edwards–​Duromedics Aortic 27 148
leaflet relative to the other in bileaflet valves may indicate re- Mitral 35 148
stricted leaflet motion. A slight asynchrony of leaflet motion is Jyros Valve 22 111
normal especially in valves in mitral position. Single-​tilting disc valves
Although it cannot visualize the leaflet of bioprostheses, it is
Bjork–​Shiley 60 0
very useful to assess the excursion of occluders in mechanical
valves, a diminished motion of the disc or poppet suggest ob- Medtronic–​Hall Aortic 75 0
struction of the prosthesis from thrombus or ingrowth of tissue Mitral 70 0
(E Fig. 18.8) [22]. Conversely, excessive tilt or rocking of the Allcarbon 60 NA
sewing ring is consistent with partial dehiscence of the valve (E Omniscience 80 12
Fig. 18.9).
NA, not available.
 Va lve pro sthesi s n or m a l fu n cti on a n d dysf un c t i on
Fig. 18.8  Cinefluoroscopy of a thrombosed St Jude Medical valve. The
left sided leaflet is stuck in closed position during the entire cardiac cycle
indicative of valve obstruction by thrombus.
assessment of valvular heart disease and prostheses. However,
cardiac magnetic resonance (CMR) may play a complemen-
tary role when transthoracic acoustic windows are poor and a
transoesophageal echocardiography (TEE) approach is undesir-
able. Therefore, its role is marginal when compared to ultra-
sounds. In the assessment of valve prostheses CMR is limited
due to the focal artefacts and signal loss relative to distortion
of the magnetic field by the metal contained in the prostheses
[23]. The artefacts are least pronounced on spin-​echo images
and more pronounced with gradient-​echo cine. On the contrary,
when the metal components are absent (as in biological valves)
the CMR exam is similar to that performed on a native valve.
However, incompatible prostheses to CMR are very rare. The
major limitations of CMR for valve assessment is spatial and
temporal resolution still suboptimal and the need for a regular
cardiac rhythm (E Fig. 18.10).
Cardiac multidetector computerized tomography. Cardiac
multidetector computerized tomography (MDCT) is an
259
emerging technique in non-​invasive cardiac imaging. Using
data recorded during cardiac cycle, it is possible to reconstruct
multiple incremental data sets throughout the R-​R interval.
These data sets can be sequentially combined to provide func-
tional imaging in a cine loop that allows evaluation of valvular
leaflet morphology and function (E Fig. 18.11). Even though
its role is expanding in the evaluation of cardiac diseases there
is no clear indication for the use of MDCT for the assessment
of valve diseases and prostheses. Moreover, concerns have
been raised on the radiation burden of MDCT scanning. In
fact, it has been estimated that about 0.4% of all cancers in
the United States may be attributable to the radiation from
MDCT studies. Therefore, the lack of a clear clinical benefit of
computed tomography (CT) for the assessment of prosthetic
valve diseases should be weighed on the potential detrimental
long-​term  risks.
Valve prosthesis normal function and
dysfunction
Normal anterograde flow. From what has been written in
the previous sections on heart valve prostheses specifications
and functional parameters (see also E Fig. 18.3), it is easy
to understand why, compared to native valves, all normally
functioning heart valve prostheses are inherently stenotic.
Therefore, the anterograde velocities and pressure gradients
across a normally functioning heart valve prosthesis will be
higher, and prosthetic EOA will be smaller than the corres-
ponding parameters measured in a normal native heart valve
in the same position.
The expected velocities, pressure gradients, and EOAs de-
pend on the specific type, size, and position of the heart valve
prosthesis, and on transprosthetic flow rate across that valve
(ETables 18.2 and 18.4). The strong dependency of pressure
gradients on transprosthetic flow rate explains the wide standard
deviation of reported values.
Fig. 18.9  Cineangiography in a
patient with partial dehiscence of a
mechanical prosthesis in the aortic
position. An excessive motion of the
prosthetic housing from diastole (a) to
systole (b) can be readily noticed.
260 CHAPTER 18   Valv ul ar prosth eses
Fig. 18.10  Allcarbon single-​disc prosthesis in mitral position. Horizontal
long-​axis steady-​state free-​precession cine magnetic resonance imaging.
Different valve types show also different patterns of antero-
grade flow at colour Doppler examination (E Fig. 18.12) which
should be known because alterations of these patterns are early
and sensitive markers of prosthetic valve obstruction, especially
in single-​disc tilting valves (E Fig. 18.13).
Normal regurgitant flow. Normally functioning mechanical
valves have physiologic regurgitant jets with a low velocity and
limited penetration into the proximal chamber, generally less
than 3 cm (E Fig. 18.14). The normal regurgitant volume can
be up to 10% of the stroke volume and very prominent, especially
at TOE examination (E Fig. 18.15 and 18.16). The main reason
for manufacturing these valves with a small amount of leakage is
to prevent a sudden and irreversible occlusion. This physiologic
regurgitation of mechanical valves is less likely to be detected in
mitral position than in the aortic position, which is due to the
shielding of the regurgitant jets by the prosthetic valve in the
mitral position. For the same reason, colour flow Doppler map-
ping is generally less sensitive than the continuous wave Doppler
Fig. 18.11  St Jude Medical bileaflet
valve in the mitral position. Sixty-​
four-​section multidetector row CT
scans show the mechanical bileaflet
valve during diastole (left panel). A
reconstructed three-​dimensional CT
image using volumetric rendering
method showing the same valve
(right panel).
Courtesy of Andrew Wood, Consultant
radiologist, University Hospital of Wales.
in detecting mechanical valve regurgitation in prothesis in mi-
tral position. Conversely, mitral valve ‘physiologic’ regurgitation
patterns are visualized particularly well with transoesophageal
colour Doppler because of its excellent image quality and spatial
resolution.
The regurgitant flow (backflow) through a normally func-
tioning valve prosthesis can be divided into ‘closure backflow’
occurring with the closure of the valve, and ‘leakage backflow’
occurring after the closure of the valve. The wide opening ex-
cursion of current mechanical valves may result in significant
closure backflow as back pressure swings the leaflets through
the long closing arc. Accordingly, a small jet occurring during
the first 40–​50 ms of systole can invariably be seen at TOE
examination in patient with tilting-​ disc mechanical valves.
Bileaflet-​tilting-​disc valves show two converging regurgitant
jets from the pivot points (designed to reduce the likelihood
of prosthesis thrombosis) one central jet, and variable number
of peripheral jets [7]‌. Bjork–​Shiley valves have a large central
regurgitant jet originating from the central disc hole and a
variable number of peripheral jets. The central regurgitant jet
makes most of colour Doppler signal but actually accounts for
30% of the regurgitant volume, the rest 70% is from the less
prominent peripheral jets. The Starr–​Edwards Ball-​Cage valves
have very low regurgitant volumes because the ball completely
occludes the primary flow orifice.
The stented bioprosthetic valves usually show only one centrally
directed regurgitant jet originating from the central part of the
valve. The prevalence of physiologic regurgitation across stented
bioprosthetic valves is 19–​25% and 26–​30% for mitral and aortic
positions, respectively. The newer generation stentless valves are
being used frequently due to their excellent haemodynamic pro-
file. The prevalence of mild aortic regurgitation with these valves
may be up to 17% but the presence of significant amount of regur-
gitation is very low.
Prosthetic valve obstruction. Prosthetic heart valve obstruc-
tion may be caused by thrombus formation, fibrous tissue in-
growth (or pannus formation), or a combination of both, or by
endocarditis. The aetiology may be difficult to determine and
requires knowledge of the clinical presentation and findings on
 Va lve pro sthesi s n or m a l fu n cti on a n d dysf un c t i on 261

Table 18.4  Published data about Doppler haemodynamic parameters of normofunctioning prosthetic valves in mitral position

Type Doppler Size (mm)

parameters
23 25 27 29 31 33
Single tilting-​disc prostheses
Bjork–​Shiley* GOA 2.5 3.1 3.8 4.6 4.6
(n = 237) PHT 115 99 ± 27 89 ± 27 79 ± 17 70 ± 14
Mean gr. 6±2 5±2 3±1 2±2
Medtronic–​Hall GOA 2.54 3.14 3.80 4.52 4.52
(n = 47) PHT 78 69 ± 15 77 ± 17
Mean gr. 5±3 4±2 3±1 3±1
Omnicarbon GOA 2.55 3.14 3.8 3.8 4.52 4.52
(n = 140)
PHT 102 ± 16 105 ± 33 120 ± 40 134 ± 31
Mean gr. 6±2 5±2 5±2 4±1 4±2 4
Allcarbon GOA 3.1 3.8 4.5 4.5
(n = 73) PHT 105 ± 29 89 ± 14 85 ± 23 88 ± 27
Mean gr. 5±1 4±1 4±1 4±1
Bileaflet-​tilting-​disc prostheses
St Jude Medical GOA 2.55 3.09 3.67 4.52 5.18
(n = 40) PHT 160 76 ± 4 72 ± 11 74 ± 15 71 ± 14
EOA* 1.03 1.4 ± 0.2 1.7 ± 0.2 1.8 ± 0.2 2.0 ± 0.3
Mean gr. 4 3±1 5±2 3±1 4±2
Duromedics GOA 3.58
(n = 69) PHT 87 ± 15 89 ± 25 86 ± 12 85
Mean gr. 5±3 3±1 3±1 2
Carbomedics GOA 1.75 2.19 2.63 3.07 3.07 3.07
(n = 75) PHT 104 81 ± 10 78 ± 19 67 ± 10 83 ± 26 79 ± 18
EOA* 1.3 2.2 ± 0.5 2.1 ± 0.6 2.1 ± 0.5 1.9 ± 0.9 2.3 ± 0.7
Mean gr. 7 4±2 4±2 3±1 3±1 3±2
Bicarbon GOA 3.45 4.14 5 5 5
(n = 68) PHT 67 ± 1 84 ± 27 81 ± 18 81 ± 15 55
Mean gr. 5±3 4±1 5±2 4±1 7
On X PHT
(n = 33) Mean gr. 5±2 5±2 5±2 5±2

Stented bioprostheses
Medtronic Intact GOA 1.34 1.51 1.65 1.86
(n = 26) EOA* 1.4 ± 0.1 1.5 ± 0.1 1.6 ± 0.1 1.8 ± 0.2
Mean gr. 8±2 5±2 4±1 4±1
Hancock I PHT 115 ± 20 95 ± 17 90 ± 12
(n = 46) Mean gr. 5±2 2±1 5±2 4±2
Hancock II PHT 105 ± 63 81 ± 23
(n = 54) Mean gr. 5±2 3±1 4±1
Hancock pericardial PHT 105 ± 36 81 ± 23
(n = 22) Mean gr. 3±1 4±1
262 CHAPTER 18   Valv ul ar prosth eses

Table 18.4 Continued

Type Doppler Size (mm)

parameters
23 25 27 29 31 33
Ionescu–​Shiley PHT 80 ± 30 79 ± 15 75 ± 19
(n = 45) Mean gr. 3±1 3±1 4±1
Carpentier-​Edwards PHT 100 110 ± 15 90 ± 11 80
(n = 12) Mean gr. 3.6 5±2 4±1 1
Mitroflow PHT 90 90 ± 20 102 ± 21 91 ± 22
(n = 24) Mean gr. 7 3±1 4±2 4±1
2 2
*monostrut; GOA = geometric orifice area provided by the manufacturer in cm ; EOA = effective orifice area (continuity equation) in cm ; Mean gr. = mean transprosthetic gradient
in mm Hg; n = examined patients.

transthoracic and TOE echocardiography. The possibility of pros-
thetic valve thrombosis or endocarditis should be ruled out in pa-
tients with embolization.
The incidence of prosthetic heart valve thrombosis has a re-
ported incidence of 13% in the first year in any valve position
and even 20% for mechanical prostheses in the tricuspid position
[24]. At any time, for prostheses in the mitral and/​or aortic pos-
ition, the overall incidence is 0.5% to 6% per patient-​year, highest
in the mitral position. The risk of thrombus in spite of adequate
oral anticoagulation has been estimated at between 1% and 4%
per year.
Echocardiography is the initial diagnostic approach patients
with suspected prosthetic heart valve obstruction. The increase of
transprosthetic pressure gradients and a reduction of the effective
area of the valve orifice, particularly in comparison with previous
data in that patient, may be diagnostic (E Fig. 18.14). In experi-
enced hands, transthoracic echocardiography can also detect an
altered anterograde flow pattern at colour Doppler suggestive of
intrinsic prosthesis obstruction (E Fig. 18.16). Increased antero-
grade transprosthetic flow velocities due to prosthesis obstruction
should be differentiated by those to high cardiac output state or
coexisting prosthesis regurgitation which may increase the an-
terograde volume flow rate across the prosthesis resulting in a
high velocity and high transprosthetic gradients. However, in case
of increased anterograde volume flow rate, the valve area remains
relatively normal.
TOE is the most accurate diagnostic technique to assess alter-
ations in the occlusive mechanism or the existence of thrombus
on heart valve prostheses, especially for valves in the mitral pos-
ition. Partial blockade of the prosthetic disc by thrombus can
easily be detected by TOE as it usually holds it in a semi-​open
position, leaving an eccentric communication open in systole
and diastole. The colour Doppler further facilitates more pre-
cise localization of prosthetic obstruction showing acceleration

Fig. 18.12  Normal colour Doppler

echocardiography appearance of
anterograde flow across different
valve types in the mitral position: a
single tilting-​disc valve with a major jet
towards the lateral wall and a minor
jet directed towards the centre of the
cavity (a); a bileaflet-​tilting-​disc valve
in which flow passes through three
well separated orifices creating a near
physiological flow pattern (b); and a
bioprosthetic valve in which there is a
single, central flow very similar to that
of native valves (c).
 Va lve pro sthesi s n or m a l fu n cti on a n d dysf un c t i on 263

Fig. 18.13  Single tilting-​disc

valve thrombosis. Colour Doppler
echocardiography at presentation
(a) shows the absence of the central
minor jet and increase of the velocity
at colour wave (CW) spectral Doppler
of the lateral major jet (c). After i.v.
thrombolysis, it was noticed the
reappearance of the normal colour
Doppler pattern of the anterograde
flow (b) and a significance decrease of
the anterograde flow velocity at CW
spectral Doppler (d).

Fig. 18.14  Colour Doppler imaging

during diastole showing the normal
appearance of three ‘physiologic’
regurgitant jets (leakage backflow,
white arrows) from a bileaflet valve (a)
and a bioprosthesis (white arrow) (b)
in aortic position.

Fig. 18.15  Transoesophageal echocardiographic depiction of leakage

backflow from a bileaflet valve in mitral position. These three jets represent Fig. 18.16  Two-​and three-​dimensional colour Doppler imaging during
the physiologic leakage from pivotal points (peripheral jets) and central diastole showing the normal appearance of ‘physiologic’ leakage jets as
closure line (central jets) and should not be interpreted as pathologic compared to a periprosthetic pathologic jet from a bileaflet valve in mitral
prosthetic regurgitation. position.
264 CHAPTER 18   Valv ul ar prosth eses

(a) (b)

Fig. 18.17  Massive thrombosis on

the atrial side of a bileaflet tilting-​
disk valve in the mitral position
(white arrow, a) at transesophageal
echocardiography. The presence
of thrombus usually holds it in a
semi-​open position that creates an
eccentric intraprosthetic regurgitation
(b). Real-​time three-​dimensional
transoesophageal echocardiography
offers a better assessment of the
extension and dimensions of the (c)
thrombus (c).

proximal to a stenosis and any associated degree of regurgita-

tion caused by lack of mobility of the occluder. In most cases,
an echogenic mass is observed on the prosthetic valve surface at
the site of the stenosis (E Fig. 18.17). Three-​dimensional TOE
allows a better spatial localization of the thrombus and its ex-
tension as well as a more accurate assessment of the thrombotic
burden (E Fig. 18.18). TOE may also be useful to differentiate
thrombus from pannus as the mechanism of prosthetic obstruc-
tion. In prosthetic thrombosis, the movement of the disc is al-
ways abnormal, whereas in 40% of patients with obstruction due
to pannus the mobility of the disc is normal. The visualization
of an echogenic mass is almost diagnostic for thrombosis, but it
can be detected in only 70% of obstructions caused by pannus.
The echogenic characteristics of the mass are very important in
differentiating thombus from pannus. The thrombus tends to
be mobile, have soft ultrasound density, and is attached to the
valve occluder (E Fig. 18.19). The pannus is firmly fixed, have
bright ultrasound density, and is attached to the valve apparatus.
In addition, finding of echo density around the sewing ring with
bright reflective echoes and adequate anticoagulation heightens
Fig. 18.18  Limited thrombosis partially obstructing one of the side holes of
the suspicion of a pannus. A thrombotic mass is usually larger
a bileaflet mechanical prosthetic valve in mitral position. Transoesophageal
than pannus. In mitral prosthetic thrombosis the mass frequently two-​dimensional visualization of the thrombotic mass on the atrial side of
extends into the atrial endocardial surface, a feature rarely seen the prosthesis (a, arrow). A three-​dimensional en-​face view of the valve in
in obstruction caused by pannus. the opening position from the atrial perspective allows a precise localization
Prosthetic valve regurgitation. Echocardiography is highly of the mass and its extension (b). Degree of obstruction and mobility of the
thrombotic mass can be assessed more accurately with a longitudinal cut of
useful in detecting prosthetic valvular regurgitation but with cer-
the three-​dimensional data set (c). An en-​face view of the prosthesis in the
tain technical limitations, the most important of which are the closing position from the atrial side allows the visualization of additional small
problem of acoustic shadowing, reverberation and beam width thrombotic masses (d, small arrow) which were not visualized using the two-​
artefacts that occurs when the ultrasound beam should traverse a dimensional modality.
 Va lve pro sthesi s n or m a l fu n cti on a n d dysf un c t i on
Fig. 18.19  Transoesophageal echocardiogram showing a thrombus (white
arrow) visualized as a soft, small, and highly mobile mass on the atrial side of a
mitral bioprosthetic valve entering the valve orifice during diastole
reflective prosthesis before entering the cardiac chamber receiving
the regurgitant jet. This occurrence may lead to non-​visualization
or underestimation of the severity of the regurgitation, especially
with mechanical valves. In addition, colour artefacts are common
in patients with heart valve prostheses and may alter detection of
abnormal jets.
For prostheses in aortic position, both parasternal and apical
approaches may be useful since the ultrasound beam reaches the
LVOT without crossing the prosthesis (E Fig. 18.20). For pros-
theses in mitral position, the parasternal approach may be helpful
if a view in which the atrial side of the prosthesis can be obtained
without acoustic shadowing. Apical views are rarely useful due
to acoustic shadowing of the prostheses, even if in some cases
a paraprosthetic regurgitant jet can be visualized from this ap-
proach (E Fig. 18.21). Therefore, the transthoracic approach
has a low sensitivity for detection and quantitation of pros-
thetic regurgitation of mitral valve prostheses and, usually, the
transoesophageal approach is needed to visualize the left atrial
size of the prosthesis. Sometimes colour Doppler may visualize
proximal flow acceleration on the ventricular side of prostheses
in mitral position as a clue for rising the suspect of a significant
paravalvular regurgitation.
Fig. 18.20  Parasternal short axis view by transthoracic approach showing a
pathologic intraprosthetic leakage of a bioprosthesis in the aortic position.
265
Fig. 18.21  Prosthetic mitral regurgitation jet (white arrow) detected by
transthoracic echocardiography despite shadowing artefacts in the left atrium
caused by the mechanical prosthesis.
When a heart valve prosthesis regurgitation is detected, the
first important question to the echocardiographer is whether
‘physiologic’ or pathologic prosthetic regurgitation is present.
Differential characteristics of ‘physiologic’ from pathologic pros-
thetic valve regurgitation are uniform colour pattern rather than
the mosaic flow disturbance, short extension into the receiving
chamber (usually less than 2 cm), and the absence of supporting
features like increased anterograde velocity, enlargement of car-
diac chambers, and/​or pulmonary hypertension.
The most likely cause of intraprosthetic pathologic regurgita-
tion in mechanical valves is the incomplete closure of occluders
due to pannus, ingrowth, thrombus formation or vegetation
growth (E Fig. 18.22). Pathologic intraprosthetic regurgita-
tion of bioprostheses is usually due to structural valve deterior-
ation (E Fig. 18.22).
Paraprosthetic regurgitation is always pathological. Small
paraprosthetic regurgitation around the circumference of a pros-
thetic valve between the sewing ring and the annulus of the na-
tive valve is common. The regurgitant jet is usually eccentric and
it extends in the receiving chamber. More than one regurgitant
jets may be simultaneously present. During the first year after
valve replacement, these regurgitations are mostly related to
Fig. 18.22  Transoesophageal colour Doppler echocardiography showing an
extensive intraprosthetic leakage of a single tilting-​disc prosthesis caused by
pannus ingrowth.
266 CHAPTER 18   Valv ul ar prosth eses

Fig. 18.23  Structural deterioration

of a bioprosthetic valve in the mitral
position causing fracture of one leaflet
which prolapses in the left atrium
(white arrow) (a). An eccentric and
turbulent jet into the left atrium is
visualized in (b).

surgical factors, are not associated with increased subclinical
haemolysis, and are generally benign. Sometimes it may be diffi-
cult to distinguish intra-​from paraprosthetic regurgitation using
the transthoracic approach. In these cases, the transoesophageal
approach is needed. Moreover, in patients with paraprosthetic
regurgitation, the three-​dimensional modality allows a more pre-
cise localization and assessment of circumferential extent of the
leak (E Fig. 18.23).
Structural valve deterioration. Structural deterioration is
generally a problem for biological valves only and usually non-​
existent for the current generation of mechanical valves. However,
in 1986 the Bjork–​Shiley convexoconcave single-​tilting-​disc valve
was withdrawn from the market after reports of fracture of the
valve ring strut, resulting in dislodgment and embolization of
disc. Similarly, the TRI Technologies mechanical valve has been
withdrawn from clinical use because of the high risk of structural
failure after several cases of occluder escape [25]. Strut fracture
usually results in the abrupt onset of dyspnoea, loss of conscious-
ness, or cardiovascular collapse due to embolization of the disc
and acute severe valvular regurgitation that can be demonstrated
at echocardiography. Cinefluoroscopy may visualize the absence
of the strut and the radiopaque disc marker within housing of the
valve. Cinefluoroscopy has also been used to identify patients im-
planted with the Bjork–​Shiley convexoconcave single-​tilting-​disc
valve who have outlet-​strut separation without complete strut
fracture. The valve prosthesis should be prophylactically replaced
in these patients.
Structural deterioration of a bioprosthetic valve usu-
ally is the result of a progressive tissue degeneration with fi-
brosis and calcification of valve leaflets resulting in increased
resistance to open (stenosis) or failure to close properly (regur-
gitation). Regurgitation may also occur because of leaflet tear
(E Fig. 18.24), or rupture of one or more of the valve cusps
(E Fig. 18.25), and in these patients the clinical presentation is
that of an acute regurgitation [26]. The risk of structural valve de-
terioration increases over time. Typically, failure of bioprostheses
occurs after 10 years from implant.
Prosthetic valve endocarditis and related complications. A
prosthetic valve represents a foreign body within the circulatory
system which is a potential site of infection. The characteristic

Fig. 18.24  Transthoracic colour

Doppler echocardiography
demonstrating severe regurgitation of
a Cryolife O’Brien bioprosthesis from
parasternal (a) and apical approach
(b). The explanted valve (c) showed a
tear within the body of the cusp in the
non-​coronary sinus of Valsalva.
 Va lve pro sthesi s n or m a l fu n cti on a n d dysf un c t i on 267

Fig. 18.25  Transoesophageal echocardiography showing degenerative calcification and rupture of a cusp (white arrow, a) determining severe regurgitation (b)
of a bioprosthesis in the aortic position.

Fig. 18.26  Real-​time three-​dimensional transoesophageal echocardiography showing a small vegetation attached to leaflet of a bioprosthetic valve in the mitral
position. Multiplane visualization of the vegetation (white arrows, a). Rendering display of the vegetation allows better assessment of the size and shape of the
vegetation (white arrow, b).

lesion of valve prosthesis endocarditis is, similar to native valves, annular support. Frequently ring or myocardial abscesses are only
vegetation. When vegetations are small, they appear as irregular, detected at surgery, suggesting the low sensitivity of the technique
immobile echogenic structures attached to the valve components for valves in this position. For prosthesis in aortic position, in-
(E Fig. 18.26). As they grow and become larger, they usually creased thickening of the aortic root, with or without echo-​free
become sessile and move following the blood flow through the space inside confirmed in two views, suggests the presence of a
valve (E Fig. 18.27). Due to the presence of the prosthetic ma- ring abscess (E Fig. 18.30). Sometimes the diagnosis is difficult
terial, the sensitivity of echocardiography (both transthoracic and the echo study should be repeated after a few days to look for
and transoesophageal) to detect vegetations on prosthetic valves an evolution of the finding (E Fig. 18.31). Fistulous communi-
is lower than in native valves. Large vegetations can occasionally cations with the right atrium, left atrium, or right ventricle can be
cause prosthesis obstruction (E Fig. 18.28). Taken into account detected with colour Doppler.
the low sensitivity of the technique, a negative transthoracic study
in a patient with moderate or high clinical suspicion of endo-
carditis does not exclude the diagnosis and transoesophageal
examination should be warranted in those cases. It has also been
reported that vegetations longer than 10 mm are associated with
an increased risk of embolization, and vegetation size is a useful
information to plan the urgency of surgical intervention. Three-​
dimensional echocardiography improves the assessment of vege-
tation size, localization of attachment point and their mobility
(E Fig. 18.29).
Prosthetic valve endocarditis may evolve with paravalvular ab-
scess formation. In the mitral position, a paravalvular abscess ap-
pears as an echo-​free space adjacent to the sewing ring. However,
often the only signs of abscess are indirect as an increased pros- Fig. 18.27  Transthoracic echocardiography showing a large and highly
thesis mobility resulting from suture dehiscence and lack of mobile vegetation on the leaflet of a bioprosthesis in the aortic position.
268 CHAPTER 18   Valv ul ar prosth eses

Fig. 18.28 Transthoracic
echocardiography showing a large
vegetation on the left ventricular
side of a bioprosthesis in the aortic
position. The vegetation enters the
valve orifice during systole obstructing
it (a) and (b). At surgery, the extensive
obstruction of the bioprosthesis was
confirmed (c).

Haemolysis. Although subclinical intravascular haemolysis (as heart valve prostheses, severe haemolytic anaemia is uncommon,
evidenced by decreased serum haptoglobin, reticulocytosis and and suggests paravalvular leakage due to partial dehiscence of the
increased lactate dehydrogenase concentrations) can be docu- valve or infection or interaction of the jet with foreign bodies like
mented in most patients with normofunctioning mechanical annular rings (E Fig. 18.32).

Fig. 18.29  Infective endocarditis with vegetations on both the aortic and mitral bioprostheses. Two-​dimensional transoesophageal long-​axis view showing
vegetations (arrows) on both valve prostheses (a). Three-​dimensional en-​face view of the aortic prosthesis from the aortic perspective showing the vegetation
(b). Three-​dimensional en-​face view of the mitral prosthesis from the ventricular perspective showing the prolapsing vegetation (c). Three-​dimensional en-​face
view of the mitral prosthesis from the atrial perspective showing the size, attachment, and mobility of the vegetation (d).
 Va lve pro sthesi s n or m a l fu n cti on a n d dysf un c t i on 269

Fig. 18.30  Transoesophageal imaging of a short axis view of the aortic root showing a prosthetic aortic valve endocarditis complicated by abscess and
pseudoaneurysm formation. In the posterior part of the aortic root an echolucent space can be visualized suggesting the degeneration of the abscess in
pseudoaneurysm of the mitral-​aortic intervalvular fibrosa (a). By colour Doppler imaging, the blood flow is visualized exiting the pseudoaneurysm into the left
ventricular outflow tract during diastole (b).

Fig. 18.31  At early stages, abscess appears as a thickening of the aortic wall which is difficult to differentiate from haematoma (a). However, a transoesophageal
echocardiogram repeated 5 days later showed evolution of the echocardiographic images with vacuolization confirming the original suspicion of an abscess.

Fig. 18.32  Severe haemolysis in a female patient after mitral annuloplasty. Transthoracic echocardiography showed a moderate regurgitant jet directed towards
the annular ring, causing fragmentation of red cells and haemolysis.

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54:  661–​7.
19. Badano LP, Pavoni D, Musumeci S, et al. Stented bioprosthetic valve
hemodynamics. How much is the supra-​annular implant better than
the intra-​annular one? J Heart Valve Dis 2006; 15: 238–​46.
20. Pibarot P, Dumesnil JG, Jobin J, Cartier P, Honos G, Durand LG.
Hemodynamic and physical performance during maximal exercise
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versus stented bioprostheses. J Am Coll Cardiol 1999; 34: 1609–​17.
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22. Muratori M, Montorsi P, Teruzzi G, et al. Feasibility and diagnostic
accuracy of quantitative assessment of mechanical prostheses leaflet
motion by transthoracic and transesophageal echocardiography in sus-
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Hernandez K. Prosthetic heart valve thrombosis: pathogenesis, diag-
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116: I-​307–​I-​313.
 CHAPTER 19

Endocarditis
Daniel Rodríguez Muñoz and
Álvaro Marco del Castillo

Contents Introduction
Introduction  271
Role of echocardiography in infective Infective endocarditis (IE) is a life-​threatening disease that occurs as a result of the in-
endocarditis  271 fection of valve tissue or a valve heart prosthesis, potentially leading to acute valvular
Indications and modalities  271
Duke diagnostic criteria and anatomic lesion dysfunction and several extremely dangerous complications. In addition, IE is a highly
description  272 embolic condition, with the ability of rapidly spreading the infectious burden throughout
Complex IE scenarios and the use of
echocardiography  277
the whole system. As it can be entailed, it is a highly lethal disease, even with early diag-
3D echocardiography and other nosis and treatment [1–​3].
modalities  278 During the last few years, some advances have been implemented regarding diagnostic
Role of computed tomography  279 approaches and therapeutic strategies [4]‌, achieving modest improvements in outcomes.
Role of magnetic resonance  279
The main cornerstone of the diagnosis is still echocardiography, but functional imaging
Role of functional imaging  279
Prognosis based on imaging  281 in the context of nuclear medicine has evolved significantly improving both the sensi-
Risk of embolism  281 tivity and specificity of the overall diagnostic performance. All the different modalities
Risk of death  281 and how to use them will be reviewed in this chapter.
Follow-​up  281
Conclusion  281

Role of echocardiography in infective endocarditis

Indications and modalities
IE is a disease that can manifest in a huge variety of ways, as embolic phenomena en-
able for the spread of the infection and can affect virtually any organ or system of the
whole organism. This means that IE can be suspected, even with a low grade of suspi-
cion, in a lot of different clinical settings. As consequences can be fatal, any suspicion
should encourage further studies to rule it out. Typical contexts that should increase sus-
picion are: persistent fever without identified source, bacteraemia (especially if caused by
Staphylococcus aureus), and embolic events of unknown source [4]‌.
Regarding the modality, transthoracic echocardiography (TTE) should be the first ap-
proach for patients with suspected IE, as it is an inexpensive test that reports back a
significant amount of information. Generally, the observed sensitivity of this modality is
modest, of around 75%, but the specificity is close to 100% [5]‌. Thus, a normal TTE in a
patient with a high level of suspicion should always be confirmed with other technique,
but a normal result in a patient with a low likelihood safely rules out IE.
Transoesophageal echocardiography (TOE) should not be performed routinely and
should not be seen as a non-​invasive test. Although the risk of complications derived
from the probe insertion and/​or handling is extremely low, the tolerance is usually poor.
The diagnostic performance of TOE is high and is globally admitted being better than
that of TTE, with a sensitivity of more than 90% and specificity of almost 100% [5–​7].
272 CHAPTER 19  E n d o carditis
The main indications for the use of TOE in the context of endo-
carditis are [4]‌:
◆ Negative or technically poor TTE in a patient with a high level
of suspicion for IE
◆ Positive TTE
◆ Patients with prosthetic heart valves or intracardiac devices
The rational for TOE after a positive TTE is based on the neces-
sity of searching for possible local complications that could be
overseen with the latter, such as ring abscesses, perforations, or
pseudoaneurysms among others. According to the current guide-
lines, after a positive TTE, TOE should be considered except in
patients with isolated right-​sided native valve IE [4]‌. In case of
negative TOE despite high clinical suspicion, it is recommended
to repeat either TTE or TOE after 5–​7 days.
Although it is not acknowledged in the guidelines, in the
opinion of the authors it seems reasonable to proceed directly to
TOE in the following cases:
◆ Left-​sided prosthetic heart valves
◆ Limited transthoracic windows (especially in patients under
mechanical ventilation in ICU care)
E Figure 19.1 represents the algorithm for the use of echocardi-
ography recommended by the European Society of Cardiology.
Duke diagnostic criteria and anatomic lesion
description
E Box 19.1 [4]‌summarizes the currently recommended diagnostic
criteria for the diagnosis IE, which are a modification of original
Duke´s criteria [8]. As reported, positive cardiac imaging for IE is
accounts as major criterion independently from the observed lesion.
The spectrum of lesions that can be found within the umbrella of IE
contains: vegetations, abscess, valve aneurysms, pseudoaneurysms,
perforation, fistula, or prosthetic valve dehiscence.
Vegetations
A vegetation is an infected mass that is found attached to either
valvular endocardial tissue or prosthetic material. Echocardio­
graphically, it is seen as an irregular, oscillating mass that is usually
dependant on a leaflet or implanted cardiac material (E Fig. 19.2).
Its movement is normally coordinated with the flow, prolapsing for-
ward to the ventricle in diastole and back to the atria during sys-
tole in atrioventricular valves (z Video 19.1), whereas it prolapses
to the ventricle in diastole and to the main blood vessels in systole
in the case of sigmoid valves (z Video 19.2). Sometimes, however,
vegetations exhibit atypical implantation sites, such as ventricular or
atrial walls, or present as non-​pediculated lesions without significant
movement. They can also be seen in intracardiac leads and devices.
Regarding echogenicity, they usually share the same characteristics
of mid-​myocardium, with irregular areas of either echolucency or
deeper echodensity. The overall sensitivity of TTE for the detection
of vegetations ranges between 55 and 75%, with a great influence in
the echocardiographer experience [9]‌, and it is enhanced by the use
of harmonic imaging [10]. TOE, on the other hand, has a great sen-
sitivity for vegetations, reported as high as 90–​95% [11].
Clinical suspicion of IE
TTE
Prosthetic valve Non-diagnosis Positive Negative
Intracardiac device TTE TTE TTE
Clinical suspicion
of IE
High Low
TOEa Stop
If initial TOE is negative but high suspicion for IE remains,
repeat TTE and/or TOE within 57 days
Fig. 19.1  Algorithm showing the role of echocardiography in the diagnosis
and assessment of infective endocarditis.
IE, infective endocarditis; TTE, transthoracic echocardiography; TOE, transoesophageal
echocardiography.
a
TOE is not mandatory in isolated right-sided native valve IE with good quality TTE
examination and unequivocal echocardiographic findings.
Reproduced by Habib G, Hoen B, Tornos P, Thuny F, Prendergast B, Vilacosta I, et al.
Guidelines on the prevention, diagnosis, and treatment of infective endocarditis (new
version 2009): The Task Force on the Prevention, Diagnosis, and Treatment of Infective
Endocarditis of the European Society of Cardiology (ESC). European Heart Journal (2009).
Courtesy of Edwards Lifesciences, Irvine, CA and Sorin Biomedica Cardio S.p.A.,
Saluggia, IT
Some authors suggest a size-​based classification [12] of the
vegetations as follows:
◆ Small (<5 mm)
◆ Medium (5–​10 mm)
◆ Large (>10 mm)
This classification has been consistently correlated with the risk
of subsequent embolic events. In 1997, Tischler and Vaitkus [13]
published a meta-​analysis in which the OR for systemic embolism
in the case of large vegetations was almost three times higher (OR
2.80) than in patients with absent or small vegetations. The size
was also correlated with the need for surgery, with an OR of 2.95
(95% CI, 1.90–​4.58; P <0.01). However, the presence of large
vegetations was not positively associated with death. A more re-
cent meta-​analysis published in 2018 by Mohananey et al. [14]
found coherent results and, furthermore, was able to establish a
negative impact of large vegetations on mortality (OR, 1.63; 95%
CI, 1.13–​2.35; P = 0.009) when compared to vegetations smaller
than 10 mm. After this results, large vegetations were included
in the current guidelines of the main cardiovascular societies
in the decision-​making algorithms for surgical interventions,
 Rol e of echo ca rdi o g r a phy i n i n fecti ve en d o c a rdi t i s 273

Box 19.1  Indications for echocardiography in suspected infective

endocarditis

Major criteria
1 Blood cultues positive for IE
a Typical microorganisms consistent with IE from 2 separate
blood cultures:
Viridans streptococci, Streptococcus gallolyticus
●

(Streptococcus bovis), HACEK group, Staphylococcus

aureus; or
Commuinity-​acquired enterococci, in the absence of a
●

primary focus; or
b Microorganisms consistent with IE from persistently positive
blood cultures:
≥2 positive blood cultures of blood samples drawn >12 h
●

apart: or
All of 3 or a majority of >4 separate cultures of blood
●
Fig. 19.2  Vegetations are usually seen as an irregular, oscillating mass that is
usually dependant on a leaflet.
(with first and last samples drawn > 1 h apart); or
c Single positive blood culture for Coxiella burnetii or phase I
IgG antibody titre > 1:800 preserving the definition of large vegetations and including ‘very
2 Imaging positive for IE large’ for those higher than 15 mm.
The differential diagnosis of vegetations should include all kinds
a Echocardiogram positive For IE
of intracardiac mass lesions, and it is also important to pinpoint
Vegetation;
●
that not all the vegetations are of infective nature. For example, le-
Abscess, pseudoaneurysm, intracardiac fistula;
sions in the context of marantic endocarditis (seen in advance ma-
●

Valvular perforation or aneurysm

●
New partial dehiscence of prosthetic valve.
●
b Abnormal activity around the site of prosthetic valve
implantation detected by 18F-​FDG PET/​CT (only if the
prosthesis was implanted for >3 months) or radiolabelled
leukocytes SPECT/​CT.
c Definite paravalvular lesions by cardiac CT.
Minor criteria
1 Predisposition such a predisposing heart condition, or
injection drug use.
2 Fever defined as temperature >38°C.
3 Vascular phenomena (including those detected by imaging
only): major arterial emboli, septic pulmonary infarcts,
infectious (mycotic) aneurysm, intracranial haemorrhage„
conjunctival haemorrhages, and Janeway’s lesions
4 Immunological phenomena: glomerulonephritis. Osleris
nodes, Roth’s spots, and rheumatoid factor.
5 Microbiological evidence: positive blood culture but does
not meet a major criterion as noted above or serological
evidence of active infection with organism consistent
with IF.
IE = infective endocarditis; FDG = fluorodeoxyglucose; PET/​CT = positron
emission tomography/​computed tomography; SPECT/​CT = single photon
emission computed tomography/​computed tomography.
Reproduced by Habib G, Lancellotti P, Antunes MJ, Bongiorni MG, Casalta
J-​P, Del Zotti F, et al. 2015 ESC Guidelines for the management of infective
endocarditis. The Task Force for the Management of Infective Endocarditis of
the European Society of Cardiology (ESC) endorsed by: European Association
for Cardio-​Thoracic Surgery (EACTS), the European Association of Nuclear
Medicine (EANM). Eur Heart J. 2015 Nov 21;36(44):3075–​128. By permis-
sion of Oxford University Press.
lignant diseases) or Libman–​Sacks masses (seen in the context of
systemic lupus erythematosus) are vegetant lesions of sterile nature.
Normal variants such as Lambl excrescences [15] (filiform forma-
tions that arise from the aortic cusps) or ontogenic right atrial
structures (Chiari network, eustachian valve) should also be con-
sidered (E Fig. 19.3).
Abscesses
After vegetations, the second most frequent observed lesions in
the context of IE are periannular abscesses. Not only they are mere
imaging phenomena, but rather severe complications associated with
high morbidity and mortality [2, 3]. Abscesses are perivalvular cav-
ities filled with intracavitary necrotic and purulent material that are
not connected to the cardiovascular lumen. Typically, they can be
seen as perivalvular areas of reduced echodensity that negatively re-
model the normal anatomy and relations between different structures
that are normally contiguous (E Fig. 19.4). The content is usually
homogeneous and has a granular aspect. When the abscess is com-
pletely formed, its detection is generally easy. However, at early stages,
they can only appear as tissue thickening and blurring (E Fig. 19.5).
The reported incidence of abscesses is between 30 and 40% [16,
17] and, traditionally, they have been ligated especially to aortic
valve IE and prosthetic valve IE [16–​19]. However, a study pub-
lished in 2007 by Hill et al. reported a significant number of pos-
terior mitral abscesses detected during surgery that were previously
undetected by TOE, particularly in the case of significant posterior
mitral annular calcification [20]. Thus, it is likely that the available
evidence could be underestimating the incidence of mitral ab-
scesses. In addition, abscesses are more frequently seen in the con-
text of coagulase-​negative staphylococcus infection [21].
274 CHAPTER 19  E n d o carditis

(a) (b) (c)

Fig. 19.3  (a) Lesions in the context of marantic endocarditis (seen in advance malignant diseases) or Libman-​Sacks masses (seen in the context of systemic
lupus erythematosus) are vegetant lesions of sterile nature. (b) Lambl excrescences, filiform formations arising from the aortic cusps. (c) Ontogenic right atrial
structures such as Chiari network or eustachian valve must be considered when vegetations are observed in the right atrium.

TOE is far more sensitive than TTE for the detection of this
complication. While several studies reported sensitivities and
specificities of around 90 and 95% respectively [7, 20] for TOE,
TTE only detects around 30% of the cases [7]‌(E Fig. 19.6).
Nevertheless, the presence of abundant calcification or imag­
ing artefacts caused by prosthetic reverberation significantly
impair these exams performance, especially in posterior mitral
region.
Abscess formation has prognostic implications. It is the most
important risk factor for heart block as a complication of IE and
mortality is 1.5–​2 times higher for risk-​matched population
without abscesses [21].
Pseudoaneurysms
Pseudoaneurysms are defined as perivalvular cavities that, as
opposed to abscesses, have a communication with the cardio-
vascular lumen. They are believed to be the evolution of normal
IE-​related abscesses that, eventually, develop liquefactive ne-
crosis and break down into a high-​pressure chamber (e.g. left
ventricle, aorta, et.). That mechanism explains their tendency
to perforate and result into fistula formation [22]. The echocar-
diographic appearance resembles that of a pulsatile abscess with
inflow colour doppler (E Fig. 19.7, z Video 19.3).
Although the exact epidemiology of pseudoaneurysms has
been poorly addressed, they are thought to appear in less than
5% of the cases [23]. As common abscesses, they are more fre-
quent at aortic position (particularly in prosthetic IE) and at
mitro-​aortic continuity.
Fistulae
Fistulae are communications between two cavities that allows
for pathological circuits and shunting. They may be the normal
evolution of both abscesses and pseudoaneurysms and are easily
recognized with the use colour doppler, by seeing colour signal
communicating both chambers (E Figure 19.8, z Video 19.4).
Their incidence is low, reported in around 1.6% of patients [24]
and significantly impair prognosis, probably due to the remark-
able haemodynamic changes they induce in a very short time.

Fig. 19.4  Abscesses are perivalvular cavities filled with intracavitary necrotic
and purulent material that are not connected to the cardiovascular lumen.
Typically, they can be seen as perivalvular areas of reduced echodensity that
negatively remodel the normal anatomy and relations between different
structures that are normally contiguous.
Fig. 19.5  When the abscess is completely formed, its detection is generally
easy. However, at early stages, they can only appear as tissue thickening and
blurring.
 Rol e of echo ca rdi o g r a phy i n i n fecti ve en d o c a rdi t i s 275

(a) (b)

Fig. 19.6  Transoesophageal echocardiography (TOE) is significantly more sensitive for the diagnosis of endocarditis than transthoracic echocardiography (TTE),
as can be seen in the example shown, where the vegetation is easily observed in TOE (b) and unclear in TTE (a).

Valve perforation and leaflet aneurysms
Valve perforation is associated with acute severe transvalvular re-
gurgitation, and is associated with an impaired prognosis if early
surgery is not performed [25]. Echocardiographically, it is seen as
a colour doppler jet through a leaflet interrupting the continuity
of endocardial tissue (E Fig. 19.9, z Video 19.5). It is generally
accepted that this complication tends to occur in IE caused by
high virulence microorganisms, such as S. aureus.
Leaflet aneurysms are rare and have not been consistently re-
ported or studied in the literature. The reported incidence for
mitral aneurysms is well below 0.5% [26, 27], being IE the most
frequent cause by far (>90% of cases). Literature regarding aortic
leaflet aneurysms, on the other hand, is even scarcer and limited
to several case reports. This is probably due to a higher tendency
of the aortic valve to perforation instead of geometric distortion,
which explains why leaflet aneurysmization is more frequently
seen in the mitral valve. The echocardiographic image is that of a
saccular distortion of the affected leaflet, commonly accompanied
by significant regurgitation (E Fig. 19.10).
New dehiscence of a prosthetic valve
The presence of a new perivalvular regurgitation should raise
the suspicion of IE, even if no other signs are present. However,

(a) (b)

(c) (d)

Fig. 19.7  TOE showing an aortic

pseudo aneurysm in a patient with
a bioprosthetic valve. This peri-​
annular complication is diagnosed
by demonstration of an echolucent
cavity within the posterior area of the
valvular annulus (a–​c, arrows) and a
flow detected by colour Doppler into
this cavity (d).
276 CHAPTER 19  E n d o carditis

Fig. 19.8 Transthoracic
echocardiography showing a large
vegetation on the left ventricular
side of a bioprosthesis in the aortic
position. The vegetation enters the
valve orifice during systole obstructing
it (a) and (b).

paravalvular regurgitation and dehiscence are not synonyms. the context of valvular dehiscence is frequently massive. TOE
The latter is defined fluoroscopically, as a rocking movement is more sensitive for this situation than TTE but, as the haemo-
of the prosthesis of more than 15 degrees in any plane. All in dynamic disruption is so extreme, is can normally be suspected
all, it is logically deduced that the paravalvular regurgitation in with TTE.

(a) (b)

(c) (d)
Fig. 19.9  TOE showing a
mitral-​aortic endocarditis with a
pseudoaneurysm of the mitral-​aortic
fibrous intervalvular area. Destruction
of the posterior commissure of a
bicuspid valve (a, white star). Large,
mobile aortic vegetations prolapsing
into the left ventricular outflow tract
during diastole and contacting the
ventricular aspect of the anterior
mitral leaflet (b, arrow). These lesions
lead to a severe aortic regurgitation
(c) and a mitral perforation (d).
 Rol e of echo ca rdi o g r a phy i n i n fecti ve en d o c a rdi t i s 277

(a) (b)

(c) (d)

Fig. 19.10  TOE showing a native

aortic valve endocarditis with a
‘valvular aneurysm’ (arrow) associated
with a perforation leading to an acute
aortic regurgitation (a, b, c, d).
Courtesy of Andrew Wood, Consultant
radiologist, University Hospital of Wales

Complex IE scenarios and the use of studies that have addressed the diagnostic yield of both tech-
echocardiography niques. Estimated sensitivity of TOE is 86–​92% against 17–​36%
for TTE, and these differences are sustained irrespectively of the
Although it has been pointed out that ultrasonography is the position or the type of prosthesis [29–​32]. TOE is also superior in
principal technique for the diagnosis of IE, there are several clin- the detection of IE-​related structural complications [7]‌.
ical scenarios in which the overall performance is significantly When comparing overall sensitivities of both TTE and TOE for
compromised. In the following situations, a normal exam should IE and PVIE, it stands out that it is slightly lower for PVIE. Thus,
be interpreted carefully: prosthetic valve IE (PVIE) and cardiac the rate of false negatives is higher and the negative predictive
implantable electronic devices (CIED) infections. value lower. All in all, this fact entails that a negative result does
not rule out PVIE in strongly suggestive cases. For those situ-
Prosthetic valve infective endocarditis (PVIE) ations, as in non-​prosthetic IE, current guidelines recommend
The role of echocardiography in the setting of prosthetic valve a repeat exam in 5 to 7 days [4]‌. However, even under optimal
IE (PVIE) is fundamental, but the provided information can be
limited by two major factors: prosthesis-​related artefacts that im-
poverish the image quality and structural postoperative changes
that can be difficult to interpret.
The anatomical changes that accompany mechanical and bio-
logical prosthesis are slightly different [28]: in mechanical valves,
infection usually occupies the virtual space between the pros-
thetic ring and the native annulus, with great facility for abscesses
and their evolutive complications (pseudoaneurysms and fis-
tulae) as well as dehiscence. On the other hand, bioprosthetic in-
fection usually involves the leaflets, leading to intrinsic prosthetic
malfunction due to perforation or vegetations (E Fig. 19.11,
z Video 19.6). However, biological prosthesis can also be affected
in the same way as mechanical ones.
Again, TTE is not reliable enough in this scenario when com-
pared to TOE. Being so, the authors consider that it is reasonable
to proceed directly with TOE in patients with suspected PVIE,
especially in the presence of mechanical prosthesis, if TTE quality Fig. 19.11  Bioprosthetic infection usually involves the leaflets, leading to
is expected to be low. This recommendation is based on several intrinsic prosthetic malfunction due to perforation or vegetations.
278 CHAPTER 19  E n d o carditis
conditions, modified Duke´s criteria have a poorer performance
in these patients, and some additional minor criteria have been
proposed in order to complement the valid ones [33].
CIED-​related infective endocarditis (CIEDIE)
This term encompasses the systemic infections that occur in pa-
tients with cardiac pacing and defibrillating systems. The most
common form of CIED-​related IE starts with a pocket infection
that disseminates through the lead´s venous access and generates
bacteraemia, but it can also happen as a result of a remote source
bacteraemia that seeds the leads. It is probably the most difficult
to diagnose form of IE.
CIEDIE represent several difficulties. Firstly, both normal and
abnormal sterile tissues can be seen attached to intracardiac leads,
as a result of endothelization or thrombus formation, and neither
TTE nor TOE have any definite parameters to face this differential
diagnosis. Secondly, it is sometimes impossible to view the lead
with enough resolution as to ascertain whether it is clean or not.
In addition, tricuspid involvement is often very difficult to assess,
as the lead interacts and artefacts the image, and TOE imaging of
right-​sided valves is frequently poor. Lastly, the modified Duke’s
criteria for the diagnosis of IE are known to have a poorer diag-
nostic precision in this population, even after implementing some
proposed adjustments [34, 35] (E Boxes 19.2 and 19.3.)
Overall, the reported TTE sensitivity for lead infection ranges
from 15 to 30% [34, 36, 37], while the TOE sensitivity is higher
than 90%. Specificity for both exams is above 90%. Thus, nega-
tive exams in patients with low suspicion allow for a safe CIEDIE
Box 19.2  Modified Duke criteria for diagnosis of infective
endocarditis on pacemaker leads
A. Definitive diagnosis
  1.  Pathological criteria
  ● Causative agents were found in cultures, or in
histological vegetation, emboli, or cardiac abscess
  ● Causative agents were found in cultures from the
electrical lead
  2.  Clinical criteria
  ● Two major criteria
  ● One major and three minor criteria
  ● Five minor criteria
B.  Possible diagnosis
  ● Findings appropriate for CDE that are not definitive or
rejected
C.  Rejected diagnosis
  ● Other solid diagnoses that explain the findings;
  ● Disappearance of the CDE syndrome during antibiotic
treatment in less than four days; or
  ● Lack of pathological proof of CDE during surgery or post-​
mortem, and less than four days of antibiotic treatment
CDE = cardiac device-​related endocarditis.
Reproduced from Klug D, Lacroix D, Savoye C, et al. Systemic infection re-
lated to endocarditis on pacemaker leads: clinical presentation and manage-
ment. Circulation. 1997;95(8):2098–​107. doi:10.1161/​01.cir.95.8.2098 with
permission from Wolters Kluwer.
Box 19.3  Definition of terms used in the proposed diagnostic
criteria
1.  Major criteria
  ● Positive blood cultures
  ● Typical causative in two different cultures
  ● Viridans groups streptococcus, streptococcus bovis,
HACEK group
     Staphylococcus aureus, Enterococcus species—​in the
●
absence of a primary source
  ● Continuous positive blood cultures
  ● Positive cultures taken at 12 h apart
  ● Three of three positive cultures or majority of four or
more cultures, when there is at least 1h between collection
of the first and last cultures
2.  Echocardiographic findings
  ● Intracardial pendulous mass attached to the lead or in the
endocardial structure in contact with the lead
  ● Abscess in contact with the lead
Minor criteria
  ● Temperature greater than 38°C
  ● Vascular findings: arterial embolus, septic pulmonary
infarcts, mycotic aneurysm, intracranial haemorrhage,
Janeway lesions
  ● mmunological findings: Glomerulonephritis, Osler’s
nodes, Roth’s spots
  ● Echocardiography: Findings supporting CDE that do not
qualify as major criteria
  ● Microbiology: Positive blood cultures that do not qualify
as major criteria
CDE = cardiac device-​related endocarditis; HACEK = haemophilus species
(Haemophilus parainfluenzae, haemophilus aphrophilus, and haemophilus
paraphrophilus), Actinobacillus actinomycetemcomitans, Cardiobacterium
hominis, Eikenella corrodens, and Kingella kingae.
Reproduced from Klug D, Lacroix D, Savoye C, et al. Systemic infection re-
lated to endocarditis on pacemaker leads: clinical presentation and manage-
ment. Circulation. 1997;95(8):2098–​107. doi:10.1161/​01.cir.95.8.2098 with
permission from Wolters Kluwer.
rule-​out, while in patients with high degree of suspicion, further
testing is required.
Most vegetations are usually attached to the lead (59–​87%)
(E Fig. 19.14), while a small proportion depend on the tricuspid
valve (13–​32%) (E Fig. 19.11) [35], and it is more frequent to
see the vegetations in the atrial part of the lead [36]. Lead-​related
vegetations can be divided into three separate groups [36]: mul-
tiple vegetations with delicate sinuses; single, round, and elong-
ated vegetations; and single or several thick vegetations. Both
types 1 and 3 are associated with a higher incidence of pulmonary
embolism.
3D echocardiography and other modalities
3D echocardiography is extremely available nowadays and is per-
formed systematically in almost every endocarditis echocardio-
graphic examination. Even though the use of 3D imaging does
not increase the sensitivity of the technique, it enhances the

(a) (b)
localization and characterization of lesions (E Fig. 19.12 and
z Video 19.7). It also enables for the recreation of surgical views,
which are useful for surgical planning.
The use of intracardiac echo can be of potential interest, as it
has a very high-​resolution and can evaluate lesions in extremely
close proximity. However, it is still an expensive technology with
scarce supportive literature in the context of IE. Taken that into
account, it is not a technique that can be routinely recommended
for the time being.
Role of computed tomography
Cardiac multislice computed tomography (MSCT) is an imag­ing
modality that has experienced a significant development during
the last decade, enabling now to acquire high-​resolution images
in small amounts of time and with a reasonable radiation.
MSCT can be used to detect and clarify the presence of struc-
tural complications, such as abscesses (E Fig. 19.13), and beyond
that, gives a wide spectrum of information regarding perivalvular
extension, anatomy, etc. that is crucial for surgical planning.
All of that is achieved with an accuracy comparable to TOE [38].
E Table 19.1 summarizes the comparative advantages and disad-
vantages of both techniques.
Fig. 19.13  Cardiac multislice computed tomography can be used to detect
and clarify the presence of structural complications, such as abscesses as the
one identified in the image (arrow).
Rol e of fu n cti ona l i m ag i n g 279
Fig. 19.12  Three-​dimensional
imaging has not proved to increase
the sensitivity of the technique,
with vegetations often being easier
to identify in 2D-​TOE (a). However,
it can facilitate the localization and
characterization of lesions (b).
Regarding the potential role in the evaluation of prosthesis,
one recent study has suggested that MSCT could even be su-
perior to TOE, especially in defining vegetations, dehiscence and
abscesses [39].
In addition, MSCT is very useful in the evaluation of periph-
eral embolism, being highly sensitive and specific for splenic and
other peripheral abscesses (E Fig. 19.14).
Finally, the risk of embolization associated with coronary angi-
ography is high and has led to the use of MSCT coronary angiog-
raphy as an alternative for patients with endocarditis that require
surgical interventions [40].
Role of magnetic resonance
There are several small-​cohort studies that have reported positive
results with cardiac magnetic resonance (CMR) for the diagnosis of
IE [41–​45]. However, the bonus information that is obtained with
CMR is of small value in most cases and it has not been validated in
large populations. All things considered, CMR should not be con-
sidered a first-​line investigation for the diagnosis of endocarditis.
However, that does not mean that there is no room for MRI in
IE, as it is the technique with the highest performance for cere-
bral complications such as infarcts or mycotic aneurysms. Several
studies with MRI during the acute phase of IE have steadily shown
that, despite symptoms, intraparenchymal lesions are as frequent
as 60–​80% [46, 47]. The systematic use of cerebral MRI in IE has,
then, a marked impact in IE diagnosis since vascular phenomena,
even asymptomatic and/​or detected only by imaging, account for
a minor criterion (E Fig. 19.15). In patients with neurological
symptoms, as they already have the minor criterion of vascular
phenomena, MRI adds no significant impact to the diagnosis, but
allows for a better characterization of the intracranial lesions.
Role of functional imaging
In this category, we have included those techniques directed to
detect inflammation and high metabolic activity: single photon
emission computed tomography (SPECT) and positron emission
tomography (PET).
280 CHAPTER 19  E n d o carditis

Table 19.1  Advantages and disadvantages of TOE and CT in IE

CT TOE
Haemodynamic effects Poorer information Excellent information: LV assessment, valve functionality
Limited planimetry
Coronary assessment CT coronary angiography perfectly feasible in most cases Only allows for ostial evaluation
May show regional wall motion abnormalities
Extracardiac findings First-​line technique for systemic embolisms
Vegetations Superior in prosthetic infections Excellent temporal resolution
Potentially worse for small vegetations (<4 mm) Poor quality in prosthetic valves
Abscesses Excellent visualization of structural complications Excellent visualization of structural complications, but
operator dependent
Fistulae Excellent visualization Excellent visualization in the hands of expert operators

SPECT imaging can be combined with normal computed tom-

Fig. 19.14  Multislice computed tomography is very useful in the evaluation
of peripheral embolism, such as splenic abscesses.
Fig. 19.15  The systematic use of cerebral MRI in IE is of high importance in
IE diagnosis since vascular phenomena, even asymptomatic and/​or detected
only by imaging, account for a minor criterion.
ography (CT) imaging, obtaining both functional and anatomic
information. However, SPECT and CT acquisition are usually per-
formed as separated processes. For endocarditis, the used tracers
are normally 111In-​oxine o 99mTc-​hexamethylpropyleneamine
oxime, which are manipulated to radiolabel autologous leuco-
cytes that will ultimately deposit in the affected tissues in a time-​
dependent fashion.
PET can also be combined with CT imaging in what is called
PET/​CT, but it can be performed by a single device. Another sig-
nificant difference between techniques is that PET traces overall
metabolic activity, since the radiotracer is radiolabelled glucose
(18F-​fluorodeoxyglucose).
SPECT isotopes are far cheaper to manipulate and have a
longer half-​life, which enables for late-​acquisition images. PET
isotopes have very short half-​lives (less than 30 minutes), require
to be generated near to the image acquisition facilities and are
much more expensive. However, the energy of positrons is much
higher that single photons. Thus, PET has a higher spatial reso-
lution than SPECT.
The main area of interest for these techniques is the ‘possible
IE’ of the Duke criteria, where they have the ability of reducing
the misdiagnosed cases. Although early studies raised to some
concerns in native valve IE due to inadmissible sensitivity [48] for
both modalities, they have been included in the current IE guide-
lines [4]‌as complementary exams for both PVIE and CIEDIE.
SPECT is more specific but less sensitive than PET. A meta-​
analysis published in 2017 by Mahmood et al. [49] reported an
overall sensitivity and specificity for PET/​CT of 76.8% and 77.9%
for native IE, and 80.5% and 73.1% for PVIE. E Figure 19.16
summarizes the role of the different imaging modalities for the
diagnosis of IE.
Nevertheless, there are some issues that must be taken into
consideration. First, early PVIE represents a huge challenge, espe-
cially for PET, as the periprosthetic cicatricial tissue is, in the end,
of inflammatory characteristics and has a high metabolic activity
that can lead to false positive misdiagnosis. Secondly, in order to
 C on c lusi on 281

Clinical suspicion of IE and, after multivariate analysis, both size and mobility were the
only independent risk factors. This observation has been repeat-
edly documented in the literature [52, 53].
Modified Duke criteria (Li)

Risk of death
Possible/rejected IE but Rejected IE
Definite IE
high suspicion Low suspicion
IE is a disease in which mortality is influenced by a lot of different
factors such as age, haemodynamic status, left ventricular (LV)
Native Prosthetic
function, valvular impairment, emboli, culprit microorganism,
valve valve presence of complications, etc. However, there are some echo-
cardiographic parameters that correlate with mortality and long-​
1 - Repeat echo (TTE + TOE)/microbiology term prognosis. Those include annular complications, severe
1 - Repeat echo (TTE + TOE)/
microbiology 2 - 18F-FDG PET/CT or Leucocytes labeled valvular dysfunction, ventricular systolic dysfunction, pulmonary
2 - Imaging for embolic SPECT/CT hypertension, and premature mitral valve closure.
eventsa 3 - Cardiac CT
3 - Cardiac CT 4 - Imaging for embolic eventsa

ESC 2015 modified diagnostic criteriab
Definite IE Possible IE Rejected IE
Fig. 19.16  Proposed algorithm for evaluating patients with suspected PVIE
(ESC 2015 diagnostic criteria for IE).
CT = computed tomography; FDG = fluorodeoxyglucose; IE = infective
endocarditis; PET = positron emission tomography; SPECT = single
photon emission computerized tomography; TOE = transoesophageal
echocardiography; TTE = transthoracic echocardiography.
a
May include cerebral MRI, whole body CT, and/or PET/CT.
b
See Table 14.
maximize the PET accuracy, it requires a pretest fat-​rich diet, a
prior fasting period in which several authors disagree in terms
of duration (6–​18 hours) and heparinization. This, together with
the variable local availability of PET, may take several days to be
arranged. If during that time the patient is on antibiotics—​which
is the usual and recommended practice—​the reliability of PET
results may be compromised [50]. Bottomline, the authors of this
text encourage the anticipation of the need for these imaging mo-
dalities in order to perform them with the less possible number of
days on antibiotic therapy.
Prognosis based on imaging
Risk of embolism
The hallmark of vegetations is embolism, which is frequent in IE
and leads to life-​threatening situations. Echocardiography can be
of great help when it comes to embolism prediction. The factors
that have been associated with embolization are size and mo-
bility of vegetations, evolution of vegetation size under antibiotic
therapy, culprit microorganism, prior embolism, multivalvular
endocarditis, and some biological markers.
Among them, the factor that has been more consistently asso-
ciated and with the higher odds is the size of the vegetation. Di
Salvo et al. [51] observed that very large vegetations (>15 mm, see
section on vegetations) were associated with embolic phenomena
Follow-​up
Literature regarding follow-​up of patients after a first episode
of IE is not abundant, thus guidelines offer no specific recom-
mendations [4]‌. However, it seems mandatory for patients to
keep follow-​up in either a heart-​valve clinic or an endocarditis
clinic, where regular echocardiographic examinations should be
arranged. Especially, the first year is more prone to exhibit com-
plications, so the authors recommend a TTE examination at least
every 3–​6 months during this period. However, the interval de-
pends on the clinical presentation, the microbiology, and the
presence of complications. Some patients can even require TOE
during follow-​up if large vegetations were present at the moment
of the diagnosis.
It is reasonable, but questioned by some authors, to perform
TTE/​TOE during antibiotic therapy to monitor the evolution
of vegetations and the appearance of structural complications.
Although only few studies addressed this issue, there is contra-
dictory evidence. Whereas Vilacosta [26] results showed that
most vegetations remain unchanged after antibiotic treatment
without prognostic worsening, Rohmann et al. [54] observed
that the vegetations that did not decrease after treatment had a
higher embolic risk. Nevertheless, the first study showed that
those vegetations that kept on growing during or after treatment
had a significantly higher embolic risk too so, all in all, vegetation
growth should be considered as a risk marker.
Conclusion
To summarize, even though IE a very complex disease in which
diagnosis must integrate several disciplines, cardiovascular
imaging is one of the cornerstones. And not only it allows for IE
diagnosis, but also for its structural complications. Particularly,
cardiac ultrasonography is and should be the main imaging mo-
dality, whereas all the other techniques can enhance the diag-
nostic performance or add significant value depending on the
clinical context. Thus, specialist who deal with IE must be aware
of the strengths and weaknesses of every test in order to improve
decision-​making in this disease.
282 CHAPTER 19  E n d o carditis
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 SECTION 4

Procedures in the
intensive cardiovascular
care unit

20 Imaging- guided transseptal puncture and transcatheter closure of patent foramen

ovale/ atrial septal defect, ventricular septal defect, and paravalvular leaks  287
Itzhak Kronzon, Juan Manuel Monteagudo, Francesco F. Faletra, Priti Mehla, and Muhamed Saric
21 Imaging for electrophysiological procedures  303
Louisa O’Neill, Iain Sim, John Whitaker, Steven Williams, Henry Chubb, Pál Maurovich-​Horvat,
Mark O’Neill, and Reza Razavi
22 Transcatheter aortic valve implantation  315
Arnold C.T. Ng, Victoria Delgado, and Jeroen J. Bax
23 Transcatheter mitral valve interventions  337
Nina C. Wunderlich, Robert J. Siegel, Ronak Rajani, and Nir Flint
24 Transcatheter tricuspid valve repair/​replacement  361
Rebecca T. Hahn
25. Transcatheter pulmonic valve replacement  377
Kuberan Pushparajah and Alessandra Frigiola
 CHAPTER 20

Imaging-​guided transseptal
puncture and transcatheter
closure of patent foramen
ovale/​atrial septal defect,
ventricular septal defect,
and paravalvular leaks
Itzhak Kronzon, Juan Manuel Monteagudo,
Francesco F. Faletra, Priti Mehla, and
Muhamed Saric

Contents
Introduction  287
Introduction
Transeptal puncture  287 Repairing structural heart diseases without surgery has been a major challenge. The title
Other imaging modalities  289
‘The Father of Interventional Cardiology’ belongs to William J. Rushkind (1922–​1986)
Patent foramen ovale and atrial septal
defect closure  289 who performed atrial balloon septostomy in newborn babies with D-​transposition as
PFO closure  289 early as 1968. He also designed devices for the transcatheter closure of atrial defects and
ASD closure  290 of patent ductus arteriosus. The introduction of better devices and skilled operators led
Ventricular septal defect closure  291
Surgical VSD closure  293
to successful procedures which are less traumatic, shorter, and in many cases significantly
Percutaneous VSD closure  293 less expensive.
Role of echocardiography in percutaneous The various modalities of cardiac imaging have become a crucial ingredient of the
VSD closure  294
preprocedural diagnosis, procedural guidance, and the assessment of procedural results
Paravalvular leak closure  295
Prevalence  295 and follow-​up.
Risk factors  295 This chapter will demonstrate and discuss the role of imaging in several catheter-​based
Clinical presentation/​features  295
Indications for intervention  295 procedures that are now commonly practised by the current generation of interventional
Evaluation and procedural guidance  295 cardiologists who are involved in structural heart disease.
Other imaging modalities  298

Transeptal puncture
The transseptal puncture technique allows a direct route to the left atrium through the
systemic venous system across the interatrial septum. The advent of electrophysiology
procedures and structural heart interventions has widely increased the use of this tech-
nique. Transseptal puncture is employed during procedures such as atrial fibrillation ab-
lation, left atrial flutter ablation, closure of left atrial appendage, closure of paravalvular
leak, or percutaneous mitral valve interventions.
The anatomy of the interatrial septum is complex and an insufficient awareness can
lead to life-​threatening complications, such as cardiac tamponade. Therefore, under-
standing the anatomy of the true septum is imperative for a safe transseptal puncture. The
288 CHAPTER 20   Tran s sep tal pu nctu re and tr a n s catheter cl o su re of paten t for a m en ova l e

SVC
Right atrial
appendage
SVC ostium
Coronary sinus
Fossa ovalis
(true septum)
IVC ostium Tricuspid
septal leaflet
IVC
Fig. 20.1  Anatomy of the true interatrial septum from the right atrial side.
SVC = superior vena cava; IVC = inferior vena cava.
anatomical interatrial septum is bounded by the ostia of the su-
perior and inferior vena cava, the coronary sinus, the septal leaflet
of the tricuspid valve, the right atrial appendage, and the posterior
wall folds [1]‌. These boundaries demarcate a relative broad area.
However, when a puncture is performed in most places of this
area, the needle leaves the heart. Thus, it is essential to distinguish
between this anatomical interatrial septum and the true septum
[2]. The true septum is the area that can be punctured without
arriving outside the heart and it is mainly built by the floor of the
fossa ovalis (E Fig. 20.1). The fossa ovalis is a depression in the
interatrial septum and represents a thin fibrous tissue that covers
the foramen ovale. The fossa ovalis is therefore the target of the
transseptal puncture technique.
Fluoroscopy has traditionally been the main imaging method
for guiding the procedure. However, in the last years, numerous
complex structural heart interventions performed via transseptal
access have emerged. For these interventions, the transseptal
puncture is a key step and the site of puncture is crucial for suc-
cess. An unsuitable puncture site limits the movements of the
guiding system and can result in more difficult and longer pro-
cedures or even in failure.
Transoesophageal echocardiography (TOE) and intracardiac
echocardiography (ICE) can provide detailed imaging of the
interatrial septum anatomy. This allows the operator to choose
the optimal location of puncture. Furthermore, the use of
ultrasound-​based imaging may increase the safety and reduce
the duration of the transseptal puncture [3, 4]. Thus, echo-​guided
transseptal puncture could be used for site-​specific puncture in
structural intervention, for complex anatomies and for increasing
safety in case of low volume operators [5]‌.
Transoesophageal echocardiography requires general anaes-
thesia or sedation and a second operator. In 2D-​TOE, multiple
echocardiography views are needed to define the optimal site
of puncture. The bicaval view (mid-​oesophagus position with a
clockwise torque, 80–​110º) allows visualization of the superior
vena cava, inferior vena cava, right atria, left atria, and interatrial
septum. A thinner central fossa ovalis is shown with a thicker
limbus superior and inferiorly. This view allows for superior and
inferior orientation. The aortic short axis view with a clockwise
torque (mid-​oesophagus position, 30–​60º) shows anterior (aortic
valve) and posterior orientation (E Fig. 20.2).
Therefore, a biplane view displaying the bicaval and the aortic
short axis views is the most helpful view during a TOE-​guided
transseptal puncture. The four-​chamber view with a clockwise
torque (mid-​oesophagus position, 0º) is helpful to determine
the height relative to the mitral valve during percutaneous mi-
tral valve interventions. Before advancing the needle, the final
site of puncture has to be assessed. To this end, visualization of
the tenting of the septum towards the left atrium produced by
the needle tip is preferred over visualization of the needle itself
(E Fig. 20.3).

(a) (b)

Fig. 20.2  Echocardiography views to

define the optimal site of puncture. (c)
(a) Bicaval view allows for superior
and inferior orientation. (b) Aortic
short axis view shows anterior (aortic
valve) and posterior orientation
(needle is too superior, outside the
fossa ovalis). (c) Four-​chamber view
helps to determine the height relative
to the mitral valve.
LA = left atria; RA = right atria; FO = fossa
ovalis; Ao = aortic valve; MV = mitral valve.
 Pat en t for a m en ova l e a n d atria l sep ta l defe c t c l o sure 289

visualization of the tenting produced by the needle tip, permitting

(a) (b)
Fig. 20.3  Two-​dimensional biplane transoesophageal imaging: visualization
of the tenting. (a) Bicaval view. (b) Aortic short axis views.
LA = left atria; RA = right atria; IVC = inferior vena cava; SVC = superior vena cava.
3D-​TOE can display an ‘en face’ perspective of the interatrial
septum. This perspective can be obtained from any 2D view (usu-
ally bicaval or four-​chamber view) and positioned with simple
rotation manoeuvres [6]‌. The produced images are similar to the
true anatomy and easily understood [7]. The key to an effective
guidance is good communication and collaboration between
the echocardiographer and the interventionist. To this end, both
must employ the same anatomical terms. E Table 20.1 shows
suggested site of puncture for different structural interventions.
Intracardiac echocardiography has some advantages over
TOE: it obviates additional sedation and a dedicated echocar-
diographer. Furthermore, it provides higher resolution. On the
contrary ICE requires an additional venous femoral access and
has a higher cost. After the ICE catheter is advanced to the right
atrium, navigation starts from the view of the tricuspid valve
(‘home view’) [12]. This view displays the tricuspid valve, right
ventricle inflow and outflow tract, and the pulmonary valve. From
this view, with posterior rotation of the catheter, the interatrial
septum is visualized. A careful assessment of the septum to look
for anatomic variation such as aneurysmal or lipomatous septum
or dilated aortic root can reduce complications [13]. ICE allows
for identification of the structures surrounding the septum and
a site-​specific transseptal puncture.
Echocardiographic-​ fluoroscopic fusion imaging is a new
imaging system which fuses the capabilities of fluoroscopy and
transoesophageal echocardiography in a single view. The large
field of view and the optimal definition of catheters and devices
of the fluoroscopy is combined with the optimal visualization of
soft tissue by transoesophageal echocardiography, compensating
some of the limitations of both techniques. The basic principle of
this imaging modality is the spatial and temporal alignment of
data from both fluoroscopic projections and TOE imaging. This
process is called co-​registration. Echocardiographic-​fluoroscopic
fusion imaging may assist in performing transseptal punc-
ture by providing easier achievement of site-​specific puncture,
patient-​ tailored fluoroscopic projections, and better eye-​ hand
coordination [14].
Other imaging modalities
Three-​dimensional electro-​anatomical mapping system has been
employed to guide non-​fluoroscopic transseptal puncture [15].
This results in a reduced radiation exposure.
Preprocedural multislice computed tomography can be em-
ployed to identify the interatrial septum and to determine the op-
timal C-​Arm fluoroscope angles that give a projection with an
axial view on the septum. The location of the fossa ovalis can be
projected onto the fluoroscopy screen to help direct the needle
for transseptal puncture [16]. Computed tomography has also
been used in combination with a 3D-​electro-​anatomical mapping
system [17].
Patent foramen ovale and atrial
septal defect closure
PFO closure
Patent foramen ovalis (PFO) is found in up to 25% of adult popu-
lation [18]. PFO has been associated with cryptogenic stroke and
migraine with aura in young population and with neurological
decompression illness in divers. While venous thrombi or ni-
trogen bubbles paradoxically crossing the PFO may explain the
cryptogenic stroke and decompression illness, respectively [19,

Table 20.1  Suggested site of puncture for different structural interventions

Structural intervention Site-​specific transseptal puncture

MitraClip® Three steps routine [8–​10]:
1. Bicaval view: The optimal location is superior from the midpoint.
2. Aortic short axis view: The optimal position is posterior from the midpoint. With the new generation
MitraClip NT®, the ideal location is more posterior compared to the previous generation.
3. Four-​chamber view: The optimal height related to the mitral valve Is between 3.5 and 5 cm, higher for
medial jets, and lower for lateral jets.
Left atrial appendage In most patient, the fossa ovalis is located superior and posterior to the orifice of the left atrial
occlusion appendage. Therefore, the optimal location is inferior and posterior [11].
Mitral paravalvular leak In patients with medial defects, the optimal location is superior and posterior.
290 CHAPTER 20   Tran s sep tal pu nctu re and tr a n s catheter cl o su re of paten t for a m en ova l e
20], there is not yet a convincing link between migraine and
PFO [21].
Though there are no undisputable evidences that PFO closure
abolishes the risk of reccurent cryptogenic stroke, divers’ illness,
or migraine, in most institutions, young patients with PFO and
cryptogenic stroke, professional divers with PFO, or young pa-
tients with intolerable migraine and large PFO are treated with
percutaneous closure.
Large PFO can be diagnosed with two-​ dimensional (2D)
or three-​ dimensional (3D) transoesophageal echocardiog-
raphy (TOE) with or without colour Doppler (E Fig. 20.4a–​c).
Medium or small-​sized PFO are better documented injecting few
millilitres of agitated saline solution into the antecubital vein.
The contrast medium must be injected during the strain phase of
the Valsalva manoeuvre with TOE images focus on the most cra-
nial part of the fossa ovalis (usually using a bicaval view or aortic
short axis view). Once the right atrium is filled with contrast, the
(a) (b)
(c) (d)
(e) (f)
Fig. 20.4  Multipanel figure of a patient with patent foramen ovalis (PFO)
during Valsalva (a, c) and after release (b, d) clearly showing the opening of
PFO (curved arrow). Panels E and F show the same case after injection of
agitated saline solution. During Valsalva manoeuvre, the contrast fills the right
atrium (RA). After Valsalva release (f) microbubbles are clearly seen in the left
atrium (LA) (arrow), through the PFO.
patient is asked to release. During the release phase the contrast
appears in the left atrium via PFO (E Fig. 20.4e, f). Transcranial
Doppler is another effective tool. Indeed, the appearance of micro
bubbles in the middle cerebral artery, is a sensitive sign a right-​to-​
left shunt through the PFO.
A PFO associated with fossa ovalis (FO) redundancy (i.e. the
so-​called septal aneurysm) has shown a stronger association with
stroke than the simple PFO. These PFO necessitate a larger device
to cover the whole aneurysm. Similarly, a larger device should be
used to cover a PFO with a long ‘tunnel’ (E Fig. 20.4). Simple
PFO may be closed with fluoroscopy alone, complex PFOs (re-
dundant tissue, long tunnel) may require TOE guidance. The pro-
gress of guide catheter through PFO, opening the left disc, pulling
back the system against the septum, opening the right disc and
final deployment are, in fact, easily guided by TOE (E Fig. 20.5).
Before ending the procedure, a pull-​push manoeuvre assures a
firmly anchorage of the device to the pliable tissue of the FO. A
minimum residual shunt may occur between the discs which dis-
appears after endothelization.
ASD closure
Atrial septal defect (ASD) is one of the most common congenital
cardiac defects with a prevalence of 1 out of 1,000 individuals.
There are five main types of ASD named in decreasing frequency:
secundum ASD (the most frequent accounting for about ¾ of all
ASDs) primum ASD, superior, and inferior sinus venosus ASD,
and unroofed coronary sinus. While all types of ASD can be
closed surgically, only secundum ASD can be treated percutan-
eously. Secundum ASD is located within the borders of the FO
and its size varies from a few millimetres to a complete absence
of the FO. Its shape is extremely variable being circular, ovoid,
triangular, or irregular. Finally, secundum ASD may be single or
having multiple holes.
Two-​dimensional (2D) and three-​dimensional (3D) transthoracic
(TTE) and transoesophageal (TOE) echocardiography are the pri-
mary imaging techniques that are able to define type, size, and
shape of ASD and its rims [18]. 3D TOE has the unique capability
to visualize the ASD ‘en face’ (E Fig. 20.6a–​d). However, TOE has
a narrow field of view and associated extracardiac anomalies such
anomalous drainage of pulmonary veins into the right atrium or
the superior vena cava can be missed. In such a case, or in case of
unexplained enlarged right ventricle, computed tomography, and
cardiac magnetic resonance can be used as well, being more ac-
curate in the diagnosis of extra cardiac anomalies.
The diameter of an ASD treated percutaneously cannot be >38
mm (in the United States) or 40 mm (in Europe) when using
an Amplatzer atrial septal occluder (St Jude Medical, Inc., Little
Canada, MN, USA) or 18 mm when using a Gore-​Helex device
(Gore Medical, Flagstaff, AZ, USA) [22]. It is important to dis-
tinguish between a maximum ASD diameter measured using
a balloon sizing technique (stretched diameter) and diameter
measured by 2D/​3D TOE (unstretched diameter). In this latter
case it is necessary to add 6 to 8 mm. ASD rims should be of suf-
ficient size for a stable anchoring the device. Several rims could

(a) (b)
(d) (e)
(g) (h)
be measured. A secure and stable anchoring requires a minimum
rim width of at least 5 mm and at least 2 mm at the aortic rim
(E Fig. 20.6e, f). Absence of the aortic rim is a major risk factor
for aortic root erosion. The most frequently implanted devices
consist of a mesh covering opposable double discs (Amplatzer,
AGA Medical Corporation, Plymouth, Minnesota), a helix
spiral occluder (Helex, W. L. Gore & Associates, Inc., Flagstaff,
Arizona), or two square umbrella-​like spring frames (STARFlex,
Inc., NMT Medical, Boston, Massachusetts) [23]. The Amplatzer
was the first device used. The size of the device is determined by
the diameter of the waist, which may range from 4 to 38–​40 mm.
The two discs extend radially, several mm beyond the diameter of
the waist, to provide a firm anchorage.
Once the device has been selected, the catheter with the de-
vice is advanced in the middle of left atrium. The left disc is then
expanded and pulled back to the left side of the septum (so that
Ven tri cu l a r sep ta l defec t c l o sure 291
(c)
(f)
(i)
Fig. 20.5  (a–​f ). Multipanel figure
showing consecutive still frames
during the PFO closure. (g-i) Same
case illustrated with fusion images.
LD = left disc; RD = right disc;
Cath = catheter.
the connecting waist remains across the defect); at this point, the
right disc is expanded in the right atrium, abutting the right side
of the septum. After a pull-​push manoeuvre that confirms that it
is firmly anchored, the device is released (E Fig. 20.7).
Ventricular septal defect closure
A ventricular septal defect (VSD) is a communication be-
tween the left and right ventricle which may be either con-
genital or acquired in origin [24]. Congenital VSDs are more
common than acquired ones. Acquired VSDs result typically
from trauma (such as a stab wound) or myocardial infarction
[25, 26]. Based on their location, VSDs are typically classified
into four types, ordered in cranial to caudal location as type
1 through type 4 (E Table 20.2) [27]. Type 1 is commonly
292 CHAPTER 20   Tran s sep tal pu nctu re and tr a n s catheter cl o su re of paten t for a m en ova l e

(a) (b) (a) (b)

(c) (d)

(c) (d)

(e) (f)

(e) (f)

Fig. 20.6  Multipanel figure showing: (a) a secundum atrial septal defect
(ASD) seen ‘en face’ from right atrial perspective, (b) fused image in antero-​
posterior projection displaying the ASD in an ‘oblique’ perspective; (c) ASD
Fig. 20.7  The panels (a), (c), and (c) show three still frames cross sectional
from a left perspective with a colour Doppler. The colour Doppler allows
images using a multiplanar reconstruction with thick slices during the closure
distinguishing the true ASD from the drop-​out artefacts (arrow); (d) Three
of ASD. Panels (b), (d), and (f), show same still frames in volume rendering
ASD (asterisks). (e) ASD from a left perspective and several rim’s diameters.
format. Panels (a) and (b) show the opening of left disc (LD); panels (c) and
With the exception of aortic rim, the size of the other rims should not be
(d) the opening of the right disc (RD), panels (e) and (f), the final deployment
inferior to 5 mm, while the size of ASD should not exceed 38–​40 mm. (f)
of the device before the detachment of the catheter (cath).
Measurements taken from a multiplanar reconstruction.

referred to as supracristal VSD; type 2 as perimembranous According to current guidelines [31], primary indications to
VSD; type 3 as inlet VSD; and type 4 as muscular VSD. Related close a VSD are:
to VSDs is an atrioventricular or Gerbode defect, which is de- ◆ Adults with a VSD and evidence of left ventricular volume
fined as a communication between the left ventricle and the overload and haemodynamically significant shunts (Qp:Qs
right atrium and may be congenital or acquired (such as after
valve surgery) [28]. Table 20.2  VSD classification
Type 1 or supracristal VSDs are seen with higher frequency
Type Synonyms
in patients East Asian (such as Chinese, Korean, and Japanese)
ancestry that in other populations. Type 2 or perimembranous Type 1 Supracristal
VSD is the most common type of VSD in post-​ neonates. Infundibular
Anatomically, they are located just caudal to the right and Subpulmonic
non-​coronary cusp of the aortic valve in and around the mem- Conal
branous ventricular septum. They often have windsock appear-
Doubly committed juxta arterial
ance due to protrusion of the membranous septum towards
the right ventricle [29]. Type 3 or inlet VSDs are typically seen Type 2 Perimembranous
in the larger context of atrioventricular (endocardial cushion) Paramembranous
defects. Type 4 or muscular VSDs may be either solitary or Conoventrucular
multiple (‘Swiss cheese VSDs’) and may be either acquired or Type 3 Inlet
congenital [30].
AV canal type
When indicated, VSDs are typically closed surgically al-
though percutaneous closure options are being developed. Type 4 Muscular
 Ven tri cu l a r sep ta l defec t c l o sure 293

≥1.5:1) should undergo VSD closure, if pulmonary artery (PA)

systolic pressure is less than 50% systemic and pulmonary vas- MUSCULAR PERIMEMBRANOUS
cular resistance is less than one-​third systemic. VSD OCCLUDER VSD OCCLUDER
Surgical closure of perimembranous or supracristal VSD is rea-
◆

sonable in adults when there is worsening aortic regurgitation

(AR) caused by VSD.
◆ Surgical closure of a VSD may be reasonable in adults with a his-
tory of infective endocarditis caused by VSD if not otherwise
contraindicated.
◆ Closure of a VSD may be considered in the presence of a net

Waist
left-​to-​right shunt (Qp:Qs ≥1.5:1) when PA systolic pressure is
50% or more than systemic and/​or pulmonary vascular resist-
ance is greater than one-​third systemic.
VSD closure is contraindicated in the following context:
• VSD closure should not be performed in adults with severe
pulmonary arterial hypertension (PAH) with PA systolic
pressure greater than two-​ thirds systemic, pulmonary vas-
cular resistance greater than two-​thirds systemic, and/​or a net
right-​to-​left  shunt. Distal Proximal LV RV
Disc Disc Disc Disc
Surgical VSD closure
Surgery has been the primary means of VSD closure. In the past
several decades, progressive improvements in surgical techniques
Amplatzer VSD Occluders
have led to marked improvements in the prognosis and survival Fig. 20.8  VSD Occluders. Amplatzer Muscular VSD Occluder (left) and
of patients with VSDs [32]. However, a surgical VSD closure re- perimembranous VSD occluder (right).
quires cardiopulmonary bypass and carries significant risk to the
patient, especially in patients with post-​myocardial infarction A variety of percutaneous devices have been used for VSD
VSDs who are often haemodynamically unstable and whose VSD closure; the following are no longer in general use due to sub-
borders are made of friable tissue and thus may be difficult to optimal performance: Rashkind double umbrella, Bard Clamshell,
suture. Button device, and Gianturco coils [39]. At present, the Amplatzer
Muscular VSD Occluder (St Jude Medical, St. Paul, MN, USA)
Percutaneous VSD closure is the only device specifically approved for VSD closure in many
The use of percutaneous catheter-​based devices has emerged
as a non-​surgical option to treat VSDs in selected patients
[33]. In 1988, the first case of percutaneous VSD closure was
reported; the VSD was closed using a double-​umbrella device
[34]. Currently approved VSD closure devices are indicated in
patients with high surgical risk for percutaneous closures of
congenital VSDs which are located away from the heart valves
(E Fig. 20.8).
Because of design limitations of current VSD closure devices,
Type 4 or congenital muscular VSDs are the principal VSD type
amenable to percutaneous closure (E Fig. 20.9). Post-​infarction
muscular VSD may also be closed percutaneously using these de-
vices in an off-​label manner (E Fig. 20.10) [35]. Furthermore,
percutaneous VSD closure devices have been utilized to close re-
sidual VSDs following prior incomplete surgical closure as well as
(a) (b)
for traumatic or iatrogenic defects occurring after surgical valve
replacements [36, 37].
Fig. 20.9  Percutaneous closure of congenital muscular VSD.
It is important to emphasize that type 2 or perimembranous
Transoesophageal echocardiogram in a mid-​oesophageal view (a) and
VSDs are generally not amenable to transcatheter device closure fluoroscopy (b) demonstrate a cribriform occluder across a congenital
unless surgical intervention is contraindicated due to their ana- muscular VSD.
tomic proximity to the heart valves [38]. Abbreviations: LA = left atrium; LV = left ventricle; RA = right atrium; RV = right ventricle.
294 CHAPTER 20   Tran s sep tal pu nctu re and tr a n s catheter cl o su re of paten t for a m en ova l e
(a)
Fig. 20.10  Percutaneous closure of acquired post-​infarction VSD. Prior to closure, acquired post-​infarction VSD is visualized by 3D TOE in cross section (a) and
en face (b). VSD was subsequently closed using an Amplatzer Muscular VSD Occluder (c).
Abbreviations: LV = left ventricle; RV = right ventricle
parts of the worlds. It consists of two discs of equal diameter sep-
arated by a waist which occludes the VSD. This VSD occluder if
offered in a variety of sizes with a width diameter ranging from 14
to 18 mm. Occasionally, an Amplatzer Cribriform occluder can
be used to close a VSD.
An Amplatzer device with eccentric discs conformation
specifically designed for closure of perimembranous VSDs
(E Fig. 20.11) has been used outside the United States and
Europe [40].
Role of echocardiography in percutaneous
VSD closure
Echocardiography plays an important role before, during, and
following percutaneous VSD closure. Before the closure, both
transthoracic and TOE can establish the presence or absence of
a VSD, define VSD type, determine the size the defect and es-
tablish its haemodynamic significance. 3D echocardiography may
be incremental to 2D echocardiography [41] by providing precise
Fig. 20.11 Percutaneous
closure of perimembranous VSD.
Perimembranous VSD closure device
is visualized on 2D TOE (Panel a; red
circle) and 3D TOE (b, arrow).
Abbreviations: AV = aortic valve; LA = left
atrium; LV = left ventricle; RV = right (a)
ventricle.
(b) (c)
visualization of the size and shape of the defect on unique en face
views of a VSD [42, 43]. Proper VSD sizing is crucial in complica-
tions from undersizing or oversizing a VSD closure device (such
as incomplete VSD closure, complete heart block, or interference
with a heart valve function).
A combined use of fluoroscopy and Intraprocedural TOE is es-
sential for guiding percutaneous VSD closure including visualiza-
tion of catheters, wires, and devices used during the procedure.
Typically, the percutaneous VSD closure requires both arterial
and venous access. After arterial puncture, a catheter is advanced
into the left ventricle in a retrograde fashion through the aortic
valve and its tip placed across the VSD. Thereafter, an antegrade
VSD closure device delivery sheath is brought to the heart via the
inferior vena cava after a venous puncture. Using techniques of
guidewire snaring and exteriorizing to form an arteriovenous
loop, the closure device is then positioned across the VSD from
the right ventricular side. The distal disc of the closure device is
opened first and positioned on the left ventricular aspect of the
(b)
 Pa r ava lvu l a r l ea k c l o sure 295

VSD. Afterwards, the proximal disc of the device is deployed chamber sizes, and function. Normal washing jets seen with
along the right ventricular side of the VSD [44, 45]. mechanical valves should be distinguished from paraprosthetic
Following percutaneous VSD closure, colour, and spectral leaks as washing jets are seen within the confines of the prosthetic
Doppler imaging together with 2D and 3D imaging is used valve ring and along hinge points.
to evaluate procedural success and possible complications. Initial evaluation with TTE, however, can be technically chal-
Successful VSD closure is characterized by a complete absence lenging due to partial or complete masking of the regurgitant
of any flow around the device between the VSD rims and the jets from shadowing artefacts, particularly for mitral prostheses
edge of the device (absence of peridevice leak). In contrast, small as compared to aortic prostheses [53]. Haemodynamic clues
amounts of colour Doppler flow through the device are normal like an abnormally or newly increased gradient across a pros-
and will resolve over time following device endothelialization. thesis in the absence of stenosis should raise suspicion of masked
regurgitation.
Some of these issues are circumvented by the use of TOE,
Paravalvular leak closure as the left atrium becomes the near field structure, thus al-
lowing better visualization of the mitral prosthetic leaks [54].
Prevalence Therefore, when clinical suspicion is high, further evaluation
Paravalvular leak (PVL) is defined as an abnormal communi- with TOE should be performed. It is important to recognize,
cation between the sewing ring of a surgical or transcatheter however, that for aortic prostheses, the anterior annulus will
valvular prosthesis and the native annulus [46]. Significant be located in the far field. As such, acoustic shadowing from
paravalvular leak is a serious, albeit infrequent, complication post the posterior ring may limit assessment of the anterior annulus.
prosthetic valve implantation. Incidences of 2–​10% in the aortic This limitation makes TTE superior to TOE for imaging the
position and 7–​17% in the mitral position have been reported anterior aortic annulus.
[47]. A majority (74%) of these leaks occur within the first year of PVL assessment requires an integrative approach using two-​
valve implantation [48]. dimensional (2D), 3-​dimensional (3D), and Doppler echocar-
diographic parameters (E Fig. 20.12). First and foremost, valve
Risk factors integrity and stability should be established by assessing for ex-
cessive rocking motion. An excessive rocking motion of the mi-
PVLs in the aortic position are more common at the supra-​
tral prosthesis compared with the annulus (>15 degrees) suggests
annular rather than at the intra-​annular position. In the mitral
significant dehiscence [55]. In aortic bioprosthesis dehiscence,
position it is more commonly seen with continuous rather than
40–​90% involvement of the annular circumference leads to dis-
interrupted sutures [49]. Mechanical valves carry a greater risk
cordant motion of the adjacent aortic root and native annulus
than bioprosthetic valves. A heavily calcified aortic annulus and
[56]. Large, dehisced areas (>25% of circumferential extent) with
endocarditis have also been associated with increased incidence
unstable prosthesis may warrant surgical rather than percutan-
[50, 51].
eous closure due to risk of device embolization [57].
Clinical presentation/​features Grading paravalvular regurgitation severity can be challen-
ging, particularly as most paraprosthetic jets are eccentric.
The majority of the PVLs are small and benign. Haemodynamically Generally, PVL grading is similar to native valve regurgita-
significant regurgitant lesions generally present with symptoms tion. The Paravalvular Leak Academic Research Consortium
of congestive heart failure, haemolytic anaemia, or infective (PLARC) expert statement recommends a five-​class grading
endocarditis. scheme for assessing PVL severity. These include mild, mild
to moderate, moderate, moderate to severe, and severe [46].
Indications for intervention Various qualitative, semi-​quantitative, and quantitative param-
Per 2014 ACC/​AHA valve guidelines, percutaneous repair of eters are used for severity grading. Commonly used parameters
paravalvular regurgitation is reasonable in patients with pros- for mitral prosthesis include jet width at its origin, jet density,
thetic heart valves and intractable haemolysis or in patients with pulmonary vein flow pattern and proximal flow convergence
New York Heart Association class III/​IV heart failure who are (E Fig. 20.13). Proximal isovelocity surface area (PISA) as-
deemed high risk for surgery and when the PVLs have anatomic sessment has not been validated in the setting of PVL, how-
features suitable for catheter-​based therapy when performed in ever the presence of prominent flow convergence is suggestive
centres with expertise in the procedure [52]. of significant regurgitation [54]. Presence of holosystolic retro-
grade flow in the pulmonary veins is a specific sign of severe
Evaluation and procedural guidance mitral regurgitation (MR) [53]. Circumferential extent of PVL
Echocardiography plays a major role not only in the initial helps in grading with <5% suggestive of mild, 10 to <20% mod-
evaluation but also in intraprocedural guidance and long-​term erate, and >30% severe MR. Similarly, for aortic prostheses,
follow-​up. Transthoracic echocardiography (TTE) provides parameters like jet density, pressure half time, presence of
a comprehensive assessment of the prosthetic valve, cardiac multiple jets, percent left ventricular outflow tract diameter
296 CHAPTER 20   Tran s sep tal pu nctu re and tr a n s catheter cl o su re of paten t for a m en ova l e

(a) (b) (c)

(d) (e) (f)

Fig. 20.12  Multiwindow two-​dimensional colour Doppler assessment allows comprehensive evaluation of paravalvular regurgitation. Mitral valve
(bioprosthetic) paravalvular regurgitation at different omniplanes: (a) at 0 degrees; (b) at 30 degrees; (c) at 60 degrees; (d) at 90 degrees; and (e) at 120 degrees.
Note that paravalvular regurgitation origin is not well visualized at 0 and 30 degrees. Regurgitation jet is noted along the posterior left atrial wall (a, b). At 60, 90,
and 120 degrees, regurgitation jet origin is noted outside the sewing ring (c, d, e). Figure 20.1f is a three-​dimensional surgical view of the mitral valve. Note the
paravalvular regurgitation jet at 5 o’clock position (white arrow)

occupied by the regurgitant jet, diastolic flow reversal in the
descending aorta and circumferential extent of PVL help define
the grade of AR.
3D TOE is especially helpful in precise localization and quan-
tification of the paravalvular leaks. An en face or surgeon’s view
of the mitral prosthesis provides the exact location and number
of dehisced areas. The en face mitral valve view improves com-
munication between the imager and the interventionalist during
percutaneous closure of a PVL. By convention, a 3D mitral valve
data set is acquired and rotated in such a manner that the aortic
valve is positioned at 12 o’clock position, left atrial appendage
at 9 o’clock and the interatrial septum at 3 o’clock. PVL occurs
more frequently at antero-​lateral (between 10 and 11 o’clock) and
postero-​medial segments (5 and 6 o’clock) of the mitral valve an-
nulus [58]. Dehisced areas can be seen as areas of echo drop-​out
adjacent to the sewing ring or valve struts (E Fig. 20.14). Colour
Doppler imaging should always be utilized to confirm the pres-
ence of true dehiscence [53].
A similar clock format is utilized for aortic prostheses leaks
with 5 o’clock pointing between left and right coronary sinus, 8
o’clock between right and non-​coronary sinus and 11 o’clock be-
tween non-​coronary and left coronary sinus [59]. Aortic PVLs are

(a) (b)

(c) (d)

Fig. 20.13  Paravalvular regurgitation

parameters indicative of significant
regurgitation. (a) Dense spectral
Doppler envelope. (b) Systolic reversal
of flow in pulmonary vein. (c) Large
proximal flow convergence (white
arrow). (d) Vena contracta width ≥7
mm (white double arrow).
 Pa r ava lvu l a r l ea k c l o sure 297

(a) (b)

Fig. 20.14  (a) Three-​dimensional

surgical view of a bioprosthetic mitral
valve. Note the echo drop-​out area
at 5 o’clock position (white arrow).
Presence of a potentially dehisced
area should be confirmed with colour
mapping. (b) Regurgitation jet at the
same position (5 o’clock) with colour
Doppler imaging, thereby confirming
a paravalvular leak.
(b)
most commonly seen between 7 and 11 o’clock (adjacent to the retrograde [60]. More than one device may be needed for large
non-​coronary cusp) [60]. sized defects [62].
Direct planimetry of dehisced areas can be done using 3D The advent of transcatheter therapies has obviated the need of
colour volume datasets. 3D colour effective regurgitant orifice surgical correction of severe PVLs. 3D TEE plays a major role in
(ERO) has shown better correlation with the degree of PVL intraprocedural guidance of wires and catheters and in evaluating
when compared to anatomic ERO. 3D colour ERO major diam- post procedural success (E Fig. 20.15). The transcatheter PVL
eter >0.65 cm is consistent with degree III and IV paravalvular closure is performed via transseptal, retrograde transaortic or
regurgitation [61]. Direct planimetry is sometimes limited retrograde transapical routes. The preferred approach depends on
when there are small and slit like regurgitant orifices due to the valve involved, type of valve, i.e. bioprosthetic vs. mechanical,
resolution limitations. Accurate sizing of the defects is of para- vascular access factors, location of the paravalvular leak, and im-
mount importance to help determine not only the type, size portantly, operator’s experience [63].
and number of closure devices used but also in selecting the When the antegrade approach is selected for mitral PVLs,
optimal access route whether it be transseptal, transapical or TOE is used to guide optimal transseptal puncture to avoid

(b)
(a) (b) (c)

(d)

Fig. 20.15  (a) Fluoroscopy image with guidewire across the paravalvular leak. (b) Corresponding three-​dimensional image of a bioprosthetic mitral valve from
the left atrial perspective. A guidewire is visualized across the paravalvular lesion at 5 o’clock. (c) Left ventricular perspective of Figure 20.4b. (d) Two AVP II
occluders in place with mild residual regurgitation.
298 CHAPTER 20   Tran s sep tal pu nctu re and tr a n s catheter cl o su re of paten t for a m en ova l e
puncturing adjacent structures like the aorta and posterior left
atrial wall. For medial/​septal paraprosthetic leaks, a more pos-
terior septal puncture is preferred to provide more working
space for manoeuvring catheters and wires. For other mitral
lesions, precise puncture site is of less importance [64]. The
transapical route is preferred in septal/​medial paraprosthetic
mitral leaks where the transeptal approach may be challenging.
The transapical route provides direct access to the valves and
is safe with careful preprocedural computed tomography (CT)
planning. The majority of aortic PVL closures are performed
using a retrograde transaortic approach. During an antegrade
approach, an arteriovenous rail can be established to increase
the stability of the catheter system [64].
For PVL device sizing, measuring the length and diameter of
the defect is key to optimal device selection. For example, the
Amplatzer septal occluder (ASO) device (which has a smaller
waist length) is preferred for shorter defects whereas devices
like the Amplatzer Muscular VSD Occluder and the Amplatzer
Duct Occluder with comparatively longer waist lengths are better
suited for longer defects. Maximum device disc size is determined
by the distance of the PVL from adjacent valve struts or leaflets
ensuring there is no device overhang or interference with valve
function [65]. Mitral PVLs are commonly crescentic or oblong
with serpiginous tracks [64]. Percutaneous intervention on these
defects with circular occluders is a challenge as large devices may
impinge on the prosthetic valve. This can be overcome by using
multiple smaller devices [63].
During device deployment, 3D TOE facilitates proper posi-
tioning and orientation of the occluder device [66]. Careful
assessment should be made of the prosthetic valve function en-
suring there is no device overhang and there is no impediment
to valve function. Device release should be done once optimal
device seating and prosthetic valve function is confirmed. Post
device deployment, a comprehensive TOE exam should be done
(a) (b)
Fig. 20.16  Three-​dimensional surgical view of a bioprosthetic mitral valve. (a) A large area of paravalvular regurgitation extending from 8 o’clock position to
11 o’clock position. (b) Two side by side AVP II occluders in place. (c) Residual regurgitation at 8 o’clock position (white arrow). (Patient proceeded to have
additional devices.)
to assess residual PVL (E Fig. 20.16). Depending upon the de-
gree of residual PVL, additional devices can be placed without
affecting prosthetic valve function. After successful deployment
of the occluders, catheters, and wires are withdrawn carefully
under TOE guidance. Upon completion of the procedure, pos-
sible complications like pericardial effusion, intracardiac clots
and intracardiac shunt (if transseptal approach) should be
excluded.
Other imaging modalities
Computed tomography (CT)
A thorough understanding of PVL anatomy ensures success of
PVL closure. With its superior spatial resolution, ECG gated CT
angiography (CTA) with 4D reconstruction techniques is widely
utilized for PVL evaluation (E Fig. 20.17). In addition to pro-
viding detailed information on PVL location, size, and shape, it
also helps with interventional planning for percutaneous PVL
closure. CT can be used to capture the full anatomical extent of
PVLs, particularly those with complicated serpiginous tracts. It
is also used to delineate the distance of the lesion from coronary
ostia and to determine optimal fluoroscopic angles for crossing
the defect [67]. Dense calcifications and prosthetic valves can
create artefacts, however, which may limit PVL size assessment
by CTA [63]. CTA requires radiation and the administration of
intravenous iodinated contrast with the attendant risks. Benefits
of obtaining diagnostic information should be weighed against
these risks especially in more vulnerable population like fe-
males, young patients, and those with renal insufficiency.
Cardiovascular magnetic resonance imaging (CMR)
Evaluating paravalvular regurgitation by echocardiography has
its own challenges as discussed previously. CMR may be useful
for quantifying the severity of regurgitant lesions in the presence
of multiple or eccentric jets. Regurgitant volume and regurgitant
(c)

(a) (b)
fraction (RF) are calculated by quantifying forward and backward
flow using phase contrast velocity mapping technique. There is
low intraobserver and interobserver variability with CMR quan-
tification [68]. Residual more than mild aortic regurgitation (AR)
following transcatheter aortic valve replacement (TAVR) has
been associated with worse outcomes [69, 70]. Rebeiro et al. used
CMR to quantify AR post TAVR and reported ≥30% RF a pre-
dictor of poorer clinical outcomes [71].
Fusion imaging
There has been a great deal of interest in fusion hybrid imaging.
Structural heart interventional procedures are mainly guided by
fluoroscopy that projects 2D information of complex 3D cardio-
vascular anatomy. Real-​time TOE provides the needed 3D spatial
information for optimal guidance of various percutaneous inter-
ventions. Traditionally, the structural interventionalist receives
information from these two modalities separately and mentally
(a) (b)
Pa r ava lvu l a r l ea k c l o sure 299
Fig. 20.17  3D Transoesophageal
echocardiography (a) and computed
tomography angiography (CTA) with
3D reconstruction (b) reveals a large
mitral paravalvular leak extending
from 1 o’ clock to 4 o’ clock position
(white arrow). Measurements of
length, width, and area are used to
determine device size.
synthesizes them together to carry out the procedure. Fusion
imaging allows for the integrated projection of relevant ana-
tomical information from different modalities like CTA (CTA-​
fluoroscopy fusion) and echocardiography (echo-​ fluoroscopy
fusion). Early clinical experiences have shown fusion imaging to
improve procedure efficacy and safety while reducing radiation
exposure, contrast usage and overall procedural time [72–​74].
Percutaneous closure of PVL is performed using transseptal,
retrograde transaortic and transapical approaches. Precision in
transseptal puncture (TSP) is critical in certain procedures. For
medial/​septal paraprosthetic leaks where a more posterior punc-
ture is preferred, placement of fusion markers on fluoroscopic
images may facilitate a more precise positioning of the transseptal
needle [75]. CTA-​fluoroscopy fusion guided transapical access
has been shown to help maintain an adequate and safe distance
from coronary vasculature, thereby reducing access related com-
plications [72] (E Fig. 20.18).
Fig. 20.18  (a) Computed
tomographic reconstructed image
identifying the paravalvular leak
(white arrow) and important
landmarks for transapical access
(arrowhead); (b) CT images are
co-​registered with fluoroscopy (CT
overlay) allowing integration of 3D
anatomical information with planar
fluoroscopy.
Picture courtesy of V. Jelnin (with
permission).
300 CHAPTER 20   Tran s sep tal pu nctu re and tr a n s catheter cl o su re of paten t for a m en ova l e
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 CHAPTER 21

Imaging for
electrophysiological
procedures
Louisa O’Neill, Iain Sim, John Whitaker,
Steven Williams, Henry Chubb,
Pál Maurovich-​Horvat, Mark O’Neill,
and Reza Razavi

Contents
Introduction  303
Introduction
Echocardiography  303 Electrophysiology is one of the most rapidly growing area of cardiology. Currently >50,000
Cardiac MRI  303 catheter ablations are performed in Europe every year and >200,000 patients receive a de-
CMR for evaluation of ventricular vice for arrhythmia treatment, sudden death prevention, or cardiac resynchronization.
arrhythmias  303
Technical approach  304 The advantages and limitations of fluoroscopy are well known. The rapid development
Clinical applications  305 of implantable cardiac devices therapies and ablation procedures all depend on accurate
Challenges  306
and reliable imaging modalities for preprocedural assessments, intraprocedural guid-
CMR for evaluation of atrial
arrhythmias  306 ance, detection of complications, and post-​procedural assessment for the longitudinal
Technical approach  306 follow-​up of patients. Therefore, over the last decades, imaging become an integral part
Application of CMR in patients with atrial of electrophysiological procedures.
fibrillation  307
Challenges  307
Real-​time CMR guidance of
electrophysiology (EP) procedures  308
Cardiac CT  308
Echocardiography
Preprocedural CT imaging  310
Post-​procedural CT imaging  311
Specific technical introduction (short)
Preprocedural imaging
Procedural imaging
Post-​procedural imaging

Cardiac MRI
Cardiovascular magnetic resonance (CMR) imaging is the reference standard non-​
invasive technique for assessment of cardiac chamber volumes, systolic function, and
tissue characterization. These advantages have established a key adjunctive role for CMR
in the planning, guidance, and follow-​up of electrophysiology ablation procedures.

CMR for evaluation of ventricular arrhythmias

In patients at risk of or with documented ventricular arrhythmias (VA) non-​invasive
imaging is a critical part of their assessment. A CMR study in an arrhythmia patient should
include the assessment of left ventricular ejection fraction (LVEF) and myocardial tissue
304 CHAPTER 21   Im aging f or elect roph ysiol o g i ca l pro cedu res

characterization, as well as specific assessments for conditions as-
sociated with arrhythmias such as hypertrophic cardiomyopathy
(HCM) and arrhythmogenic right ventricular cardiomyopathy
(ARVC) where indicated. Ventricular late gadolinium-​enhanced
(LGE)-​CMR is the most widely used tissue characterization ap-
plication for ventricular myocardium and its key strength is the
accurate identification and quantification of myocardial scar [1]‌.
There is also growing interest in the use of quantitative tissue
characterization in the field of arrhythmia, within which T1 map-
ping has been most widely used [2].
Technical approach
Ventricular scar assessment is usually performed at 1.5 T or 3 T, each
with specific strengths and challenges associated with acquisition
[3]‌, and is most commonly performed using a late post-​contrast
(i.e. LGE) inversion recovery sequence [4] to generate traditional
‘white-​blood’ scar images [5], as shown in E Figure 21.1.
Two challenges in using standard LGE imaging for assessment
and guidance of ventricular arrhythmia procedures are the need
for 3D coverage of the ventricle and accurate visualization of the
endocardial border. Although Early studies in patients with ar-
rhythmias used two-​dimensional LGE imaging to define scar,
more recently with the development of robust 3D LGE sequences
[6]‌, these are now generally preferred because of the possibility
for improved registration with 3D electro-​anatomical mapping
(EAM) data [6]. For improved endocardial visualization, the
use of black-​blood scar imaging techniques, which typically use
a modified inversion recovery sequence, for example incorpor-
ating an additional T2 preparation pulse [7, 8], may be particu-
larly helpful.
A major challenge restricting the use of CMR in a large pro-
portion of VA patients is the presence of cardiac implantable elec-
trical devices (CIED). While not affecting the preimplant patient
selection assessment, the majority of patients requiring invasive
treatment of VA have CIED. If appropriate safety procedures are
followed, the safety of CMR in patients with simple pacemakers
[9]‌and Implantable cardioverter-​defibrillators (ICDs) [10] has
now been established, however achieving adequate image quality
in patients with CIED remains challenging. New techniques
including wide band CMR [11] may facilitate improved imaging

Fig. 21.1  Examples of LGE imaging, in this case used in a segmentation challenge. Top row shows clinical LGE imaging with arrows indicating areas of
enhancement corresponding to infarct. Bottom row shows imaging from an experimental model of myocardial infarction.
Reproduced from Karim R, Bhagirath P, Claus P, et al. Evaluation of state-​of-​the-​art segmentation algorithms for left ventricle infarct from late Gadolinium enhancement MR images.
Med Image Anal. 2016;30:95–​107. doi:10.1016/​j.media.2016.01.004 with permission from Elsevier (http://​creativecommons.org/​licenses/​by/​4.0/​).
 CM R for eva luati on of ven tri cu l a r a rrh y t h m ias
in patients with CIED, however at present the precise and ac-
curate anatomical assessment of substrate is frequently very diffi-
cult to achieve using standard sequences.
Clinical applications
Diagnostic refinement
Current guidelines recommend the use of CMR in patients with
VA as second line investigation after echocardiography (level of
evidence IIa) in patients with suspected structural heart disease
and note the particular value of CMR in the identification of con-
ditions such as HCM and ARVC [12, 13]. Furthermore, there is
evidence that the routine use of CMR alongside other standard
investigations including coronary angiography and echocardi-
ography in patients with documented VA can be of incremental
diagnostic value, where it may identify a structural cause in up
to a third of patients, and resulted in modification of treatment
in 12% [14]. The value appears greatest in those patients with VA
who are not previously known to have structural heart disease
(SHD) and those with sustained ventricular tachycardia (VT) or
aborted sudden cardiac death (SCD), in which the proportion of
patients that CMR identified a structural cause was 43% and 55%,
respectively [14].
Patient selection for cardiac implantable
electrical device
A key intervention in the field of electrophysiology is the implant-
ation of CIEDs, which includes ICD and cardiac resynchronization
therapy devices (CRT). When used as a primary prevention
strategy, ICDs reduce the incidence of SCD [15–​18] and improve
medium-​and long-​term mortality [19, 20]. The key assessment
that informs a decision to offer implantation of a prophylactic
CIED is the risk of SCD in an individual and their overall prog-
nosis, and CMR offers valuable information that is contributory
to this assessment [21]. In current guidelines, the most important
non-​invasive risk stratification used is LVEF [12, 22, 23], which
is normally evaluated by echocardiography, although there is
good evidence that CMR provides increased accuracy [24]. Most
common CMR method to measure LVEF is a stack of short-​axis
two-​dimensional balanced steady-​state free precession (bSSFP)
cine images to assess cardiac chamber volumes throughout the
cardiac cycle [25]. The use of bSSFP imaging has demonstrated
excellent correlation with tissue mass [26] and demonstrates less
variability than echocardiographic measurements [24], and as a
result, although results are not strictly interchangeable, in current
practice left ventricular (LV) function assessment using CMR is
often preferred.
The presence of ventricular scar identified using LGE-​CMR is
associated with increased risk of SCD, recurrent VT, and appro-
priate ICD discharge in patients with impaired LV systolic func-
tion, regardless of aetiology [21, 27].
Native ventricular T1 and extracellular volume mapping may
be of value for the identification of patients with or at risk of VA
(E Fig. 21.2). In patients with non-​ischaemic cardiomyopathy,
global native ventricular T1 is an independent predictor of VA,
305
(a) (b)
Fig. 21.2  (a) Example of an extracellular volume (ECV) map in a chronic
(experimental) infarct. (b) Corresponding dark blood LGE image showing
enhancement in the region of increased ECV.
Reproduced from Whitaker J, Tschabrunn CM, Jang J, et al. Cardiac MR Characterization
of left ventricular remodeling in a swine model of infarct followed by reperfusion
[published online ahead of print, 2018 Mar 9]. J Magn Reson Imaging. 2018;10.1002/​
jmri.26005. doi:10.1002/​jmri.26005 with permission from John Wiley and Sons.
even after correcting for LVEF and the presence of LGE [28].
Parametric mapping may be of particular value in specific con-
ditions associated with diffuse myocardial fibrosis, including
neuromuscular disease, such as Duchenne’s and Becker’s mus-
cular dystrophy, in which an elevated native T1 is associated
with adverse outcome including ventricular arrhythmia [29] and
HCM, in which an increased extracellular volume (ECV) (as well
as septal thickness) was independently associated with VA [30].
Other global ventricular characteristics on in-​vivo CMR imaging
have been identified as being associated with an increased ar-
rhythmia risk including LV shape [31] and myocardial fibrosis
texture [32], quantified as ‘entropy’ [33].
While the use of LGE, parametric mapping, and other novel
parameters assessed using CMR have shown an association with
ventricular arrhythmia in observational studies [34], they have
not as yet been incorporated into guidelines for patient selection
for ICD. However, there is widespread acknowledgement that the
sole use of LVEF to risk stratify patients is inadequate [35], with
the majority of SCD occurring in patients who do not meet cur-
rent criteria for prophylactic ICD implantation. Therefore, it may
be hoped that more sophisticated risk assessments incorporating
novel parameters will be assessed in randomized controlled trials
(RCTs) and may then contribute to the development of more ac-
curate risk stratification models for patient selection for prophy-
lactic CIED to reduce the incidence of SCD.
Relationship between electrophysiological
characteristics and CMR derived anatomical substrate
The strong relationship between the presence and character-
istics of scar on LGE-​CMR and outcomes associated with VA
has prompted consideration of the mechanisms underlying
the predisposition to arrhythmia that are identified by these
306 CHAPTER 21   Im aging f or elect roph ysiol o g i ca l pro cedu res
global structural features, and suggested the association of spe-
cific electrophysiological properties that are proposed to be
arrhythmogenic with local imaging features [36]. Subsequent
studies have considered the relationship between local tissue
characteristics and specific components of electrophysiologic-
ally defined re-​entrant VT circuits. A number of retrospective
studies have compared electrophysiological characteristics to
local imaging features and have shown that critical isthmus
sites of clinical VTs tend to localize to areas of LGE-​CMR de-
fined scar and the transition to normal tissue, the border-​zone
(BZ) [36–​ 38]. LGE-​ CMR appears to identify electrophysio-
logical surrogates for arrhythmogenic tissue with good specifi-
city [38], but modest sensitivity, with approximately 50% of the
‘conducting channels’ identified on EAM not being visualized
using LGE-​CMR. This relationship appears strongest in patients
with ischaemic cardiomyopathy (ICM) [39], additionally dem-
onstrating that the use of image integration is associated with an
improved long-​term outcome [40].
Image integration to guide electrophysiological
ablation procedures
The use of preprocedural LGE-​CMR to localize arrhythmogenic
substrate prior to clinical VT ablation has been demonstrated to
be associated with improved procedural outcomes in idiopathic
dilated cardiomyopathy (DCM) through localization of mid-​
myocardial substrate requiring longer ablation delivery [41] and
has been proposed as a preprocedural tool to identify the need for
first-​line epicardial access at the time of ablation [42].
The demonstration of the accuracy of localization of
arrhythmogenic substrate and the relationship between imaging
and electrophysiological features prompted trials integrating
CMR imaging information to guide the delivery of therapy
during electrophysiological ablation procedures. In a series of 159
patients, subjects were randomized to have preprocedural LGE-​
CMR imaging incorporated into the EAM prior to VT ablation
or for VT ablation to be carried out without image integration.
In this study the group in whom image integration was incorpor-
ated had lower rates of radiofrequency (RF) delivery and a higher
rate of non-​inducibility at the end of the procedure, a result that
appeared to be explained by the superior identification of areas
of substrate, resulting in more focused and effective RF delivery.
Despite the reported success of this approach, it should be noted
that in this report approximately one in five of CMRs were un-
usable and participants with a prior ICD implant were ineligible
for this study, representing a significant limitation to the gen-
eralisability of this technique to the patient population most at
risk of VT [43]. The results from this study raised the possibility
that high-​resolution LGE-​CMR may be helpful to assist with the
identification of arrhythmogenic substrate, and its use in this way
may complement the EAM by allowing the operator to identify
important regions to focus attention on. At present, the avail-
ability of LGE-​CMR as well as the expertise required to acquire,
incorporate and apply imaging information during a clinical VT
ablation procedure as well as the absence of a robust demonstra-
tion of the reproducibility of imaging and image-​incorporation
techniques has limited the widespread adoption of such a strategy
beyond a small number of centres.
Challenges
Registration
The registration of electrophysiology and imaging data represents
a major challenge when attempting to establish the structural
basis for observed electrophysiological phenomena. Change in
the shape of the LV during electrophysiology procedures due to
differences in the loading conditions in comparison to the time of
the CMR represents an additional challenge, as do absolute limita-
tions in the accuracy of the localization of electrogram signals due
to catheter-​tissue contact and the presence of far field effects. The
degree to which registration error affects the accuracy of results
is difficult to quantify and is not accurately described by surface
distance between EAM systems and imaging data. Registration
therefore represents an unsolved challenge to extensive uptake of
image guidance during VT ablation procedures.
CMR for evaluation of atrial
arrhythmias
Dedicated imaging of the atria, and in particular the left atrium,
plays an increasing role in substrate characterization for patients
with atrial fibrillation. A CMR study of the left atrium should
include an assessment of left atrial volume in end-​systole and
end-​diastole, ejection fraction, and pulmonary vein anatomy. In
addition, over the last decade the potential of LGE-​CMR to de-
lineate and quantify native atrial fibrosis and post-​ablation atrial
scarring has been demonstrated, and atrial CMR imaging is now
used routinely as part of pre and post-​ablation assessment in
many centres.
CMR remains the only available technique for non-​invasive
assessment of atrial fibrosis, Atrial fibrosis has been identified
histologically in patients with atrial fibrillation (AF) [44] and in
those with risk factors for AF [45, 46] and is a key component
of structural remodelling in AF. However, strong histological evi-
dence linking atrial fibrosis to gadolinium enhancement is cur-
rently lacking [47].
Despite this, several studies have shown a correlation between
LGE and low bipolar voltage amplitude, a common surrogate for
fibrosis. Areas of scar identified by late enhancement imaging
show lower voltage compared to non-​scar regions and LGE de-
tects areas of low voltage (<0.5mV) with a high sensitivity (84%),
though with a lower specificity (68%) [48].
Technical approach
Assessment of left atrial volumes is made using a standard bSSFP,
cine imaging sequence, with slices planned to include the left
atrium. While acquisition of 3D atrial sequences varies slightly
between centres in terms of certain scanning parameters in
general the following acquisition protocol is adhered to. First,
a 3D MR angiography (MRA) sequence, in axial orientation, is

acquired after bolus or infusion of gadolinium-​based contrast
(generally 0.1–​0.2 mmol/​kg). After 15–​30 minutes, a 3D, elec-
trocardiograph (ECG) triggered, respiratory navigated inversion
recovery sequence of the atria is the acquired in axial orientation
with scan parameters and coverage as for the MRA. The optimal
inversion time (TI) is determined from a preceding ‘TI scout’ or
‘Look locker’ sequence with the TI set to nullify the signal from
ventricular myocardium. Slice thickness and in plane resolution
differ between centres and scan times are on average 10–​15 mins
depending on heart rate and breathing patterns.
In order to quantify fibrotic tissue from LGE-​CMR images,
software platforms allowing segmentation of the anatomical
structure of the atrial wall and subsequent detection of fibrotic
regions within the wall are required. This has limited the applica-
tion of this technique to a small number of centres with specialist
CMR capabilities [49–​51]. However, either through provision of
core lab facilities or by centres making their software available,
there have been a number of multicentre studies carried out to
evaluate LGE-​CMR of the LA in AF [52].
T1 mapping has emerged as an alternative imaging technique
to assess atrial fibrosis. As a quantitative technique, native and
post-​contrast T1 mapping offers theoretical advantages over LGE-​
CMR imaging. Decreasing T1 relaxation times have been shown
to be strongly associated with decreasing myocardial voltage, the
presence and duration of AF as well as the risk of recurrence post-​
ablation [53]. Native T1 mapping prior to contrast administra-
tion offers obvious advantages over standard LGE sequences, by
avoiding confounding factors such as haematocrit variations and
time delays post-​contrast injection and can be implemented even
in those with severe renal impairment. Nevertheless, this tech-
nique has not yet been widely adopted.
Application of CMR in patients with atrial
fibrillation
Patient selection for AF ablation
Native atrial fibrosis is associated with disease severity in AF and
has emerged as one of the strongest predictors of outcome fol-
lowing AF ablation. The Utah fibrosis score classifies native left
atrial fibrosis into categories of severity depending on the per-
centage fibrosis in the left atrial wall on LGE-​CMR (minimal
(<5%), mild (5–​20%), moderate (20–​35%), and severe (>35%))
[54] and subsequent studies have demonstrated a strong associ-
ation between severity of fibrosis and the likelihood of arrhythmia
recurrence using this and other scoring systems. The DECAAF
study, a prospective multicentre observational study across 15
countries echoed these findings and identified a significant asso-
ciation between atrial LGE on LGE-​CMR, and likelihood of re-
current arrhythmia, with risk of recurrence increasing according
to Utah stage [52, 55]. As such, by identifying those patients most
likely to benefit from atrial fibrillation ablation, this imaging
strategy can help guide patient selection and may help guide the
ablation strategy itself whereby a more extensive ablation beyond
pulmonary vein isolation (PVI) alone could be applied to those
with more extensive preablation fibrosis on CMR imaging [56].
CM R for eva luati on of atria l a rrh y t h m ias 307
Additionally, parameters of left atrial systolic and diastolic
function, as assessed by MRI have been shown to be predictive
of outcome and may help guide patient selection (E Fig. 21.3).
The left atrial stiffness index, a surrogate of diastolic function de-
rived from invasive pressure and CMR volumetric measures of
the LA, is associated with increasing age and disease severity in
AF as well as recurrence post-​ablation [57]. Furthermore, CMR
measurements of LA emptying fraction and strain rates have been
found to be significantly associated with outcome with lower LA
emptying fractions and strain rates seen in those patients with re-
current arrhythmia [58].
Procedure planning
In addition to tissue characterization from atrial LGE-​ CMR
imaging, contrast-​enhanced MR angiography of the atria pro-
vides detailed anatomical information and is a useful tool for pul-
monary vein delineation prior to the ablation procedure. Similar
to cardiac computed tomography (CT), this sequence can identify
variations in pulmonary venous anatomy in advance of the pro-
cedure and can be merged with contemporary EA mapping sys-
tems to guide the operator intraprocedurally.
Post-​ablation detection of gaps and outcome
prediction
LGE-​CMR is an established and reproducible tool in the as-
sessment of post-​ablation atrial scar formation [50, 59]. The re-
lationship between AF recurrence and the extent of atrial LGE
post-​ablation has been previously explored with higher recur-
rence rates reported in those with less post-​ablation left atrial wall
enhancement, consistent with less ablation injury. Arrhythmia
recurrence post-​ablation is often attributed to electrically con-
ducting gaps in ablation lesion sets representing failure of for-
mation of durable, transmural lesions [60]. LGE-​CMR has also
been applied to the post-​ablation assessment of ablation lesion
gaps, however conflicting results exist in terms of the ability of
this technique to accurately identify the sites of electrically con-
ducting gaps at repeat procedure [61–​63]. While the extent of
pulmonary vein scarring appears to predict success, the use of
LGE-​CMR to guide further ablation has not yet been adopted
into routine clinical practice.
Challenges
Despite its introduction over a decade ago [64], clinical imple-
mentation of LGE-​CMR evaluation of the atria has not become
widespread. This is in part due to concerns over the reproduci-
bility and transparency of image processing techniques. Highly
variable descriptions of the reproducibility of CMR LGE as a tool
for atrial fibrosis assessment exist. Some centres describe almost
perfect agreement between observers [65–​67] whereas others re-
port poor agreement both between observers and between scans
[68]. Further, it has also been shown that varying the threshold at
which signal intensity is described as fibrosis significantly affects
scan reproducibility [69]. Sources of variation may originate from
different imaging parameters, observer experience, and software
platform used.
308 CHAPTER 21   Im aging f or elect roph ysiol o g i ca l pro cedu res
(a)
Fig. 21.3  3D LGE images acquired
using a.15 T MRI scanner. (a) and (b)
show minimal and moderate levels (c)
of atrial fibrosis across the posterior
wall respectively (red arrows). (c)
and (d) show oblique posterior-​
3
anterior (AP) and PA projections of
a left atrium following ablation and
post processing with custom-​made
software (M https://​www.cemrg.
com). (1. Left upper pulmonary
vein, 2. left lower pulmonary vein, 3.
right upper pulmonary vein, 4. right 4 4
lower pulmonary vein, 5. left atrial
appendage, 6. inferior aspect of mitral
valve annulus.)
Real-​time CMR guidance of
electrophysiology (EP) procedures
Many of the strengths of CMR may also be leveraged in the use
of real-​time MR guidance for EP procedures. These advantages
may be delineated in three main domains: detailed assessment of
the arrhythmia substrate, real-​time CMR image-​guided catheter
manipulation, and real-​time titration (or very early evaluation) of
ablation lesion formation [70].
As discussed previously, the arrhythmia substrate may be
amenable to CMR imaging, but the precise targeting of small re-
gions is impaired by the inherent limitations of image registration.
Real-​time CMR guidance virtually eliminates registration errors,
and this could prove essential in optimizing ablation of LGE-​
CMR-​identified substrate such as VT conduction channels (typ-
ically as small as 2 mm wide)[71] or atrial fibrosis, if the ongoing
DECAAF2 trial presents evidence of efficacy. The catheters them-
selves are visualized within the MR scanner using a passive or ac-
tive tracking technique (E Fig. 21.4). In brief, a passive tracking
technique relies upon the contrast in MR signal between the
catheters and surrounding soft tissue to allow the operator to de-
lineate the location of the catheters. Such a technique provides a
clear visualization of the catheter in relation to contiguous struc-
tures, but is often cumbersome and time consuming as catheters
are only visible when they lie within the relatively narrow imaging
plane [72]. Therefore, active tracking techniques have been de-
veloped whereby the catheter contains small micro-​receive coils
(b)
(d)
1
1
5
3
2
6
that are able to detect a location-​specific tracking signal [73]. This
allows the instantaneous calculation of the position of multiple
catheters within 3-​dimensional space, and this can be overlaid
upon a detailed multichamber cardiac roadmap. Finally, lesions
may be visualized during ablation, using techniques such as MR-​
thermometry [74], or immediately following ablation using na-
tive or contrast-​enhanced techniques [75].
At the current time, MR-​guided EP has been performed in clin-
ical trials only for patients with atrial flutter [73, 76].
The vast majority of cases have been performed using active
tracking catheters, with a high degree of safety and improving ef-
ficacy as the learning curve associated with the completely new
technology evolves. In the longer term, VA may stand to benefit
most from MR-​guided EP, but advances in complementary tech-
nologies such as MR-​conditional 12-​lead ECG and defibrillator
are required [77].
Cardiac CT
Multidetector-​ row computed tomography (MDCT) with its
submillimetre isotropic spatial resolution and fast gantry rota-
tion of less than 270 ms is uniquely suited to image the cardiac
anatomy. Due to the comprehensive information provided by
CT electrophysiologists are increasingly requesting this cross-​
sectional imaging modality to plan procedures and to follow-​
up patients who underwent electrophysiological interventions
[78]. Therefore, the main application of MDCT include pre-​and
 C a rdiac   C T 309

(a) (b) (c)

(d)

Fig. 21.4  Clinical MR-​guided ablation of atrial flutter. Upper panels (a–​c) demonstrate passive tracking of ablation catheter (white arrow) during ablation at the
cavotricuspid isthmus. Lower panel (d) shows the utility of active tracking, with the ablation catheter (red) and pacing catheter (green, within coronary sinus)
delineated by icons on the multiplanar reconstruction (MPR) and electroanatomic map (EAM), complete with activation time mapping.

post-​procedural imaging. The image acquisition techniques vary
depending on the main indication, patient characteristics, and
manufacturer. In general, it is recommended to use modern
scanners with at least 64 slices and ECG-​gated image acquisition
technique. Images are acquired from the carina to the diaphragm
with an inspiratory breath hold. A tube kVp of 70–​120 is used
depending on patient weight and body habitus. In addition, one
should consider the main clinical question when setting up the
image acquisition parameters. Imaging for EP procedures may
not require such a high contrast to noise ratio as coronary CT
angiography (CTA), therefore lower kVp might be sufficient to
image the cardiac chambers. In addition, the lower kVp values
(70–​100 kVp) result in lower effective radiation dose and lower
iodinated contrast material doses due to the increased iodine at-
tenuation. If coronary artery evaluation is of interest oral and/​
or intravenous beta-​blockers are administered to achieve a heart
rate of <65 bpm. Prospective ECG triggering is employed for
patients with sinus rhythm. In patients with higher heart rates
and arrhythmia retrospective ECG-​gating should be considered.
However, with modern CT scanners prospectively ECG triggered
acquisition mode provides excellent image quality even in this
challenging patient population. The optimal contrast injection
310 CHAPTER 21   Im aging f or elect roph ysiol o g i ca l pro cedu res
protocol and image acquisition timing is decided in advance
depending on the clinical question and required anatomic de-
tail. In general, the amount injected contrast material and the
rate of injection is similar to that of coronary CTA and an iodine
delivery rate (IDR) of 2 g/​s provides and optimal opacification
for a scan with 120 kVp. For lower kVp-​s lower IDR values are
sufficient. The left atrium is in general a safe position for placing
the region of interest (ROI) in bolus racking. It can be used both
when assessing the left atrium, pulmonary veins, or the coronary
arteries. When imaging the coronary veins a short delay (3–​5
seconds) should be added to allow opacification of the coronary
sinus and vein. To differentiate between thrombus and contrast
medium (CM) mixing artefact in the appendage, a scan with a
40–​60 s delay should be applied. Recent data suggest that dual en-
ergy image acquisition may facilitate the differentiation between
thrombus and artefacts.
Preprocedural CT imaging
Pulmonary vein isolation is the most common procedure per-
formed in electrophysiology laboratories in today’s practices. It
is an effective and established therapy in patients with atrial fib-
rillation who do not respond adequately to conservative med-
ical therapy. The goal of the ablation procedure is to electrically
isolate the pulmonary veins from the left atrium as a means of
preventing the initiation of atrial fibrillation by ectopic elec-
trical foci. For the isolation of the pulmonary veins a circum-
ferential ablation around the veno-​atrial junction is performed
with a catheter that delivers either heat (radiofrequency) or
cold (cryo) to the atrial tissue to create uninterrupted lines of
scar (E Fig. 21.5). Supplementary ablation lines may also be
performed on the posterior wall and roof of the left atrium, in
the region of the mitral valve annulus, or in the region of the
coronary sinus.
The main application of CT is to evaluate the left atrial anatomy
and dimensions and to assess the pulmonary veins. Identifying
the pulmonary vein and left atrial anatomy variations is critical
(a)
Fig. 21.5  Pulmonary vein isolation using point-​by-​point circumferemcial radiofrequency ablation. The volume rendered CT images provide an anatomical
map for the PVI procedure. Panel A shows posteroanterior view, whereas panel B shows an antero-​posterior view. The white arrows indicate diagnostic Lasso
catheter in the right inferior pulmonary vein, the white arrowheads indicate the ablation catheter in the left common pulmonary trunk. Red dots stand for
ablation points.
LCPT = left common pulmonary trunk; RPVs = right pulmonary veins.
Courtesy of Nandor Szegedi, Semmelweis University, Budapest, Hungary.
to the performance of the pulmonary vein isolation procedure.
The most common alterations are supernumerary pulmonary
vein ostia and common ostia (E Fig. 21.6). The volume ren-
dered reconstructions depicting the complex left atrial and pul-
monary venous anatomy provide important information that
may guide the operator in catheter selection and approach for
the procedure [79, 80].
Left atrial appendage is the most prominent site for left atrial
thrombus formation, especially in patients with AF. While
transoesophageal echocardiography (TOE) remains the gold
standard for the detection of appendage thrombi prior to abla-
tion procedures, several studies have shown an excellent negative
predictive value (98%) of CT. The presence of thrombus in the
left atrial appendage is identified by a low attenuation filling de-
fect. However, if a thrombus is suspected based on an apparent
filling defect, a confirmatory delayed phase can be performed to
distinguish between a genuine thrombus and a pseudothrombus
(due to poor filling of the left atrial appendage (LAA) with con-
trast secondary to venous stasis and/​or poor left atrial function),
E Fig. 21.7. Furthermore, spatial orientation of the left atrium
and the pulmonary veins to the oesophagus can be easily as-
sessed by CT and is beneficial in risk reduction of lethal compli-
cations such as atrio-​oesophageal fistula caused by the ablation
procedure [81].
CT is also of value in assessing the anatomy of the superior vena
cava (SVC) and inferior vena cava; identifying the location and
course of the oesophagus; as well as identifying the fossa ovalis,
and any anomalies that may interfere with transeptal puncture,
such as lipomatous hypertrophy of the interatrial septum.
Both CT and MRI images can be fused with electroanatomic
maps and/​or overlaid onto real-​time fluoroscopic images. The
combination of volume rendered reconstruction of the cardiac
anatomy with electrophysiological information aims to minimize
the radiation exposure to patient and healthcare providers; en-
hance procedural outcomes; shorten procedure times; and min-
imize the potential for procedure-​related complications.
(b)

(a) (b)
Fig. 21.6  The three-​dimensional volume rendered reconstructions of the most common variations of pulmonary vein anatomy. (a) Normal configuration of
pulmonary veins (70%). (b) Left common pulmonary trunk (12.4%). (c) Middle pulmonary vein on the right side (4.6%).
LSPV = left superior pulmonary vein; LIPV = left inferior pulmonary vein; RSPV = right superior pulmonary vein; RIPV = right inferior pulmonary vein; LCPV = left common
pulmonary vein; RMPV = right middle pulmonary vein.
Reproduced from Karády, J., Whitaker, J., Rajani, R. et al. State-​of-​the-​Art CT Imaging of the Left Atrium. Curr Radiol Rep 4, 45 (2016). https://​doi.org/​10.1007/​s40134-​016-​0171-​y with
permission from Springer Nature.
There are many patients with AF in whom anticoagulation is
contraindicated or who continue to have embolic events des-
pite anticoagulant therapy. An alternative treatment strategy in
such patients is percutaneous device-​based occlusion of the left
atrial appendage. The planning and the selection of appropriate
device are based largely on CT imaging, which can provide ac-
curate information on the size and morphology of the left atrial
appendage, presence thrombus, and regarding the dimensions
and position of the left atrial appendage ostium. The presence of
left atrial appendage thrombus is an absolute contraindication to
appendage closure.
Finally, an important and growing indication for CT imaging
is assessing the cardiac morphology in patients with heart failure
or advanced cardiomyopathy by whom ICD or CRT device im-
plantation is planned. Most important information derived by CT
imaging is depiction of the coronary venous anatomy to assist in
lead placement. In addition, the visualization of myocardial scar
can also alter the lead placement strategy. Cardiac MRI is the cur-
rent gold standard in the detection of myocardial scar, however
(a) (b)
Fig. 21.7  The arterial phase CT scan (a) shows contrast filling defect (white
Asterix) in the appendage. The venous phase CT images (b) do not show
the contrast filling defect present, which rules out appendage thrombus.
RIPV: right inferior pulmonary vein; LSPV: right superior pulmonary vein.
C a rdiac   C T 311
(c)
using delayed phase (10–​15 min) imaging CT can also visualize
scar in some extent.
Post-​procedural CT imaging
Pulmonary vein stenosis and oesophageal injury are nowadays
infrequent, yet known and severe complications following cath-
eter ablation procedures. In patients with symptoms suggestive
of pulmonary venous stenosis, CT is a robust modality to assess
the pulmonary venous anatomy. Due to the wide variation in pul-
monary venous anatomy, acquisition of a pre-​procedural scan for
comparison purposes is important especially to detect cases with
only mild-​to-​moderate stenosis that may progress with time. An
incidence of 0.29% is reported, and when severe can cause com-
plete occlusion of the vein with subsequent venous infarction and
pulmonary hypertension (E Fig. 21.8).
Oesophagitis and atrio-​oesophageal fistulae can arise following
ablation of the posterior left atrial wall as the oesophagus des-
cends in the posterior mediastinum and is often separated from
the posterior wall of the LA by a thin fat pad. CT findings of oe-
sophageal injury are similar to those of mediastinitis centred on
the posterior aspect of the LA and may feature stranding of the
mediastinal fat, localized gas locules, or fluid collections. Gas
within the LA confirms the presence of an atrio-​oesophageal
fistula.
Post-​procedural imaging of left atrial appendage occlusion
is helpful to confirm the correct positioning of the device and
evaluate peridevice leakage. The presence of a peridevice gap of
<3 ± 2 mm is generally considered acceptable and not thought to
confer an addition risk of stroke.
Cardiac CT can be of help to determine lead position if perfor-
ation is suspected. However, metal artefacts and sever blooming
artefacts hamper the assessment of the precise location of the lead
tip. In such cases the lead often appears to protrude through the
myocardium by 1–​2 mm. Caution is advised in interpreting such
images, especially when secondary signs of perforation such as
pericardial effusion are absent.
312 CHAPTER 21   Im aging f or elect roph ysiol o g i ca l pro cedu res

(a) (b) (c)

(d) (e) (f)

Fig. 21.8  Left atrial CT angiography of a patient who underwent PVI and developed two-​sided pulmonary vein stenosis. Images of (a) and (d) were acquired
one year after PVI. The ostium of the RSPV shows mild stenosis, whereas the right middle pulmonary vein is occluded (indicated by the blue arrow). Panels
(b) and (e) represent images acquired two years after PVI. Severe stenoses are visible in the ostia of RSPV, RIPV, and LSPV. The LIPV shows moderate luminal
narrowing. Panels (c) and (f) show images acquired one year after stent implantation in the RSPV, RIPV, and LISV. All stents show mild instant restenosis indicated
by white arrowheads.
LSPV = left superior pulmonary vein; LIPV = left inferior pulmonary vein; RSPV = right superior pulmonary vein; RIPV = right inferior pulmonary vein.
Reproduced from Karády, J., Whitaker, J., Rajani, R. et al. State-​of-​the-​Art CT Imaging of the Left Atrium. Curr Radiol Rep 4, 45 (2016). https://​doi.org/​10.1007/​s40134-​016-​0171-​y with
permission from Springer Nature.

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Contents
Introduction  315
Imaging techniques to select patients for
TAVI  316
Imaging for procedural planning  316
Imaging for risk stratification of patients
undergoing TAVI  322
Imaging techniques to guide transcatheter
aortic valve implantation  325
Late follow-​up  327
Future perspective and conclusions  333
CHAPTER 22
Transcatheter aortic valve
implantation
Arnold C.T. Ng, Victoria Delgado, and
Jeroen J. Bax
Introduction
Transcatheter aortic valve implantation (TAVI) is an established therapeutical alter-
native for patients with symptomatic severe aortic stenosis who have contraindica-
tions for surgical aortic valve replacement (SAVR) or patients with intermediate and
high operative risk in whom the heart team considers that TAVI is a better option
than SAVR [1–​4]. Recent clinical trials randomizing patients with symptomatic severe
aortic stenosis and low operative risk to TAVI versus SAVR have shown that TAVI
provides better outcomes in terms of all-​cause mortality, stroke and rehospitalization
at 1 year [5, 6]. While in the initial clinical trials including patients with contraindi-
cations for SAVR or with intermediate and high operative risk the mean age was
above 80 years old, in the trials including patients with low operative risk the mean
age was 72 years old showing for the first time the possibility to extend this therapy
to younger patients with indication for biological valves (current guidelines recom-
mend a biological aortic prosthesis in patients aged 60 years or older) [7, 8]. The
requirements to extend TAVI to younger and lower operative risk populations have
included a performance of the transcatheter aortic valve similar to that of surgical
biological aortic prosthesis (i.e. low transvalvular gradients, low rate of paravalvular
regurgitation, durability), low rate of conduction abnormalities needing permanent
pacemaker implantation as well as allowing the possibility of performing percutan-
eous coronary intervention after the implantation if needed. The manufacturers have
improved the design of the transcatheter valve prostheses and delivery systems to
meet those requirements and enormous effort has been done in order to speed the
learning curve and reach proficient implantation skills across the catheterization la-
boratories. Furthermore, imaging techniques have been pivotal to select patients for
TAVI, accurately size the aortic annulus and select the prosthesis size minimizing
the rate of paravalvular regurgitation or other complications such as coronary artery
ostia occlusion and annulus rupture. The procedure has been significantly simplified
and currently is mostly performed under local anaesthesia using fluoroscopy as the
main imaging technique for guidance. The imaging techniques used in the follow-​up
of these patients have provided new insights into the durability of transcatheter aortic
valves and have led to standardized definitions of structural and haemodynamic de-
terioration of the prostheses [9]‌. This book chapter summarizes the use of imaging
techniques in patients with severe aortic stenosis who will be treated with TAVI, fo-
cusing on the patient selection, procedural guidance, and follow-​up.
316 CHAPTER 22   Tran s cath eter aort ic valve i m pl a n tati on

Table 22.1  Imaging modalities to assess the various relevant variables for prosthesis selection and procedural planning and for risk
stratification of patients

Variable TTE/​TEE CT CMR Fluoroscopy

Relevant to prosthesis (type and size) selection and procedural planning
  Aortic valve anatomy and calcification location ++ +++ ++ –​
  Aortic annulus size + +++ ++ +
  Dimensions of the aortic root and ascending aorta + +++ +++ +
  Height of the coronary ostia + +++ + ++
  Femoral and iliac arteries size –​ +++ –​ +
  Non-​transfemoral accesses + +++ –​ –​
Relevant to risk stratification
  LV and RV function +++ + +++ –​
  Mitral and tricuspid valve regurgitation +++ –​ +++ +
  Coronary artery disease –​ +++ ++ +++
Abbreviations: CMR = cardiovascular magnetic resonance; CT = computed tomography; LV = left ventricular; RV = right ventricular; TEE = transoesophageal echocardiography;
TTE = transthoracic echocardiography.

evaluation of the anatomy of the aortic valve and the differenti-

Imaging techniques to select patients
for TAVI
The main aspects that need to be evaluated in the selection pro-
cess of patients with symptomatic severe aortic stenosis who will
be treated with TAVI and the imaging techniques to be used are
summarized in E Table 22.1. The diagnosis of severe aortic sten-
osis and its challenges are discussed in Chapter 11. Transthoracic
echocardiography (TTE) and computed tomography (CT) are
the main imaging techniques to be used in the selection of the
transcatheter valve prosthesis and procedural planning as well as
in the risk stratification of the patients. In addition, fluoroscopy is
used to assess the presence of significant coronary artery disease
that may need revascularization. Cardiovascular magnetic reson-
ance (CMR) can be performed to assess many of the variables in-
cluded in the prosthesis selection process, procedural planning,
and risk stratification of the patients. However, it is seldom used
due to the time needed to perform it, presence of devices such
as pacemakers that may interfere in the image quality and long
time needed to perform the full protocol of data acquisition and
postprocessing. Nuclear imaging techniques have very minimal
role and are therefore not included in the table.
Imaging for procedural planning
Aortic valve anatomy and calcification location. The trials testing
the safety and efficacy of TAVI, included only patients with tri-
cuspid valve [1–​6]. Subsequently, large registries have demon-
strated that TAVI is also safe in patients with bicuspid aortic valve
[10, 11]. The anatomy of the aortic valve in patients with severe
aortic stenosis can be assessed with TTE in the majority of pa-
tients. However, when the valve is heavily calcified, the fusion of
two cusps due to the degeneration process may challenge the diag-
nosis. Transoesophageal echocardiography (TEE) can improve the
ation between tricuspid and bicuspid valve. However, CT is the
imaging technique that provides the best accuracy to define the
aortic valve anatomy (E Fig. 22.1). In addition, CT permits clear
visualization of the extent and location of the aortic valve calcifi-
cations which have been associated with the risk of paravalvular
regurgitation [12, 13], coronary ostium occlusion [14], or aortic
annulus rupture (E Fig. 22.2) [15].
Aortic annulus size. Accurate assessment of the aortic annulus
dimensions is pivotal to optimize the results of TAVI. Three-​
dimensional imaging techniques are mainstay in the measure-
ment of the aortic annulus since they can visualize the oval shape
of this virtual structure. CT is the technique that provides high
spatial resolution, isotropic data from which the cross-​sectional
area of the aortic annulus can be reconstructed by aligning the
multiplanar reformation planes at the level of the nadir points of
the aortic cusps (E Fig. 22.3). CT data should be acquired with
ECG-​gating and if possible in systolic and diastolic phase. Murphy
et al. [16] showed that measurements of the aortic annulus per-
imeter and area in diastole led to undersizing of the prosthesis in
45% of patients as compared with the measurements performed
in systole. Current available prostheses base the sizing of the pros-
thesis mainly on CT data and the recommendations of the manu-
facturers are summarized in E Table 22.2. Three-​dimensional
TEE can provide good estimates of the aortic annulus area and
perimeter. Several studies have compared the accuracy of 3D
TEE versus CT to measure the aortic annulus and size the pros-
thesis [17, 18]. The majority of the studies have shown that 3D
TEE underestimates the area or perimeter of the aortic annulus
as compared to CT, leading to the selection of smaller prosthesis
size. This is particularly relevant in patients with heavily calci-
fied aortic valves, where the calcium may significantly shadow
the borders of the aortic annulus. However, the use of automated
postprocessing tools that aid in the analysis of the 3D TEE data
 I m ag i n g techn i qu es to sel ect pati ents f or   TAV I 317

TTE TEE CT

Fig. 22.1  Assessment of aortic valve morphology. Examples of bicuspid aortic valve visualized with transthoracic (TTE) or transoesophageal (TEE)
echocardiography and computed tomography (CT). The upper panels show a bicuspid aortic valve with two commissures and two cusps (without raphe). The
lower panels show a bicuspid aortic valve with a fusion raphe between the left and the right coronary cusps (arrow). Note the difficulty to differentiate these
two morphologies with TTE, while TEE and CT provide better resolution.

(a) (c)

(b) (d)

Fig. 22.2  Evaluation of aortic valve

calcification. Calcification burden of
the aortic valve is usually assessed
on non-​contrast-​enhanced CT (a).
On contrast-​enhanced CT, the exact
location of bulky calcifications can
be assessed. Panel (b) shows large
calcification of the aorto-​mitral
continuity. Using commercially
available software (3Mensio, Medical
Pie), automatic segmentation of the
aortic valve cusps can be performed
(c) and the volume of calcification in
each cusp can be quantified (d).
318 CHAPTER 22   Tran s cath eter aort ic valve i m pl a n tati on

(a) (b)

Fig. 22.3  Measurement of the aortic

annulus with computed tomography.
Using proprietary software (3Mensio,
Medical Pie), the centreline through (c)
(d)
the left ventricular outflow tract,
valve and aortic root is automatically
defined on the coronal (a) and sagittal
(b) planes and the aortic annulus
plane is set by marking the nadirs
of the aortic valve leaflets (panel c,
green, yellow, and red dots). Panel (d)
shows the virtual plane on the three-​
dimensional volume rendering. The
perimeter, area, minimum, maximum,
and average diameter of the aortic
annulus can be measured.

and reduce the variability of the measurements has shown that
the agreement between 3D TEE and CT improves significantly
(E Fig. 22.4) [17, 18]. In addition, the acquisition of the 3D TEE
data off-​axis overcomes the limitation of the aortic valve calcifi-
cations leaving the perimeter of the aortic annulus clearly defined
to perform the automated measurements [17]. CMR can also be
used to assess the aortic annulus dimensions [19]. Prespecified
acquisition planes should be set in order to obtain the cross-​
sectional area of the aortic annulus when the data are acquired
from breath-​held cine images. In patients with renal dysfunction
in whom the use of iodinated contrast should be kept to min-
imum, 3D CMR data acquisition with commercially available
navigator-​echo methods such as non-​contrast ECG-​gated steady-​
state free precession magnetic resonance angiography is a good
alternative to CT. This methodology synchronizes respiratory and
cardiac gating for 3D data set acquisition and multiplanar recon-
structions of the aortic annulus can be obtained off-​line similarly
to CT. When 3D imaging modalities are not available, measure-
ment with 2D imaging techniques such as TEE or balloon sizing
and aortography can be used.
Dimensions of the aortic root and ascending aorta. The di-
mensions of the aortic root and ascending aorta are important in
the decision making of patients with severe aortic stenosis candi-
dates to TAVI. In patients with low operative risk and dimensions
of the aortic root and/​or ascending aorta >50 mm, the indication
of SAVR with concomitant aortic root and/​or ascending aorta
replacement may prevail over TAVI [7]‌. In patients with contra-
indications for SAVR or high operative risk, the presence of di-
lated aortic root and/​or ascending aorta does not contraindicate
TAVI. In patients with bicuspid aortic valve stenosis, the pres-
ence of dilated aortic root and/​or ascending aorta is more fre-
quent than in patients with tricuspid aortic valve stenosis. In
addition, it is also common the presence of an horizontal orien-
tation of the aortic root and ascending aorta that may challenge

Table 22.2  Prosthesis sizing according to aortic annulus dimensions

Annular dimension SAPIEN valve size

20 mm 23 mm 26 mm 29 mm
Nominal area (mm2) 328 406 518 661
2
Annular range for SAPIEN 3 (mm ) 273–​345 338–​430 430–​546 540–​683
Annular dimension CoreValve transcatheter valve size
23 mm 26 mm 29 mm 31 mm
Nominal perimeter (mm) 72.24 81.7 91.1 94.5
Perimeter range (mm) 56.5–​62.8 62.8–​72.3 72.3–​84.8 81.7–​91.1
 I m ag i n g techn i qu es to sel ect pati ents f or   TAV I 319

(a) (d)

Fig. 22.4  Measurement of the

aortic annulus on three-​dimensional
transoesophageal echocardiography.
From the three-​dimensional volume
of the left ventricular outflow tract,
aortic valve, and aortic root, the
sagittal (a) and coronal (b) planes are
(b) (c) (f) reconstructed and by aligning the axis
through the nadirs of the aortic cusps,
the cross-​sectional plane of the aortic
annulus is reconstructed (c). In addition,
a 3-​dimensional cast is reconstructed
following the borders of the left
ventricular outflow tract, aortic annulus,
and aortic root (d). The measurements
are provided for the aortic annulus in
a systolic frame. The graph shows the
measurements of the various levels
above and below the aortic annulus
(SAX plane, green dotted line; f).

the co-​axial implantation of the transcatheter aortic valve (E Fig. valve-​in-​valve procedures are performed and when the height
22.5) [20]. In contrast, when the aortic root is small (<30 mm), of the coronary ostia is low) (E Fig. 22.6). CT is the imaging
the risk of potential complications such as occlusion of the cor- technique of first choice to evaluate these aspects. CMR can be
onary ostia should be evaluated (particularly when transcatheter also used.

(a) (b)

Fig. 22.5  Horizontal aorta in bicuspid

aortic valve stenosis. Horizontal aorta
is defined by an acute angle between
the longitudinal axis of the aorta and
the plane that crosses the domes
of the diaphragms (a). In this patient
(c) (d)
with a bicuspid aortic valve (fusion
raphe between the left [LC] and the
right [RC] coronary cusps, arrow)
the angle is 30°. On fluoroscopy, an
horizontal aorta can challenge to
define the plane of deployment of the
transcatheter valve which is defined
by the nadir of the aortic valve cusps
(b). This step is crucial to orient the
transcatheter valve co-​axial to the
plane of implantation (c) and achieve a
successful deployment of the valve (d).
Abbreviations: LC = left coronary cusp;
NC = non-​coronary cusp; RC = right
coronary cusp.
320 CHAPTER 22   Tran s cath eter aort ic valve i m pl a n tati on

(a) (b)

(c) (d)
Fig. 22.6  Transcatheter aortic valve
implantation in narrow aortic root
and ascending aorta. Example of a
patient with bicuspid aortic valve
stenosis and narrow aortic root. At
the level of the sinus of Valsalva, the
dimensions are 28 mm (coronal plane)
and 35 mm (sagittal plane) (a). The
left main (LM) origin is above the
posterior commissure and the risk of
occlusion by the aortic cusp when the
transcatheter valve is implanted is less
(b). Plane (c) shows the fluoroscopic
view that corresponds to the coronal
view on CT. A Medtronic Evolut
23 mm was successfully implanted
and the LM remained patent (d).

Besides the dimensions of the aortic root and ascending aorta,
the presence of extensive calcifications and large, mobile ath-
erosclerotic plaques should be evaluated. Porcelain aorta pre-
cludes SAVR and TAVI becomes the treatment of first choice
(E Fig. 22.7) [7]‌. However, porcelain aorta frequently co-
incides with severe peripheral artery disease that precludes
transfemoral TAVI. In those circumstances, a direct transaortic
or transsubclavian access are preferred over transapical access.
The area to access through the thoracic aorta should be free of
calcifications [21]. Large, mobile atherosclerotic plaques in the
ascending aorta justify the use of cerebral protection devices to
minimize the risk of embolic events (E Fig. 22.7) [22]. These
factors are best assessed with TEE and CT.
Height of coronary ostia. The height of the coronary ostia
relative to the annular plane should be assessed to predict the
risk of coronary ostia occlusion by the native, bulky calcified
aortic valve leaflets. This complication is more frequent when the
height of the coronary ostia is <11 mm, the aortic root diameter
is <30 mm and when the native aortic leaflets length exceeds the
height of the coronary ostia and have severe, bulky calcifications.
Although the height of the coronary ostia can be measured with
3-​dimensional TEE [23], CT is the best method to measure it and
to assess all the factors that influence the probability of coronary
ostia occlusion. Using stretched, curve multiplanar reconstruc-
tions, the distance between the aortic annulus plane and the cor-
onary ostia can be measured (E Fig. 22.8). On fluoroscopy, the
risk of coronary ostia occlusion can be assessed during balloon
dilation of the native valve by visualizing the motion of the bulky
calcified leaflets towards the coronary ostia. However, this is not
always feasible.
Femoral and iliac arteries size. The transfemoral access
is the preferred procedural access since it is associated with
less complications and better outcomes [7]‌ . New designs
have significantly reduced the size of the delivery sheaths al-
lowing transfemoral access in almost all patients. The internal
lumen dimensions, presence of circumferential calcification
and tortuosity are important factors that determine the feasi-
bility of transfemoral TAVI and are best evaluated with CT
angiography (E Fig. 22.9). Curved stretched multiplanar re-
constructions allow the assessment of the internal lumen di-
mensions throughout the descending aorta, iliac, and femoral
arteries. With specific postprocessing software, the centreline
 I m ag i n g techn i qu es to sel ect pati ents f or   TAV I 321

(a) (b)

Fig. 22.7  Porcelain aorta and

atherosclerosis of the ascending
aorta. Panel (a) shows circumferential
calcification of the ascending
aorta that affects the aortic arch
(c) (d) as well (b). With transoesophageal
echocardiography, protruding plaques
with mobile strands can be visualized
(c, arrow). Devices such as the Sentinel
transcatheter cerebral embolic
protection device (Claret Medical,
Santa Rosa, California) can be used to
reduce the risk of embolism (d).
Reproduced from Kapadia SR, Kodali
S, Makkar R, et al. Protection Against
Cerebral Embolism During Transcatheter
Aortic Valve Replacement. J Am Coll
Cardiol. 2017;69(4):367–​77. doi:10.1016/​
j.jacc.2016.10.023 with permission from
Elsevier.

is automatically displayed throughout the vessels and the di-
mensions can be automatically assessed. The minimal dimen-
sions of the femoral arteries to allow a transfemoral TAVI are 9
mm. Vessel tortuosity can be observed in the 3D volume ren-
derings of the vessels or using colour-​coded scheme displayed
on the curved stretched multiplanar reconstructions. Tortuous
vessels with significant calcifications of the vessel wall require
careful consideration since the delivery sheath may not be able
to stretch the vessel and pass through. In contrast, tortuous
vessels without calcifications do not represent significant
challenge since the delivery system may be able to stretch the
vessel and advance through. Location of the calcifications is
important, particularly in the area of puncture and where sig-
nificant tortuosities are present.
Non-​ femoral TAVI access. When transfemoral access is
not feasible, several alternative accesses should be evaluated
and can be performed based on the expertise of the centres.
Transsubclavian access is the option of second choice. CT is

(a) (b) (c)

Fig. 22.8  Height of the coronary ostia relative to the aortic annular plane. After establishing the centreline and plane of the aortic annulus, the height of the
coronary ostia can be assessed. Panel (a) shows the three-​dimensional rendering where the centreline, aortic annulus plane, and the origin of the coronary
arteries can be visualized. Using the stretched two-​dimensional renderings of the aortic root and ascending aorta based on the centreline, the height of the right
(b) and the left (c) coronary ostia can be measured (18 mm for the right and 14.2 mm for the left coronary ostia).
322 CHAPTER 22   Tran s cath eter aort ic valve i m pl a n tati on

(a)

(b)

Fig. 22.9  Evaluation of ilio-​

femoral arteries with CT prior to
transfemoral transcatheter aortic valve
implantation. The three-​dimensional
volume rendering of the ilio-​
femoral arterial system in (a) shows
heavily calcified arteries without
tortuosity. The curved multiplanar
reconstructions on the left show the
stretched vessels with circumferential
calcification. The example in (b) shows
tortuous iliac arteries but without
calcification as can be observed in the
stretched views on the right panels.

the imaging technique of choice to evaluate the dimensions
(E Fig. 22.10). As third option, the direct transaortic access
can be performed if the ascending aorta is not calcified and
there is enough distance between the aortic annular plane and
the tip of the sheath to allow deployment of the balloon (≥50
mm). In addition, the position of the ascending aorta relative
to the sternum should be assessed to define the site of puncture:
when the ascending aorta lies behind the sternum (left-​sided
aorta) and the distance between the sternum and the aorta is
>60 mm a mini-​J thoracotomy can be performed whereas a
mini-​right thoracotomy on the right second space intercostal
can be performed with there is a right-​sided aorta (>50% of the
ascending aorta is located on the right of the sternal border)
(E Fig. 22.10) [24].
The transapical access can be performed when a balloon-​
expandable transcatheter aortic valve is used. Currently is
considered the last option since it is associated with higher mor-
bidity as compared with the transfemoral access. To perform this
access, the apex of the left ventricle should be identified. It can be
performed with transthoracic echocardiography periprocedure
or with CT. Specific software permits full planning of the
transapical TAVI with simulation of the location of the delivery
sheath (E Fig. 22.10).
There is less experience with transvenous access, reaching the
descending aorta through the inferior vena cava [25]. The arterio-
venous shunt created can be closed with specific closure device
when the procedure is finalized.
Imaging for risk stratification of patients
undergoing TAVI
Other factors that need to be taken into consideration when
evaluating the patients that will benefit from TAVI include the left
and right ventricular systolic function, presence of concomitant
severe valvular heart disease (mitral and tricuspid) and presence
of significant coronary artery disease. These factors are important
particularly in patients with low and intermediate operative risk
since they can be treated during SAVR.
Left and right ventricular systolic function. Transthoracic
echocardiography is the imaging technique of first choice to
evaluate the left and right ventricular systolic function in pa-
tients with severe aortic stenosis undergoing TAVI. Reduced left
 I m ag i n g techn i qu es to sel ect pati ents f or   TAV I
(a) (b)
Transsubclavian
(a) (b)
Direct transaortic
(a) (b)
Transapical
ventricular (LV) ejection fraction is associated with poor out-
come in patients with severe aortic stenosis. However, relieve of
the valvular afterload may result in improvement in LV ejection
fraction over time. Currently, reduced LV ejection fraction is a
criterion to indicate aortic valve replacement in patients with
asymptomatic severe aortic stenosis but it is not a criterion that
contraindicates TAVI or SAVR in patients with symptomatic se-
vere aortic stenosis. The cause of reduced LV ejection fraction is
multifactorial and can be caused due to the valvular afterload and
myocardial ischaemia leading to myocyte apoptosis and replace-
ment fibrosis. With late gadolinium enhanced CMR, the pres-
ence of replacement fibrosis can be assessed. The British Society
of CMR Valve Consortium demonstrated that 51% of patients
with symptomatic severe aortic stenosis can have replacement
323
(c)
Fig. 22.10  Non-​transfemoral
access for transcatheter aortic valve
implantation: transsubclavian, direct
transaortic, and transapical. Panels (a)
and (b) of the transsubclavian access
show the 3-​dimensional renderings of
the thoracic aorta and the subclavian
artery on the posteroanterior and
lateral left view. Panel (c) shows the
curved multiplanar reconstruction
with the centreline from the
subclavian artery to the aortic valve.
In the direct transaortic access, the
position of the ascending aorta
relative to the sternum determines the
site of puncture: mini-​J thoracotomy
when the ascending aorta lies behind
the sternum (left-​sided aorta, panel a)
and a mini-​right thoracotomy on the
right second space intercostal can be
performed with there is a right-​sided
aorta (panel B). In the transapical
access, the three-​dimensional volume
rendering shows the simulated
introductory sheath between the ribs
(a) and the axial image shows the
angulation between the apical access
and the aortic annulus plane.
fibrosis, with the majority corresponding to non-​infarct delayed
enhancement [26]. Patients with replacement myocardial fibrosis
had worse survival as compared with patients without, regardless
of the treatment received (TAVI or SAVR). As much as 15% of
patients with severe aortic stenosis referred to TAVI can have car-
diac amyloidosis [27]. The LV hypertrophy caused by the aortic
stenosis can mask the presence of deposits of cardiac amyloid
that lead to reduced LV systolic function. In these patients, the LV
ejection fraction can be normal but the use of speckle-​tracking
echocardiography and the assessment of LV global longitudinal
show that the LV systolic function is impaired with the charac-
teristics sparing of LV strain in the apex (E Fig. 22.11). The use
of technetium-​99m pyrophosphate (99mTc-​PYP) cardiac scin-
tigraphy permits detection of transthyretin cardiac amyloidosis
324 CHAPTER 22   Tran s cath eter aort ic valve i m pl a n tati on
(a) (b)
Fig. 22.11  Cardiac amyloidosis in patient with severe aortic stenosis. Panel (a) shows a zoomed view of the parasternal short-​axis view of the aortic valve. Note
the thickened and calcified cusps. In panel (b), the apical four-​chamber view is shown with concentric hypertrophy of the left and right ventricles, thickened
mitral leaflets, and large atria. When analysing left ventricular global longitudinal strain (GS), the bull’s eye plot presents the typical appearance of apical cherry,
indicating preserved systolic shortening in the apex (apical sparing) and impaired shortening in mid and basal segments (c).
by showing diffuse uptake of the tracer or by semi-​quantitative
visual score ≥2 or by quantitative heart-​to-​contralateral ratio of
total counts ≥15.
In patients with reduced LV ejection fraction, the presence
of low-​flow low-​gradient severe aortic stenosis is common. The
use of low-​dose dobutamine stress echocardiography has been
advocated to discern between true severe aortic stenosis (when
the mean transvalvular gradient increases and the aortic valve
area remains <1 cm2) and pseudosevere aortic stenosis (when
the aortic valve area increases along the increase in transvalvular
mean gradient). However, recent data has shown that the use of
this technique to identify the patients with LV contractile reserve
has no impact on the clinical outcomes for patients treated with
TAVI [28].
Finally, it is important to assess the right ventricular (RV)
systolic function since various studies and meta-​analyses have
shown that an impaired RV systolic function (either meas-
ured with fractional area change, tricuspid annulus plane sys-
tolic excursion or longitudinal strain) is associated with poor
survival [29].
Concomitant severe valvular heart disease. The presence
of significant mitral and tricuspid valve regurgitation is rather
common in patients with severe aortic stenosis who are candi-
dates to TAVI [30, 31]. In patients with low and intermediate
operative risk, the presence of significant mitral and tricuspid
valve regurgitation may favour SAVR as the therapy of first
choice since they can be fixed during the same surgical pro-
cedure [7]‌. However, in patients with high operative risk and
contraindications for surgery, the evolution of significant mi-
tral and tricuspid regurgitation after TAVI should be evaluated
since they impact negatively on the clinical outcomes. The ma-
jority of the patients have secondary mitral regurgitation due to
the LV remodelling and increased LV pressure overload caused
by the stenotic aortic valve. Once the valve is replaced, the LV
(c)
pressure overload is normalized and mitral regurgitation may
improve. Similarly, significant tricuspid regurgitation is mostly
secondary to the increased pressures in the pulmonary vascu-
lature, RV remodelling, and tricuspid annulus dilation. After
TAVI, tricuspid regurgitation may also improve. However, when
mitral and tricuspid regurgitation do not improve and remain
significant limiting the symptomatic improvement of patients,
other transcatheter repair solutions should be considered.
Echocardiography is key to grade the severity of mitral and tri-
cuspid regurgitation and the various criteria are discussed in
Chapter 14.
Mitral stenosis due to severe calcification of the mitral an-
nulus is also frequent in patients with severe aortic stenosis and
it has been associated with poor outcome [32]. The diagnostic
criteria to define severe mitral stenosis are discussed in Chapter
13. However, the presence of mitral stenosis due to calcification
of the mitral annulus is relevant to this chapter since there are
data showing the safety of valve-​in-​mitral annulus calcification
to improve the symptoms of patients treated with TAVI. CT is
the imaging technique of choice to evaluate the suitability of this
procedure in these patients and the factors that need to be as-
sessed are the dimensions of the mitral annulus and the residual
LV outflow tract after valve-​in-​mitral annulus calcification pro-
cedure (risk of LV outflow tract obstruction) (E Fig. 22.12).
Coronary artery disease. In patients with severe aortic
stenosis the presence of obstructive coronary artery disease is
common. Invasive coronary angiography remains the imaging
technique of choice to evaluate whether the patients need con-
comitant revascularization or not. However, there are data that
the CT performed to assess the aortic valve annulus dimensions
may be used to rule out the presence of significant coronary
artery disease [33]. Current guidelines recommend performing
invasive coronary angiography to help in the decision-​making
of the patients [7, 8]. The evaluation of myocardial ischaemia
 Imaging t ech niqu es to g u i de tr a n s catheter aorti c va lve i m pl a n tat i on 325

(a) (b)

Fig. 22.12  Concomitant mitral stenosis in patient with severe aortic stenosis undergoing transcatheter aortic valve implantation. On the reconstructed
short-​axis of the mitral valve, the severe calcification of the mitral annulus can be noted (a, arrows). When evaluating the suitability for transcatheter
mitral valve implantation in mitral annulus calcification, commercially available software permits to segment the structures of interest and simulate the
implantation of the transcatheter valve in the mitral valve allowing visualization of the neo-​left ventricular outflow tract (b, red polygon). The centreline
of the left ventricular outflow tract, aortic valve, and ascending aorta are demarcated, the mitral annulus is depicted and the model of the transcatheter
valve is placed in (b).
Abbreviations: AV = aortic valve; MV = mitral valve.

in patients with symptomatic aortic stenosis is not very well
studied.
Imaging techniques to guide
transcatheter aortic valve
implantation
The procedural guidance is performed with fluoroscopy. The
technology has evolved dramatically allowing the performance of
the procedure under conscious sedation without the need to use
general anaesthesia and intubate the patients. Therefore, TEE has
been abandoned in the majority of the centres and it is only used
in specific circumstances (i.e. non-​transfemoral access). TTE is in
stand-​by and it is frequently used to assess the presence of signifi-
cant residual paravalvular regurgitation and when there are com-
plications such as pericardial effusion and cardiac tamponade.
After accessing the femoral artery, the guidewire is advanced
until the aortic root and the catheter is advanced into the left ven-
tricle to subsequently pass the wire that will be secured in the left
ventricle. Through the femoral artery is then advanced the intro-
ductory sheath and the system is advanced until the plane of the
aortic annulus (E Fig. 22.13). The fluoroscopy projection is set to
obtain the nadir of the aortic cusps aligned and the transcatheter
valve is placed co-​axial to that plane (E Fig. 22.13). Each manu-
facturer has specific indications to place the prosthesis and deploy
it. After deployment of the prosthesis, the presence of residual
leakage should be assessed. It can be performed with aortography
(E Fig. 22.13). One proposed invasive measurement to assess the
severity of aortic regurgitation is the aortic regurgitation index
which is calculated as the difference between diastolic blood pres-
sure (DBP) and LV end-​diastolic pressure (LVEDP), divided by
the systolic blood pressure (SBP), and expressed as a percentage:
[(DBP – LVEDP/SBP)] × 100 [34, 35]. A progressively lower aortic
regurgitation index is indicative of worsening aortic regurgitation
severity, and has been shown to be independently associated with
increased 1-​year mortality on multivariable Cox regression ana-
lysis [34]. However, there is considerable overlap between aortic
regurgitation index and different grades of paravalvular aortic re-
gurgitation severity on echocardiography. In addition, it is also
inversely associated with heart rate as the total diastolic duration
decreases with higher high rate [34, 36]. As such, an alternative
heart rate adjusted index has been proposed and calculated as:
[(DBP – LVEDP/Heart Rate)] × 80 [36]. However, both the aortic
regurgitation index and heart rate adjusted index are also influ-
enced by other variables such as aortic and LV compliance (i.e. ele-
vated LVEDP due to diastolic dysfunction in patients with aortic
stenosis will reduce the pressure difference between LVEDP and
DBP). Furthermore, aortography does not differentiate between
paravalvular or central (transvalvular) regurgitation and this is an
important aspect due to the therapeutic implications. When there is
doubt about the severity of the aortic regurgitation, the use of echo-
cardiography is recommended. With TTE or TEE, the location and
severity of the leakage should be assessed from various views (E Fig.
22.14). E Table 22.3 summarizes the criteria of severe transcatheter
valvular regurgitation [37, 38]. If the aortic regurgitation is mod-
erate or severe and the origin of the jet is paravalvular, ballooning of
the transcatheter valve can be performed to reduce the leakage (E
Fig. 22.15). In contrast, if the origin of the regurgitant jet is central,
a valve-​in-​valve procedure would be the best option (E Fig. 22.15).
Furthermore, it is important to assess the haemodynamics of
the transcatheter valve immediately after the implantation or be-
fore discharge. This haemodynamic assessment will be the base-
line measures to define the function of the implanted valve and to
compare with during follow-​up.
326 CHAPTER 22   Tran s cath eter aort ic valve i m pl a n tati on

(a) (b)

(c) (d)

Fig. 22.13  Fluoroscopic guidance of transcatheter aortic valve implantation. The example shows the sequential steps in the implantation of a self-​expandable
transcatheter aortic valve. First, the fluoroscopic projection for valve implantation should be set to visualize the aortic annulus plane (a). The aortic annulus
plane is set when the nadirs of the three aortic valve cusps are aligned. The balloon is advanced through the guidewire and the aortic valve is ballooned (b).
Then the transcatheter valve is advanced and its deployment is monitored performing aortograms to visualize the alignment of the prothesis with the aortic
annulus (c). After complete deployment, an aortography is performed to evaluate the position and the presence of residual regurgitation (d).
Abbreviations: LC = left coronary cusp; NC = non-​coronary cusp; RC = right coronary cusp.

(a) (b)

(c) (d)

Fig. 22.14  Assessment of paravalvular regurgitation. Example of paravalvular (white arrow) and central (orange arrow) regurgitation immediately after transcatheter
aortic valve implantation (a). The central regurgitation is caused by the guidewire. Biplane views acquired with three-​dimensional transesophageal or transthoracic
probes allow assessment of the paravalvular regurgitation simultaneously on the long-​and short-​axis of the transcatheter valve frame (b). Note that the paravalvular
regurgitation observed in the left panel (arrow) can be broader when assessed in the short-​axis view (right panel). From transgastric views, the residual regurgitation is
best assessed (c, arrows) and the continuous wave Doppler of the regurgitant jet can be obtained (d).
 L ate f ol l ow -up 327

Table 22.3  Doppler quantification of aortic regurgitation severity after transcatheter aortic valve replacement

Mild Moderate Severe Pitfalls

Qualitative
  Colour Doppler ◆ May be obscured from attenuation from valve
struts/​frame
    –​proximal flow convergence Absent May be present Present
  Continuous wave Doppler Influenced by ultrasound settings
◆
Influenced by Doppler angle
◆
    –​spectral density Incomplete/​faint Dense Dense
  Pulsed wave Doppler ◆ May be present at baseline before TAVR due to
reduced left ventricular compliance
    –​proximal descending aorta Brief early diastolic May be Holodiastolic
flow reversal holodiastolic with end-​diastolic
velocity ≥20 cm/​s
    –​abdominal aorta flow reversal Absent Absent Present
Semi-​quantitative
  Colour Doppler ◆ Limited utility with multiple small regurgitant
jets
    –​vena contracta width <3 mm 3–​6 mm >6 mm
    –​vena contracta area <0.10 cm2 0.10–​0.29 cm2 ≥ 0.30 cm2
    –​circumferential extent <10% 10–​29% ≥ 30%
  Continuous wave Doppler ◆ Influencedby left ventricular and aortic
compliance
    –​pressure half time >500 ms 200–​500 ms <200 ms
Quantitative
  Regurgitant volume <30 ml 30–​59 ml >60 ml Not feasible during TAVR procedure
◆
For calculation of systemic stroke volume:
◆
  Regurgitant fraction <30% 30–​49% ≥ 50%
Frequent underestimation of left ventricular
●

  Effective regurgitant orifice area <0.10 cm2 0.10–​0.29 cm2 ≥ 0.30 volumes by 2D echocardiography
Limited accuracy if calculating mitral annular
●

area especially when significant calcifications

present
Potential error in calculating LVOT area
◆

LVOT = left ventricular outflow tract; TAVR = transcatheter aortic valve replacement.
Source data from Kappetein AP, Head SJ, Généreux P, et al. Updated standardized endpoint definitions for transcatheter aortic valve implantation: the Valve Academic Research
Consortium-​2 consensus document. Eur Heart J. 2012;33(19):2403–​18. doi:10.1093/​eurheartj/​ehs255.
AND
Zoghbi WA, Asch FM, Bruce C, et al. Guidelines for the Evaluation of Valvular Regurgitation After Percutaneous Valve Repair or Replacement: A Report from the American
Society of Echocardiography Developed in Collaboration with the Society for Cardiovascular Angiography and Interventions, Japanese Society of Echocardiography, and Society
for Cardiovascular Magnetic Resonance [published correction appears in J Am Soc Echocardiogr. 2019 Jul;32(7):914–​17]. J Am Soc Echocardiogr. 2019;32(4):431–​75. doi:10.1016/​
j.echo.2019.01.003.

Structural valve deterioration. Structural valve deterioration is

Late follow-​up defined as intrinsic permanent changes in the bioprosthetic valve
leading to degeneration and/​or haemodynamic dysfunction [9]‌. It
As the long-​term durability of transcatheter aortic valve re-
is usually classified into either haemodynamic or morphological
placement (TAVR) is currently unknown, it is recommended
dysfunction, and can be caused by different pathologies such as
that all patients undergo regular follow-​ up surveillance
leaflet fibrosis and calcification, pannus formation, or flail leaflets.
imaging to detect complications such as structural valve de-
Haemodynamic valve deterioration is usually quantified by
terioration, non-​structural valve deterioration, transcatheter
TTE and stratified into moderate vs. severe dysfunction based on
valve thrombosis, and infective endocarditis [39]. TTE is
mean transvalvular gradient or intravalvular aortic regurgitation
the diagnostic imaging modality of choice, and all patients
as outlined in E Table 22.4 [73]. Usually, severe haemodynamic
should have echocardiograms prior to hospital discharge, at
valve deterioration is defined as an absolute mean gradient ≥40
30 days, and then at least annually to assess valvular haemo-
mmHg, change in mean gradient ≥20 mmHg compared to base-
dynamics (i.e. peak velocity, mean gradient, valve area) and
line, or new severe or >2+/​4 worsening of intravalvular regur-
valve regurgitation [39].
gitation [9]‌. In contrast, morphological dysfunction is based on
328 CHAPTER 22   Tran s cath eter aort ic valve i m pl a n tati on

(a) (d)

(b)

(e) (f)

(c)

Fig. 22.15  Implications of immediate assessment of aortic regurgitation after transcatheter aortic valve implantation. Panel (a) shows severe transvalvular
regurgitation due to immobile leaflet. On the left the long-​axis view shows wide vena contracta occupying the entire diameter of the valve. The simultaneous
short-​axis view on the right shows central regurgitation occupying 50% of the central lumen of the valve. In this situation, acute valve-​in-​valve implantation
(b) is the best solution to solve the regurgitation (c). When the regurgitation is paravalvular, reballooning of the transcatheter valve is recommended. Panel (d)
shows simultaneous visualization of the short-​axis view of the transcatheter aortic valve without (left) and with (right) colour. Note the wide vena contracta
of the regurgitant jet between the native non-​and left coronary cusps. On the log-​axis view, the regurgitant jet can be visualized (e) and disappeared after
reballooning of the valve (f).

anatomical changes in leaflet structure (e.g. flail leaflets causing
regurgitation, thickening/​calcification causing stenosis) or valve
struts/​frame (E Fig. 22.16). These morphological changes may
or may not result in haemodynamic changes on echocardiogram.
It is important to note that paravalvular regurgitation and patient-​
prosthesis mismatch are classified under non-​structural valve de-
terioration as the abnormality is not intrinsic to the valve itself.
There are currently limited data on the long-​term durability
and structural valve deterioration for patients treated with TAVI.
Both the self-​expanding (Medtronic CoreValve) and balloon-​
expandable (Edwards Sapien) transcatheter valves showed ex-
cellent valve haemodynamics at 5 years, with a respective mean
gradient of 12.8 ± 10.9 mmHg and 10.7 mmHg [40, 41]. In the
Placement of Aortic Transcatheter Valves (PARTNER 1) trial,

Table 22.4  Quantification of haemodynamic structural valve deterioration by ESC/​EACTS

Moderate SVD Severe SVD

Absolute mean gradient ≥20 mmHg and <40 mmHg ≥40 mmHg
Change in mean gradient from baseline ≥10 mmHg and <20 mmHg ≥20 mmHg
Intravalvular regurgitation New moderate or >1+ worsening New severe or >2+ worsening
ESC = European Society of Cardiology; EACTS = European Associate for Cardio-​Thoracic Surgery; SVD = structural valve deterioration.
Source data from Capodanno D, Gori T, Nef H, et al. Percutaneous coronary intervention with everolimus-​eluting bioresorbable vascular scaffolds
in routine clinical practice: early and midterm outcomes from the European multicentre GHOST-​EU registry. EuroIntervention. 2015;10(10):1144–​53.
doi:10.4244/​EIJY14M07_​11.

(a) (b)
(c) (d)
valve haemodynamics were comparable between transcatheter
and surgical aortic valve prostheses at 5 years [41]. No patients
required surgical valve replacement due to structural valve deteri-
oration, and nearly all aortic regurgitations were paravalvular in
origin [41, 42]. However, any aortic regurgitation was associated
with reduced 5 year survival [41].
Prosthetic valve regurgitation. Quantification of aortic regur-
gitation post-​TAVI is mostly performed with echocardiography.
However, CMR can be useful when there are doubts about the
severity of the leakage. Echocardiography is the mainstay for
quantifying intravalvular and paravalvular regurgitation post-​
TAVI. However, it often can be challenging due to artefacts
arising from the valve frame/​struts, multiple eccentric and ir-
regularly shaped regurgitant jets, and reduced aortic and LV
compliances leading to erroneous Doppler assessments. Current
guidelines recommend grading of aortic regurgitation severity
using a combination of qualitative, semi-​quantitative, and quan-
titative techniques by Doppler as outlined in E Table 22.3 [37,
38]. Significant attention should be paid to optimize the 2D im-
ages and Doppler signals. However, it is important to remember
all Doppler signals are flow and pressure dependent and will
therefore affect the various semi-​quantitative and quantitative
measurements. For example, patients with severe aortic stenosis
will have reduced LV compliance with resultant elevated LVEDP.
This will lead to reduced pressure difference between LVEDP
and DBP and therefore overestimation of aortic regurgitation se-
verity by pressure half time (similar to the aortic regurgitation
index). Likewise, reduced aortic compliance (i.e. increased aortic
L ate f ol l ow -up 329
Fig. 22.16  Structural degeneration of
transcatheter aortic valve. Example of
an 83-​year-​old female who presented
with dyspnoea on exertion after 2
years of transcatheter aortic valve
implantation. On the transthoracic
echocardiography, the leaflets of the
transcatheter valve appear thickened
and restricted (a, arrow) and the
(e)
continuous wave Doppler shows
increased transvalvular gradient with
a peak velocity of 4 m/​s (b). On CT,
the transcatheter valve leaflets appear
restricted but they do not show
significant hypoattenuated thickening
(c and d). A valve-​in-​valve procedure
was not feasible due to the small
size of the transcatheter valve (23
mm) and the patient was referred for
surgical aortic valve replacement. The
explanted valve showed degenerated
leaflets with significant ingrowth (e).
stiffness) with age and hypertension will increase diastolic flow
to the upper body and therefore diastolic flow reversal on spec-
tral Doppler in the aortic arch [43]. The various potential pitfalls
for quantifying aortic regurgitation severity are summarized in
E Table 22.3.
CMR can overcome some of the echocardiographic limitations
such as inadequacy of acoustic window, Doppler angulation, etc.
Several studies have shown that echocardiography underesti-
mates aortic regurgitation severity compared to CMR [44, 45].
Furthermore, phase contrast imaging can also directly quantify
regurgitant volume and has been shown to better predict develop-
ment of symptoms or other indications for surgery [46].
The prognostic implications of residual significant aortic regur-
gitation make this assessment clinically relevant. Recent meta-​
analysis that included 12,926 patients treated with TAVI reported
that the pooled estimate of moderate or severe aortic regurgita-
tion after the procedure was 11.7% (95% confidence interval (CI)
9.6–​14.1%), and was associated with increased mortality at 30
days (odds ratio 2.95, 95% CI 1.73–​5.02, P = 0.001) and 1 year
(hazard ratio 2.27, 95% CI 1.84–​2.81, P = 0.001) [47]. Similar
prognostic data was observed in patients moderate-​severe aortic
regurgitation after TAVI when assessed with CMR [48]. However,
it is important to understand that the adverse prognostic outcome
associated with post-​procedural aortic regurgitation is dependent
on the preprocedural function/​life expectancy. For example, in
inoperable patients with severe aortic stenosis, the 5-​year all-​
cause mortality in patients with post-​procedural moderate to
severe paravalvular aortic regurgitation was similar to patients
330 CHAPTER 22   Tran s cath eter aort ic valve i m pl a n tati on

with no or mild paravalvular aortic regurgitation (78% vs. 69%,
P = 0.51) [42]. In ‘lower’ risk patients, 5-​year mortality risk was
higher in the patients with moderate or severe aortic regurgita-
tion (AR) after TAVI compared to those with mild aortic regur-
gitation (72% vs. 57%, P = 0.003) [41]. Even the presence of mild
aortic regurgitation was associated with lower survival at 5 years
compared to those without aortic regurgitation [41].
Transcatheter valve thrombosis. Historically, bioprosthetic
valve thrombosis was usually diagnosed based on surgical series
with a reported overall incidence of <1% [49, 50]. However, this
is likely a significant underestimation as the reported incidence
is higher with the advent of routine echocardiography and 4D
multidetector computed tomography (MDCT) imaging fol-
lowing TAVI. The overall published incidence ranged from as low
as 0.6% and up to 40% (E Tables 22.5 and 22.6) [51–​68]. Current
uncertainties include in the choice of imaging modality, criteria
used to define transcatheter valve thrombosis, appropriate follow-​
up surveillance intervals, antiplatelet/​ anticoagulant treatment
protocol immediately post-​transcatheter valve implantation and
after diagnosis of transcatheter valve thrombosis.

Table 22.5  Transcatheter heart valve thrombosis by echocardiography

Author Number of Number Time to Mean gradient Definition Clinical sequelae

(year) patients of THV diagnosis (mmHg)
thrombosis
(Prevalence)
Latib [57] 4,266 26 (0.6%) Median 181 40.5 ± 14.0 mmHg THV dysfunction: 65%
◆ worsening
(2015) days (IQR Mean gradient ≥20 mmHg or AVA
◆ dyspnoea
45–​313) <1.2 cm2 or peak velocity ≥3 m/​s; or ◆ No stroke
new moderate or greater aortic
◆ Did not compare
regurgitation to patients without
THV thrombosis: thrombosis
THV dysfunction secondary to
◆
thrombosis based on response to
anticoagulation therapy, imaging
modality (echocardiography or
MDCT), or histopathology findings; or
mobile mass suspicious of thrombus,
◆
irrespective of dysfunction, and in the
absence of infection
Del Trigo [53] 1,521 68 (4.5%) –​ 26.1 ± 11.0 mmHg Mean gradient ≥10 mmHg Compared to patients
(2016) without thrombosis:
similar total mortality,
◆
cardiovascular
mortality, and stroke
Franzone [54] 1,396 10 (0.71%) Median 36.4 ± 8.3 mmHg Mean gradient ≥20 mmHg, or mean ◆ 70% worsening
(2017) 379 days gradient increase by 50%, or recent or dyspnoea
(IQR 35–​524) new onset heart failure 0% stroke
◆
Did not compare
to patients without
thrombosis
Jose [56] 642 18 (2.8%) Median 34 ± 14 mmHg Mean gradient >20 mmHg, or AVA ◆ 38.9% worsening
(2017) 181 days <1.2 cm2, or > mild new aortic dyspnoea
(IQR 25–​297) regurgitation secondary to 5.5% stroke
◆
thrombosis diagnosed by response Did not compare
to anticoagulation or ‘typical’ to patients without
echocardiographic or MDCT findings, thrombosis
or mobile mass suspicious of thrombus.
‘Typical’ echo findings include
◆
immobile or restricted leaflets,
thrombotic mass, or thickened
leaflets)
‘Typical’ CT findings is HALT
◆

Vollema [66] 434 2 (3%) –​ –​ Mean gradient ≥20 mmHg and AVA See E Table 22.2
(2017) ≤1.1 cm2
Spartera [65] 621 13 (2.1%) 179.5 ± 36.2 ± 16.5 mmHg Mean gradient ≥20 mmHg and peak –​
(2018) 252.9 days velocity ≥3 m/​s, PLUS response to
anticoagulation therapy, and/​or HALT
detected on MDCT
 L ate f ol l ow -up 331

Table 22.5 Continued

Author Number of Number Time to Mean gradient Definition Clinical sequelae

(year) patients of THV diagnosis (mmHg)
thrombosis
(Prevalence)
Abdel-​Wahab  [51] 300 valve- 23 (7.6%) –​ –​ ◆ New valve dysfunction (mean ◆ 1 stroke
(2018) ​in-​valve gradient >20 mmHg or increase
by >50%) that responds to
anticoagulation
Imaging evidence of thrombosis on
◆
echo or HALT on MDCT
2 criteria = definite valve thrombosis
1 criterion = probable valve thrombosis
Reardon [62] 912 16 (1.8%) –​ –​ Mean gradient ≥20 mmHg and peak No death
◆
(2019) velocity ≥3 m/​s, PLUS response to No stroke
◆
anticoagulation therapy, and/​or HALT
detected on MDCT
Overtchouk [60] 2,555 140 (5.5%) Median 12 –​ Increase in mean gradient by ≥10 –​
(2019) months mmHg, or new mean gradient >20
(IQR 11–​15 mmHg
months)
AVA = aortic valve area; HALT = hypoattenuated leaflet thickening; IQR = interquartile range; MDCT = multidetector computed tomography; THV = transcatheter heart valve.

Table 22.6  Transcatheter heart valve thrombosis by MDCT

Author Number of Number Time to Mean gradient (mmHg) Definition Clinical sequelae
(year) patients of THV diagnosis
thrombosis
(Prevalence)
Makkar [59] 55 22 (40%) Median 32 days 10.5 ± 4.3 mmHg At least Compared to patients
(2015) (IQR 28–​37) moderately without RLM:
(≥50%) RLM Similar mortality
◆
Similar stroke
◆

132 17 (13%) 228 ± 459 days 8.4 ± 2.9 mmHg Compared to patients
without RLM:
Increased risk of TIA
◆

Leetmaa [58] 140 5 (4%) Median 91 days 19.2 ± 6.3 mmHg HALT No stroke
◆
(2015) (IQR 66–​92) 1 heart failure
◆

Pache [61] 156 16 (10.3%) Median 5 days 14.9 ± 5.3 mmHg HALT ◆ No stroke
(2016) (IQR 5–​6)
Hansson [55] 405 28 (6.9%) Median 43 days 10 ± 7 mmHg HALT 18% heart failure
◆
(2016) (IQR 28–​57) Compared to patients
without HALT:
Similar mortality rates
◆
Similar stroke rates
◆

Chakravarty [52] 890 106 (11.9%) Median 83 days 13.8 ± 10.0 mmHg At least Compared to patients
(2017) (IQR 33–​281) moderately without RLM:
(≥50%) RLM Similar mortality
◆
Higher rates of TIA
◆

Ruile [63] 660 93 (15%) Median 5 days –​ HALT –​

(2018) (IQR 5–​6)
Sondergaard [74] 84 HALT: 159 ± 177 days HALT: HALT with or ◆ 2 patients with HAM
(2017) 32 (38.1%)
◆ 7.0± 3.2 mmHg at time point 1
◆ without HAM had TIA/​stroke
HAM: 7.1± 4.5 mmHg at time point 2
◆ (i.e. at least
7 (20.2%)
◆ HAM: ≥50% RLM)
7.2± 2.4 mmHg at time point 1
◆
5.7± 3.3 mmHg at time point 2
◆

(continued)
332 CHAPTER 22   Tran s cath eter aort ic valve i m pl a n tati on

Table 22.6 Continued

Author Number of Number Time to Mean gradient (mmHg) Definition Clinical sequelae
(year) patients of THV diagnosis
thrombosis
(Prevalence)
Vollema [66] 128 16 (12.5%) Median 35 days 12.4 ± 8.0 mmHg HALT with or ◆ No TIA/​stroke
(2017) (IQR 19–​210) without HAM
Yanagisawa [67] 70 10 (14.3%) –​ 8.3 ± 0.8 mmHg HALT Compared to patients
(2017) without HALT:
Similar mortality
◆
Similar TIA rates
◆

Ruile [64] 754 120 (15.9%) Median 5 days 11.3 ± 4.9 mmHg HALT Compared to patients
(2018) (IQR 4–​6) without HALT:
Similar all-​cause
◆
mortality
Similar CVA/​TIA
◆

Yanagisawa [68] 485 Early HALT: Median 3 days 12.9 ± 5.6 mmHg HALT Compared to patients
(2019) 45 (9.3%)
◆ >30 days without HALT:
Late HALT: Similar all-​cause
◆
8 (12.3%)
◆ mortality
Similar rehospitalization
◆
for heart failure
Similar stroke rates
◆

HALT = hypoattenuated leaflet thickening; HAM = hypoattenuation affecting motion; IQR = interquartile range; MDCT = multidetector computed tomography; RLM = reduced
leaflet motion; TIA = transient ischaemic attack; THV = transcatheter heart valve.

Echocardiography is often the first imaging modality of choice
to detect and define transcatheter valve thrombosis due to its
widespread availability and absence of ionizing radiation. Its main
advantage is quantification of haemodynamic severity of valvular
obstruction and direct correlation with clinical symptoms [57].
However, a major limitation is the highly variable diagnostic cri-
teria used to define transcatheter valve thrombosis as highlighted
in E Table 22.5. Despite that, a new mean transvalvular gra-
dient ≥20 mmHg is frequently used as a diagnostic criterion. The
second major limitation is its lower sensitivity in detecting and
quantifying ‘thickened leaflets’ or ‘reduced leaflet mobility’ due
to significant acoustic shadowing and ring-​down artefacts arising
from the valve struts.
Compared to echocardiography, 4D MDCT is more sensitive at
detecting transcatheter valve thrombosis due to its superior spatial
resolution. Unlike the assessment of transvalvular haemodynamics
on echocardiography, 4D MDCT identifies anatomical abnormal-
ities such as ‘hypoattenuated leaflet thickening’ (HALT, E Fig.
22.17), the pathognomonic hallmark of transcatheter valve throm-
bosis. To a lesser degree, 4D MDCT also provides semi-​quantitative
functional valvular assessment by means of ‘reduced leaflet motion’
(RLM) based on maximal leaflet opening during the systolic phase.
Leaflet motion is usually stratified into normal, mild (<50% RLM),
moderate (50–​70% RLM), severe (>70% RLM), or immobile (100%
RLM) leaflets. Majority of patients with transcatheter valve throm-
bosis on 4D MDCT do not have significant haemodynamic ob-
struction on echocardiography or on clinical presentation such as
myocardial infarctions, strokes, or sudden death. In contrast, up to
65% of patients with transcatheter valve thrombosis on echocardi-
ography had clinical symptoms of aortic stenosis [57]. Currently,
the long-​term implications of transcatheter valve thrombosis on
valve durability is unknown.

(a) (b)

Fig. 22.17 Hypoattenuated
leaflet thickening. Example of
hypoattenuated leaflet thickening
as assessed with CT. In panel (a),
the double oblique reconstruction
of the transcatheter valve shows
hypoattenuated thickening of the
three leaflets. Panel (b) shows the
sagittal view of the transcatheter valve
and the hypoattenuated material
covering the aortic side of the leaflets.

Thrombosis vs. pannus. Although transcatheter valve throm-
bosis is considered as reversible, it can lead to long-​term irre-
versible valvular dysfunction such as pannus formation, thereby
causing permanent structural valve deterioration. Pannus tissue
is comprised of chronic inflammatory cells (e.g. lymphocytes,
macrophages, giant cells and myofibroblasts), capillary blood
vessels, and calcification [69]. It initially originates from outside
the sewing ring and proliferates onto the inflow and outflow sur-
faces of the valve. Both transcatheter valve thrombus and pannus
may be associated with each other over time, with initial valve
thrombosis leading to pannus formation, or significant pannus
compromising blood flow across the valve leading to thrombus
formation. MDCT may be a useful imaging modality to differ-
entiate between these two pathologies by utilizing the difference
in their post-​contrast attenuation values [70]. Using a cut-​off
Hounsfield Unit of ≥145, Gunduz et al. [70] were able identify
pannus with a sensitivity of 87.5% and specificity of 95.5% (area
under the curve 0.96, P <0.001). Currently, no studies have evalu-
ated the natural history or risk factors for pannus formation.
Further reading
Barbanti M, Yang TH, Rodes Cabau J, et al. Anatomical and procedural
features associated with aortic root rupture during balloon-​
expandable transcatheter aortic valve replacement. Circulation
2013; 128: 244–​53.
Capodanno D, Petronio AS, Prendergast B, et al. Standardized
definitions of structural deterioration and valve failure in
assessing long-​term durability of transcatheter and surgical aortic
bioprosthetic valves: a consensus statement from the European
Association of Percutaneous Cardiovascular Interventions (EAPCI)
endorsed by the European Society of Cardiology (ESC) and the
European Association for Cardio-​Thoracic Surgery (EACTS). Eur
Heart J 2017; 38: 3382–​90.
Chakravarty T, Sondergaard L, Friedman J, et al. Subclinical leaflet
thrombosis in surgical and transcatheter bioprosthetic aortic valves:
an observational study. Lancet 2017; 389: 2383–​92.
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Contents
Introduction  337
The mitral valve complex  337
Imaging methods to assess MV disease and
guide MV procedures  337
Imaging modalities used prior to a MV
procedure  338
Imaging modalities used during MV
procedures  339
Transcatheter techniques to treat mitral
stenosis (MS)  340
Preprocedural evaluation of MS patients  340
PMBC—​the procedure  341
Transcatheter techniques to treat MR  342
Evaluation of MR patients prior to a
transcatheter procedure  342
Imaging approaches during specific
interventions  344
Conclusion  354
CHAPTER 23
Transcatheter mitral valve
interventions
Nina C. Wunderlich, Robert J. Siegel,
Ronak Rajani, and Nir Flint
Disclosure: Nina C. Wunderlich is a consultant for Edwards Lifesciences.
Introduction
In this chapter we review transcatheter mitral valve (MV) interventions for mitral sten-
osis (MS) and mitral regurgitation (MR) (E Fig. 23.1).
The mitral valve complex
To appropriately select patients for specific mitral procedures and to guide procedures
effectively and safely the pathology of the MV and the relationship and interaction of the
MV with neighbouring structures needs to be fully understood. The MV complex con-
sists of multiple components including the anterior (AML) and the posterior mitral leaf-
lets (PML) which form two commissures (anterolateral and posteromedial), the mitral
annulus (MA) which is connected to both leaflets at the level of the atrioventricular junc-
tion, the chordal structures and the anterolateral and posteromedial papillary muscles
which represent the connection to the left ventricular (LV) musculature and both adja-
cent cardiac chambers: the LV and the left atrium (LA). MV dysfunction may result from
aberrations of any portion of the MV apparatus, due to mechanical, traumatic, infectious,
degenerative, congenital, or metabolic causes.
The subdivision of the two mitral leaflets in three segments each (PML: P1 (= lateral
segment), P2 (= middle segment), P3 (= medial segment) and correspondingly the AML:
A1 (= lateral segment), A2 (= middle segment), A3 (= medial segment) [1]‌) as well as the
functional characterization of leaflet motion [2] (type I = normal leaflet motion, type II =
excessive leaflet motion due to a prolapse/​flail, type IIIa = restricted leaflet motion in
systole and diastole, and type IIIb = restricted leaflet motion in systole only) both sug-
gested by Carpentier paved the way for a widely adopted nomenclature. This allows for a
detailed depiction of MV anatomy, pathology, and function, which in turn enables better
understanding of the MV complex and thus facilitates communication and MV repair.
Imaging methods to assess MV disease and guide
MV procedures
Echocardiography is the cornerstone for evaluating the MV, for the selection of suit-
able patients and in the preplanning and guidance of transcatheter mitral interventions.
338 CHAPTER 23   Tran s cath eter mit ral valv e i n terven ti on s
Mitral valve pathology
Mitral stenosis (MS)
Rheumatic
PMBC*
MS
Bio-prosthetic
VIV implantation***
MS
Severely
TMVR*** calcified native
MS
Fig. 23.1  Overview of available transcatheter options for the treatment of mitral valve pathologies.
* Recommendation in current guidelines/​randomized controlled trials
**Early clinical studies
* **Case reports/​small case series
Abbreviations: MV= mitral valve.
Real-​time (RT) 3D imaging has enhanced our understanding of
MV disease by providing clear appreciation of the true shape of
cardiac structures and the spatial relationships between them in
the beating heart.
However, due to complex imaging tasks that are associated with
many newly emerging devices and procedures a combination of
different imaging modalities is often needed to adequately plan
and guide these procedures.
Imaging modalities used prior to a MV
procedure
Two-​dimensional (2D) and three-​dimensional (3D)
transthoracic echocardiography (TTE)
2D TTE enables a detailed analysis of all components of the MV
apparatus and is the primary imaging modality to define MR/​MS
severity, to assess the haemodynamic impact on left-​sided cardiac
chambers and on the pulmonary circulation, to evaluate the poten-
tial suitability for various transcatheter treatment strategies as well
as to identify factors that may have prognostic implications [3, 4].
Moreover, 3D TTE adds crucial morphological information in
more than one-​third of patients compared to that obtained from
2D echocardiography [5]‌. 3D TTE provides more accurate and re-
producible data in the evaluation of LV geometry (size, volumes)
and function[6] and in conjunction with colour Doppler MR
quantification showed better correlation with cardiac magnetic
resonance (CMR) measures than conventional 2D TTE methods
particularly in the presence of multiple MR jets [7]. However, in
case the MR is paravalvular next to a surgically implanted ring or
mechanical valve TTE imaging is limited due to artefacts caused
by the sewing ring, the mechanical valve, or calcification.
Mitral regurgitation (MR)
Edge-to-edge repair*
Primary MR Chordae implatation**
TMVR***
Edge-to-edge repair*
Secondary MR Annuloplasty
(direct/indirect)**
TMVR***
PVML PVML closure*
Failure after
VIR implantation***
surgical
Edge-to-edge repair***
annuloplasty
Bio-prosthetic
VIV implantation***
MR
In MS patients the 3D-​derived MV area (MVA) is more ac-
curate and better correlated with the invasively measured MVA
than 2D derived measurements [8]‌.
2D/​3D transoesophageal echocardiography (TEE)
As a TEE provides superior imaging resolution, it is usually per-
formed prior to a surgical or transcatheter procedure to obtain a
more precise analysis of the entire MV apparatus. A multiplane 2D
TEE with the focus on three key-​views with and without colour
Doppler is recommended: (1) a four-​chamber view at ~0°; (2) an
intercommissural view at ~60°; and (3) a long-​axis (left ventricular
outflow tract (LVOT)) view at ~130–​150° [9]‌. A TEE is also useful
to exclude intracardiac thrombi as well as for grading MS/​MR se-
verity in uncertain cases, as image quality may be better and the de-
lineation of the proximal isovelocity surface area (PISA) radius may
be more accurate and pulmonary vein flow is more easily assessed.
RT-​3D TEE is currently the preferred imaging method for
understanding the complex MV morphology and for evaluating
geometry, dynamic changes, and function of the MV prior to a
surgical or transcatheter intervention [10, 11]. Moreover, colour
Doppler 3D TEE has shown to be beneficial in localizing and
analysing multiple MR jets due to multiple prolapses/​flail leaflets
in different MV segments or multiple paravalvular mitral leaks
(PVML) [12, 13] and in defining MR severity by allowing meas-
urements of 3D vena contracta areas [14]. In addition, 3D TEE is
superior in identifying specific MV lesions such as gaps, fissures,
and perforations which remain frequently undiagnosed by 2D
TEE [15]. Newly developed automated 3D software applications
allow for numerous anatomical MV measurements and may po-
tentially lead to a higher diagnostic accuracy and a better inter-​
and intraobserver reproducibility [16] (E Fig. 23.2).
 Imaging m ethod s to as ses s M V di sease a n d g u i de M V pro c e dure s
(a)
Fig. 23.2  Dynamic 3D transoesophageal echocardiography reconstruction. Newly developed automated software allows for the dynamic reconstruction of
the mitral/​aortic valve and root and for multiple measurements throughout the cardiac cycle (Siemens Healthineers, Erlangen, Germany). (a) Diastolic and
(b) systolic frame of a patient with ischaemic functional mitral regurgitation.
Exercise testing
Exercise testing may be particularly helpful in the evaluation of
asymptomatic patients with severe MS/​MR and of those who
show discrepancies between symptoms and MS/​MR grade. It
may also be useful to predict how well women with MS will tol-
erate pregnancy [17]. Mild MS is generally well tolerated during
pregnancy, but heart failure may develop in nearly 25% of preg-
nant women with moderate MS and in nearly half of those with
severe MS and a MVA <1.0 cm² [18]. A low-​dose dobutamine
stress echocardiography is useful to assess the potential of reverse
remodelling in patients with heart failure and functional mitral
regurgitation (FMR) prior to a MV procedure [3]‌.
Computed tomography (CT) angiography
The evaluation of MV anatomy, geometry and function is feasible
with CT imaging [19–​21]. In case of limited echocardiographic
imaging quality CT can be used as alternative method for plan-
imetry of the MVA in MS patients [22] In patients with FMR the
origin of the MR jet, coaptation dimensions, leaflet tethering and
the interpapillary muscle distance can be adequately character-
ized by CT [19]. Periprosthetic mitral leaks can also be adequately
described and localized [20]. For transcatheter MV therapies de-
signed to modify the MA or to replace the MV altogether (valve-​in-​
valve [VIV] implantation, valve-​in-​ring [VIR] implantation, valve
in mitral annulus calcification [valve-​in-​MAC] or a transcatheter
MV replacement [TMVR]), cardiac CT angiography should be
used to determine device suitability and procedural planning. CT
is the preferred imaging modality to assess for the distribution
and extension of mitral annular calcification (MAC), the calcifica-
tion of leaflets and anatomical relationships to important adjacent
structures (e.g. the left circumflex coronary artery, the coronary
sinus, as well as the LVOT [21]). CT angiography can also be used
to evaluate the status of the coronary arteries.
Cardiac magnetic resonance (CMR) imaging
CMR imaging can be helpful in quantifying MR severity by using
planimetry of the anatomic regurgitant orifice area, quantification
of forward and backward flow, phase-​contrast imaging, or phase-​
contrast velocity mapping [23, 24]. This is most helpful when
echocardiographic evaluation is equivocal [25]. Cardiac volumes,
339
(b)
LV ejection fraction as well as aortic flow volume, MR volume and
regurgitation fraction can be determined [26]. In patients with is-
chaemic FMR, regional and global myocardial function and via-
bility can be evaluated at rest and under stress (administration of
adenosine) in a single examination [27]. The MVA can also be
reliably calculated [28]. Disadvantages of CMR imaging include a
limited temporal and spatial resolution, as well as limited data on
patient management based on CMR measurements.
Imaging modalities used during MV
procedures
Coronary angiography, cardiac catheterization, and
fluoroscopy
A coronary angiography is used to evaluate the status of the cor-
onary arteries prior to [3, 4] or during a procedure, e.g. when cor-
onary spasm or injury is suspected during a direct transcatheter
mitral annuloplasty. In cases where there is a close relationship
of the circumflex coronary artery to the MA a guidewire in the
vessel may be helpful to avoid injury.
LV ventriculography with injection of contrast media can be
used to estimate LV ejection fraction and MR severity by using a
semi-​quantitative four-​grade  scale.
The MVA can also be calculated by performing a right and left
heart catheterization and using of the Gorlin equation. Cardiac
output can be obtained via thermodilution (in the absence of sig-
nificant tricuspid regurgitation) or the Fick method [3, 4]. The
Gorlin equation is less reliable in case of a decreased cardiac output
or directly after percutaneous mitral balloon commissurotomy
(PMBC) [29]. Cardiac catheterization is useful in patients with
severe pulmonary hypertension (PH), as it allows for the direct
measurement of absolute pressure within the cardiac chambers
as well as pulmonary vascular resistance which may be helpful in
surgical risk stratification.
Fluoroscopy is indispensable for procedural guidance of all
kind of MV interventions and provides 2D imaging with a clear
delineation of catheters, wires, delivery sheaths, and the kinetics
of devices and mechanical valves. However, it does not allow for
adequate soft tissue imaging or the visualization of 3D structures
and 3D anatomical relationships.
340 CHAPTER 23   Tran s cath eter mit ral valv e i n terven ti on s
2D and 3D TEE
3D TEE provides depiction of the complex 3D structures of the
MV apparatus and their relationship with surrounding struc-
tures as well as the 3D relationship of catheters/​wires/​devices to
the target lesion(s). Therefore it is considered as first line ancillary
imaging modality in conjunction with 2D TEE to support fluoros-
copy in the guidance of MV repair or replacement procedures [30].
Intracardiac echocardiography (ICE)
Experience with ICE during MV interventions is limited, but it
constitutes an alternative imaging method to guide MV interven-
tions in selected patients, specifically when general anaesthesia
is not used, when TEE is not applicable (e.g. in the presence of
oesophageal disease), or when it is the only available imaging mo-
dality. ICE provides imaging from within the heart, thus providing
shorter image distances to target structures and higher image
resolution. Limitations of ICE include the need for additional
venous access with a potentially increased risk of vascular com-
plications, higher costs, and a learning curve for interventionists.
Edge-​to-​edge MV repair [31] as well as PVML closure [32] have
been described as feasible under ICE guidance. A 10 F RT-​3D ICE
system with a volume image of 22° × 90° (AcuNav V catheter;
Siemens, Inc, Mountain View, CA) is available. Transducers that
allow for wider angle image acquisition could potentially increase
the acceptance of ICE during transcatheter MV interventions.
Fusion imaging
As percutaneous procedures are becoming more complex
multimodality cardiac imaging plays an increasingly important
role in the understanding of the anatomical structures and rela-
tionships, both for procedural planning and guidance. Combining
anatomical, morphological, and functional information derived
from different imaging modalities such as fluoroscopy, angiog-
raphy, advanced CT technologies, TEE, and CMR into a single
image, may overcome some of the limitations of each standalone
imaging method. This results in more comprehensive imaging and
improved diagnostic accuracy. The use of multiple imaging tech-
niques independently during procedures is often challenging and
requires the operator to mentally fuse images. The combination
of all information into one image can result in less instrument
manoeuvring during the procedure, improved communication
between operators and imagers, and a reduction in procedure
time. As most of the fused images are static, the combination of
TEE and fluoroscopy is currently of particular interest as it allows
for RT image fusion during interventional procedures [33, 34].
Transcatheter techniques to treat
mitral stenosis (MS)
Preprocedural evaluation of MS patients
Determination of MS aetiology
MS is characterized by an obstruction of LV inflow at the level
of the MV due to structural abnormalities of the MV apparatus.
In over >90% of the cases, the aetiology of MS is previous acute
rheumatic fever [35]. This is an autoimmune inflammatory pro-
cess that is related to Group A beta-​haemolytic streptococcal
infections. Rheumatic heart disease and MS typically occur dec-
ades after the episode of acute rheumatic carditis. With time, the
MV apparatus becomes thickened, calcified, and contracted, and
commissural fusion develops, ultimately resulting in MV ob-
struction. The clinical course of MS is highly variable but a con-
tinuous, lifelong progression typically occurs with a worsening
in MV area between 0.1 and 0.3 cm2 per year [36]. Though the
incidence of acute rheumatic fever has markedly decreased over
the last decades, rheumatic heart disease still represents 22% of
valvular heart diseases in Europe [37] affecting mainly elderly and
younger immigrants. In developing countries, rheumatic heart
disease remains the most common valvular heart disease with a
high number of unrecognized cases [38] and a high mortality rate
(23% within 12 years of follow-​up [39]).
Other less common aetiologies for MS include degenerative MS,
carcinoid heart disease, mucopolysaccharidoses of the Hunter–​
Hurler phenotype, Fabry disease, systemic lupus erythematosus,
Whipple disease, rheumatoid arthritis, drug therapy, radiation
therapy, and congenital MS.
The aetiology of MS is important. Commissural fusion is usu-
ally present in rheumatic MS, but absent in patients with non-​
rheumatic MS. Consequently, these patients are typically not
suitable for a PMBC as the procedure is based on splitting fused
commissures.
Grading of MS severity
Current guidelines suggest a multimodality approach to charac-
terize MS severity including the calculation of MVA (planimetry
of the MVA is considered as reference standard in this regard)
and the assessment of mean Doppler gradients and pulmonary
artery pressures as indicators of the haemodynamic consequences
of MS. Severe MS is determined by a MVA <1 cm2 and a mean
transvalvular gradient >10 mmHg in patients with sinus rhythm
in the European guidelines[40] and by a MVA ≤1.5 cm2 and a
transmitral gradient of 5–​10 mmHg at normal heart rate in the
American guidelines [4]‌.
Patients with a MVA >1.5 cm2 are typically asymptomatic and
have a good 10-​year survival rate [41]. A PMBC in these patients
may only be considered when symptoms cannot be explained by an-
other cause and when the anatomy is favourable [3]‌. An intervention
is generally recommended in symptomatic patients with rheumatic
MS and a MVA ≤1.5 cm2, when contraindications are excluded and
clinical and anatomical characteristics are favourable [3, 4].
Evaluation of associated valve disease
In a recent study, including 3,441 patients from sub-​Saharan
Africa, with at least one mild rheumatic lesion verified by echo-
cardiography, MR was seen in 52.8% of cases, aortic regurgitation
was present in 32.1% of cases, MS in 13.4% and aortic stenosis
in 1.8%. Lesions involving more than one valve were observed
in 13% of cases [42]. The presence of severe aortic or tricuspid
disease requiring surgery is a contraindication for PMBC [3, 4].
 Tra n s catheter techn i qu es to treat m i tr a l st e n o si s  (M S )
Assessment of haemodynamic consequences
Significant MS leads to chronic LA pressure overload, which re-
sults in structural remodelling and enlargement of the LA and
decreased LA function. This adverse process leads to a higher
prevalence of atrial fibrillation and an increased risk of thrombus
formation [43] with an 18-​fold increased risk of thromboembolic
events [44].
Furthermore, the restricted MV opening in MS patients limits
the filling of the LV and forward stroke volume is therefore typ-
ically reduced. Fibrosis and shortening of the subvalvular appar-
atus in MS patients cause shortening of the longitudinal LV axis,
a spherical remodelling of the LV and diastolic dysfunction as the
morbidly altered papillary muscles and chordae are connected to
the LV wall [45]. This may be aggravated when atrial fibrillation
is present due to an increased heart rate with reduced filing times
and the loss of LA contraction, thus contributing to a higher MV
gradient, reduced forward stroke volume and, consecutively, a
significant increase in LA pressure. Long-​term adverse outcomes
in MS patients correlate with LA dimension (>50 mm) and LV
end-​systolic dimension (<28 mm) [46].
The development of PH due to MS reflects the overall haemo-
dynamic consequences of the disease in which the elevated LA
pressure is transferred retrograde into the pulmonary veins and
capillaries. The presence of PH is a strong marker of adverse prog-
nosis, with 3-​year survival significantly limited when severe PH
is present [47]. Chronic PH may lead to right ventricular dila-
tation, right ventricular hypertrophy, and potentially right heart
failure in late stages. Pulmonary artery pressures should therefore
be routinely assessed in MS patients [3, 4].
Evaluation of relevant factors for a percutaneous mitral
balloon commissurotomy (PMBC)
Contraindications
There are contraindications to PMBC which are discussed in the
guidelines and summarized in E Box 23.1 [3, 4]. In this context,
a TEE study is preferable as its sensitivity for thrombus detection
is significantly superior to TTE [48].
Evaluation of predictors of procedural success
The prediction of a successful PMBC is based on multiple clin-
ical, haemodynamic, and anatomical factors. The patient’s age
and functional status, the presence of atrial fibrillation, PH, a
Box 23.1  Contraindications for performing a percutaneous mitral
balloon commissurotomy
Mitral valve area >1.5 cm²
◆ and post-​procedural MR as well as assess the final result and
Presence of a left-​sided cardiac thrombus
◆ potential complications.
Presence of moderate or severe mitral regurgitation
◆ Echocardiography is used to select balloon size by measuring
Bi-​commissural/​ severe calcification
◆ the maximal intercommissural diameter from the anterolateral
Absence of commissural fusion
◆
Severe concomitant valve or coronary artery disease requiring
◆
surgery
341
history of previous commissurotomy, MVA and presence and se-
verity of MR need to be considered [49]. Specific morphological
characteristics of the MV apparatus such as the mobility and
flexibility of the leaflets, thickness of both leaflets, commissural
adhesions, calcification of the MV apparatus, particularly in the
commissural area and subvalvular extension of the fibrotic/​scar-
ring process are used in different scores to describe the expan-
sion of the rheumatic damage, to determine if a patient is suitable
for a PMBC procedure and to predict procedural outcomes. All
scoring systems have advantages and disadvantages and should
be used as integrative components in the overall evaluation of MS.
No single method should be used to decide about an interven-
tion. The most commonly used Wilkins score [50] uses 2D TTE
valve characteristics including leaflet mobility, thickening, calci-
fication, and subvalvular involvement, with each characteristic
divided into four grades (score range: 4–​16). A score ≥8 predicts
less favourable outcomes and is associated with poor short-​and
long-​term results [50, 51]. 3D TEE evaluation [52] shows good
reproducibility and inter-​and intraobserver agreement and is su-
perior to 2D in evaluating the subvalvular MV apparatus. The
morphological factors used for a new ‘revisited’ TTE echocar-
diographic score include a very small MVA (≤1 cm2), maximum
leaflet displacement (≤12 mm), a commissural area ratio ≥1.25
and subvalvular involvement. This score is particularly helpful in
predicting outcome for patients at intermediate risk and seems to
be better predictive than the Wilkins score [53]. Of note, none of
the scores includes preprocedural MR, one of the strongest pre-
dictors of outcome following PMBC [54] and the most frequent
contraindication for PMBC, specifically when the MR grade is
more than mild [3, 4].
PMBC—​the procedure
The Inoue balloon catheter, introduced in1984, was the first
method to treat MV disease percutaneously. Subsequently, it has
emerged as the preferred technique to treat selected symptomatic
patients with severe MS [55–​57] with results comparable to sur-
gery. In experienced centres procedural success rates of >95% and
a median post-​procedural MVA of 1.9 cm² (range 1.5–​2.2 cm²)
are achievable [58].
The procedure is usually performed under conscious sed-
ation or general anaesthesia. TEE is useful to support fluoro-
scopic guidance, select an adequate balloon size, to avoid
undersizing (in this case balloon inflation would be ineffective)
and oversizing (increases the risk of leaflet rupture), to exclude
thrombi prior to a transseptal puncture (TSP), to guide safe bal-
loon positioning at the level of the mitral leaflets, to assess pre-​
to the posteromedial commissure in short-​axis TTE [59] or
transgastric short-​axis TEE views in mid-​diastolic still frames
images (or alternatively by using multiplanar reconstruc-
tions of a 3D data set). Transfemoral venous access is usually
342 CHAPTER 23   Tran s cath eter mit ral valv e i n terven ti on s

(a) (b) (c) (d) (e)

(f) (g) (h) (i) (j)

(k)

Fig. 23.3  Multimodal imaging guidance during percutaneous mitral balloon commissurotomy. (a) 3D enface view of the MV from the ventricular aspect
showing severe rheumatic MS with fused commissures. (b) 3D TEE image of the TSP with wire crossing into the LA. (c) Inoue balloon in the LA. (d) Inoue
balloon positioned between the MV leaflets with the distal part in the LV. (e) 2D TEE and (f) fluoroscopic images show the inflation of the distal part of the
balloon. (g) 2D TEE and (h) fluoroscopic images show further inflation of the proximal part of the balloon. The waist of the balloon is at the level of the mitral
leaflets. Full inflation of the balloon is seen in (i) 3D TEE and (j) fluoroscopy. (k) Post-​procedural 3D TEE image showing the increased MV opening with split
commissures.
Abbreviations: MS = mitral stenosis; MV = mitral valve; TEE = transoesophageal echocardiography; TSP = transseptal puncture.

preferred for the procedure, followed by a TSP to gain access
into the LA. The Inoue balloon is subsequently introduced
and then directed into the LV below the MV, where it is in-
flated step-​wise. The individual procedural steps (E Fig. 23.3)
and the main imaging tasks during each step are summarized
in E Table 23.1.
Transcatheter techniques to treat MR
Prior to the development of transcatheter methods, the re-
commended treatment strategy for patients with severe symp-
tomatic MR was either surgical MV repair or replacement.
Subsequently, there has been a proliferation of technologies to
treat MR using minimally invasive transcatheter approaches
[60–​62] (E Fig. 23.4). However, the MV is a complex 3D
structure with complexities unlike semi-​lunar valves. There
are multiple mechanisms that can result in MR. The saddle
shape of the MA, leaflet anatomy, the dynamic and variable
deformation of the annulus during the cardiac cycle [63], the
LA and LV anatomy, the subvalvular MV apparatus and the
relationship of the MA to the LVOT needs to be taken into
consideration when evaluating patients for a transcatheter ap-
proach to treat MR.
Evaluation of MR patients prior to a
transcatheter procedure
The first device allowing for the percutaneous treatment of pa-
tients with MR became available in 2008 with the introduction
of the MitraClip (Abbott vascular, Abbott Park, IL, USA). Since
that time an impressive number of novel catheters-​based mitral
interventions has emerged [64] and further increase in proced-
ural numbers can be expected in the next years. As percutaneous
options to treat MV disease can involve a number of different
techniques including edge-​to-​edge repair, chordal replacement,
direct/​indirect, annuloplasty approaches, and the implantation
of transcatheter replacement devices, preprocedural imaging and
procedural guidance require an understanding of the design and
 Tra n s catheter techn i qu es to treat m i tr a l st e n o si s  (M S ) 343

Table 23.1  Percutaneous mitral balloon commissurotomy—​procedural steps and imaging key points for procedural guidance

Procedural step Imaging key points for procedural guidance

1. Transseptal puncture (TSP) Preferred TSP site: mid-​fossa or slightly posterior-​inferior
◆
Exclude a thrombus prior to TSP (2D/​3D TEE)
◆
The TSP site is defined by using three 2D TEE views:
●

4-​chamber view at ~0° (to evaluate the height above the MV)

●

Short-​axis view at ~30–​45° (for anterior-​posterior orientation)

●

Bi-​caval view at ~90–​135° (for superior-​inferior orientation)

●

X-​plane imaging renders short-​axis and bi-​caval views in a single image and facilitates TSP
◆
A clear ‘tenting’ (tent-​like protrusion of the IAS towards the LA) should be seen to ensure the position of the needle
◆
in the fossa ovalis (2D/​3D TEE)
Large atria, interatrial septum aneurysms, a scoliosis, or a prior pneumectomy may impede TSP
◆

2. Positioning of the Inoue balloon Fluoroscopy is mainly used to navigate the balloon below the MV
◆
2D/​3D TEE can help to avoid probing/​perforation of the LAA and to optimize balloon positioning between the
◆
mitral leaflets and to avoid entanglement of the balloon with chordae
3. Step-​wise balloon inflation The balloon is step-​wise inflated from distal to proximal
◆
Balloon inflation is best observed fluoroscopically (balloon filling = contrast: saline = 1:5)
◆
Complete opening of the commissures is best seen fluoroscopically when the constriction in the middle of the
◆
balloon disappears
Balloon inflation in the subvalvular space may cause chordal rupture (2D/​3D TEE)
◆
Transient haemodynamic deterioration may occur during balloon inflation and dense spontaneous echo contrast
◆
may be visible in the LA (2D/​3D TEE)
Meticulous care is warranted in the elderly, in patients with significant comorbidities, asymmetric MV opening, severe
◆
commissural calcification, and in pregnant woman
4. Evaluation of result Determination
◆ of immediate procedural success includes [3, 4]:
● MVA ≥1.5 cm² or >1 cm²/​kg/​m² BSA (preferably by 2D/​3D planimetry. The pressure half-​time method is mostly
unreliable due to haemodynamic changes; Doppler gradients should be obtained)
No occurrence of MR grade >1
●

Complete opening of at least one commissure

●

Satisfactory leaflet mobility

●

◆ If the result is not satisfactory balloon inflation can be repeated by increasing the balloon size step-​wise in 1–​2 mm
increments
Re-​assessment of procedural success criteria and complications after each balloon inflation
◆
Size and shunt evaluation of the iatrogenic interatrial septum defect using 2D/​3D TEE
◆

5. Monitoring of complications The assessment of complications by 2D/​3D TEE includes particularly:

Leaflet rupture in a non-​commissural area
◆
MR ≥grade 2
◆
Pericardial effusion/​cardiac tamponade
◆
Thrombus formation
◆
Air embolism
◆

BSA = body surface area; LAA = left atrial appendage; IAS = interatrial septum; BSA = body surface area; MR = mitral regurgitation; TEE = transoesophageal echocardiography.

MitraClip PASCAL (CE mark

MitraClip NeoChord NTR/XTR expected for 2019)

2008
2010 2011 2012/2013 2014 2015 2016 2017 2018 2019
2009

Carillon mitral Enhanced mitral Cardioband Bident mitralign

contour system contour system

Fig. 23.4  Timeline of currently available mitral valve repair techniques.

344 CHAPTER 23   Tran s cath eter mit ral valv e i n terven ti on s

implantation technique of each device, along with the anatomical
suitability criteria and the complications that can ensue with in-
correct device selection.
Determination of MR aetiology
It is of major importance to classify MR either as degenerative
(DMR) or functional (FMR) as treatment options are inherently
different [65] (E Fig. 23.1). In DMR one or multiple components
of the MV apparatus are directly affected and responsible for the
occurrence of MR. Conversely, in FMR the MV is structurally
normal and MR is a consequence of annular dilatation due to LA
enlargement [66] or geometrical alterations of the LV secondary
to ischaemic or non-​ischaemic cardiomyopathy. In the western
world 60–​70% of MR patients undergoing surgery have DMR,
followed by ischaemic MR in ~20% of the cases [67–​69]. DMR
and FMR may occur at the same time, thus resulting in a ‘mixed’
MR. In these cases, the more dominant component needs to be
determined.
Grading of MR severity
MR quantification should be performed by integrating qualitative,
semi-​quantitative and quantitative parameters [3, 4]. The defin-
ition of severe MR includes an abnormal MV morphology (flail
leaflet, ruptured papillary muscle, large coaptation gap), a very
large MR jet in colour Doppler, a dense/​triangular continuous
wave Doppler signal of the MR jet, a large flow convergence zone,
a vena contracta width >7 mm (>8 mm for biplane), a systolic
pulmonary vein flow reversal in the upstream vein flow, a dom-
inant E-​wave ≥1.5 m/​s in the mitral inflow, a time-​velocity inte-
gral (TVI) mitral/​TVI aortic ratio >1.4, an effective regurgitant
orifice area (EROA) of ≥40 mm² and a regurgitant volume of ≥60
ml/​beat for DMR. In addition, LA and LV dilatation is usually
present, reflecting chronic volume overload.
Notably, there is currently no consensus between the American
and the European guidelines concerning quantitative parameters
to define severe FMR. In the European guidelines [3]‌severe FMR
is quantitatively defined as an EROA ≥20 mm² and a regurgitant
volume ≥30 mm/​beat whereas the American guidelines [4] use
the same definition as for DMR (EROA ≥40 mm², regurgitant
volume ≥60 ml/​beat).
Imaging approaches during specific
interventions
Edge-​to-​edge  repair
By mimicking the surgical concept of Alfieri who sutured the middle
scallops of both mitral leaflets thus creating a double MV orifice,
transcatheter edge-​to-​edge approaches connect the anterior and pos-
terior leaflet either by applying a Clip (MitraClip; Abbott Vascular
Structural Heart, Menlo Park, CA, USA) [61, 70, 71] or a clasp
(PASCAL device (under CE mark evaluation); Edwards Lifesciences,
Irvine, USA) [72]. Currently, the MitraClip system represents the
most widely used technology to address percutaneous repair of
DMR or FMR in patients at higher risk for surgery. To date, more
than 75,000 MitraClip procedures have been performed worldwide.
Procedural planning
2D and 3D TEE is essential for procedural planning as it allows
for the assessment of MR mechanisms and the morphological
suitability of the MV for applying an edge-​to-​edge technique and
predicting procedural success. Factors that may pose difficulties
to achieve good procedural results such as an uncertain origin of
a very eccentric, wall-​hugging MR jet or large substantial defects
in the leaflets need to be identified as an ideal location for leaflet
grasping may not be present in these cases. Favourable echocar-
diographic morphological criteria for performing a percutaneous
edge-​to-​edge MV repair are basically derived from the EVEREST
criteria [70, 71] and are summarized in E Table 23.2, as well as
unfavourable morphological characteristics. MitraClip implant-
ation in patients with intermediate morphological MV character-
istics may be technically more demanding, but has been shown to
be feasible and associated with similar rates of 12-​months safety
and efficacy [73].
Procedural guidance
Precise clip/​clasp positioning is important for optimal results
with reduction of MR to a grade less than moderate, with

Table 23.2  Morphological characterization by echocardiography for predicting procedural outcome for an edge-​to-​edge-​approach

Favourable morphological characteristics Unfavourable morphological characteristics

Origin of the MR jet in the A2/​P2 segments of the MV
◆ Leaflet perforations/​large clefts
◆
Non-​rheumatic/​ non-​endocarditic  MR
◆ Rheumatic or endocarditic MV disease
◆
Absence of leaflet calcification in the grasping region
◆ Opening area of the MV ≤3 cm² [114]
◆
Opening area of the MV ≥4 cm2
◆ Severe calcification in the grasping region
◆
Mobile posterior leaflet length ≥10 mm
◆ Large coaptation gap
◆
In DMR: flail width ≤15 mm and flail gap ≤10 mm
◆ Severe tenting (coaptation depth ≥11 mm)
◆
In FMR: coaptation length of at least 2 mm
◆ Mobile posterior leaflet length <7 mm
◆
Coaptation depth <11 mm
◆ Effective regurgitant orifice area >70.8 mm² [114]
◆
Presence of multiple significant MR jets in different regions of the MV
◆
(e.g. Barlow’s disease)
Abbreviations: DMR = degenerative mitral regurgitation; FMR = functional mitral regurgitation; MR = mitral regurgitation; MV = mitral valve.
Source data from Boekstegers P, Hausleiter J, Baldus S et al. Percutaneous interventional mitral regurgitation treatment using the Mitra-​Clip system. Clinical Research in Cardiology
2014;103:85–​96.
 Tra n s catheter techn i qu es to treat m i tr a l st e n o si s  (M S ) 345

(a) (b) (c)

(d) (e) (f)

(g) (h) (i)

Fig. 23.5  Imaging guidance with 2D and 3D transoesophageal echocardiography during edge-​to edge-​repair with the PASCAL device (Edwards Lifesciences;
Irvine, USA) in a patient with functional mitral regurgitation.
(a) Severe MR in x-​plane TEE imaging with colour Doppler (left: intercommissural view, right.: LVOT view). A coaptation gap of 2 mm was measured (not
shown). (b) TSP in x-​plane imaging. Short axis (left) and bi-​caval (right). (c) 3D TEE enface view demonstrating the device orientation in the LA perpendicular
to the line of coaptation. (d) The opened PASCAL device is placed below the MV and (e) subsequently both leaflets are grasped as seen in x-​plane views (left:
intercommissural view; right: LVOT view). (f) Device closure. (g) Residual MR in an intercommissural view after placement of two PASCAL devices. (h) 3D TEE
enface view of final result. (i) Mean gradient post procedure: 5 mmHg.
Abbreviations: LA = left atrial; LVOT= left ventricular outflow tract; MR= mitral regurgitation; MV = mitral valve; TEE = transoesophageal echocardiography.

elimination of all significant MR jets [74], without creating
haemodynamically relevant MS. Procedural steps are similar
for both the MitraClip and the PASCAL device. 3D TEE and
x-​plane imaging facilitate each step of the procedure and re-
duce procedure times when compared to 2D TEE as standalone
imaging modality to support fluoroscopy [75]. After TSP, the
guide catheter is introduced into the LA and subsequently the
delivery system is inserted. Next the device is positioned above
the MV, and orientated perpendicular to the line of coaptation
above the targeted MR jet. The selected device is then advanced
into the LV where clip/​clasp orientation is re-​assessed, then the
clip/​clasp is pulled back to the leaflets and in the next step the
leaflets are grasped. When proper leaflet insertion is confirmed,
the MitraClip/​PASCAL device is finally closed and fully de-
ployed when the effect on MR reduction is satisfactory. In most
cases, the implantation of the devices typically creates a double
MV orifice. If the result is suboptimal the clip/​clasp can be re-​
opened and re-​positioned multiple times or additional clips/​
clasps can be implanted.
The procedural workflow for both, the PASCAL device
(E Fig. 23.5) and the MitraClip (E Fig. 23.6) implantation is
similar and detailed in E Table 23.3 along with imaging key
points for each procedural step.
PVML closure
Clinically relevant PVMLs after surgical valve replacement occur
in ~3% [76, 77] of patients and can develop in association with
all valve types. Most commonly PVMLs are related to suture
dehiscence or infective endocarditis. The occurrence of heart
failure symptoms or clinically relevant haemolysis constitutes an
346 CHAPTER 23   Tran s cath eter mit ral valv e i n terven ti on s

(a) (b) (c)

(d) (e) (f)

(g)

Fig. 23.6  Imaging guidance with 2D and 3D transoesophageal echocardiography during edge-​to-​edge repair with a MitraClip XTR (Abbott vascular, Abbott
Park, IL, USA) in a patient with degenerative mitral regurgitation.
(a) 3D enface view: posterior prolapse with ruptured chords is seen. (b) 2D TEE with colour Doppler: the eccentric MR jet towards the anterior mitral leaflet is
seen. (c) The MitraClip is digitated towards the MV under x-​plane imaging guidance and (d) orientated perpendicular to the line of coaptation as seen in a 3D
TEE enface view. (e) After one MitraClip XTR is placed, (f) only trivial MR is visible in x-​plane images with colour Doppler. (g) The implantation of two MitraClips
in another patient is seen by using real-​time fluoro/​echocardiography overlay.
Abbreviations: 2D = two-​dimensional; 3D = three-​dimensional; MR = mitral regurgitation; MV = mitral valve; TEE = transoesophageal echocardiography.
Images courtesy of Patric Biaggi.

Table 23.3  Edge-​to-​edge repair—​procedural steps and imaging key points for procedural guidance
Procedural steps
1. Transseptal puncture (TSP)
2. Introduction of the Guide
catheter
3. Introduction of the delivery
into the left atrium (LA)
4. Positioning and orientation
of the device above the
mitral valve (MV)
5. Device advancement into
the left ventricle (LV)
6. Leaflet grasping
7. Device detachment
8. Evaluation of result
Tra n s catheter techn i qu es to treat m i tr a l st e n o si s  (M S ) 347
Imaging key points for procedural guidance
Preferred TSP site: superior and posterior in the fossa ovalis.
◆
An optimal TSP site avoids complex steering manoeuvres.
◆
With a MitraClip the height above the MV should be
◆
~3.5 cm in FMR patients
●
~4.5 cm in DMR patients
●
With a PASCAL device the height above the MV should be optimally ≥4.5 cm (apart from this see Table 23.1; TSP)
◆
The Guide catheter/​dilator assembly is introduced over the wire. This step is best guided by 2D/​3D TEE and fluoroscopy
◆
2 cm of the guide catheter is positioned in the LA; next, the dilator/​guidewire assembly is retrieved
◆
Damage to the free LA wall needs to be avoided during this step (2D/​3D TEE)
◆
◆ The location of the delivery system and the tip of the device in relation to the LA wall should be continuously imaged by
3DTEE/​ x-​plane imaging
◆ The positioning of the device above the MV is best guided with 3D TEE
medial-​lateral device adjustments are monitored in an intercommissural view (~60°)
●
anterior-​posterior adjustments are monitored in LVOT(~150°) views
●
The device is positioned above the targeted MR jet and the Clip/​clasp arms are orientated perpendicular to the line of
◆
coaptation
When a PASCAL device is used, the function of the clasps is confirmed by opening both clasps together and then
◆
independently
◆ Device advancement into the LV is best monitored by fluoroscopy and x-​plane imaging (intercommissural (~60°) and
LVOT (~150°) views)
In the LVOT view the Clip/​claps arms should be fully visible whereas in the intercommissural view no Clip/​clasp arms
◆
should be seen.
The opened Clip/​clasp is then advanced into the LV
◆
As the Guide catheter with the device may rotate, the Clip/​clasp orientation in the LV needs to be re-​assessed, preferably
◆
with 3D TEE (lower gain to visualize the device in the LV)
In case an additional device is implanted, the device is usually closed during translation from the LA to the LV and re-​opened
◆
below the MV leaflets
Leaflet
◆ grasping is best performed by using x-​plane imaging (intercommissural (~60°) and LVOT (~150°) views)
◆ The selected device is fully closed after demonstrating adequate insertion of both leaflets, a reduction in MR severity and
no relevant MS.
Leaflet insertion should be assessed in multiple imaging planes.
◆
Adequate leaflet insertion avoids partial device detachment/​embolization
◆
With the MitraClip both leaflets need to be grasped in one step whereas the PASCAL device allows for independent
◆
grasping of both leaflets
A spacer between the two clasps may be useful to further reduce MR
◆
◆ 3DTEE is useful to evaluate the ultimate orientation of the grasp, and to assess for MV distortion due to off-​axis device
implantation
The result needs to be evaluated after each device implantation and should include:
Assessment of residual MR severity
◆
Echocardiographic machine settings and haemodynamic parameters should be comparable before and after device
●
implantation to adequately define residual MR severity
A multimodal approach is recommended to assess residual MR
●
Artefacts caused by the implanted device may impair echocardiographic assessment of residual MR
●
The PISA method/​vena contracta width is not validated for multiple jets (however, small MR jets, even if multiple, are
●
usually consistent with mild MR)
The evaluation of pulmonary vein flow is very useful. Elimination of systolic flow reversal and/​or a shift from D
●
dominant to S dominant flow pattern reflect a drop in LA pressure and a reduction in MR
3D vena contracta area and real-​time-​3D volume colour flow Doppler improve MR quantification after percutaneous
●
edge-​to-​edge repair [115–​117])
Residual MR should be ≤moderate by eliminating all significant jets [74]
●
CMR is very useful when echocardiographic MR grading is uncertain [118]
●
Evaluation of MVA
◆
Mean Doppler gradients should be ≤5 mmHg [119].
●
A planimetric MVA <1.5cm² indicates severe MS (can be obtained either with transgastric 2D or 3D TEE views) [120]
●
In case additional devices need to be implanted fluoroscopy is particularly helpful in the positioning of additional devices,
◆
as these should be aligned as parallel as possible to the previous device. A significant MR jet between two devices may be
uncorrectable and should be avoided
Size and shunt evaluation of the iatrogenic interatrial septum defect using 2D/​3D TEE
◆
(continued)
348 CHAPTER 23   Tran s cath eter mit ral valv e i n terven ti on s

Table 23.3 Continued
Procedural steps
9. Monitoring of complications
Imaging key points for procedural guidance
The assessment of complications by 2D/​3DTEE includes particularly:
chordal entrapment by the device
◆
partial device detachment/​embolization
◆
thrombus formation on wires/​catheters/​devices
◆
pericardial effusion/​tamponade
◆
air embolism
◆

Abbreviations: 2D = two-​dimensional; 3D = three-​dimensional; DMR = degenerative mitral regurgitation; FMR = functional mitral regurgitation; MR = mitral regurgitation; MV =
mitral valve; MVA = mitral valve area; TEE = transoesophageal echocardiography.

indication for surgical PVML closure [3, 4]. However, each redo
surgical procedure is associated with a significant increase in mor-
tality and re-​occurrence rate of PVMLs [78]. Thus transcatheter
PVML closure constitutes an important alternative method for
patients at a high risk for surgery with morphologically suitable
characteristics for percutaneous PVML closure (Class IIb/​level
of evidence C recommendation in current European guidelines
[3]‌and class IIa/​level of evidence B recommendation in cur-
rent American guidelines [4]). A reduction in the grade of MR
after PVML closure is associated with an improvement in heart
failure symptoms [79] and results in significant improvement in
short-​term and midterm survival and functional class [77, 80].
Therefore, every attempt should be made to reduce paravalvular
MR as much as possible. PVMLs can be isolated or multiple. In
case >2 PVMLs are present, successful paravalvular MR reduc-
tion is less likely [77]. For the prevention of haemolysis, a more
modest effect can be expected, with better results in patients with
mechanical valves [81].
Procedural planning
A multimodal approach is generally recommended to assess
for PVMLs [82]. The mainstay of evaluating PVMLs is with
echocardiography-​based techniques. These have the ability to
evaluate blood flow at a high temporal resolution.
The quantification of paravalvular MR may be challenging
and requires and integrative approach. As there is no uniform
definition on what constitutes a severe PVML a recent expert
statement paper suggests using qualitative/​semi-​quantitative
primary parameters (abnormal sewing ring motion, wide jet
width, multiple jets, visible flow convergence zone, % LVOT
diameter ≥60%) and secondary parameters (moderately/​se-
verely dilated LV, vena contracta width >6 mm, dense spectral
Doppler profile, holodiastolic flow reversal, pressure half-​time
>200 ms ((increased mean gradients and high transmitral flow
compared with LVOT flow in the setting of a normal pres-
sure half-​time indicate relevant regurgitation), end-​diastolic
velocity >20–​30 ms). In addition, the following quantitative
parameters are suggested to define severe paravalvular MR:
regurgitant volume ≥60 ml, regurgitant fraction ≥50%, EROA
>0.3 [83]. 3D planimetry of the vena contracta area of the
leaks by using multiplanar reconstructions of a 3D colour data
better correlates with the degree of paravalvular MR than 2D
methods. A major diameter of the 3D colour regurgitant ori-
fice ≥0.65 cm was associated with low-​moderate paravalvular
MR [84].
TTE is superior in estimating pulmonary artery pressure, as-
sessing transvalvular mitral gradients, ventricular and atrial
sizes, and function compared with TEE. However, MR evalu-
ation may be hindered or impossible due to shadowing caused
by sewing rings, mechanical prostheses, or calcifications. 2D and
particularly 3D TEE is preferable to localize the leak(s), assess
the number, exact shape, and dimensions as well as the distance
and the orientation of the leak(s) to the implanted ring or the
mechanical prosthesis [85]. This information is important for the
selection of an adequate device type and size and optimal best
access route.
Patients with an unstable mechanical MV indicated by rocking
movements of the valve [86] or evidence of active endocarditis
should undergo surgery and should not be considered as candi-
dates for a transcatheter PVML closure procedure.
Where there is diagnostic uncertainty or further information is
required, cardiac CT may be considered as an adjunctive investi-
gation. The assessment of PVMLs on cardiac CT can be challen-
ging with different prosthetic heart valves being subject to varying
degrees of hard beam artefact that influence image interpretation.
However, currently implanted prosthetic heart valves usually have
good image quality on multidetector CT and are suitable for CT
evaluation [87, 88].
Procedural guidance
Fluoroscopy and 2D/​3D TEE imaging are integral for procedural
guidance. A clock-​model is widely used to describe the position of
the leak(s) and to facilitate procedural guidance by improving the
communication between imagers and interventionalists. Thereby
a surgical RT-​3D TEE view is used with the aorta as major land-
mark positioned at 12 o’clock at top of the MV (anterior) and the
left atrial appendage in an approximately 9 o`clock position (lat-
eral) [89] (E Fig. 23.7a).
Careful 2D and particularly 3D TEE monitoring [84]
throughout all procedural steps is essential to confirm: (1) ad-
equate TSP in case an antegrade approach is chosen; (2) correct
probing of the targeted lesion(s) with wires/​catheters/​delivery
sheaths; (3) proper and stable device position and orientation
(particularly important when an oval shaped device is used)
 Tra n s catheter techn i qu es to treat m i tr a l st e n o si s  (M S ) 349

(a) (b) (c)

(d) (e)

Fig. 23.7  Paravalvular mitral leak closure. (a) Schematic: LA enface view of the MV. The aortic valve (AV) is positioned at 12 o’clock ( = anterior), opposite is
posterior at 6 o’clock. The left atrial appendage (LAA) is positioned at approximately 9 o`clock (lateral), opposite is medial at 3 o’clock (landmark: interatrial
septum (IAS)). (b) A severe PVML is seen at 4 o’clock in a posteromedial position (yellow arrow) in a 3D TEE enface view and (c) in a 2D TEE with colour
Doppler; (d) The implanted device is seen in a 3D TEE enface view (red star); (d) Colour Doppler shows no evidence of relevant residual paravalvular mitral
regurgitation medially (yellow arrow).
MVP = mitral valve prosthesis; PVML= paravalvular mitral leak; TEE = transesophageal echocardiography.

Table 23.4  Paravalvular mitral leak closure—​procedural steps and imaging key points for procedural guidance

Procedural step Imaging key points for procedural guidance

1. Access
2. Wiring/​probing of the defect
Three options to get percutaneous access to a PVML:
1. Antegrade: Most operators prefer this least invasive transseptal approach to gain access to PVML leak from the LA
side (see E Table 23.1; TSP)
2. Retrograde: By using a retrograde approach via the aortic valve the leak can be wired more easily in the direction of
the regurgitant jet but an additional TSP may be needed to snare the wire in the LA and externalize it through the
femoral vein. Such an arterio-​venous loop may provide better stability during device deployment
3. Transapical: this access (best preplanned by CT) is more invasive but allows for a more direct guidewire passage
from the LV across the ventricular aspect of the PVML and is preferred by some operators, particularly when the
PVML is located close to the septum
Correct canalization of the targeted PVML needs to be verified by 2D/​3D TEE imaging
◆
A steerable sheath may be helpful to probe the PVML and is best navigated by using 3D TEE imaging
◆

3. Advancement of the delivery 2D/​3D TEE is used to monitor the advancement of the specific delivery sheath for the selected device through the PVML
◆
sheath through the leak Due to the irregular shapes of the PVML tracts severe friction may prohibit a smooth advancement. The use of
◆
hydrophilic sheath/​stabilizing wires may overcome this problem
4.  Device deployment This
◆ step is best monitored with 2D/​3D TEE and fluoroscopy (orthogonal views of the MV are usually most helpful)
◆ Once the leak is crossed with the delivery sheath either the LA or LV disc (this depends on the access way) of the
selected device is deployed first
Subsequently, the device is pulled back to the implanted valve ring, and if proper device placement is permitted and
◆
the device is aligned to the leak, the second disc either on the LV or LA disc is deployed
With retrograde access, meticulous care is needed not to damage LV structures (e.g. trabeculae, papillary muscles,
◆
chordae)

(continued)
350 CHAPTER 23   Tran s cath eter mit ral valv e i n terven ti on s

Table 23.4 Continued

Procedural step Imaging key points for procedural guidance

5.  Evaluation of result
The determination of procedural success by 2D/​3DTEE imaging includes particularly:
A stable device position without any interference with a mechanical MV prosthesis or adjacent structures [80]
◆
The predominant reason for procedural failure is prosthetic leaflet impingement [121]
●

An immobile leaflet of a mechanical prosthesis is easiest seen in fluoroscopy

●

An immediate1-​grade reduction of paravalvular MR as this has relevant impact on mortality, haemolysis, the
◆
functional status, and the need for repeat surgery [80]
Size and shunt evaluation of the iatrogenic interatrial septum defect using 2D/​3D TEE
◆

6.  Monitoring of complications The assessment of complications by 2D/​3D TEE includes:

Pericardial effusion/​tamponade
◆
Thrombus formation
◆
Wire entrapment in a mechanical valve
◆
Device embolization due to a mismatch of the device size and the defect
◆
Prosthetic valve leaflet impingement
◆
Air embolism
◆

Abbreviations: 2D = two-​dimensional; 3D = three-​dimensional; CT = computed tomography; LA = left atrial; PVML = paravalvular mitral leak; TEE = transoesophageal
echocardiography; TSP = transseptal puncture.

after deployment; (4) no prosthetic leaflet impingement; (5)
successful paravalvular MR reduction (at least 1-​grade regur-
gitation reduction [80]); (6) safe retrieval of catheters/​sheaths;
and (7) absence of a relevant iatrogenic interatrial septal shunt
and complications. The individual procedural steps and key
points for imaging guidance are summarized in E Table 23.4
and E Figure 23.7.
Direct and indirect annular approaches
Patients with FMR are typically at high risk for surgery and
transcatheter techniques to perform a mitral annuloplasty there-
fore represent an important option for these patients.
Feasibility and safety data are available for three CE marked
devices: (1) The Carillon Mitral Contour system® (Cardiac
Dimensions, Kirkland, WA, USA) is composed of two self-​
expanding nitinol anchors with a curvilinear nitinol wire
connecting them. The device is implanted mainly under fluoro-
scopic guidance into the coronary sinus via transjugular ac-
cess. Once in correct position, tension on the system is applied
in order to shorten the system thus resulting in an indirect
cinching effect on the posterior MA [90, 91]. (2) The Mitralign
Percutaneous Annuloplasty System (Mitralign, Tewksbury,
MA, USA) represents a direct annuloplasty approach. A retro-
grade access via the aorta is used to reach the MA from the
LV side. The MA is then punctured by using radiofrequency
wires and one or two pair of pledgets are inserted at the level of
the commissures and then assembled and locked to plicate the
MA [92]. (3) The Cardioband mitral repair system (Edwards
Lifesciences, Irvine, USA) is another direct annuloplasty ap-
proach and replicates a surgical annuloplasty band. It is im-
planted step-​wise from the antero-​lateral to the postero-​medial
commissure by screwing 12–​17 anchors into the LA side of the
MA. Once all anchors are in place, the band is cinched until
a satisfactory MR reduction is seen in 2D/​3DTEE with colour
Doppler [93, 94] (E Fig. 23.8).
Preprocedure, a 2D/​ 3DTEE is mainly used to define the
mechanism(s) of MR and to grade MR severity whereas a CT is
the most useful imaging modality to define the exact geometry
and dimensions of the MA, to assess for the extent and contribu-
tion of MAC and the variable anatomical relationship (height and
distance) of the coronary sinus and the left circumflex coronary
artery to the MA [95] which may impact procedural success
rates and to predefine optimal TSP sites and fluoroscopic angles.
Fluoroscopy and 2D/​3DTEE is then used in conjunction for pro-
cedural guidance.
Implantation of artificial chords
The NeoChord DS1000 system (NeoChord Inc., St. Louis Park,
MN, USA) allows for the off-​pump transapical implantation
of artificial neo-​chords in patients with severe MR due to MV
prolapse, thus replicating a proven effective surgical concept
[96]. Thereby, the coaptation of the mitral leaflets can be re-
stored on the beating heart. Several studies confirmed the feasi-
bility and safety of the procedure, as well as short-​term efficacy
and clinical improvements [97–​100]. Ideal candidates with iso-
lated or combined prolapses in the P2/​P3 region with no rele-
vant annular dilatation showed very good and durable 5-​year
results [101]. 2D and 3D TEE is usually sufficient to adequately
describe the site(s) of prolapse and grade MR severity and to
select eligible patients. The length of both mitral leaflets in re-
lation to the annulus needs to be assessed in long-​axis LVOT
views to ensure that adequate leaflet tissue is present for poten-
tial coaptation surface (E Fig. 23.9a). It could be shown that
a leaflet-​to-​annulus index of >1.25 is a strong predictor of MR
≤mild at 1-​year follow-​up [102].
For the procedure a transapical access slightly posterolateral
to the LV apex is generally preferred to introduce the NeoChord
system into the LV. The system is then directed between the mi-
tral leaflets and the prolapsed segment is grasped between the
expandable jaws of the device under 2D TEE guidance. Once
 Tra n s catheter techn i qu es to treat m i tr a l st e n o si s  (M S ) 351

(a) (b)

(c) (d)

(e)

Fig. 23.8  Cardioband implantation. A preprocedural CT data set is reconstructed to measure (a) the posterior mitral annulus length from trigone-​to-​trigone
(white line) to select the appropriate band size, and (b) the distance of the selected anchor site to the hinge point of the MV and the left circumflex coronary
artery (Lcx; red line) or the coronary sinus (CS; blue line) for each anchor region. In addition, the best fluoroscopic angles for procedural guidance (c) and the
preferred TSP site (d) can be predefined. (e) Annular dimensions are measured pre (top) and post (bottom). Cardioband implantation by using multiplanar
reconstructions. In this case a mitral annular area reduction of ~30% was achieved.
Abbreviations: CT = computed tomography; MV = mitral valve; TSP = transseptal puncture.
352 CHAPTER 23   Tran s cath eter mit ral valv e i n terven ti on s

(a) (b) (c)

(d) (e) (f)

Fig. 23.9  NeoChord implantation in a patient with degenerative mitral regurgitation due to a P2 prolapse. (a) A PML prolapse (red line) is seen. The leaflet-​
PML + AML
to-​annulus index= > 1.2 can be calculated in this long-​axis 2D TEE view to ensure adequate leaflet tissue for coaptation surface after NeoChord
AP diameter
implantation. (b) Colour Doppler verifies an eccentric MR jet (yellow arrow). (c) 3D enface TEE view: the P2 prolapse (red arrow) and a ruptured chord (red star) is
seen. (d) After implantation of four neo-​chords (NeoChord., Inc., St. Louis Park, MN, USA) trivial MR (yellow arrow) is visible. (e) The restored coaptation surface is
visible in a 3D TEE enface view. (f) Additional colour Doppler confirms trivial residual MR (yellow arrows).
3D = three-​dimensional; AML = anterior mitral leaflet; AP = anterior-​posterior; MR = mitral regurgitation; PML = posterior mitral leaflet; TEE= transesophageal echocardiography.
Images courtesy of Krzysztof Wróbel and Katarzyna Kurnicka.

adequate grasping is confirmed, the suture is attached to the pro-
lapsing segment and pulled back through the LV apex. The length
of the artificial chord is subsequently adapted under RT-​TEE and
colour Doppler monitoring until a satisfactory MR reduction is
visible. To obtain optimal results, the implantation of multiple
chords is generally needed. E Figure 23.9 provides an example
of a successful NeoChord implantation.
Although 2D/​3DTEE is of major importance to characterize
and grade MV disease and to guide TMVR procedures, a cardiac
CT scan currently forms the cornerstone of patient screening as a
detailed analysis can be performed to confirm the suitability and
implantability for the TMVR device.
The key elements for consideration for TMVR replacement in
these CT analyses include [111, 112]:

Transcatheter mitral valve replacement (TMVR)
techniques
The feasibility of implanting transcatheter heart valves (THV)
originally designed for aortic valve replacement into failed MV
bioprostheses (VIV) [103–​ 106] (E Fig. 23.10), failed mitral
annuloplasty rings (VIR) [105, 106], or in a severely calcified na-
tive annulus (valve-​in-​MAC) [105–​109] (E Fig. 23.11) with MS,
MR, or both, by using transseptal or transapical access has been
demonstrated in several case studies, small case series, or regis-
tries. Several specifically designed TMVR devices are also in dif-
ferent stages of development [110].
1 Measurements of MA size across the cardiac cycle: The MA
area and perimeter should be measured as a D-​shaped struc-
ture during systole and diastole to provide an accurate es-
timate for device sizing. Measurements should also include
the anterior-​posterior and intercommissural distances. Note
should be made of the presence and extent of mitral leaflet and
annular calcification.
2 LA size and relationship of the MA to the left atrial appendage
and pulmonary veins.
3 The aorto-​
mitral angulation during end-​systole: This is a
measurement of the angle of the MA plane to the LVOT. The
 Tra n s catheter techn i qu es to treat m i tr a l st e n o si s  (M S ) 353

more acute the angle the greater the perceived risk of LVOT
obstruction.
4 The Neo-​ LVOT: Where possible the proposed valve size
should be superimposed onto the cardiac CT data set to geo-
metrically predict for the occurrence of LVOT obstruction
(E Fig. 23.12).
5 LV characteristics: The multiphase CT scan may be used for
a 3D evaluation of LV shape, volume, and ejection fraction.
A severe impairment of LV function (<30–​35%) is gener-
ally considered to be a contraindication to TMVR. The LV
should also be evaluated for its size and ability to accommo-
date a TMVR device without causing LVOT obstruction.
6 Access ways: the interatrial septum needs interrogation when a
transseptal access is needed. The papillary muscle architecture
should also be reviewed and specifically the distance between
the papillary muscle heads and the distance from these to the
MA plane. For transapical access the LV apex shouldn’t be
thinned out (<5 mm may not allow for secure transapical ac-
cess). In addition, the optimal transapical access point that will
allow for coaxial valve deployment needs to be determined.

(a) (b)

(c) (d)

Fig. 23.10  Valve-​in-​valve implantation. (a–​d) TEE: (a) St. Jude Epic valve in the MV position on the 0° view. (b) Severe MR through the prosthesis. (c) 3D
and (d) colour Doppler appearances respectively of the MV once a Sapien 3 valve (Edwards Lifesciences, Irvine, USA) has been implanted within the failing
bioprosthesis. (e–​j) CT-​fluoroscopy fusion used in the same patient during the procedure. From the preprocedural cardiac CT scan, various anatomical
landmarks can be annotated. (e) The marking of various anatomical landmarks and image segmentation from the cardiac CT scan is shown. (f, g) The co-​
registration of these prepared images onto the real-​time fluoroscopic image acquisitions in two different views is shown. Once co-​registration has been
performed the cardiac CT scan images can be used to provide additional imaging data and optimal fluoroscopic projections to guide the procedure. (h) CT
volume rendered fluoroscopic image fusion and (i) CT outline fluoroscopic image fusion is seen (the yellow arrow points out the guidewire into the LV through
the failing MV bioprosthesis). (j) The subsequent implantation of the Sapien 3 valve is shown (the white arrow points out the successful inflation of the Sapien
3 valve within the failing bioprosthesis). The CT planning and fusion software package was performed with Valve ASSIST 2 (GE Healthcare, Chicago, IL) and the
multimodality workstation for image processing and fusion imaging: Advantage Workstation (GE Healthcare, Chicago, IL).
Abbreviations: 3D = three-​dimensional; CT = computed tomography; MR = mitral regurgitation; MV = mitral valve.
354 CHAPTER 23   Tran s cath eter mit ral valv e i n terven ti on s
(e)
(g)
(i)
Fig. 23.10 Continued
As each TMVR device has device-​specific criteria individually ad-
justed imaging protocols need to be developed for each TMVR
system. Imaging key points regarding TMVR are summarized in
EBox 23.2.
Combined transcatheter mitral procedures
Similar to surgical procedures, it may be necessary to combine
different transcatheter mitral repair/​replacement techniques
to achieve optimal results regarding MR reduction. A surgical
procedure generally aims for a one-​step approach to eliminate
all MR components in order to avoid a redo operation. Unlike
surgery transcatheter methods allow for a staged approach for
example in mixed MV disease or when failure of a primarily
implanted device occurs during follow-​ up. Experience is
(f)
(h)
(j)
currently limited to case reports describing the combination of
annuloplasty approaches and edge-​to-​edge-​repair or chordal
implantation and VIV or VIR implantation combined with
PVML closure.
Conclusion
The past decade has been a revolution in the use of percutan-
eous procedures for MV therapy, and currently there are over
45 devices in different stages of development. The enhanced
imaging with 3D TEE as well as CT and fusion imaging, has led
to better understanding of MV anatomy, which in turn helped
promote the development of new devices, as well as being crucial
 C on c lusi on 355

(a) (b) (c) (d)

(e) (f) (g) (h)

Fig. 23.11  Valve in severe mitral annular calcification. (a) TEE with colour Doppler demonstrates an accelerated diastolic flow through the MV and (b) severe
MR in systole. (c) Severe mitral annular calcification and a narrowed MV opening is visible in a 3D TEE enface view. (d) Mean gradient: 9 mmHg. (e) A 29 mm
Sapien 3 aortic valve (Edwards Lifesciences; Irvine, USA) is implanted under rapid pacing. (f) No relevant MR is visible post implantation. (g) A 3D TEE enface
view demonstrates normal leaflet motion. (h) Mean gradient post implantation: 3 mmHg.
Abbreviations: 3D = three-​dimensional; MR = mitral regurgitation; MV = mitral valve; TEE = transoesophageal echocardiography.

for procedural guidance and effective valve repair or replace-
ment. In addition to the new devices, fusion imaging promises
to result in even better outcomes in the future, by enhancing
device deployment. While initially device development for the
MV focused on degenerative MR, more recent studies have
demonstrated that reducing the severity of functional MR with
transcatheter techniques (namely the MitraClip [61]), provides
symptomatic benefit with regards to cardiac heart failure and
improved survival. Percutaneous therapies for the MV, as they
are less invasive, have many advantages that may supplant sur-
gical techniques, provided that they reduce morbidity and mor-
tality and have comparable efficacy.

(a) (b) (c)

Fig. 23.12  Computer simulation for valve in mitral annular calcification: from a preprocedural CT data set, heart segmentation is performed followed by finite
element modelling. This accounts for the tissue properties of the mitral annulus calcification, leaflets, chords, and papillary muscles. Virtual valves can then be
implanted onto the CT data set to determine the optimal height of deployment, the neo-​LVOT area, and the calcium deformation. (a) shows the marking of the
neo-​LVOT plane (red line), (b) the view of a Sapien 3 valve from the LA with a valve implanted inside the mitral annulus calcification; and (c) the measurement
of the anticipated neo-​LVOT area.
Neo-​LVOT = neo left ventricular outflow tract once a transcatheter heart valve is implanted; CT = computed tomography; LA = left atrium; LVOT = left ventricular outflow tract.
356 CHAPTER 23   Tran s cath eter mit ral valv e i n terven ti on s
Box 23.2  Considerations regarding transcatheter mitral valve replacement techniques
General considerations
◆ LVOT obstruction:
Multiple factors including small, hyperdynamic LVs, septal
●
bulging, aorto-​mitral annular angle, long, bulging AMLs,
greater device protrusion and TMVR devices with a greater
length determine LVOT obstruction [122].
TMVR device embolization:
◆ the THV.
Very large and/​or elliptically shaped MA increase the risk of
●
embolization.
Undersized valves may lead to valve embolization and/​or
●
post-​procedure higher MR grades.
An oversize of 15–​25% is usually applied to select the TMVR
●
device size.
Severe and protruding MAC may avoid a good appos-
●
ition of TMVR systems with a higher risk of emboliza-
tion thereby creating a substrate for the development
of PVMLs.
The presence of significant paravalvular MR at baseline may re-
◆ valve may be preferable [124].
quire concomitant PVML closure.
Bulky valve designs increase the risk for valve thrombosis.
◆ Valve-​in-​MAC:
Patients should be able to tolerate at least short-​term (3 months)
anticoagulation. Appropriate anticoagulation therapy concepts
need to be developed.
Specific considerations
◆ VIV implantation: the properties of the bioprosthesis (height,
stent internal diameter, and true internal diameter) need to be
considered.
References
1. Carpentier A. Cardiac valve surgery—​the ‘French correction’. J Thorac
Cardiovasc Surg 1983; 86: 323–​37.
2. Carpentier A. [Reconstructive valvuloplasty. A new technique of mi-
tral valvuloplasty]. La Presse Medicale 1969; 77: 251–​3.
3. Baumgartner H, Falk V, Bax JJ, et al. 2017 ESC/​EACTS Guidelines
for the management of valvular heart disease. Eur Heart J 2017; 38:
2739–​91.
4. Nishimura RA, Otto CM, Bonow RO, et al. 2017 AHA/​ACC Focused
update of the 2014 AHA/​ACC Guideline for the Management of Patients
with Valvular Heart Disease. Circulation 2017; 135: e1159–​e95.
5. Lange A, Palka P, Burstow DJ, Godman MJ. Three-​dimensional echo-
cardiography: historical development and current applications. J Am
Soc Echocardiogr 2001; 14: 403–​12.
6. Lang RM, Badano LP, Mor-​Avi V, et al. Recommendations for cardiac
chamber quantification by echocardiography in adults. Eur Heart J
Cardiovasc Imaging 2015; 16: 233–​70.
7. Heo R, Son JW, Ó Hartaigh B, et al. Clinical implications of three-​
dimensional real-​time color doppler transthoracic echocardiography in
quantifying mitral regurgitation: a comparison with conventional two-​
dimensional methods. J Am Soc Echocardiogr 2017; 30: 393–​403.e7.
8. Zamorano J, Perez de Isla L, Sugeng L, et al. Non-​invasive assessment
of mitral valve area during percutaneous balloon mitral valvuloplasty:
role of real-​time 3D echocardiography. Eur Heart J 2004; 25: 2086–​91.
● Knowledge on which THV size can be safely implanted in a
specific bioprosthesis is required [123]).
The reported valve size by the manufacturers are different
●
from the measured inner stent diameters.
The valve size should be confirmed by using multimodality
●
imaging (2D/​ 3D TEE/​ CT) in order to avoid mis-​ sizing of
◆ VIR implantation: the implanted ring type, geometry, and size
needs to be considered.
Knowledge on which THV size can be safely implanted in a
●
specific ring is needed [123].
A more proper fit can be reached with semi-​rigid rings than
●
with rigid ones.
A complete ring may offer better fixation for a transcatheter
●
heart valve than an incomplete ring.
A primarily selected surgical ring brand/​size which allows for
●
a good placement of a THV in case of failure of the surgical
Results are less favourable compared to VIV procedures.
●
◆
The absence of circumferential calcification may prohibit
●
secure anchoring of the THV.
Results are less favourable compared to VIV procedures.
●
AML = anterior mitral leaflet; CT = computed tomography; LV = left ventricle;
LVOT = left ventricular outflow tract; MA = mitral annulus; MAC = mitral
annular calcification; MR = mitral regurgitation; PVML = paravalvular mitral
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 CHAPTER 24

Transcatheter tricuspid
valve repair/​replacement
Rebecca T. Hahn

Dr Hahn reports the following disclosures:

Contents Speaker for: Abbott Vascular, Boston Scientific, Bayliss, Edwards Lifescience, Philips
Introduction  361
Tricuspid valve anatomy  362
Healthcare, Siemens Healthineers.
Imaging of the native tricuspid valve
apparatus  362 Consultant/​advisory board: 3Mensio, Abbott Vascular, Edwards Lifescience, GE Healthcare,
Considerations for transcatheter tricuspid Gore&Associates, Medtronic, Navigate, Philips Healthcare, Siemens Healthineers.
valve devices  363   She is the Chief Scientific Officer for the Echocardiography Core Laboratory at the
Future perspectives  371
Cardiovascular Research Foundation for multiple industry-​sponsored trials, for which
Conclusion  374
she receives no direct industry compensation.

Introduction
The most common cause of tricuspid regurgitation (TR) is secondary or ‘functional’ re-
gurgitation [1]‌. Secondary or functional TR represents an important unmet treatment
need given its prevalence, adverse prognostic impact, and symptom burden associ-
ated with progressive right heart failure [2, 3]. Although surgical treatment of severe,
symptomatic functional disease is currently primarily indicated only with concomitant
treatment of left heart disease, isolated treatment of the tricuspid valve (TV) is a Class
IIa indication for treatment [4, 5]. Interest in the transcatheter solutions for TR has in-
creased in recent years with the recognition of the impact of secondary TR on outcomes
[6–​9] and the high in-​hospital mortality associated with isolated TV surgery [10, 11].
Studies evaluating surgical results of TV repair or replacement give insight into the
current population presenting for transcatheter interventions and the possible expected
outcomes. An analysis of 54,375 patients from the Society of Thoracic Surgeons (STS)
database undergoing TV surgery between 2000 and 2010 showed that 89% of TV sur-
geries involved repair procedures (annuloplasty only in 75.5% of repairs), usually per-
formed with concomitant left heart surgery [12]. During this 10-​year period, operative
mortality decreased from 10.6% to 8.2%. A more recent 10 year study of 5,005 patients in
the Unites States National Inpatient Sample, showed that isolated TV surgeries increased
from 290 in 2004 to 780 in 2013 [11]. In-​hospital mortality was 8.8% and remained con-
sistent over the study period. A similar 10-​year analysis utilizing the same database in-
cluded 9,194 patients undergoing TV surgery [10] showed that isolated TV surgery is
uncommon (15%) and in most patients the TV is treated during concomitant cardiac
surgery (85%). The patients undergoing isolated TV surgery are older with a higher risk
profile and suffered high rates of postoperative morbidities as well as protracted hos-
pitalizations. In-​hospital mortality after isolated TV surgery was similarly high (10.9%
with replacement vs. 8.1% with repair) and has not changed significantly during the last
362 CHAPTER 24   Tran s cath eter t ricu spid va lve repa i r /repl acem en t
decade. This study also reported a higher rate of permanent pace-
maker implantation with isolated replacement compared to re-
pair (34.1% vs. 10.9%).
Differences in in-​hospital mortality between replacement and
repair may not be related to surgical technique. Borger et al. re-
ported the first contemporary series comparing the results of TV
repair with TV replacement. In that series (178 repairs and 72
replacements) TV repair improved perioperative, midterm, and
event-​free survival compared with replacement. However, when
compared with the TV repair group, the replacement group had a
higher incidence of preoperative cardiogenic shock, more urgent
operations, and more redo cardiac surgery. Moraca et al. com-
pared propensity-​matched cohorts undergoing TV replacement
versus TV repair. They found operative mortality was similar for
TV repair and replacement (13% and 18%) as was medium (5-​
year) and long-​term (10-​year) survival. Importantly, 40% of pa-
tients died at follow-​up highlighting the significant early and late
mortality associated with this disease [13]. Other studies have also
suggested that TV surgical mortality is associated late presenta-
tion and treatment. Kim et al. [14] found that the independent
determinants of mortality with isolated TV surgery were: age (HR
= 1.03; 95% CI 1.01–​1.05), male gender (HR = 1.96; 95% CI 1.29–​
2.99), NYHA functional class IV (HR = 2.08; 95% CI 1.31–​3.30),
liver cirrhosis (HR = 2.51; 95% CI 1.11–​5.68), preoperative levels
of haemoglobin (HR = 0.89; 95% CI 0.80–​0.99), albumin (HR =
0.52; 95% CI 0.33–​0.81) and GFR (HR = 0.86; 95% CI 0.78–​0.95).
In patients undergoing concomitant TR repair at the time of
mitral surgery, persistent severe TR is still present in 11% at 3
months, and 17% at 5 years [15]. Re-​intervention for recurrent
TR carries an in-​hospital mortality of up to 37% [16]. Thus when
important predictors of residual TR or recurrence following re-
pair are present, replacement should be considered. Predictors for
residual regurgitation after surgical repair have been identified:
greater preoperative TR severity, higher pulmonary artery pres-
sures, mitral replacement rather than repair, worse left ventricular
dysfunction, presence of pacemaker leads through the valve area
[17]. Other predictors of residual TR following annuloplasty in-
clude TV tenting height and tenting area [17] as well as tenting
volume [18].
The predictors of recurrence following annular repair thus iden-
tify patients who may also have less benefit from transcatheter an-
nular repair: patients with torrential regurgitation [19], significant
arterial or venous pulmonary hypertension, or marked tethering
of the leaflets. The latter has been associated with dislocation of
the papillary muscles in the setting of either right ventricle (RV)
free wall or septal displacement [20–​22].
Tricuspid valve anatomy
An understanding of TV anatomy is essential for understanding
not only device design but also in determining the appropriate
device for patient-​specific anatomy. The TV is the most apically
positioned and largest of the four cardiac valves with a normal
orifice area between 7 and 9 cm2 [23]. Because of its large size
and the low pressure differences between the right atrium (RA)
and RV, peak transtricuspid diastolic velocities are typically lower
than 1 m/​s with mean gradients of <2 mmHg [23]. The TV appar-
atus can be divided into four components: the leaflets, the pap-
illary muscles and chordal attachments, and the annulus (with
adjacent atrium and ventricle) [24–​29]. Whereas there are typic-
ally three leaflets (anterior, posterior, and septal) of unequal size,
in many cases, two (bicuspid), or more than three leaflets may
be present [23, 30]. In the tri-​leaflet configuration, the anterior
and septal leaflets are usually the largest circumferentially, thus
the anterior-​septal commissure is the longest explaining why sec-
ondary TR often occurs between these leaflets.
There are two distinct papillary muscles (anterior, posterior)
and a third variable (septal) papillary muscle. The large anterior
papillary muscle is located along the anterior/​lateral wall and
provides chordae to the anterior and posterior leaflets [31]. The
smaller posterior papillary muscle has chordal attachments to the
posterior and septal leaflets. The variable septal papillary muscle
is the smallest or may be a complex of minor muscles with chordal
attachments to the anterior and septal leaflets. Chordae frequently
arise directly from the interventricular septum (IVS) to the an-
terior and septal leaflets [31]. Thus, unlike the mitral valve, two
leaflets of the TV (anterior and posterior) are dependent upon a
large anterior papillary muscle along the antero-​lateral RV wall
and two leaflets (septal and anterior) are connected to the IVS.
Coaptation of the TV leaflets at or just apical to the annular
plane, with a leaflet coaptation length of 5–​10 mm, depends on
papillary muscle position and adequate chordal length [32] which
is accordingly influenced by RV and IVS size/​position and func-
tion. With RV or left ventricular (LV) dilatation resulting in pap-
illary muscle or septal wall displacement, tenting, or tethering of
the leaflets result in reduced coaptation length. In this setting, an-
nular dilatation alone is not the only cause of TR and thus annular
reduction in these patients may not improve leaflet coaptation as
evidenced by the known predictors for residual tricuspid regur-
gitation after surgical repair include tenting height and tenting
area [17] as well as tenting volume [18]. Determinants of RV and
IVS remodelling include primary left ventricular disease (i.e. is-
chaemic or non-​ ischaemic cardiomyopathy) and pulmonary
hypertension (i.e. precapillary and postcapillary increases in pul-
monary pressures). The RV has long been believed to be more
sensitive than the LV to acute increases in afterload [33] with
experimental models showing that a pressure load on the right
ventricle is less well tolerated than a volume load [34]. Changes
in RV function at increasing afterloads are maintained through
structural remodelling, as opposed to modifying myocardial
function [35]. Adaptive and maladaptive RV remodelling are
important concepts in relation to TV function. Adaptive remod-
elling is characterized by more concentric hypertrophy (higher
mass-​to-​volume ratio) with mild RV dilatation. With progression
of the primary disease process, there is maladaptive remodelling
associated with more eccentric hypertrophy and thus marked RV
dilatation and reduced systolic and diastolic function [36].
 C onsider ati on s for tr a n s catheter tri cu spi d va lv e dev i c e s 363

Although the term annulus implies a distinct, fibrous structure, two-​dimensional imaging, but also advanced three-​dimensional
on histologic examination there appears to be very little fibrous quantitation and strain imaging [39]. Additional measures of
tissue or collagen along the RV free-​wall segment which may help RV and TV morphology should also be made (E Fig. 24.6).
explain the pattern of annular dilatation involving this segment. Assessment of TR severity by current guidelines requires a
Most of the free-​wall annulus is composed of epicardium and multiparametric, integrative process (E Table 24.1) [42, 43].
endocardium on either side, with the right coronary artery and Because of differences between the high pressure left heart and
veins in the atrioventricular groove surrounded by adipocytes low pressure right heart, as well as differences in leaflet morph-
[37]. While the proximal portion of the right coronary artery is ology and the shape of the regurgitant orifice, the usual colour
relatively distant from the annulus, the mid and distal vessel is Doppler parameters may not be appropriate for the assessment
typically within the atrioventricular groove and can be used as of TR. Newer methods for TR quantitation by echocardiog-
a marked for the annular plane. The distance to the endocardial raphy (E Fig. 24.7) [23] as well as cardiac magnetic resonance
surface however is highly variable, and typically narrows toward imaging and computed tomography [44, 45].
the inferior segment of the annulus [38]. One of the most important screening tasks for echocardiog-
Other important adjacent structures include the non-​coronary raphy is the estimation of systolic pulmonary artery pressures
sinus of Valsalva which is adjacent to the commissure between (sPAP), mean PAP and pulmonary valve replacement (PVR). The
the anterior and septal leaflets. Venous inflow to the RA includes TR jet velocity is generally used to estimate RV systolic pressure
the superior and inferior vena cavae, and the coronary sinus. using the simplified Bernoulli equation (4v2, where v is the max-
The latter structure is a relatively consistent anatomic landmark, imum velocity of the TR jet). An estimated RA pressure (based on
entering the RA at the level of the annulus and at the commis- the size and collapsibility of the inferior vena cava visualized in
sure between the septal and posterior leaflets. Finally, the atrio- the subcostal window) is added to the peak systolic pressure gra-
ventricular node and the bundle of His, crosses the septal leaflet dient of the TR continuous wave spectral Doppler to obtain RV
attachment 3–​5 mm posterior to the anteroseptal commissure. systolic pressure [39]. The RV systolic pressure should approxi-
mate the sPAP in the absence of pulmonary valve stenosis and
RV outflow tract obstruction. A recent large (n = 1,695) single
Imaging of the native tricuspid valve site study compared within 5 days from each other Doppler echo-
cardiographic and invasive measures of sPAP and RA pressure
apparatus in a mixed population of patients (with and without PH) [46].
Echocardiography is the imaging modality of choice for the initial The correlation between methods was very high (r = 0.87, P
evaluation of TV and right heart morphology and function [23, <0.0001). Bland-​Altman analysis showed a bias of –​2.0 mmHg
39]. A number of transthoracic (E Fig. 24.1) and transoesophageal for sPAP (95% limits of agreement –​18.1 to +14.1 mmHg) and
(E Fig. 24.2, AVI 1–​4) imaging windows are used to assess right +1.0 mmHg for RAP (95% limits of agreement +0.1 to +1.9
heart structures. TV imaging by transoesophageal echocardiog- mmHg). Non-​invasive diagnosis of pulmonary hypertension with
raphy is typically more difficult than mitral valve imaging be- Doppler echocardiography had a good sensitivity (87%) and spe-
cause of a number of factors: the leaflets are thinner, the anatomy cificity (79%), positive and negative predictive values (91% and
is more variable, the path of the oesophagus does not allow on-​ 70%), as well as accuracy (85%) for a sPAP cut-​off value of 36
axis en-​face imaging and acoustic shadowing occurs in mid-​ mmHg (AUC 0.91, P <0.001, CI 0.90–​0.93). This study identified
oesophageal views from the fibrous crux of the heart and left sources of error for Doppler measurements and severe TR typic-
heart structures. Deep oesophageal views often yield the best im- ally led to an underestimation of sPAP. Interestingly, respiration
ages of the valve since left heart structures are not in the imaging dynamics of the inferior vena cava (IVC) were misinterpreted in
plane. Three-​dimensional (3D) imaging has become an essential 11% of cases and led to both under-​and overestimations of sPAP,
tool to evaluate the complex TV anatomy. The en-​face 3D view is highlighting the pitfalls of using this method to estimated right
easily generated using any imaging plane that optimizes the TV atrial pressures. Other studies however have suggested that sPAP
leaflets (E Fig. 24.3). The surgical view of the leaflets places the is overestimated in the setting of severe TR with overestimation of
septal leaflet at 6 o’clock [40] position (E Fig. 24.3, step D or E) the RA pressure being a major contributor [47, 48].
however for intraprocedural TV imaging, positioning the septal A summary of the comprehensive assessment of secondary TR
leaflet at the 12 o’clock position (E Fig. 24.3, step C) is com- is shown in E Table 24.2.
monly used (AVI 5 and 6) [41]. Interventionalists easily recog-
nize the position of the posterior leaflet (on the diaphragm), the
septal leaflet (attached to the interatrial septum) and the anterior Considerations for transcatheter
leaflet (adjacent to the aorta and RV outflow tract). In addition,
rapid assessment necessitates eliminating unnecessary steps in
tricuspid valve devices
3D image display. Transcatheter TV devices currently under investigation or devel-
A comprehensive assessment of RV size (E Fig. 24.4) opment (E Fig. 24.8) can be roughly divided into those treating
and function (E Fig. 24.5) should use not only standard annular dilatation (i.e. Trialign, Cardioband, TriCinch, Millipede,
364 CHAPTER 24   Tran s cath eter t ricu spid va lve repa i r /repl acem en t

Anterior Anterior

RV
RV

Ao
LV Ao
RA
LA
LA

Parasternal Long-Axis View Parasternal Short-Axis (AV Level)

Anterior
Lateral
An
RVOT te
rio
RV r

PA

Infe
LV

rior
MV

Parasternal Outflow View Parasternal Short-Axis (MV Level)

Lateral

An
An

te
te

rio
rio

r
r
RV RV

Inf
eri

Infe
RA
or
PM

rior
PM LV
EV

Parasternal Inflow View Parasternal SAX (Pap Muscle Level)

al
Later

RV
Lateral

RA LV
LV
RV

LA
RA LA

Apical 4-Chamber View RV Subcostal 4-Chamber View

Anterior

RV

RVOT
RV
ral

LV RA
Late

LA
Ao
RA
LA PA

RV Modified 4-Chamber View Subcostal Short-axis View

Fig. 24.1  Transthoracic echocardiographic

views for imaging the right heart and tricuspid
valve. Parasternal views (blue box), apical views LV
HV
Lateral

(red box) and subcostal views (green box) are RV

shown. IVC
LA RA
Abbreviations: Ao = aorta, EV = Eustachian valve,
RA
HV = hepatic vein, IVC = inferior vena cava, LA = left
atrium, LV = left ventricle, PA = pulmonary artery,
PM = papillary muscle, RA = right atrium, RV = right
ventricle, RVOT = right ventricular outflow tract.
Apical RV Focused View Subcostal IVC View
 C onsider ati on s for tr a n s catheter tri cu spi d va lv e dev i c e s 365

(a) (c)

(b) (d)

Fig. 24.2  Transoesophageal echocardiographic views for imaging the right heart and tricuspid valve. There are four important levels from which the right heart
and tricuspid valve can be imaged. Panel (a) (AVI 1) is an example of simultaneous multiplane imaging at the mid-​oesophageal depth. The four-​chamber view
permits visualization of the septal (yellow line) and typically the anterior (blue line) leaflet; simultaneous biplane imaging may help clarify which leaflet is imaged
since the anterior leaflet is typically seen adjacent to the aorta and the posterior leaflet (green line) is adjacent to the posterolateral wall. Low oesophageal views
(b, AVI 2)) at the level of the coronary sinus (CS) eliminates the left heart from the near field and may bring the tricuspid valve closer to the probe. Advancing
the transoesophageal echocardiography (TEE) probe into the stomach and using right and ante-​flexion results in the transgastric long axis (c, AVI 3) with the
orthogonal short-​axis view. This short-​axis view may also be obtained as the primary view by using a mechanical rotation 50–​90° without right flexion and
slight ante-​flexion. This is the only two-​dimensional (2D) view that provides simultaneous visualization of all three tricuspid valve leaflets and the commissures.
Advancing the TEE probe to the apex of the heart and using ante-​flexion produces a deep transgastric view of the TV (d, AVI 4) which may align the insonation
beam for optimal Doppler assessment. Abbreviations as in E Figure 24.1.
Reproduced from Hahn RT. State-​of-​the-​Art Review of Echocardiographic Imaging in the Evaluation and Treatment of Functional Tricuspid Regurgitation. Circ Cardiovasc Imaging.
2016;9(12):e005332. doi:10.1161/​CIRCIMAGING.116.005332 with permission from Wolters Kluwer.

Cardiac Implants), those approaching leaflet malcoaptation (i.e.
MitraClip, PASCAL, FORMA), heterotopic valve implantation
(i.e. Cavi, Tricentro) and orthotopic transcatheter TV replace-
ments (i.e. Navigate, Trisol). Important anatomical consider-
ations for transcatheter TV therapy are listed in E Table 24.3.
A description of some of the current devices in development or
in early feasibility trials are shown in E Table 24.4. This list is
not exhaustive since there is ongoing new devices development.
The appropriate selection of the device for the individual patient
anatomy depends on a number of anatomic and device-​specific
features.
Access to the tricuspid valve: A number of access sites can be
considered for delivery of a transcatheter TV device: transvenous
(superior vena cava [SVC] or IVC), transapical, or transatrial. The
optimal approach primarily depends on: (1) the size of the de-
livery system; (2) the position of the intended device; and (3) the
anatomy of the access route. The transvenous route clearly has
significant advantages. Transjugular access, obtained either per-
cutaneously or surgically, offers a relatively straight angle of ap-
proach to the TV, with a delivery system that may require less
steering. The smaller venous calibre and focal narrowing under
the clavicle may limit this approach for sheaths >35 Fr. The fem-
oral vein on the other hand, is a large calibre vessel however the
angle between the IVC and posterior TV annulus is acute and thus
requires extensive guide torque. The transatrial or transapical ap-
proaches are minimally invasive and require either a right or left
thoracotomy. For the current transcatheter TV replacement de-
vices, where a very large device results in a high profile delivery
system, transatrial access has been used in the majority of cases
due to a >40 Fr delivery sheath.
Method of device anchoring: Because the tricuspid annulus
is non-​fibrotic and does not calcify, annular devices should an-
chor in the thickest portion of annular tissue, while avoiding
the right coronary artery within the atrioventricular groove.
Anchoring into the RV myocardium beneath the annulus is
another option. The Cardioband device uses up to 17 cork-
screw anchors implanted around ~60–​75% of the annulus. The
TriCinch device uses a single anchor through the lateral annulus
and RV free wall. A single anchor through RV myocardium,
this time at the apex, is also the method of anchoring use by the
366 CHAPTER 24   Tran s cath eter t ricu spid va lve repa i r /repl acem en t

ACQUISITION
(a) (b)

Use biplane views to check that the tricuspid valve

annulus is centered within the acquisition plane
Rotate to the right
PRESENTATION atrial enface view
(e) (d) (c)

Rotate 180°
to place the
IAS at the 6
o’clock
position
Standard tricuspid valve view from Standard tricuspid valve view
the right ventricular perspective from the right atrial perspective

Fig. 24.3  Three-​dimensional echocardiographic acquisition and en-​face presentation of the tricuspid valve. Similar to the mitral valve, a user-​defined
volume is centred on the tricuspid valve annulus from an oesophageal view (a). The 3D volume is then acquired (b) and the en-​face view is obtained by
rotating the volume down (atrium facing the screen) (c). From this view, the septal leaflet (S) is at 12 o’clock, the anterior leaflet is far-​field and to the right
(A) and the posterior leaflet far-​field and to the left (P). The surgical or standard view (d) is obtained by rotating the image 180° thus placing the septal
leaflet (S) is at 6 o’clock, the anterior leaflet is near-​field and to the left (A) and the posterior leaflet near-​field and to the right (P). Turning the volume to
the right ventricular perspective, the septal leaflet (S) is at 6 o’clock, the anterior leaflet is near-​field and to the right (A) and the posterior leaflet near-​field
and to the left (P).

FORMA spacer device. Because the spacer sits in the tricuspid
annular space, it relies on leaflet apposition with the spacer to
reduce TR. Cardiac dimensions creates its own annulus in a
two-​stage procedure where an annular plication suture is ini-
tially positioned using small barb-​like anchors with no force
applied. Once the suture is fibrosed to the annular tissue, es-
sentially forming a new fibrous annulus, the suture is plicated
to reduce the annular area.
Devices that attach directly to the leaflets must rely on leaflet
and chordal tensile strength to anchor. The TriClip or Pascal de-
vices have small tines either along the clip arms, or at the top of
the clip arms to attach to the leaflets. Unfortunately, the tricuspid
leaflets are remarkable thin and leaflet trauma or detachment may
be more of an issue for the TV compared to the mitral valve.
The challenge of anchoring a transcatheter TV replacement de-
vice is similar to the mitral side [49]. Valve prostheses used to
treat TR in native valves need to be anchored into a dynamic, D-​
shaped non-​calcified structure however the systolic forces acting
on the tensor apparatus is a fraction of that on the mitral side.
Mechanisms for anchoring thus may include: (1) ventricular an-
chors to grasp the free margins of the native leaflets; (2) atrial
and ventricular flanges that engage the TV annulus and leaf-
lets/​chordae; (3) a series of anchors around the edge of the valve
that either pierce the TV tissue or provides friction with radial
interference; and (4) use of oversizing and radial force along of
the valve stent along the annular rim. Although TV specific de-
vices are being developed [50, 51].
Interaction with adjacent anatomy: The atrioventricular (AV)
node lies in the muscular portion of the atrioventricular septum,
near the ostium of the coronary sinus (at the apex of the tri-
angle of Koch). The bundle of His is a direct continuation of the
AV node and it passes through the right trigone of the central
fibrous body to reach the ventricular septum. This area is near
to the commissure between septal and anterior tricuspid leaflets
[31, 52]. Percutaneously implanted bioprostheses will likely not
be able to avoid stretching that area and similar to surgical TV
replacement, the incidence of rhythm disturbances will likely be
higher than with repair devices. With newer leadless pacemakers,
this additional procedure may not be a significant consideration
for transcatheter valve replacement devices [53].
For annular repair devices, a more significant issue is the prox-
imity of the right coronary artery to the annulus and hinge-​point
of the leaflets. The proximity of the right coronary artery, par-
ticularly along the inferior/​posterior annulus, may challenge any
device which requires anchoring in this region.
Antithrombotic regimen: Since the prevalence of atrial fibrilla-
tion in this patient population is high, there is frequently a clin-
ical indication for anticoagulant therapy. In the absence of this
 C onsider ati on s for tr a n s catheter tri cu spi d va lv e dev i c e s
indication however, the need for antithrombotic therapy may de-
pend on the device profile and the residual TR. Low profile devices
such as the Trialign device may not require treatment. Whereas
no evidence is available on the selection of antithrombotic
regimen specifically following transcatheter valve replacement
[54, 55], the recent findings of subclinical valve thrombosis in the
transcatheter aortic valve replacement (TAVR) population [56,
57], the lower flow on the right-​side of the heart and the larger
size of the prosthesis, may be arguments for life-​long anticoagu-
lant therapy.
Durability and recurrence: Concerns regarding structural
valve degeneration remains an important drawback of surgical
and transcatheter bioprostheses [58]. There is scarcity of evidence
regarding the durability of bioprostheses in the tricuspid position.
In the study of by Chang et al., 125 patients who received 138
TVRs (35 bioprosthetic valves in 35, and 103 mechanical valves
in 90 patients), the mean follow-​up period was 7.1 ± 5.0 years
(9.7 ± 6.7 years for bioprostheses and 6.4 ± 4.1 years for mech-
anical). The linearized incidence of reoperation was somewhat
higher in the bioprosthetic valve group (2.68%/​patient-​year) than
in the mechanical valve group (1.25%/​patient-​year) (P = 0.45).
367
Fig. 24.4  Standard right ventricular
size measurements. The recommended
right ventricular measurements with
the mean ± standard deviation and
range of normal values for each
measurement are listed.
Reproduced from Lang RM, Badano
LP, Mor-​Avi V, et al. Recommendations
for cardiac chamber quantification by
echocardiography in adults: an update from
the American Society of Echocardiography
and the European Association of
Cardiovascular Imaging [published
correction appears in Eur Heart J Cardiovasc
Imaging. 2016 Apr;17(4):412] [published
correction appears in Eur Heart J Cardiovasc
Imaging. 2016 Sep;17 (9):969]. Eur Heart
J Cardiovasc Imaging. 2015;16(3):233–​70.
doi:10.1093/​ehjci/​jev014 with permission
from Oxford University Press.
Currently there is no data on transcatheter valve replacement
durability and implants to date have been performed on a com-
passionate use basis with limited duration of follow-​up.
Recurrent TR remains a significant issue for annular repair de-
vices. Important lessons from the surgical literature suggest that
very large coaptation gaps with significant leaflet tethering, typ-
ically associated with marked RV dilatation and dysfunction or
pulmonary hypertension, will not result in a durable annular re-
pair procedure. A recent review by Latib et al. suggests that pa-
tients presenting very late in the disease process may indeed not
be appropriate for any procedure (E Table 24.5) [59]; however,
if annular dilatation is the primary aetiology of TR, annular re-
pair devices may be ideal. If however the primary process causing
TR is related to RV remodelling then an annular device may not
suffice and combination therapy with a leaflet device may be ap-
propriate [60, 61].
Although complete elimination of TR is the goal of surgical
repair or replacement, this could have adverse consequences
particularly in the end-​stage patient. The RV is very sensitive to
afterload changes [33]. In addition, RV dysfunction is common
in patients with TR, either subtle or overt [60, 62]. Complete
368 CHAPTER 24   Tran s cath eter t ricu spid va lve repa i r /repl acem en t

Fig. 24.5  Standard right ventricular

function measurements. The
recommended right ventricular
measurements with the mean ±
standard deviation and range of normal
values for each measurement are listed.
Reproduced from Lang RM, Badano
LP, Mor-​Avi V, et al. Recommendations
for cardiac chamber quantification by
echocardiography in adults: an update from
the American Society of Echocardiography
and the European Association of
Cardiovascular Imaging [published
correction appears in Eur Heart J Cardiovasc
Imaging. 2016 Apr;17(4):412] [published
correction appears in Eur Heart J Cardiovasc
Imaging. 2016 Sep;17 (9):969]. Eur Heart
J Cardiovasc Imaging. 2015;16(3):233–​70.
doi:10.1093/​ehjci/​jev014 with permission
from Oxford University Press.

(a) (b) (c)

Fig. 24.6  Additional measures of right ventricular and tricuspid valve morphology. Echocardiographic measurements of RV and TV morphology. Panel (a) is
a parasternal short-​axis view at the midventricular level. The line connecting the ventricular septum and the RV free wall and also crossing the midpoint of the
septum (a = white line) and the RV longest lateral distance (b = red line) drawn perpendicular to the line a, are used to calculate the RV eccentricity index as the
ratio of a to b. Panel (b) is an apical four-​chamber view in end-​diastole with the tricuspid annulus (TA = yellow arrow) diameter measured between the hinge
points of the leaflets with the RV free wall and the septal wall. RV long-​axis length (c = blue arrow) measured from the true RV apex to the midpoint of TA, and
the RV short-​axis width (d = green arrow) measured as the distance between the RV free wall and the septum perpendicular to TA at its midpoint, are used to
calculate the RV sphericity index as the ratio of c to d. Panel (c) shows the end-​systolic measurements of the tricuspid annulus (orange arrow) tenting height
(yellow arrow) and tenting area (red dotted area).
Reproduced from Kim YJ, Kwon DA, Kim HK, et al. Determinants of surgical outcome in patients with isolated tricuspid regurgitation. Circulation. 2009;120(17):1672–​8. doi:10.1161/​
CIRCULATIONAHA.109.849448 with permission from Wolters Kluwer.
Table 24.1  Assessment of TR severity by current guidelines

Parameters Mild Moderate Severe

Qualitative
TV morphology Mildly abnormal leaflets (e.g. mild Moderately abnormal leaflets (e.g. Severe valve lesions (e.g. Flail leaflet, ruptured
rheumatic thickening, limited prolapse) moderate thickening or prolapse) papillary muscle, severe retraction, large
perforation or vegetation
Interventricular septal motion Normal Typically normal Paradoxical/​volume overload pattern
Color flow TR jet Small RA penetration or not moderate RA penetration or large Deep RA penetration and holosystolic jet
[Note: not recommended for sole holosystolic penetration and late systolic
grading of severity]
flow convergence aone Not visible, transient or small Intermediate in size and duration Large throughout systole
CW signal TR jet Faint/​parabolic or partial contour dense, variable contour Dense, triangular with early
peaking contour (peak <2 m/​s in very severe TR)
IVC diameter Normal 2.1-​2.5cm >2.5cm
Semi-​quantitative
Color flow jet area (cm2) <5 5-​10 >10
[Central Jet]a
Color jet areal:RA area % 10-​20 10-​33 >33
Vena contracta (cm) <0.3 <0.6 >0.7
PISA Radius (cm)b <0.5 0.6-​0.9 >0.9
Hepatic vein flow Systolic dominance Systolic bluntingc Systolic flow reversal
Tricuspid inflow E-​wave < 1m/​sec or A-​wave dominant Variable E-​wave > 1.0 m/​sec
Quantitative
EROA (mm2) [by PISA] <20 20-​39d >40
EROA(mm2) [by 3D] Unknown Unknown >75
Regurgitant volume (mL) [by PISA] <30 30-​45d >45
RV and RA size Usually normal Usually normal or mild dilatation Usually dilatede
CW=continuous wave; EROA=effectve regurgitant orifice area; RA= right ventricular;TR=tricuspid regurgitation; TV=tricuspid valve valve
Bolded qualitative and semi-​quantitative signs are considered specific of their TR grade
^ There may to uncertainty between mild and moderate or between moderate and severe; consider further evaluation (eg cardiac magnetic resonance imaging, exercise
echocardiography, right and left heart cath) to clarify, if clinically indicated or needed for clinical trial classification
a
With Nyguist limit >50-​60 cm/​s
b
With Baseline Nyguist Iimit shift of 28 cm/​s
c
Signs are non-​specific and are influnenced by many other factors (RV diastolic function, atrial fibrillation. RA pressure). A cutoff of 18
d
There is little data to support further separation of these valves
e
RV and RA can be within the “normal” range for patients with acute sevre TR or with chronic severe TR associated with restrictive cardiomyopathy
Reproduced from Hahn RT. State-​of-​the-​Art Review of Echocardiographic Imaging in the Evaluation and Treatment of Functional Tricuspid Regurgitation. Circ Cardiovasc Imaging.
2016;9(12):e005332. doi:10.1161/​CIRCIMAGING.116.005332 with permission from Wolters Kluwer.

Fig. 24.7  Newer methods for

tricuspid regurgitation quantitation
by echocardiography.
In this figure, the three methods for
quantifying tricuspid regurgitation are
listed with the required measurements
and calculations.
Reproduced from Hahn RT. State-​of-​
the-​Art Review of Echocardiographic
Imaging in the Evaluation and Treatment
of Functional Tricuspid Regurgitation. Circ
Cardiovasc Imaging. 2016;9(12):e005332.
doi:10.1161/​CIRCIMAGING.116.005332
with permission from Wolters Kluwer.
Table 24.2  A summary of the comprehensive assessment of secondary tricuspid regurgitation

Comprehensive Evaluation of Secondary Tricuspid Regurgitation

Parameter Measurement Clinical
Tricuspid Qualitative Doppler parameters
◆ ◆ Severity of disease associated with poor outcomes in
Regurgitation Vena contracta width (biplane average)
◆ natural history studies and mutliple disease processes
Severity Quantitative Assessment:
◆ (i.e. CHF, MR, AR, AS, post-​TAVR and post-​ETE Repair).
●​  PISA EROA and RegVol Many parameters are both preload and afterload sensitive.
◆
●​  Quantitative Doppler EROA and RegVol

●​  3D vena contracta area and RegVol

Tricuspid Annular ◆ Annular diameter May be a surrogate for TR severity.

◆
Dilation ●​  >40 mm or 21 mm/​m2 (apical 4ch view) Predicts progression of disease following left valve
◆
Annular area
◆ Area criteria and dynamism parameters not yet defined
◆
Change in dynamism
◆

Leaflet Tethering Tenting length and area (2D echo, 4Ch view)

◆ ◆ Leaflet tethering may be a surrogate for TR severity in
Tenting volume (3d echo)
◆ absence of adequate quantitative measures.
Leaflet angles
◆ Tethering measurements predict TV repair (annuloplasty)
◆
failure and recurrence
Right Ventricular ◆ RV size (2D and 3D) Outcomes may be determined by RV size and function.
◆
Remodeling and ◆ Multiparametric assessment of regional and global RV function: Accurate measures of RV diastolic and systolic volumes
◆
Function ●​ ​TAPSE (given complex contraction pattern) require further study.
●​ ​S'TDI Measures of RV plasticity and capacity to reverse remodel
◆
●​ ​FAC still lacking
●​ ​RV  dP/​dT

●​ ​2D-​longitudinal  strain

●​ ​3D-​RVEF

●​ ​4D flow

RV-​PA Coupling Pulmonary artery pressures and resistance

◆ ◆ Pulmonary hypertension (pre-​and post-​capillary) is a
RV-​PA Coupling
◆ determinant of TR severity.
●​  RV contractility indexed to afterload Non-​invasive RV-​PA Coupling measures require further
◆
validation
Left Heart Size and Measures of LA and LV size
◆ ◆ LA compliance may play role in RV-​PA coupling (i.e. Post-​
Function Multiparametric assessment of LA and LV function
◆ capillary pulmonary hypertension)
Concomittant left valve disease
◆ LV size/​function affect RV size/​function
◆

Clinical Parameters Renal Function

◆ ◆ Clinical parameters associated with poor surgical outcome
Liver function
◆
Other: Albumin, Hemoglobin
◆

Abbreviations: 3D: three-​dimensional, 4Ch: four chamber, 4D: four-​dimensional, AR: aortic regurgitation, AS: aortic stenosis, CHF: congestive heart failure, dP/​dT: change in pressure
divided by the change in time, EROA: effective orifice area, ETE: edge-​to-​edge, FAC: fractional area change, LA: left atrium, LV: left ventricle, PA: pulmonary artery, PISA: proximal
isovelocity surface area; RegVol: regurgitant volume, RV: right ventricle, RVEF: right ventricular ejection fraction, S'TDI: systolic peak tissue doppler imaging, TAPSE: tricuspid annulus
plane systolic excursion, TAVR: transcatheter aortic valve replacement, TR:tricuspid regurgitation

Mechanism New Technologies

Annuloplasty
(Direct and
Indirect) Device
TriAlign Cardioband 4Tech Millepede Pasta Cardiac Implants MIA PolyCor Anchors

Leaflet Device

Forma MitraClip PASCAL Mistral

Heterotopic
Valve (in
IVC/SVC) Trinity /Sapien TriCentro SAPIEN in IVC

Orthotopic Valve
Replacement
Navigate Trisol LUX Tri-Cares

Fig. 24.8  Transcatheter tricuspid valve devices currently under investigation or development.
 Fu tu re pe r spe c t i v e s 371

Table 24.3  Anatomical considerations for transcatheter tricuspid valve therapy

Tricuspid leaflets and commissures Interventional considerations

2
◆ Large orifice (7–​9 cm ) ◆ Stenosisis unlikely with central orifice devices (i.e. edge-​to-​edge repair or
spacer devices)
Usually three leaflets but variable with cleft, and folds
◆ Imaging leaflet anatomy challenging
◆
Very thin, translucent
◆ Leaflets may not be ideal for anchoring devices
◆

◆ Anterior leaflet is typically the largest, with the greatest motion ◆ High leaflet stress with greater leaflet motion
◆ Anterior-​septal commissure is the longest ◆ Regurgitant jet is frequently along this commissure
Chordae and papillary muscles Interventional considerations
◆ Anterior papillary muscle is largest, supplying chordal support to the ◆ Anterior papillary muscle serves as an imaging landmark for these leaflets
anterior and posterior leaflets
◆ Septalleaflet chordae insert directly into septum or with multiple, small ◆ ‘Tenting’ or tethering of the septal leaflet is common aetiology of
papillary muscles secondary tricuspid regurgitation
Capturing this leaflet for edge-​to-​edge repair may be difficult
◆

◆ Average of 25 chordae with varying configurations which are less distensible ◆ Chordae may interact with catheters and devices. Marked tethering results
(straight collagen bundles) from dilatation of the right ventricle or displacement of papillary muscles
Tricuspid annulus Interventional considerations
◆ Dilatationin disease states occurs along the unsupported lateral and ◆ Devices targeting this region may be effective in reducing regurgitation
posterior free-​wall portion of the annulus with more planar, circular shape
◆ Dynamic (larger in end-​systole, early diastole, and atrial systole) ◆ Dynamic changes in shape must be accounted for with device design
◆ Average perimeter = 12 ± 1 cm Average area = 11 ± 2 cm2 ◆ In the setting of dilatation, large annular devices required
◆ Heterogeneity in muscle and fatty tissues with discontinuous fibrous ◆ Deviceanchoring stability may vary along the circumference of the
support annulus
◆ Right
coronary artery within the AV groove (variable transverse distance ◆ Short (~3–​4 mm) transverse distance along the inferior annulus (adjacent
from annulus) to the posterior leaflet)
◆ Atrioventricular
node (AVN), Bundle of His crosses the septal leaflet ◆ Risk for heart block with devices in this region
attachment 3 to 5 mm posterior to the anteroseptal commissure
◆ Non-​coronary aortic root sinus of Valsalva borders the septal-​anterior ◆ Risk for perforation with devices in this region
commissure
Right atrium, right ventricle and venous inflow Interventional considerations
◆ Right atrium is thin-​walled, markedly dilated in advanced disease ◆ Large space to manoeuvre devices but more difficult for imaging
SVC
◆ = mean length ~7 cm, maximum diameter ~2 cm, irregular in shape ◆ Venous access considerations for new devices may be limited by SVC
◆ IVC = largest vein in the body (normally <21 mm) diameters and non-​linear shape. IVC-​annular angle may pose issues for
device placement
◆ No continuity between inflow and outflow ◆ Little risk for right ventricular outflow tract obstruction
Source data from Dahou A, Levin D, Reisman M, Hahn RT. Anatomy and Physiology of the Tricuspid Valve. JACC Cardiovasc Imaging. 2019;12(3):458–​68. doi:10.1016/​
j.jcmg.2018.07.032.

elimination of TV replacement may result in acute increases in
RV afterload and in the already compromised patient, further RV
decompensation and adverse outcomes.
Future perspectives
In this early stage of transcatheter device development, feasibility
and safety have been the focus of current trials. Determining effi-
cacy has been limited by the known pitfalls of echocardiographic
assessment of native valve TR severity [23] with even greater dif-
ficulty and little validation for assessing TR after devices are im-
planted. Nonetheless, the reduction in TR with most devices is
modest, yet patients show clinically significant improvements in
symptoms and quality of life [63–​66]. The lack of efficacy is in
part explained by the late presentation with not only end-​stage
changes in valvular and ventricular morphology but also multiple
comorbidities. This results in a very heterogeneous group of pa-
tients where choosing the correct treatment may be challenging.
A more comprehensive understanding of TV disease and the re-
lationship to the RV and pulmonary circulation, as well as how to
best evaluate the pathophysiology should lead to earlier diagnosis
and improved timing of intervention. Importantly, if devices
have a high safety profile, then the trade-​off of efficacy for func-
tional improvement may tip the balance in favour of transcatheter
therapies.
Table 24.4  Description of current devices in development or in early feasibility trials

Device name Construction Status international Description

Trialign (a) (b) ◆ SCOUT I (US EFS trial) completed ◆ Involves delivery of polyester pledgets via right internal
enrolment of 30 patients. jugular approach
SCOUT II (CE mark trial) enrolling
◆ The pledget is a polyester implant with a suture
◆
attached that serves as a suture buttressed anchor for
plication of the annulus.
A stainless steel lock tracks over the sutures and once
◆
adequate plication is achieved, locks the pledgeted
sutures together
Cardioband CE mark awarded April 2018
◆ ◆ Adjustable, sutureless annuloplasty band of polyester
US EFS trial enrolling
◆ fabric through which stainless steel anchors (6 × 2.5
mm) are inserted
Implanted through the transfemoral route
◆
Designed to reduce the septo-​lateral annular diameter
◆

Tricinch Coil ◆ CE mark trial ongoing in Europe and Antero-​posterior annuloplasty solution

◆
4Tech Australia Coil anchor design provides significant surface area to
◆
US EFS enrolling
◆ distribute tensioning force with haemostatic forces
Transfemoral access
◆
Stent deployed in IVC to anchor tension device
◆

Millepede ◆ FIM implant in tricuspid position ◆ Adjustable complete annular ring

performed under direct surgical
view

Cardiac implants A First in Human Study to Assess Safety ◆ Complete flexible ring deployed around the valve
and Performance of the DaVingi™ TR annulus using a proprietary ring delivery scaffold system
system in the treatment of patients Tissue healing creates bonds with barbed anchors
◆
with functional tricuspid regurgitation to secure implant from dehiscence before loads are
Currently enrolling:
◆ applied
Israel
◆ Target predictable and reliable circumferential annular
◆
Czech Republic
◆ reduction with adaptable band
Spain (IRB pending)
◆
Additional sites to be added in EU
◆
US EFS planned for 2019
◆

Minimally invasive ◆ STTAR Surgical Study (open 16.8 F MIA Steerable Guiding Sheath
◆
Annuloplasty implants) performed with no Proprietary Polypropylene PolyCorTM Anchors
◆
(MIA) dehiscence connected by suture
STTAR Percutaneous Study planned
◆ High speed delivery system for anchors
◆
2019 Plication, lock, and cut
◆

Tricuspid valve ◆ Trialto Evaluate Treatment with The

◆ TVRS configuration consists of two parts: (1) a clip
repair system Abbott Transcatheter Clip Repair delivery system, which includes an implantable Clip
(TVRS) System in Patients with Moderate (MitraClip® NT device), a Steerable Sleeve and a Delivery
or Greater Tricuspid Regurgitation Catheter; and (2) a steerable guide catheter which
(TRILUMINATE) is enrolling in both includes a dilator
US and Europe ◆ The implantable Clip is fabricated with metal alloys
and polyester fabric that are commonly used in
cardiovascular implants
PASCAL ◆ Compassionate cases performed in ◆ Independent leaflet clasping system to perform
tricuspid position transcatheter edge-​to-​edge
Feasibility trial in mitral position
◆ Transfemoral route
◆
ongoing
Table 24.4 Continued

Device name Construction Status international Description

FORMA ◆ Early Feasibility Study of the Edwards ◆ Spacer is positioned within regurgitant orifice and
FORMA Tricuspid Transcatheter provides a surface for native leaflets to coapt
Repair System completed Advanced from left subclavian vein
◆
EFS with device redesign enrolling
◆ Rail tracks the spacer into position
◆
Anchored at RV apex and subclavian vein
◆

Mistral Compassionate use cases completed

◆ 8.5 F delivery system carrying a spiral-​shaped device
◆
Short-​term clinical improvement
◆ The novel transcatheter spiral shape device gathers
◆
shown chordae together improves leaflets coaptation by gently
grasping chords from two adjacent leaflets

Cavi FIM study completed

◆ ◆ Two self-​expanding percutaneous heart valves were
Ongoing trial in US and Europe
◆ custom-​made to provide 10–​20% oversizing of the
superior vena cava (SVC) and inferior vena cava (IVC)
(TricValve)
Bicaval vs. IVC only possible
◆
The IVC valve protrudes into the right atrium (RA),
◆
preventing backflow while avoiding obstruction of the
hepatic veins (HV)
The SVC valve is funnel-​shaped, with a skirt covering
◆
the entire base of the valve to prevent paravalvular
leakage
Same approach using off label TAVR aortic prostheses
◆

Tricentro ◆ European CE mark trial enrolling ◆ Heterotopic valve implantation to reduce backflow in
the venous system

Navigate ◆ 40 compassionate use cases ◆ Temperature Shape Memory NiTinol tapered stent
performed (inflow = 30 mm/​outflow = 40 mm)
Early feasibility in the US planned for
◆ Up to 54 mm size available
◆
late 2019 Height profile 21 mm, truncated cone configuration
◆
with a diffuser effect
Annular winglets for secure anchoring of annulus and
◆
tricuspid valve leaflet
Chemically preserved xenogeneic (equine) pericardium
◆

Trisol ◆ Advanced preclinical stage ‘Sail’ like pericardial leaflets enables larger RV
◆
closing volume with RV pressure relief and function
preservation
Simple and intuitive positioning and anchoring through
◆
a 30 Fr delivery system with optional repositioning/​
retrieval

Tricuspid valve-​ ◆ 178 cases reports from the VIVID Mostly

◆ performed through femoral route; jugular and
in-​valve and Registry (156 VIV; 22 VIR) transatrial have been also reported
valve-​in-​ring ◆ Sapien XT, Sapien 3, and Melody used
◆ PVL common after VIR

Source data from Hahn RT, Nabauer M, Zuber M, et al. intraprocedural imaging of transcatheter tricuspid valve interventions. JACC Cardiovasc Imaging. 2019;12(3):532–​53.
doi:10.1016/​j.jcmg.2018.07.034.
374 CHAPTER 24   Tran s cath eter t ricu spid va lve repa i r /repl acem en t

Table 24.5  A proposed classification of patients presenting with FIR and potential treatment options.
Stage 1 Stage 2 Stage 3 Stage 4 Stage 5

Symptoms None None* None-​vague* Current or previous Overt RHP and/​or

episodes of RHF end-​organ damage due
to chronic RV volume
overload#
TR grade Less than modrate >Modrate Severe Severe Torrential
annular remodelling Normal Normal of mildly Present Modrate-​Severe Severe
remodelled
Leaflet coaptation Normal Midly abnormal Abnormal Coaptation gap Large Coaptation gap
Tethering None None or midly abnormal Abnormal (usually Significantly Abnormal Significantly Abnormal
(<8 mm) <8mm) with varying degree of (usually >8mm)
tethering
RV function and Normal Normal function Absent Mild RV dysfunction > Moderate dysfunction Severe RV dysfunction
remodelling or mild remodelling and/​or remodelling and remodelling and remodelling
Medical No treatment but regular None or low-​dose Diuretics Moderate to high-​ Multiple admissions
clinical and echo follow-​ diuretics dose diuretics and/​ for RHF. Frequent need
up in patients with high or requirement for IV for IV diuretics and/​or
likelihood of developing diuretics high-​dose combination
TR progression such as diuretics
those in Table 1
Surgical treatment No Consider TV surgery TV surgery (preferably Isolated TV surgery Prohibitive intra-​and
(preferably repair) at repair) at time of left-​ (repair or replacement) peri-​operative risk
time of left-​sided surgery sided surgery. Isolated either isolated or at time
TV surgery (preferably of left-​sided surgery in
repair) in presence of the absence of server
symptoms or progressive pulmonary hypertension
RV remodelling and and server comorbidities.
comorbidities High risk of perioperative
RV dysfunction.
Percutaneous No Potential future target Potential candidates for Current group of Prohibitive risk and
treatment for percutaneous isolated TR Surgery who patients being treated potentially futile.
options as minimally could be enrolled in in EFS if high-​risk for (Palliative procedures
Invasive option could upcoming IDERCTs surgery. May require can be considered in
change natural combination of highly selected patients)
history with minimal fish annuloplasty and leaflet
device or TVR
Although this Staging scheme implies linear progression of the disease, in the fact there maybe patents with little tethering and RV remodelling but with severe TR secondary to
severe right atrial dilatation, such as patients with idiopathic FR. *Consider exercise test to evaluate functional capacity objectively # Multidisciplinary evaluation maybe needed. EFS,
early feasibility studies FTR: functional tricuspid regurgitation; IDE investigational device exemption; IV: intra venous; RCT randomised controlled trial; RHF; right heart failure; RV right
ventricular; TR tricuspid regurgitation; TV: tricuspid valve; TVR: tricuspid valve replacement
Reproduced from Latib A, Grigioni F, Hahn RT. Tricuspid regurgitation: what is the real clinical impact and how often should it be treated?. EuroIntervention. 2018;14(AB):AB101–​11.
doi:10.4244/​EIJ-​D-​18-​00533.

morphology and TR severity, as well as ventricular size and func-

Conclusion tion, and pulmonary vascular haemodynamics. Surgical interven-
tion has been associated with high mortality paving the way for
Secondary or functional TR represents an important unmet
less invasive treatment options. Numerous devices using different
treatment need given its prevalence, adverse prognostic impact,
tricuspid apparatus targets, methods of access, and anchoring, are
and symptom burden associated with progressive right heart
under development.
failure. Imaging plays an integral role in the assessment of TV

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 CHAPTER 25

Transcatheter pulmonic
valve replacement
Kuberan Pushparajah and Alessandra Frigiola

Contents Introduction
Introduction  377
Background  377 Background
Percutaneous pulmonary valve replacement
(PPVI)  377 The number of patients born with congenital heart disease, surviving to adulthood
Patient assessment  381
is steadily increasing [1–​4] due to advances in the fields of medicine, surgery, and
Conclusion  389
transcatheter intervention. The majority of these patients, however, require further
re-​interventions due to the presence of residual haemodynamic lesions, the most
common of which is right ventricular outflow tract (RVOT) dysfunction in the form of
pulmonary valve regurgitation, stenosis or as a mixed lesion of a native outflow tract or
of a previously implanted right ventricle (RV) to pulmonary artery (PA) conduit. The
most common congenital lesions which present with RVOT dysfunction before or fol-
lowing initial repair, are represented by tetralogy of Fallot, pulmonary atresia, truncus
arteriosus, double outlet right ventricle, transposition of the great arteries, aortic valve
disease requiring Ross procedure and absent pulmonary valve syndrome. Over the
time, RVOT dysfunction inevitably leads to right ventricular dilatation and dysfunc-
tion, exercise intolerance, increased incidence of arrhythmias and sudden death [5–​7].
Timely pulmonary valve replacement (PVR) is therefore advocated in order to pre-
serve ventricular function and avoid unfavourable outcomes and numerous authors
have shown significant remodelling of the RV after surgery with a decrease in RV vol-
umes and improvement of left ventricular cardiac output as a result of better left ven-
tricular (LV) filling; these changes are mirrored by improvement in patients’ exercise
capacity and symptoms [8–​13].

Percutaneous pulmonary valve replacement (PPVI)

Balloon-​expandable pulmonary valves
A surgical approach to RVOT dysfunction was the only possible option until early
2000’, when the introduction of a percutaneously deliverable stent valve opened a new
era in the history of congenital heart disease. The first transcatheter pulmonary valve
(Medtronic, Minneapolis, MN) was made of a bovine jugular venous valve sutured
inside a balloon-​expandable platinum-​iridium stent (NuMED Inc., Hopkinton NY,
USA). The valve stent is crimped on a balloon-​in-​balloon front-​loading delivery system
(Ensemble; Medtronic) (E Fig. 25.1a) and can be expanded, while maintaining its
competence, up to 22 mm diameters. After the first implant performed by Bonhoeffer
et al. [14] in a 12-​year-​old boy with a stenotic and regurgitant RV to PA conduit,
the Melody valve has been accepted by the regulatory agencies for use in Europe
and Canada since 2006 and adopted as alternative method of treatment of RVOT
378 CHAPTER 25   Tran s cath eter pu lmonic va lve repl acem en t
(a)
Fig. 25.1  (a) Medtronic Melody
Percutaneous Pulmonary Valve with
its proximal and distal (blue suture)
ends; (b) Edward Lifesciences SAPIEN
XT23 mm.
Courtesy of Dr. Butera.
dysfunction in patients who presented with suitable anatomy.
The valve then received FDA final approval in 2010. After an
initial learning curve which saw as main complications early
re-​stenosis caused by hammock effect [15], stent fracture [16],
coronary artery compression, branch PA jailing, homograft
rupture, and valve dislocation, the results of the transcatheter
pulmonary valve replacement (PPVI) showed favourable and
comparable outcomes to the surgical approach with the advan-
tage of reduced periprocedural morbidity and reduced hospital
stay [17]. The valve design was improved by suturing the venous
valve along the whole stent length thus avoiding the ‘Hammock
effect’ and with the adoption of a prestenting technique the
incidence of stent fractures, which were due mainly to valve
distortion, was minimized [17]. Accurate patient selection was
also understood to be key for the success of the procedure with
particular attention to the RVOT size, morphology, distensi-
bility, and main PA and coronary arteries anatomy. Similar
to the surgically treated patients, ventricular remodelling was
seen also in patients treated with PPVI with associated increase
in cardiac output and exercise capacity [18–​20]. The Melody
valve remained suitable for outflow tracts with a diameter be-
tween 14 and 22 mm, with calcified and stenotic RV to PA con-
duits representing the ideal substrate given the safe anchoring
point for the stent valve.
In the initial experience of a percutaneous approach, only 15%
of patients with RVOT dysfunction were eligible for such treat-
ment. It was only a few years later with the introduction of the
Edwards SAPIEN valve (Edwards Lifesciences, Irvine, CA), a
pericardial valve mounted inside a balloon-​expandable stainless-​
steel stent, that larger outflow tracts up to 29 mm could be treated
percutaneously [21] (E Fig. 25.1b). The Edwards SAPIEN valve
was initially designed to be deployed in the aortic position but
was successfully used to treat a malfunctioning pulmonary valve
on compassionate grounds in 2005. The SAPIEN valve received a
CE Mark in May 2010. The SAPIEN XT valve received FDA ap-
proval in March 2016 for sizes 23, 26, and 29 mm. Since then it
has become an alternative choice to the Melody valve especially
for larger RV-​PA conduits and with the new design (SAPIEN S3)
also for native outflow tracts [22].
(b)
Self-​expandable pulmonary valves
Native outflow tracts however remained a challenge due to the
large sizes and dynamic nature of them. Furthermore, anatom-
ical variability, irregular and unpredictable shape represents
real challenges for the balloon-​ expandable valve. New self-​
expandable valves have been recently developed and proven to
be safe, versatile, and effective solution for these anatomies with
promising results.
To date there are three valves currently being used in clin-
ical trials. Following the results of the very first implantation of
a custom designed self-​expanding pulmonary valve on a com-
passionate basis in a 42-​year-​old man in 2010 [23], Medtronic
produced a porcine pericardial tissue valve mounted on a
covered nitinol self-​expanding frame, the Medtronic Harmony
Transcatheter Pulmonary Valve (E Fig. 25.2). The valve comes
in one single size (length 55 mm, valve section 23.5 mm, inflow
42 mm, and pulmonary outflow 34 mm) and has been used so
far in 20 patients with good results in the majority of them [24];
the valve however will need to undergo re-​design with increased
available sizes before being used in the clinical setting.
Promising results have been obtained with the Venous-​P-​
Valve (Venus MedTech, Hangzhou, China), a porcine pericar-
dial tissue valve mounted on a self-​expandable nitinol support
frame. The valve comes available in a variety of sizes between
18 and 36 mm (in 2-​mm increments) and lengths between 20
and 35 mm (in 5-​mm increments). The device is flared at the
proximal and distal ends and the distal outflow row of cells is
left uncovered to allow for unobstructed branch pulmonary ar-
tery flow (E Fig. 25.3). The valve was first valve implanted in
China in 2013 and initial results have recently been published
[25]. Between October 2013 and April 2017, outside Asia, 37
valves were implanted. In one patient the procedure was aban-
doned. Thirty-​seven valves were successfully implanted with
significant reduction in pulmonary valve (PV) regurgitation
and RV volumes at 6 and 12 months follow-​up. Valve migration
(n = 2) and stent fractures (27%) were the main complications.
Lastly Edwards Lifesciences, Irvine, CA, has designed a self-​
expanding nitinol frame with polyethylene terephthalate fabric.
The device, Alterra Adaptive Prestent is designed to re-​shape

the RVOT thus preparing a good landing zone for the 29-​mm
SAPIEN 3 transcatheter valve within the RVOT. The stent has a
symmetric shape (E Fig. 25.2) with inflow and outflow diam-
eters of 40 mm and a central section of 27 mm. The distal flare
is uncovered to facilitate blood flow into the branch pulmonary
arteries. The stent is still at its initial evaluation with only one
case report to date [26].
Results
The overall procedural success rate from published studies is re-
ported being 96.2% (95% confidence intervals [CI], 94.6–​97.4)
with a conduit rupture rate of 4.1% (95% CI, 2.5–​6.8) and cor-
onary complication rate of 1.3% (95% CI, 0.7–​2.3). Incidence
of reintervention is 4.4 per 100 person-​years overall (95% CI,
3.0–​5.9) with a marked reduction in studies reporting ≥75%
prestenting (2.9 per 100 patient-​year [95% CI, 1.5–​4.3] versus 6.5/​
100 patient-​year [95% CI, 4.6–​8.5] P <0.01). Surgical conversion
is required in 1.7 per 100 patient-​years (95% CI, 1.2–​2.2) for stent/​
I n t roduc t i on 379
Fig. 25.2  Top panels: Harmony™
Transcatheter Pulmonary Valve and
Delivery Catheter System. (courtesy
of Medtronic, Inc, Minneapolis, MN);
Bottom panels Alterra Adaptive
Prestent (left), and Alterra Adaptive
Prestent with implanted SAPIEN 3
(right).
Courtesy of Edwards Lifesciences LLC,
Irvine, CA.
valve dislodgement, conduit rupture, coronary compression, ob-
struction of branch PAs, and stent compression causing acutely
elevated gradient. Catheter reintervention is required in 2.7 per
100 for patient-​year (95% CI, 1.7–​3.7) mainly for re-​stenosis and
valve insufficiency. Stent fractures, which is the main cause of
re-​stenosis, had a pooled incidence of 4.4 per 100 patient/​years
(95% CI, 2.4–​6.3), whereas type 2/​3 stent fractures were noted in
1.3 per 100 patient/​years (95% CI, 0.5–​2.0) [27]. E Figure 25.4
shows examples of complications seen during PPVI.
One of the initial concerns with the PPVIs was a higher inci-
dence of infective endocarditis (IE) in patients treated with the
Melody valve. Cumulative analysis of published studies suggests
an annualized incidence rate ranging from 1.3% up to 9.1% per
patient-​year [28]. Some authors suggested that bovine jugular
valves are at the highest risk for IE with the Melody presenting
with an incidence 5–​8 times higher as compared to other valves
corresponding to 4.8 per 100 cases-​year [29]. These results may
be related to specific tissue immunological characteristics, which
380 CHAPTER 25   Tran s cath eter pu lmonic va lve repl acem en t

(a) (b)

(c) (d)

Fig. 25.3  Venous-​P-​valve: Panel

(a) shows the valve in its length
with the proximal and distal ends,
whereas panel (b) shows the
uncovered pulmonary outflow
which is specifically designed to
avoid obstruction of flow into the
branch pulmonary arteries. Bottom
panels show the angiography pre-​
(c) and post-​(d) Venous-​P-​Valve
implantation.
Courtesy of Professor Shakeel Qureshi.

may favour the formation of non-​bacterial thrombotic endocar-
ditis as the first step towards positive predictive value (PPV) of IE,
although there is no proof of this hypothesis [29, 30]. Predisposing
factors to IE are thought include early discontinuation of aspirin
with consequent thrombosis and flow turbulences, the presence
of multiple stents and stent fractures with residual gradients
leading to turbulent flow [30, 31].
Clinically, patients report a significant improvement in their
symptoms with most patients in NYHA class I and II at mid-​term
follow-​up. This is mirrored by an objective improvement of their
exercise capacity on cardiopulmonary exercise testing with some
authors reporting improvement in peak VO2 on cardiopulmonary
exercise testing in patients treated mainly for pulmonary stenosis
(PS) and in VE/​VCO2 slope only on patients treated for predom-
inant pulmonary regurgitation (PR) [15, 21, 32, 33]. Immediately
post PPV implantation there is a significant reduction of RV-​PA
pull back gradients with most patients not having more than mild
residual obstruction; these results are sustained at later follow-​up
especially in those patients who do not have more than 25 mmHg
residual gradient immediately post-​procedure [17]. Pulmonary
valve regurgitation is also effectively treated with only mild regur-
gitation in most patients at early and late follow-​up. On cardiac
magnetic resonance (CMR) there is evidence of significant reduc-
tion in RV volumes with improvement in LV filling (increased LV
end diastolic volume) and biventricular cardiac output [15, 17,
20, 21, 32, 33].
To date more than 10,000 valves have been implanted percu-
taneously in the pulmonary position with continuous expansion
of indications as larger and native outflow tracts can now safely
be dealt with. In the UK, it is estimated that every year almost 350
pulmonary valves are being replaced; of these replacements 77%
are surgically performed and the remaining via a transcatheter
approach (23%) [34]. It is very likely that these figures will see
a further change with a growing number of patients who will be

(a) (b)
(c) (d)
treated percutaneously thanks to new valve designs which will
allow larger and native outflow tracts to be dealt with safely and
effectively.
Patient assessment
Clinical indications
Indications as to when replace the pulmonary valve percutan-
eously mirror those of surgical PVR. The specific anatomical
characteristics (size, shape, distensibility) of the RVOT, of the
main pulmonary artery and its branches and the position of the
coronary arteries will indicate the preferred method. Patients
who present with significant RVOT/​PV obstruction are most
likely to present with symptoms of reduced exercise capacity and
shortness of breath whereas patients with severe pulmonary valve
regurgitation may be asymptomatic for a long time. Numerous
papers have been published as to when is best to intervene given
that to date there is not yet an ideal valve substitute with most
valves needing a replacement 15 years after initial implantation
[35–​38] thus exposing patients to a high number of procedures.
Though guidelines are available for cardiologists and cardiac
surgeons each patient should be treated individually and indi-
cations should be based on clinical presentation (symptoms),
I n t roduc t i on 381
Fig. 25.4  Complications seen post
PPVI. (a) Guidewire perforation of the
left pulmonary artery; (b) coronary
artery compression; (c) Melody valve
and covered CP stents contained
rupture of severe calcified RV-​PA
homograft; (d) unsatisfactory position
of Venus valve—​right pulmonary
artery origin occluded.
imaging data obtained with echocardiography, CMR, and com-
puted tomography (CT) when indicated and on formal assess-
ment of exercise capacity with cardiopulmonary exercise testing
(CPET) [39]. In patient assessment, it is important to look for
changes which indicate disease progression. The consensus is
to offer PVR when the RV pressure equals 2/​3 of systemic in
the presence of severe pulmonary valve stenosis, with evidence
of reduced exercise capacity (less than 65% of predicted peak
VO2). In the presence of severe pulmonary valve regurgitation
(regurgitant fraction greater than 40% on CMR), PVR is re-
commended in presence of significant RV dilatation (RV end
diastolic volume index greater than 160 ml/​m2, RV end-​systolic
volume index ≥80 ml/​m2 or RV:LV ration greater than 2) with
one or more of the following criteria: evidence of progressive
RV dilatation on serial imaging, reduced RV function (ejection
fraction [EF] less than 44%), reduced exercise capacity reported
by patient or formally assessed with CPET, presence of arrhyth-
mias which indicated the haemodynamic instability caused by
the volume overload and finally presence of associated lesions
(e.g. severe branch pulmonary arteries stenosis, residual shunt,
tricuspid valve regurgitation) [39, 40]. Special consideration
should be offered to patients wishing to embark into pregnancy
as a competent valve would allow an easier management of the
382 CHAPTER 25   Tran s cath eter pu lmonic va lve repl acem en t

Table 25.1  Summarized indications for pulmonary valve replacement

I Asymptomatic pts with 2 or > of the following criteria II Haemodynamically significant lesions III Symptomatic pts
2
◆ RVEDV >150 ml/​m or RV/​LV EDV volume >2 ◆ RVOTO with RV systolic pressure 2/​3 systemic ◆ Peak VO2 < 60% of predicted
◆ RV ESV >80 ml/​m2 ◆ Severe branch Pas stenosis
◆ RV EF <47% ◆ Moderate TR IV Special considerations
◆ LV EF <55% ◆ L to R shunt with Qp: Qs ≥1.5 ◆ Women considering pregnancy
◆ QRS duration >140 ms, sustained tachyarrhythmia ◆ Severe AR
◆ Severe aortic dilatation (diameter 5 cm)

patient and PVR might then be offered sooner. E Table 25.1
summarizes current indication for PVR.
Size and morphology of the right ventricular
outflow tract
The size, morphology, and dynamic nature of the RVOT, main
pulmonary artery (MPA), and branch pulmonary arteries affects
suitability for PPVI and can vary significantly despite knowledge
of previous surgical procedures. Prescreening of patients by means
of MRI or CT allow for delineation of the morphology to facilitate
better patient selection. The RVOT morphology has been classified
into five descriptive anatomical groups to help define this [41]. As
an example, a pyramidal shaped RVOT which narrows towards
the PA bifurcation is at increased risk of valve dislodgement due
to the lack of a suitable anchoring site. Additionally, severe origin
stenosis of the left PA can also lead to difficulty in manoeuvring
the delivery system for PPVI. These three-​dimensional geometric
variations should be established prior to any proposed catheter
procedure. Sizing of these structures is an important consider-
ation for suitability and device selection for PPVI and is based on
multimodality imaging techniques.
Transthoracic echocardiography
Transthoracic echocardiography (TTE) is the first line imaging
tool in all patients presenting for PPVI due to its wide availability
and use in routine clinical care for screening and serial assess-
ment [42]. The focus of imaging is to confirm the underlying
anatomy by sequential segmental analysis, evaluate ventricular
size and function, identify intracardiac shunts, and assess for
RVOT stenosis and regurgitation, including proximal branch PA
stenosis (E Fig. 25.5). It is generally possible to make an assess-
ment of the size of the RVOT and proximal branch pulmonary
arteries. The acoustic windows for assessment of the RVOT can
be challenging, particularly with anteriorly positioned surgical

(a) (b)

Fig. 25.5  (a) Four-​chamber TTE

image of a dilated and hypertrophied
right ventricle. (b)TTE short axis image
of a dilated and hypertrophied right
ventricle. (c) TTE parasternal short
axis view of the RVOT with moderate
pulmonary regurgitation seen on
colour Doppler. (d) and continuous
wave Doppler demonstrating
(c) (d)
moderate pulmonary regurgitation.

conduits in postoperative cases. The standard views include an
angled parasternal long axis view and parasternal short axis view.
The branch pulmonary arteries are best seen from a parasternal
short axis view and modified suprasternal view. A combination
of pulsed and continuous wave Doppler is used to assess the se-
verity of RVOT and branch PA stenosis. It must be recognized
that the true gradient can be overestimated in long tunnel-​like
segments of RVOT narrowing or underestimated in the presence
of distal branch PA stenosis. Interpretation of the RVOT gradi-
ents should be made in combination with assessment of RV sys-
tolic pressures derived from Doppler assessment of tricuspid
regurgitation. Assessment of direction of flow across any residual
intracardiac shunts is also helpful to understand the underlying
haemodynamics.
Echocardiography can underestimate the severity of pul-
monary regurgitation but is felt to be reliable in cases where it is
haemodynamically significant [43]. This can be assessed by pres-
sure half time, ratio of colour flow Doppler regurgitation jet width
to the pulmonary valve annulus and the presence of diastolic flow
reversal from the MPA and branch pulmonary arteries on colour
Doppler.
Assessment of RV and LV size and function can be made using
TTE using 2D and 3D measurements as recommended by con-
sensus guidelines [44]. However, conventional thresholds for
intervention are mainly based on ventricular volumes and func-
tion derived from CMR. Three-​dimensional echocardiographic
techniques can be used for screening and serial assessments with
the understanding that it underestimates the values obtained by
CMR despite having a good correlation [45] (z Video 25.1). An
alternative method of estimating 3D volumes from multiple 2D
TTE images using knowledge-​based reconstruction algorithms
have similar results [46]. Thus, volumes derived from echo-
cardiographic methods have a role in serial assessment but are
not interchangeable with CMR. They have a role in the serial
I n t roduc t i on 383
Fig. 25.6  3D TTE multiplanar
reformatted image of a Venus P-​valve
post deployment demonstrating
optimal valve positioning and valve
leaflets excursion (zVideo 25.2)
Acknowledgement to Saleha Kabir, Evelina
London Children’s Hospital.
assessment of patients particularly in centres where CMR is not
readily available.
Implantation of the PPV is mainly guided by fluoroscopy and
angiography alone, but intracardiac echocardiography [47] has
been shown to be extremely helpful to assess valve function and
leaflet mobility. 3D echocardiography is also useful in this re-
gard despite the anterior position of the RVOT (E Fig. 25.6 and
z Video 25.2) as it allows for visualization of leaflet mobility in
post-​procedure assessment. Post implantation, echocardiography
has a role in identifying vegetations in isolated cases of suspected
bacterial endocarditis, but TTE alone is negative in up to 70%,
whereas TTE plus transoesophageal echocardiography is positive
in 75% of affected patients [48].
Magnetic resonance imaging
Cardiac magnetic resonance imaging (CMR) is a well-​established
imaging modality and essential tool in the management of patients
with congenital heart diseases [38, 42, 49–​53]. Non-​invasively
and without radiation exposure, CMR allows accurate assessment
of ventricular volumes, systolic function, cardiac anatomy, and
flow analysis including degree of valve-​conduit stenosis, valve
regurgitation, and residual shunts. Unlike TTE it is not affected
by patient’s body habitus and flow can be assessed in any plane.
CMR is particularly useful in the assessment of the RV given its
crescentic shape and retrosternal position which make echocardi-
ography particularly challenging. Patients with established RVOT
dysfunction should undergo serial CMR imaging in order to as-
sess changes in ventricular volumes and systolic function. Scans
should be performed yearly in patients with severe pulmonary
valve regurgitation and every 3–​5 years in patients who are well
with no significant RVOT dysfunction or residual lesions [39].
Intra-​and interobserver variability is low [54] however, having
a structured approach to analysis, reporting and a well-​established
methodology within the department is very important in order
384 CHAPTER 25   Tran s cath eter pu lmonic va lve repl acem en t
Fig. 25.7  Segmentation of end-​
diastolic (top left panel) and end-​
systolic (bottom left panel) volumes
for the left and right ventricle.
The right panels show the volume
rendered image of the calculated
volumes in diastole (EDV) and
systole (ESV).
to make data reproducible and accurate. Ventricular volumes are
obtained from semi-​automatic segmentation with manual cor-
rection of end-​systolic and end-​diastolic cine images, generally
acquired from a short axis stack although a transverse stack can
also be used (E Fig. 25.7). It is very important to decide whether
to include or exclude muscle bundles from the blood pool as this
can lead up to 30 ml difference in the calculated volumes. This is
particularly important when timing PVR as clinicians are looking
for changes to guide the decision. It is good practice that the same
observer re-​calculates the volumes of previous scans to reduce
variability and improve accuracy.
Flows are assessed using phase contrast velocity encoded
imaging (E Fig. 25.8). Standard assessment includes through
plane pulmonary flow generally acquired 1–​2 cm distal from
the pulmonary valve in order to minimize the effects of the
turbulent flow which would affect accuracy of data. Branch
pulmonary arteries should also be interrogated (E Fig. 25.9)
with assessment of proportional right to left PA flow as these
often present with focal narrowing or may be uneven in size;
residual lesions may also be target for catheter intervention at
the time of PPVI or may preclude catheter valve replacement.
Pulmonary valve flow peak velocity is obtained from the ac-
quired data, but it generally underestimates the true velocity
given that data acquired are an average of several cardiac cycles
and temporal resolution of CMR is lower than that of echo-
cardiography; pulmonary valve regurgitant fraction is calcu-
lated as the proportion between the regurgitant flow and the
antegrade flow and expressed as percentage. A regurgitant frac-
tion between 20 and 39% is considered moderate, whereas a
regurgitant fraction greater than 40% is severe. Caution must
be applied in data interpretation of patients who present with
restrictive RV physiology [55] since the stiff myocardium
would limit the degree of RV dilatation but also the degree of
pulmonary valve regurgitation.
Anatomical information is key for the interventional cardiolo-
gist in order to establish suitability for PPVI. Three-​dimensional
(3D) data can be obtained from MR angiography (MRA), which
allows quick visualization of the RVOT/​MPA and branch PAs
(z Video 25.3); these data however are not electrocardiogram
(ECG) gated and less accurate for measurements. 3D balanced
steady-​state free-​precession (SSFP) images are currently the gold
standard for anatomical information. Data can be acquired in
systole or in diastole although a dual phase acquisition is also
possible but less used [56]. The following information should
be obtained from multiplanar reconstruction of 3D data using
two cross sectional planes: proximal and distal MPA diameter;
proximal and distal branch PA diameter; and coronary artery
anatomy, in particular their relationship to the pulmonary valve
(E Figs. 25.10 and 25.11). For patients who may be suitable for
self-​expanding pulmonary valves, additional measurements need
to be added such the RVOT diameter measured 1 cm below the
pulmonary valve, the largest MPA diameter and the length of the
MPA (valve to bifurcation).
Metallic implants such as pacemakers, stents, or stent valves
may preclude accurate anatomical assessment. CT imaging would
therefore be recommended as a viable alternative especially for
the assessment of stent fractures. The use of black blood imaging
however might be sufficient to answer the question about patency
 300
Fig. 25.8  MR imaging assessment
of pulmonary valve function: top
200 panels show cross sectional view of
the RVOT/​MPA cine images; middle
Flow (mL\s)

100 panels show the magnitude (left)

and phase (right panel) images of
0 the phase contrast MR imaging;
the bottom panel show the results
of the off-​line post processing
–100 analysis with evidence of pulmonary
valve regurgitation (area under the
200 400 600 baseline).
Time (ms) RVOT = right ventricular outflow tract;
MPA = main pulmonary artery.

(a) (b) (c)

Fig. 25.9  3D SSFP images showing left pulmonary artery (LPA) stenosis. The two cross sectional planes (a and b) are used to plan the image (c) for flow analysis.
Quantification of proportional RPA to LPA flow is an important part of CMR assessment.
386 CHAPTER 25   Tran s cath eter pu lmonic va lve repl acem en t
Fig. 25.10  Proximal MPA diameter obtained from multiplanar reconstruction of 3D SSFP images.
of stents and stent valves since this is less affected by flow and
metal artefacts (E Fig. 25.12).
Finally, potential associated lesions such as tricuspid valve re-
gurgitation, aortic root dilatation, aortic valve, or mitral valve re-
gurgitation, should be reported in the same fashion.
The use of late gadolinium enhancement (LGE) for the as-
sessment of RV and LV myocardial fibrosis has promising elec-
trophysiological implications [57] but assessment of association
with outcomes in a prospective study is still pending. LGE
has been so far limited to research protocols; Babu-​Narayan
et al. described an increased incidence of arrhythmias and re-
duced exercise capacity in patients with higher burden of RV
fibrosis [58].
Cardiac computed tomography
Cardiac computed tomography (CT) is now in routine clinical
use as an alternative to CMR. It is particularly useful in patients
who have contraindications to CMR due to metallic implants
or in patients who cannot tolerate the MRI procedure due to
Fig. 25.11  Relationship of coronary arteries to the pulmonary valve and
main pulmonary artery assessed using 3D SSFP images.
claustrophobia or the inability to lie still for a long period of
time. Although there is a recognized burden of ionizing radi-
ation and the need for intravenous iodinated contrast in CT, the
newer generation of dual source CT technology, acquisition and
postprocessing protocols have allowed for further reductions in
radiation exposure while maintaining a high spatial resolution
and short acquisition time [59]. The high-​resolution imaging al-
lows for the visualization of coronary artery anatomy in relation
to the RVOT, clear assessment of the branch pulmonary arteries
and peripheral vascular tree and extracardiac structures such as
the lungs and thoracic cage (E Fig. 25.13 and z Video 25.4).
Imaging of the coronary arteries requires some form of ECG
triggering with good image quality achievable with prospective
triggering with lower radiation [60]. Assessment of the risk of cor-
onary artery compression at time of PPVI includes the proximity
of the coronary artery to the RVOT and is particularly relevant in
patients with anomalous coronary anatomy and in transposition
of the great arteries [61]. Assessment of ventricular function can
be achieved with CT but at a lower temporal resolution than echo
or MRI and comes at a higher radiation cost to standard static
imaging.
CT allows clear visualization of calcium in RVOT, metallic
stents or valve support material, and intraluminal assessment
within stented structures. This is particularly relevant as heavy
calcification of the RVOT is a risk factor for right ventricular out-
flow tract rupture [62]. In the setting of post-​procedure PPVI, the
use of CT includes assessment of stent fracture (E Fig. 25.14) in
addition to patency and anatomy of the RVOT and branch pul-
monary arteries.
Angiography and balloon testing
The initial non-​invasive imaging facilitates patient selection, de-
vice preselection, and identification of the risk of coronary artery
compression. However, repeat imaging with diagnostic cardiac

(a) (b)
Fig. 25.12  Sagittal views of the RVOT post Venous-​P-​Valve implantation. Note is made of reduced artefacts as we move from left to the right panel. (a)
Standard SSFP cine image; (b) flash gradient echo image; and (c) black blood image.
catheter angiography is routinely performed with balloon sizing
of the RVOT to confirm the final dimensions of the RVOT for
implantation. Typically, this involves a simultaneous RV angio-
gram during balloon inflation to ensure there is a true waist in
the RVOT which is often very expansile to avoid undersizing the
valve. Simultaneous selective coronary angiography is also per-
formed with balloon inflation in the RVOT to exclude any po-
tential compression of the coronary arteries. This is seen in E
Figure 25.15 and z Video 25.5. Three-​dimensional rotational
angiography has also been used to augment assessment of for
coronary compression and aortic root distortion during balloon
Fig. 25.13  Rendered image of the RVOT in yellow, and left coronary system
in beige (z Video 25.4).
I n t roduc t i on 387
(c)
inflation [63] (E Fig. 25.16). The presence of coronary artery
compromise with test balloon inflation will preclude proceeding
with a PPVI.
Image overlay techniques (fusion imaging) can be helpful
in the initial part of the procedure to help guide the interven-
tional cardiologist, particularly in cases of complex RVOT
geometry. Pre-​acquired CT or MRI images or rotational angi-
ography images acquired at the start of the procedure can be
superimposed on fluoroscopic imaging planes to limit the
need for repeated intravenous contrast angiography and im-
prove the planning of imaging projections, thus reducing the
number of acquisitions and total radiation exposure [64, 65]
(E Fig. 25.16).
Future perspectives
3D printing has also been used in select complex cases to sup-
port preprocedural planning of PPVI [66, 67]. In complex
cases, this allows the interventional cardiologist to simulate
the proposed PPVI. A challenge of this technique is the ability
of the printed material to mimic the heterogenous mechanical
characteristics of the RVOT due to patches, calcification, and
localized disease.
Finite element modelling using preprocedural CT imaging
shows promise in providing patient-​specific simulations in
complex RVOT morphology [68]. These models allow integra-
tion of the valve size, location, and dimensions in relation to
the RVOT and its distensibility. Rapid prototyping has been
shown to be beneficial over conventional CMR alone [69].
Current models of the RVOT include the aortic root, coronary
arteries, and calcification, where the device and these struc-
tures have a mechanical interplay for comprehensive simula-
tion for successful prediction of case selection [68]. However,
these methods still require significant computational and time
resource and are therefore limited to more borderline cases for
PPVI selection.
388 CHAPTER 25   Tran s cath eter pu lmonic va lve repl acem en t

Fig. 25.14  CT image demonstrating

a stent fracture in the RVOT on an
axial (left panel) and sagittal (right
panel) views.
Courtesy of Vivek Muthurangu, Great
Ormond Street Hospital, London.

Fig. 25.15  Fluoroscopic images

of balloon sizing of the RVOT
with simultaneous selective left
coronary angiography demonstrating
obstruction of the left anterior
descending coronary artery
(black arrows) on balloon inflation
(z Video 25.5).

(a) (b) (c) (d)

Fig. 25.16  Images of a patient post Ross Operation with 18 mm homograft and severe homograft degeneration and RPA stenosis. Images demonstrate RPA
stenting and PPVI with image overlay. (a–​d) Siemens Artis Zee with DynaCT (3D rotational angiography). (a) Import of pre-​cath CT angiogram (Siemens Force)
and fusion with 3DRA system for 3D guidance of PPVI based on computed tomography angiogram (CTA), retroaortic RPA stenosis and severe homograft
calcification (green), LCA close to RPA; (b) 3DRA with balloon interrogation RPA with BIB 16 mm and LCA angiography to prove sufficient distance; (c) 3DRA
guidance of RPA-​MPA stenting (3 ev3 Max LD stents 36 mm on BIB 16 mm), homograft stenting (Begraft Aortic 16 × 38 mm) and SAPIEN three-​valve 20 mm
implantation, adaptation of MPA stents up to 16–​18–​20 mm with Atlas balloon, (d) pre—​post overlay of CT pre-​cath and 3DRA post PPVI.
Abbreviations: 3D = three-​dimensional; 3DRA = three-​dimensional rotational angiography; CT = computed tomography; LCA = left coronary artery; RPA = right pulmonary artery;
RPA-​MPA = right pulmonary artery/​main pulmonary artery; PPVI = percutaneous pulmonary valve implantation.
Images courtesy of Gregor Krings, Children’s Heart Center, University Medical Center Utrecht, The Netherlands.

Conclusion
RVOT dysfunction is the most common lesion following repair
of congenital heart diseases. Since the early 2000s, percutan-
eous pulmonary valve implantation has opened a new era in the
medical field with the possibility to replace the malfunctioning
pulmonary valve without need for cardiopulmonary bypass and
therefore with a reduced morbidity for patients and reduced hos-
pital stay. Results have proven to be excellent with effective relief
of pulmonary valve stenosis and regurgitation, remodelling of
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9 For additional multimedia materials please visit the online version of the book at M oxfordmedicine.com/esccvimaging3
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 SECTION 5

Coronary artery disease

26 Echocardiography and detection of coronary artery disease  395

Thor Edvardsen, Marta Sitges, and Rosa Sicari
27 Nuclear cardiology and detection of coronary artery disease  403
Richard Underwood, James Stirrup, and Danilo Neglia
28 PET-​CT and detection of coronary artery disease  421
Marcelo F. Di Carli
29 MDCT and detection of coronary artery disease  435
Stephan Achenbach and Pál Maurovich-​Horvat
30 CMR and detection of coronary artery disease  447
Eike Nagel, Juerg Schwitter, and Sven Plein
31 Non-invasive imaging of the vulnerable atherosclerotic plaque  467
Rong Bing, David E. Newby, Jagat Narula, and Marc R. Dweck
32 Imaging of microvascular disease  481
Paolo G. Camici and Ornella Rimoldi

Contents
Chronic coronary syndromes  395
Global and segmental left ventricular
function  395
Myocardial deformation imaging: added
value in assessing patients with coronary
artery disease  396
Chronic ischaemic functional or secondary
mitral regurgitation  397
Stress echocardiography in stable CAD  398
Risk stratification in stable CAD  398
The role of echocardiography in
acute CAD  399
CHAPTER 26
Echocardiography and
detection of coronary
artery disease
Thor Edvardsen, Marta Sitges, and Rosa Sicari
Chronic coronary syndromes
In patients with established or suspected coronary artery disease, echocardiography pro-
vides useful information on the status of global and segmental myocardial function, the
presence of functional mitral regurgitation and potentially of other signs of myocardial
ischaemia [1]‌. Inducible ischaemia is typically evaluated by stress echocardiography and
will be discussed in this chapter.
Global and segmental left ventricular function
Evaluation of global and segmental left ventricular (LV) function is one of the most fre-
quent indications for echocardiography. Myocardial ischaemia causes abnormalities in
LV regional motion (an early, sensitive, and specific marker of ischaemia) and global
dysfunction (a late and non-​sensitive sign). It is well known that when coronary per-
fusion is stopped, the dependant myocardium quickly gets involved in the ischaemic
cascade leading to hypokinesia and finally to myocardial necrosis if coronary flow is not
restored [2]‌. The diagnostic accuracy of echocardiography to diagnose coronary artery
disease is mainly based upon its ability to detect abnormalities in segmental wall motion
[3]. Current echocardiographic systems with harmonic and optimized imaging provide
adequate images for that purpose in most of the patients [4]. Additionally, use of intra-
venous echo-​contrast enhances this diagnostic accuracy by improving the delineation of
the endocardial border (E Fig. 26.1, z Videos 26.1–​26.2). The extent of the abnormality
in segmental wall motion, from mild hypokinesia to akinesia, depends on the transmural
extension of myocardial necrosis. Abnormal segmental motion is defined by two essen-
tial parameters in echocardiography: wall displacement and more importantly, endocar-
dial systolic thickening. Both define the status of wall motion that can be characterized as
normal, hypokinetic (reduced displacement and endocardial thickening), akinetic (ab-
sent displacement and endocardial thickening), dyskinetic (outward displacement and
endocardial thinning) or aneurysmatic (diastolic wall deformation and endocardial thin-
ning) (E Fig. 26.2, z Videos 26.3–​26.5). The reduction of endocardial thickening is the
most sensitive and specific sign of underlying coronary artery disease, since abnormal
wall displacement can be also observed in other diseases which imply abnormal electrical
activation of the heart such as the presence of preexcitation, pacemaker, or left bundle
branch block. The presence of endocardial thickening in the latter situations allows for
ruling out coronary artery disease. Additionally, the interaction of segments with ab-
normal motion with neighbouring segments with normal function, might induce passive
396 CHAPTER 26   E c ho cardio graph y and det ecti on of c orona ry a rtery di sease

Fig. 26.1  Definition of endocardial border can be enhanced and

significantly improve accuracy for detection of abnormal wall motion
abnormalities with the use of intravenous contrast. Note a patient
with poor endocardial definition of the lateral wall of the left ventricle
(left panel E Fig. 26.1, z Video 26.1). Administration of contrast is
allowed for opacification of the left ventricular cavity and improved
lateral wall endocardial border definition and depicted a hypokinesia
of this lateral wall (right panel E Fig. 26.1, z Video 26.2).

displacement of the hypo/​akinetic myocardial segment, poten-
tially leading to misinterpretation of segmental motility. Again,
the absence of endocardial thickening in the ‘passive’ segment
confirms the underlying ischaemic aetiology. This potential limi-
tation of looking only at segmental wall displacement led to the
development of myocardial deformation techniques, that allow
for quantification of segmental myocardial deformation, with less
load-​dependency and independently of passive motion induced
by normally contracting neighbouring segments (see next).
Global ventricular systolic motion can be preserved even in the
presence of mildly abnormalities in segmental wall motion, par-
ticularly when surrounding myocardial segments show compen-
satory hypercontractility. Typically, global LV motion is evaluated
by the modified biplane Simpson’s method. In patients with is-
chaemic heart disease, the use of M-​mode based methods should
be avoided as segmental abnormal motion is frequently present
inducing false normal ejection fraction by the Teichholz method.
However, 3D echocardiography provides the best accuracy to
measure LV volumes and ejection fraction and should be always
recommended  [5]‌.
Finally, diastolic function of the left ventricle is early involved
in the ischaemic cascade and can indicate underlying coronary
disease particularly in those with marked abnormalities such as a
restrictive pattern or signs or elevated filling pressures [6]‌.
Myocardial deformation imaging:
added value in assessing patients
with coronary artery disease
Myocardial deformation either using Tissue Doppler or Speckle
Tracking imaging has been extensively studied in coronary ar-
tery disease [7–​9]. When local myocardial perfusion decreases,

Fig. 26.2  z Video 26.3 shows a short axis view of the left ventricle
from the transoesophageal approach depicting an akinesia of the
anterolateral wall of the left ventricle. z Video 26.4 shows an long axis
apical view of a patients with an inferolateral myocardial infarction;
the video shows a thinned, hyperechogenic inferolateral wall that
moves outward the cavity in systole defining the presence of a
dyskinesia in this patient. z Video 26.5 and E Figure 26.2 shows an
apical four-​chamber view depicting an apical aneurysm of the left
ventricle which is defined by a thinned non-​contracting wall with
shape deformation in diastole (arrows in E Fig. 26.2).
 Ch ronic ischa em i c fu n cti ona l or sec on da ry m i tr a l reg u rg i tat i on
the contractile force is linearly reduced and therefore, local de-
formation will decrease. Similarly, if contractility is increased
(e.g. by administration of dobutamine), deformation (and espe-
cially the speed of deformation, i.e. strain rate) will increase (as
long as a very fast heart-​rate does not prevent complete filling). If
hypoperfusion persists chronically, the tissue elasticity will add-
itionally change due to fibrosis and necrosis and deformation will
even decrease more.
Moreover, the interaction of neighbouring segments with ab-
normal and preserved perfusion will develop signs that can be
identified as a consequence of myocardial ischaemia. When adja-
cent segments develop a different amount of force during systole,
their deformation at early and end-​systole will be different [10].
When the aortic valve closes and the pressure drops, this differ-
ential deformation will result in exaggerated interaction of the
segments and the segment with the lesser contractile force will
start to show post-​systolic shortening/​thickening, which does
not contribute to ejection [11]. A normal myocardium is able to
shorten during the abrupt increase of LV pressure during early
systole due to its active forces, while an ischaemic myocardium
will be stretched during this early systolic phase [12]. The com-
bination of reduced systolic deformation together with an early
systolic stretch and post-​systolic deformation provides a sign of
myocardial ischaemia in a myocardial segment [8, 13]. This can
be easily observed by segmental analysis of traces of segmental
deformation from both Doppler tissue and speckle tracking im-
ages or even with a simple M-​mode scan.
Besides local reduction of deformation of given myocardial
segments, patients with coronary artery disease can show a global
reduction of deformation of their left ventricle depending on the
extension of the area with impaired flow due to ischaemia or even
necrosis (E Fig. 26.3).
Direct evaluation of epicardial arterial flow have clear limita-
tions since only the large primary vessels can be reliably imaged,
and there might be difficulties imaging all three major coronary
arteries [14].
397
Chronic ischaemic functional or
secondary mitral regurgitation
The presence of secondary or functional mitral regurgitation
(MR) further worsens the outcome of patients with coronary
artery disease [15, 16]. The prognosis is worse with increasing
amounts of MR and indeed, has a worse prognosis than primary
MR: for the same size or regurgitant orifice (20 mm2), the survival
at 5-​year follow-​up of a patient with primary MR is 90% while it is
only 37% for a patient with secondary MR due to ischaemic heart
disease. Therefore, the early identification of secondary MR in pa-
tients with coronary artery disease is important to aggressively
treat them and closely follow them up. This is sometimes challen-
ging, as the quantification of secondary MR is still cumbersome
due to its dynamic nature and its dependence on loading condi-
tions [17]. Additionally, physical examination is not always useful
as the murmur of these patients is typically not intense and hard
to listen to. Consequently, echocardiography plays an important
role in early detection of MR among patients with coronary artery
disease [18].
Pathogenesis of functional MR involves multiple factors,
including increased mitral leaflet tethering due to the outward dis-
placement of the papillary muscles caused by global and regional
LV remodelling, decreased LV closing forces and deformation of
the whole mitral apparatus including the annulus (E Fig. 26.4,
z Videos 26.6–​26.7) [19]. In some patients with advanced LV sys-
tolic dysfunction, differences in the timing of cardiac chambers or
even between myocardial segments contraction, namely mechan-
ical dyssynchrony, can contribute to the development of more in-
sufficiency of the mitral valve. Experimental studies have indeed
shown that rather than the ischaemia of the papillary muscle per
se, it is the unbalance of the closing and opening forces on the
mitral valve apparatus that lead to the development of secondary
MR: specifically, the reduction in contractility (segmental and
global) and the distortion of the normal mitral valve geometry
Fig. 26.3  This image shows an analysis of global (dashed white
trace) and segmental (coloured traces) longitudinal myocardial
strain of the left ventricle from the four-​chamber view and based
on speckle tracking echocardiography. Note that global longitudinal
strain is reduced (11%) but there is clear heterogeneity in segmental
strains. While apical segments (purple and green traces) show
markedly reduced deformation, the anterobasal (yellow trace) and
laterobasal (red trace) segments show more preserved longitudinal
strains. The mid basal (light blue) and laterobasal (dark blue)
segments show intermediate values of longitudinal strain with a clear
postsystolic thickening (arrows).
398 CHAPTER 26   E c ho cardio graph y and det ecti on of c orona ry a rtery di sease

Fig. 26.4  This image shows a patient with ischaemic

cardiomyopathy and secondary mitral regurgitation. Distortion
of the mitral valve geometry occurs with severe tethering of
the posterior leaflet (white arrow) and loss of the coaptation
surface (yellow arrow) (left panel, E Fig. 26.4 and z Video 26.6).
Consequently, severe mitral regurgitation develops (right panel,
E Fig. 26.4 and z Video 26.7).

both induce a lost in the surface of coaptation of the mitral valve with heart failure and risk of malignant arrhythmias [25]. An
leaflets [20]. implantable cardioverter defibrillator (ICD) is recommended in
patients with asymptomatic LV systolic dysfunction (LVEF ≤30%)
Stress echocardiography in stable CAD due to CAD, when assessed at least 40 days after acute myocar-
dial infarction. Most patients have, however, a better LVEF than
Stress echocardiography is an established technique for the as-
30% after the introduction of modern revascularization therapy.
sessment of extent and severity of coronary artery disease. The
Echocardiographic assessment of global longitudinal strain pro-
combination of echocardiography with a physical, pharmaco-
vides incremental information to LVEF and may be considered
logical, or electrical stress allows to detect myocardial ischaemia
when LVEF is >35% [26–​28].
with an excellent accuracy. A transient worsening of regional
Assessment of regional wall motion abnormalities might be
function during stress is the hallmark of inducible ischaemia. The
particularly relevant for patients suspected of CAD and the pres-
three most commonly used stressors are exercise, dobutamine,
ence (or absence) of inducible wall motion abnormalities sep-
and dipyridamole. Exercise is the prototype of demand-​driven is-
arates patients with different prognoses. Information has been
chaemic stress and the most widely used. However, out of five pa-
obtained from data banks of thousands of patients—​also with
tients, one cannot exercise, one exercises submaximally and one
multicentre design—​for exercise [29–​33], dobutamine [34–​36],
has an uninterpretable electrocardiogram (ECG). Thus, the use
and dipyridamole [37–​ 40]. A normal stress echocardiogram
of an exercise-​independent approach allows diagnostic domain
yields an annual risk of 0.4–​0.9% based on a total of >11,000 pa-
of a stress test laboratory to be expanded [21, 22]. Pharmacologic
tients, the same as for a normal stress myocardial perfusion scan.
stressors minimize factors such as hyperventilation, tachy-
Thus in patients with suspected CAD, a normal stress echocardio-
cardia, hypercontraction of normal walls, and excessive chest
gram implies excellent prognosis and coronary angiography can
wall movement which render the ultrasonic examination difficult
safely be avoided. The positive and the negative response can be
during exercise. All these factors degrade image quality and—​in
further stratified with interactions with clinical parameters (dia-
stress echo—​worse image quality dramatically leads to higher
betes, renal dysfunction, and therapy at the time of test), resting
interobserver variability and lower diagnostic accuracy.
echo (global LV function), and additive stress echo parameters
Dipyridamole (or adenosine) and dobutamine act on different
(LV cavity dilatation, coronary flow velocity reserve (CFVR),
receptor populations: dobutamine stimulates adrenoreceptors
and previous revascularization). While the ischaemic or necrotic
while dipyridamole (which accumulates endogenous adeno-
pattern are associated with markedly increased risk of death or
sine) stimulates adenosine receptors [23]. They induce ischaemia
myocardial infarction, a normal test is predictive of a generally fa-
through different haemodynamic mechanisms: dobutamine pri-
vourable outcome particularly in non-​diabetic patients [41]. The
marily increases myocardial oxygen demand and dipyridamole
ischaemic response can be further stratified with additive stress
(or adenosine) mainly decreases subendocardial flow supply.
echo parameters, such as the extent of inducible wall motion ab-
normalities and the workload/​dose. The higher the wall motion
Risk stratification in stable CAD score index and the shorter the ischaemia-​free stress time are, the
A resting echocardiography is recommended to quantify LV lower is the survival rate [35]. As for the prognostic implication
function in all patients with suspected CAD [24]. A low left ven- of the different pharmacological stress modalities, a similar prog-
tricular ejection fraction (LVEF) is related to poor prognosis nostic value has been reported for dobutamine and dipyridamole

testing [42]. Anti-​ischaemic therapy heavily modulates the prog-
nostic impact of pharmacological stress echocardiography [43].
Inducible myocardial ischaemia in patients on medical therapy
identifies the subset of patients at highest risk of death. On the
opposite end, the incidence of death in patients with a negative
test off therapy is very low. At intermediate risk are those patients
with a negative test on medical therapy or a positive test off med-
ical therapy [43].
In recent years the evaluation of coronary flow reserve by
combining transthoracic Doppler assessment of coronary flow
velocities with vasodilator stress has entered the echo lab as
an effective modality for both diagnostic and prognostic pur-
poses. The use of coronary flow reserve as a stand-​alone diag-
nostic criterion suffers from two main limitations. In fact, only
left anterior descending artery is sampled with very high suc-
cess rate. Moreover, coronary flow reserve cannot distinguish
between microvascular and macrovascular coronary disease.
Therefore, it is much more interesting to assess the additional
diagnostic value over conventional wall motion analysis. CFVR
of left anterior descending artery is a strong and independent
indicator of mortality, conferring additional prognostic value
over wall motion analysis in patients with known or suspected
CAD [44]. A negative result on stress echocardiography with a
normal CFVR confers an annual risk of death <1%. Moreover,
CFVR yields useful prognostic information in several clinical
subsets, such as diabetics with unchanged wall motion during
stress, hypertensives, patients with intermediate coronary sten-
osis, left bundle branch block, and normal or near normal cor-
onary arteries [45–​50]. A CFVR <2.0 is an additional parameter
of ischaemia severity in the risk stratification of the stress echo-
cardiographic response whereas patients with a negative test
for wall motion criteria and CFVR >2.0 during dipyridamole
stress echocardiography have a favourable outcome. Similar re-
sults have been obtained when perfusion imaging was added to
wall motion analysis [51]. In diabetic patients, a normal CFVR
is associated with tighter glycaemic control [52] and better
long-​term event-​free survival both considering unselected pa-
tients [53] and patients with angiographically normal coronary
arteries [50]. Anti-​ischaemic medication at the time of testing
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nondiabetic patients with known or suspected coronary artery dis-
ease. J Am Coll Cardiol 2006; 47: 605–​10.
42. Pingitore A, Picano E, Varga A, et al. Prognostic value of pharmaco-
logical stress echocardiography in patients with known or suspected
coronary artery disease: a prospective, large-​ scale, multicenter,
head-​to-​head comparison between dipyridamole and dobutamine
test. Echo-​Persantine International Cooperative (EPIC) and Echo-​
Dobutamine International Cooperative (EDIC) Study Groups. J Am
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43. Sicari R, Cortigiani L, Bigi R, et al. Prognostic value of pharmacological
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44. Cortigiani L, Rigo F, Gherardi S, et al. Coronary flow reserve during
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45. Cortigiani L, Rigo F, Gherardi S, et al. Additional prognostic value
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Additive prognostic value of coronary flow reserve in patients with
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RE F E RE N C E S 401
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R. Prognostic meaning of coronary microvascular disease in type
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Contents
Introduction  403
Spectrum of coronary artery disease  403
The ischaemic cascade  404
Impact of pretest likelihood of coronary
artery disease on imaging strategy  404
Methods of cardiac stress  404
Dynamic exercise  404
Pharmacological stress  405
Stable CAD  405
Diagnosis  405
Prognosis  408
Cost-​effectiveness  411
Current guidelines  413
Future directions  414
Acute coronary syndromes  414
Diagnosis  414
Prognosis  415
Cost-​effectiveness  415
Guidelines  415
Future directions  415
Conclusion  415
CHAPTER 27
Nuclear cardiology and
detection of coronary
artery disease
Richard Underwood, James Stirrup, and
Danilo Neglia
Introduction
Experience with radionuclide assessments of myocardial perfusion can be measured over
decades. Myocardial perfusion scintigraphy (MPS), performed by either single-​photon
emission computed tomography (SPECT) or positron emission tomography (PET), has
been validated for the diagnosis and prognosis of coronary artery disease (CAD) and
is embedded in national and international guidelines. With multiple alternative cardiac
imaging modalities available, it is important to understand the principles, indications,
and pitfalls of each option. No single technique provides a complete assessment of the
heart; many provide complementary rather than equivalent information. In this chapter,
the value of cardiac radionuclide imaging in stable CAD and acute coronary syndromes
(ACS) is discussed, with a particular emphasis on the role of SPECT MPS, the most com-
monly used technique in nuclear cardiology.
Spectrum of coronary artery disease
CAD is characterized by the progressive development of atheromatous plaques within the
intima of the coronary artery. Familiarity with the development and progression of ath-
eroma is helpful in order to put the cardiac imaging techniques into context. Techniques
concerned mainly with coronary artery anatomy, such as invasive coronary angiography
(ICA) or computed tomography coronary angiography (CTCA), are particularly suitable
to detect and quantify coronary luminal narrowing resulting from atheromatous plaques
and to characterize plaque features known to be associated with increased risk. However,
purely anatomical information correlates imperfectly with the impact of these plaques on
coronary flow and/​or myocardial perfusion. Both ICA and more recently CTCA can be
complemented by functional measurements, such as fractional flow reserve (FFR), which
are useful to establish the haemodynamic significance of a coronary lesion. Nevertheless,
the impact of coronary plaques on downstream myocardial perfusion can only be truly
assessed by those techniques that directly measure myocardial perfusion, such as MPS.
Ultimately, in patients with suspected or known CAD, the clinical scenario determines
the choice of cardiac imaging test used to make the diagnosis and guide subsequent man-
agement. If the first aim is to exclude CAD of any type or severity, such as in a 40-​year-​old
patient with atypical symptoms and a family history of premature CAD, a noninvasive
anatomical test such as CTCA is indicated. If the aim is to identify whether inducible
ischaemia is the cause of symptoms, as in a 60-​year-​old patient with typical angina, an
imaging functional test is the better choice.
404 CHAPTER 27   Nuc lear cardiol o gy and detecti on of c orona ry a rtery di sease
hypoperfusion
metabolic alterations
Myocardial perfusion
diastolic dysfunction
systolic dysfunction
ECG Changes
angina
Signs of ischaemia
Fig. 27.1  The ischaemic cascade.
The ischaemic cascade
Myocardial ischaemia is the result of oxygen demand exceeding
its supply. This is usually due to impairment of myocardial per-
fusion, which in turn is usually the result of obstructive CAD.
Occasionally, the cause is non-​obstructive CAD causing resultant
microvascular/​endothelial dysfunction. Excessive demand, such
as in high-​output heart failure or prolonged tachycardia, may also
have the same effect. Ischaemia leads to a cascade of events on the
cardiac myocyte, the manifestation of which depends on severity
(E Fig. 27.1). The precursor to ischaemia is impaired myocar-
dial perfusion, which, once sufficiently severe, leads to metabolic
abnormalities such as switching of the primary myocardial en-
ergy source from fatty acids to glucose. It is only after alterations
in myocardial metabolism that the cellular machinery within the
cardiac myocyte becomes sufficiently deranged to cause abnor-
malities of first diastolic and then systolic left ventricular func-
tion. These changes lead to electrical abnormalities, which may
be seen on the surface electrocardiogram (ECG), and symptoms,
such as chest pain. Functional imaging tests interrogate different
parts of this cascade. As impairment of myocardial perfusion pre-
cedes both ischaemic wall motion and ECG abnormalities, MPS
is potentially more sensitive than imaging modalities assessing
wall motion and certainly more sensitive than stress ECG.
Impact of pretest likelihood of
coronary artery disease on imaging
strategy
When a patient presents with symptoms of possible coronary dis-
ease, the decision to investigate, along with the appropriate choice
of test, should be informed by the pretest likelihood of significant
CAD. It is helpful to consider the usefulness of any diagnostic test
in Bayesian terms [1]‌. In summary, the post-​test likelihood of
having disease can be computed from the pretest likelihood and
the accuracy of the test (E Fig. 27.2). The pretest likelihood of
significant CAD has classically been estimated using a number of
100
80
Post-test probability
60
40
20
0
0 10 20 30 40 50 60 70 80 90 100
Pre-test probability
ECG + ECG − MPI + MPI −
Fig. 27.2  Impact of pretest probability on post-​test likelihood of disease.
In a patient with a 50% pretest likelihood of coronary artery disease, positive
stress electrocardiography renders the post-​test likelihood around 75%. This
is not sufficient to make the diagnosis with confidence. If the same patient
goes on to have a positive myocardial perfusion scan (MPS), the probability is
refined further to around 96%, which is certainly sufficient to be confident of
the diagnosis. If MPS had been performed as the initial test, pretest likelihood
would have been revised from 50% to around 90% based on a positive
result, after which further testing would not be required. ECG +/​–​Stress
electrocardiogram positive/​negative; MPI+/​–​Myocardial perfusion imaging
positive/​negative.
nomograms. Among these, the original Diamond and Forrester
predictive table integrated three clinical variables (quality of
chest pain, gender, and age) to provide an estimate of the likeli-
hood of angiographically significant coronary stenosis [2]. More
recently, it has been shown that, in patient populations referred
for screening of CAD, the prevalence of significant disease is
decreasing. Several large-​scale studies have documented much
lower prevalence of obstructive CAD than predicted by classical
nomograms [3–​5]. Using updated predictive models, revised pre-
test likelihoods for patients with chest pain and dyspnoea have
been incorporated into the 2019 European Society of Cardiology
(ESC) Guidelines for the investigation of chronic coronary syn-
dromes [6]. In general terms, false-​positive and false-​negative test
results are more likely in patients at very low and very high pretest
likelihoods, respectively. However, most of the patients currently
referred for diagnostic tests will remain in the intermediate pretest
likelihood category and will have the most to gain from further
investigation—​positive or negative test results allowing revision
of pretest likelihood to either high or low post-​test likelihoods,
respectively [7].
Methods of cardiac stress
Dynamic exercise
This is the preferred method of cardiac stress as it most accur-
ately replicates the physiological stresses that occur in ordinary
life. Additionally, changes in haemodynamic and ECG variables
 Sta b l e   C A D 405

during stress allow estimation of prognosis incremental to per-
fusion findings [8, 9]. However, exercise may be either difficult in
those with limited mobility or contraindicated, such as in patients
with severe left ventricular outflow tract obstruction or severe left
main stem disease. Furthermore, certain conditions, such as left
bundle branch block and permanent pacing, can be associated
with stress-​induced perfusion abnormalities at peak heart rates
even in the absence of obstructive coronary disease.
Pharmacological stress
Myocardial perfusion reserve can be assessed directly using
coronary vasodilators such as adenosine, dipyridamole, and the
adenosine A2A receptor agonist, regadenoson (E Table 27.1).
Endogenous adenosine is the active agent in coronary autoregu­
lation. When given in exogenous form, stimulation of adenosine
A2A receptors leads to coronary arteriolar dilatation and an up
to fivefold increase in myocardial blood flow compared to base-
line levels. Dipyridamole causes the same effects, albeit indirectly
through an increase in endogenous adenosine levels due to in-
hibition of local adenosine reuptake. Additional stimulation of
receptors within the sinoatrial and atrioventricular nodes and in
bronchial smooth muscle may lead to heart block and broncho-
spasm respectively, making the use of these agents in those with
existing nodal disease or obstructive airways disease problem-
atic. Selective stimulation of the A2A receptor using regadenoson
may mitigate some of these effects. An alternative in these pa-
tients is dobutamine, which is an α1, β1, and β2 adrenergic re-
ceptor agonist that causes secondary coronary vasodilatation
by increasing myocardial demand in a similar way to dynamic
exercise. At higher doses, dobutamine causes direct coronary
vasodilatation and can therefore be used to study perfusion het-
erogeneity even if target heart rate is not achieved.
Stable CAD
Diagnosis
Comparative performance of MPS, sECG, and CTCA
The typical clinical presentation of stable CAD is characterized
by predictable episodes of substernal chest discomfort of char-
acteristic quality and duration, provoked by exertion or emo-
tional stress and relieved by rest or nitrates within minutes. It
may also be associated with more atypical symptoms, meeting
two or (rarely) only one of the previous characteristics. Stable but
progressive atherosclerosis causes reduction in myocardial perfu-
sion reserve, ultimately leading to myocardial ischaemia during
periods of increased myocardial demand. Stress electrocardiog-
raphy (sECG) is commonly used to investigate chest pain because
it is widely available, easy to administer, and does not involves
radiation exposure. sECG provides a physiological evaluation of
symptoms, exercise tolerance, haemodynamic response, and ECG
changes during exercise that is usually equal to or greater than the
normal level of exertion for the patient. However, in the most re-
cent meta-​analysis, the sensitivity and specificity of sECG is only
58% and 62% respectively [10]. This means that both positive and
negative predictive values for sECG are poor [10]. Furthermore,
sECG has even lower value when exercise capacity is limited or
in the presence of an abnormal resting ECG that precludes ST-​
segment assessment. MPS is theoretically more suited to the diag-
nosis of stable CAD because of its ability to detect, localize, and

Table 27.1  Characteristics of forms of stress commonly used for myocardial perfusion scintigraphy

Exercise Adenosine Regadenoson Dipyridamole Dobutamine

Action Reflex coronary vasodilatation Direct adenosine Selective A2A Endogenous adenosine Beta-​adrenergic agonist
in response to increased receptor stimulation adenosine receptor reuptake inhibitor
myocardial work antagonist
Half-​life –​ l0s Hyperaemia 2–​5 min, 40 min 2 min
side effects 15–​30 min
Side effects Tachyarrhythmia Bronchospasm Heart Headache, Flushing Bronchospasm Heart Tachyarrhythmia
block Dyspnoea Block Hypotension
Limitations Limited mobility Severe asthma 2nd or 3rd degree heart Severe asthma History of ventricular
block without PPM tachyarrhythmia
Severe 3-​vessel disease 2nd or 3rd degree heart 2nd or 3rd degree heart Severe 3-​vessel disease
block without PPM block without PPM
Severe LVOTO Severe LVOTO
Protocol Dynamic exercise with 1–​2 140 mcg/​kg/​min 400 mcg IV bolus over 0.56 mg/​kg over 4 min 5–​40 mcg/​kg/​min
minute increments up to 20 s
maximum achievable
Duration of test Terminate test and inject 6 min ~4 min 4 mins Terminate infusion and
tracer once target heart rate inject tracer once target
Radionuclide 2–​3 minutes after start 10–​20 s after injection 3–​5 minutes after
achieved or at peak exercise heart rate achieved or after
injection time of infusion of regadenoson bolus completion of infusion
3 minutes at 40 mcg/​kg/​min
Abbreviations: PPM = permanent pacemaker; LVOTO = left ventricular outflow tract obstruction.
406 CHAPTER 27   Nuc lear cardiol o gy and detecti on of c orona ry a rtery di sease

(a) Test Pre-test probability of ICA-significant CAD (b) Test Pre-test probability of FFR-significant CAD
Results 0% 50% 100% Results 0% 50% 100%

+ +
Stress ECG ICA
− −

+ +
CCTA CCTA
− −

+ +
PET PET
− −

Stress + Stress +
CMR − CMR −

Stress + +
Echocardiography SPECT
− −

+ 15% 85%
SPECT
−

15% 85%
Pre-test probability range where test
can rule-in CAD (Post-test probability will rise above 85%)
Pre-test probability range where test
can rule-out CAD (Post-test probability will drop below 15%)

Fig. 27.3  (a) Pretest probability of ICA-​significant CAD; (b) Pretest probability of FFR significant CAD.

quantify impaired myocardial perfusion reserve, a phenomenon
that occurs earlier than both wall motion and electrocardio-
graphic abnormalities in the ischaemic cascade.
This was confirmed in the aforementioned metanalysis [10],
which included (i) 28 664 patients from 132 studies that used
anatomically-​significant CAD (>50% coronary stenosis) at ICA as
diagnostic reference; and (ii) 4,131 patients from 23 studies using
functionally significant CAD (FFR ≤0.8) as the diagnostic refer-
ence (E Fig 27.3). As expected, the ability to diagnose either ana-
tomical or functional disease by SPECT (sensitivity 87% and 73%,
specificity 70% and 83%, respectively) or PET (sensitivity 90% and
89%, specificity 85% and 85%, respectively) was clearly higher than
by sECG. Also as expected, CTCA had a lower specificity than MPS
for the recognition of functionally significant disease. Interestingly,
the ranges of pretest likelihood in which each test could reliably
reclassify patients into a post-​test probability that defines (>85%)
or excludes (<15%) significant CAD was also estimated. CTCA was
confirmed as the optimal test to rule-​out anatomical CAD virtually
at any level of pretest likelihood of disease. However, this ability de-
creased when functionally-​important CAD was the diagnostic end-​
point. On the other hand, MPS performed better when FFR was the
reference, outperforming CTCA. PET was superior to SPECT but
was performed in a limited number of more recent studies.
Clinical use of SPECT MPS for diagnosis of stable CAD
Although differences exist in the physical properties, myocardial
uptake and localization and elimination of the three SPECT MPS
tracers available commercially, all have comparable accuracy for
the detection of CAD [11]. Normal myocardial perfusion after
stress (E Fig. 27.4) indicates the absence of functionally signifi-
cant CAD and is associated with a low likelihood (<1%) of future
coronary events [12, 13]. It should be noted that normal stress
perfusion does not equal absence of CAD, as coronary athero-
sclerosis may not cause stenosis of sufficient severity to impair
perfusion reserve (E Fig. 27.5). Such disease, when not asso-
ciated with inducible ischaemia, is unlikely to be the cause of
exertional symptoms. However, the presence and extent of cor-
onary atherosclerosis, as can be evaluated by cardiac CT, still re-
tains independent prognostic value [14].
From the clinical perspective, a patient with angina and normal
stress SPECT MPS does not warrant invasive assessment solely
for risk stratification according to current guidelines [6]‌. Despite
the various tracers and stress techniques available, the results of
both older [15] and more recent [10] metanalyses demonstrate
that SPECT MPS may be considered a reasonably good single
diagnostic test, in particular (i) to rule-​out functionally signifi-
cant obstructive CAD in patients at lower pretest likelihood of
disease, and (ii) to identify and quantify inducible ischaemia in
patients at higher pretest likelihood. In contemporary popula-
tions with low prevalence of obstructive CAD, the technique has
greater sensitivity and positive predictive value than stress echo-
cardiography or magnetic resonance imaging [16]. Compared
with echocardiography, SPECT MPS is less operator-​dependent
and the technique is still more widely available than MRI. The
diagnostic performance of SPECT MPS is improved by ECG
gating [17] and attenuation correction [18]. ECG gating pro-
vides information on global and regional ventricular function
that, aside from providing important prognostic information,

(a)
(b)
aids in the distinction of artefact from true perfusion defects,
improving specificity and normalcy. Fixed defects in the anterior
and inferior walls, commonly due to breast and diaphragmatic
attenuation in women and men, respectively, can be mistaken
for myocardial infarction but for the fact that myocardial mo-
tion and thickening in these areas are normal on gated images.
Similarly, attenuation correction recovers counts in these areas
and further improves the recognition of artefact and hence diag-
nostic accuracy (E Fig. 27.6). New SPECT cameras and proto-
cols, such as solid-​state detector cameras, stress-​only imaging,
and preferential use of 99mTc labelled radiotracers, have signifi-
cantly improved the exam duration, image quality, and radiation
dose to the patient, with doses lower than 5 mSv now routinely
achievable [19]. Quantification of myocardial perfusion—​a do-
main previously the exclusive purview of PET MPS—​has also
been demonstrated using state-​of-​the-​art SPECT [20–​23].
The extent and depth of inducible perfusion abnormalities can
provide diagnostic information and guide subsequent manage-
ment (E Figs. 27.7–​27.9). Ultimately, after positive SPECT MPS,
Sta b l e   C A D 407
Fig. 27.4  Normal myocardial perfusion scintigraphy. A 70-​year-​
old lady with diabetes, hyperlipidaemia, and hypertension presents
to a rapid access chest pain clinic with atypical chest pain. Stress
electrocardiography was equivocal and subsequent invasive coronary
angiography showed 30% distal left anterior descending artery (LAD)
and 50% mid-​right coronary artery (RCA) stenoses. Stress-​rest MPS
(a) showed minor reduction in counts in the basal anterior wall
(asterisks) consistent with breast attenuation artefact. Evaluation of
raw data (z Video 19.1a) demonstrates breast shadows. There is
otherwise homogeneous myocardial tracer uptake during both stress
and rest. ECG gating of the resting tomograms (b, z Video 19.1b)
shows normal global and regional left ventricular function.
the clinician must decide whether, in addition to optimal medical
management, to offer ICA and possible revascularization. Debate
concerning the appropriateness of each in the management of
CAD continues. Results from the COURAGE trial in particular
suggest that, in patients with stable CAD and objective evidence
of myocardial ischaemia, revascularization fails to reduce the risk
of death, myocardial infarction, or other major cardiovascular
events when added to optimal medical therapy [24]. Although
subanalysis suggests that the addition of PCI leads to greater re-
duction in ischaemia on MPS, the prognostic importance of this
remains unclear [25]. Selection bias leading to the inclusion of
many low-​risk patients with minimal ischaemia is one of the
limiting factors of available studies. The ISCHEMIA trial appeared
to cast doubt on the value of routine coronary angiography in pa-
tients presenting with stable chest pain and moderate or severe
inducible ischaemia, compared with initial medical therapy alone
but with angiography reserved for patients whose symptoms are
insufficiently controlled [26]. However, many patients in the trial
were only mildly symptomatic, they did not necessarily have
408 CHAPTER 27   Nuc lear cardiol o gy and detecti on of c orona ry a rtery di sease
Fig. 27.5  Atheromatous plaques identified in the right coronary
artery on computed tomography coronary angiography (arrows).
These plaques are not of sufficient severity to cause abnormalities on
myocardial perfusion scintigraphy.
severe ischaemia judged by imaging as opposed to by treadmill
exercise testing, and the specificity of stress echocardiography in
women for anatomically significant coronary stenosis was par-
ticularly low [27]. It is therefore unclear whether the findings
apply in populations with more significant disease. There was,
for instance, a trend towards improved outcome in patients with
more severe ischaemia that might have become significant with
more accurate assessment of ischaemia. There was an early symp-
tomatic benefit in the routine invasive group, but at the expense
of a greater early event rate from complications of intervention.
Thus, while stress imaging guided appropriate revascularization
is beneficial, inappropriate procedures may simply predispose to
adverse events [28, 29, 30]. Assessment of myocardial perfusion
therefore remains central to the management of stable CAD and
current guidelines still recommend revascularization to improve
symptoms and prognosis in patients with significant inducible
ischaemia.
PET MPS for diagnosis of stable CAD
Although previously used primarily to assess myocardial viability,
PET MPS using pharmacological stress is now more commonly
used to assess myocardial perfusion and perfusion reserve. The
technique is generally considered the non-​invasive gold standard
for this indication and is discussed in detail in Chapter 29.
Although cyclotron-​produced radiotracers, such as 13N-​ammonia
or 15O-​water, are regularly used, efforts have focused also on the
use of rubidium-​82. This tracer is produced by a generator, com-
pares favourably with other PET tracers for measurements of
myocardial perfusion [31], and is an attractive option for hos-
pitals without easy access to a cyclotron. PET MPS offers higher
resolution images (when using cyclotron-​produced tracers and
compared with conventional gamma camera SPECT, at least) and
provides quantification of perfusion in absolute terms (ml/​g/​min).
Non-​quantitative PET may have better sensitivity and specificity
than SPECT MPS for the detection of CAD, particularly where
there is severe multivessel disease and in obese patients [32, 33].
Two meta-​analyses with PET demonstrated 90–​93% sensitivity
and 81–​88% specificity for CAD detection, superior to myocardial
perfusion SPECT [34, 35]. Quantification of absolute myocardial
perfusion further improves diagnostic accuracy, especially in pa-
tients with multivessel disease (E Fig. 27.10), and can be used
to monitor the effects of various therapies [36]. Quantitative PET
MPS is superior to standard SPECT MPS for the diagnosis of FFR-​
positive coronary lesions at ICA [37]. With PET imaging in gen-
eral becoming more widely available, mainly for oncology, PET
MPS may become an increasingly practical option, particularly
with the introduction of 18F-​labelled myocardial perfusion PET
radiotracers that do not require an on-​site cyclotron. PET MPS
could also be performed in combination with exercise testing [38].
Nevertheless, these new tracers have not yet entered clinical use
and their cost-​effectiveness will need to be demonstrated if the
technique is to supplant SPECT MPS as the default radionuclide
imaging test for inducible ischaemia [39].
Prognosis
The risk of future cardiac events, such as myocardial infarction
(MI) or death, is a significant determinant of treatment type and
intensity. A number of factors, such as angina threshold; total is-
chaemic burden; extent of CAD; degree of left ventricular (LV)

(a)
(b)
(c)
Fig. 27.6  Diaphragmatic attenuation artefact. A 73-​year-​old man with hypertension
and hyperlipidaemia presents with central chest pain unrelated to exertion and
occasional palpitation. Uncorrected images (a) show mild reduction of counts in the
whole inferior wall that is present in both stress and resting images. Evaluation of raw
data (z Video 19.2a) shows the presence of the diaphragm in the lateral projections.
X-​ray computed tomography attenuation correction (b) of the images recovers
counts in the inferior wall to normal. Additionally, ECG gating of the uncorrected
images (c, z Video 19.2b) demonstrates normal wall motion and thickening inferiorly
despite the reduced counts. In this case, the clinical history, attenuation-​corrected
images, and ECG gating all point to diaphragmatic attenuation rather than partial
thickness myocardial damage as a cause for the reduction in counts inferiorly.
Sta b l e   C A D 409
dysfunction; presence of diabetes or other arterial disease; and
other CAD risk factors contribute to the annual risk of cardiac
events. This risk may be classified as low (<1%), intermediate (1–​
3%) or high (>3%) in patients with established chronic coronary
syndromes; in asymptomatic, apparently healthy subjects, the
risk cut-​offs are somewhat lower (low-​to-​moderate risk <0.5%,
high risk 0.5–​1.0%, very high risk >1%) [6]‌. MPS has incremental
prognostic value even when clinical history, sECG, and ICA are
available [40]. The role of MPS in risk stratification and patient
management has been validated extensively. Normal MPS is asso-
ciated with a 0.7% mean annual risk of MI and cardiac death, which
is similar to the general population [13, 41]. This has important
implications because a normal study generally renders further
invasive investigation or treatment unnecessary. The annual risk
quoted represents an average figure and a normal perfusion study
should always be interpreted in the context of the individual pa-
tient. Patients with normal myocardial perfusion but significant
ST-​segment depression during adenosine stress are at increased
risk of non-​fatal MI, with an event rate of 7.6% compared with
0.5% in patients without such findings [42]. Specific groups, such
as the elderly and those with diabetes or known CAD, have an an-
nual event rate somewhat higher (1.4–​1.8%) despite normal MPS.
The ‘warranty period’ of normal MPS in this setting is around 2
years, depending on risk factor control, after which repeat scan-
ning may be warranted to redefine prognosis [43].
An abnormal scan confers a sevenfold increase in annual car-
diac events compared with a normal study [13, 40]. The likeli-
hood of a cardiac event increases with the extent and severity of
the inducible perfusion abnormalities (E Figs. 27.11 and 27.12)
[12, 44, 45]. Those with only mild inducible ischaemia have an an-
nual event rate of around 3%, rising to 7% in those with severe is-
chaemia (E Fig. 27.12) [12]. The presence of corollary markers of
severe three-​vessel disease, such as transient left ventricular dilata-
tion (E Fig. 27.13) or increased lung uptake of thallium-​201, in-
creases the event rate still further [46, 47]. On this basis, coronary
revascularization is recommended on prognostic grounds if >10%
of the left ventricular myocardium is ischaemic [27]. Patients with
significant ischaemia and without extensive scar on MPS realize
a survival benefit from early revascularization, while those with
minimal ischaemia are better served by optimal medical therapy
alone [48]. While perfusion data are most useful in predicting the
risk of ischaemic events, left ventricular function provides an inde-
pendent estimate of the risk of cardiac death (E Fig. 27.14) [37].
PET MPS has significant prognostic value in patients with sus-
pected or known stable CAD that is further increased by the add-
ition of quantitative measurements of myocardial perfusion and
perfusion reserve [33, 49, 50].
MPS is not generally recommended to assess prognosis
in asymptomatic individuals except in certain settings [49].
Documenting or excluding the presence of CAD could reclassify
the estimated cardiovascular risk in asymptomatic subjects with
intermediate-​to-​high risk based on traditional risk factors. As
already mentioned, it is known that the absence of inducible is-
chaemia on MPS identifies subjects with very low (<1% per year)
event rates during the following 2–​3 years [13, 51, 52]. Only a
few studies, however, have specifically evaluated the value of MPS
410 CHAPTER 27   Nuc lear cardiol o gy and detecti on of c orona ry a rtery di sease

Fig. 27.7  Pure inducible ischaemia on stress (a) and rest (b)
imaging and polar plots (c). A 62-​year old man with a family
history of premature coronary artery disease and hyperlipidaemia
presents to a rapid access chest pain clinic with typical angina. Stress
electrocardiography demonstrated no ECG changes, although the
patient did get chest pain during Stage 4 of the Bruce protocol. On (a) (b) (c)
MPS, there is reduction of tracer uptake on stress imaging (arrows),
severe at the apex, and mild in the anterior wall, which returns to
normal at rest.

in asymptomatic individuals. Similar to the data from symp-
tomatic populations, moderate-​to-​severe ischaemia on MPS in
asymptomatic populations is associated with a high risk of major
cardiac events [53]. However, no large trials are available that
demonstrate improved outcomes in intermediate-​to-​high risk
asymptomatic subjects managed by a strategy including MPS (or,
for that matter, any other non-​invasive imaging test). Due to the
large number of patients that would be eligible, costs and poten-
tial risks of imaging, routine screening of these individuals is not
recommended. Nevertheless, the 2019 ESC Guidelines on chronic
coronary syndromes [6]‌consider non-​invasive stress imaging,
including SPECT MPS, appropriate for advanced cardiovascular
risk assessment in selected asymptomatic individuals. In par-
ticular, stress imaging can be considered in patients with diabetes,
with a strong family history of CAD, or when previous risk assess-
ments suggest a high risk of CAD (Class IIb recommendation).
For patients with diabetes, a meta-​ analysis of 31 studies
including 69,655 diabetic and non-​diabetic patients showed that
the average annual rate of cardiac death or MI was 0.85% in dia-
betic patients with a normal MPS but rose to 5.9% in patients
with diabetes and moderate-​or-​worse MPS abnormalities [48].
Similarly, over almost 5 years of follow up in the Detection of
Silent Myocardial Ischemia in Asymptomatic Diabetics (DIAD)
prospective trial [54], the presence of moderate-​or-​worse re-
versible perfusion defects was associated with a significantly
higher event rate (2.4% per year) compared with patients with
normal perfusion or small perfusion abnormalities (0.4% per
year). However, moderate-​or-​worse perfusion defects were not
frequent (6% of patients) and the trial showed no overall differ-
ence in outcome between the two strategies. Thus, in the 2019
ESC Guidelines on chronic coronary syndromes [6]‌, imaging
screening for myocardial ischaemia in asymptomatic diabetic pa-
tients receives only a Class IIb indication. A position statement of
the Working Group of Nuclear Cardiology and Cardiac CT of the
ESC [55], in agreement with recommendations of the American
Diabetes Association [56], suggests that selected asymptomatic

Fig. 27.8  Pure myocardial infarction on stress (a) and rest (b)
imaging and polar plots (c). A 64-​year-​old man with previous
myocardial infarction and two-​vessel coronary artery bypass grafting
is referred for preoperative assessment prior to umbilical hernia
surgery. Although suffering from occasional atypical chest pain,
stable exertional breathlessness was the patient’s main symptom.
Evaluation of raw data (z Video 19.3a) shows a dilated left ventricle
with absent uptake at the apex. There is absent uptake at the apex on
stress images that is unchanged at rest (arrows), indicating myocardial
infarction without superimposed ischaemia. ECG gating of the resting
tomograms (z Video 19.3b) confirms the dilated left ventricle. There
is absent motion and thickening in the apex and apical anterior wall
and moderate reduction in the adjacent apical parts of the anterior
septum and the inferior wall. There is further reduced motion but (a) (b) (c)
preserved thickening in the remainder of the septum consistent with
left bundle branch block (LBBB). The absence of inducible ischaemia
indicates that the risk of perioperative coronary events is not high.

(a) (b)
diabetics might reasonably undergo nuclear MPS if significant
CAD has been demonstrated by CTCA. In fact, Anand and col-
leagues [57] reported that the prevalence of abnormal MPS find-
ings in asymptomatic diabetic patients without known CAD rose
in line with the coronary artery calcium score (CACS), from
18% prevalence in patients with CACS 10–​100 to 71% in pa-
tients with CACS >1,000. In this same group, no patients with
absent or minimal CAC had abnormal MPS. Again, while it is
clear that an integrated imaging strategy including CT angiog-
raphy (now preferred over CAC score) and possible MPS would
(a)
(b)
Sta b l e   C A D 411
Fig. 27.9  Mixed inducible ischaemia and partial thickness myocardial
infarction on stress (a) and rest (b) imaging and polar plots (c). A
45-​year old man with known previous myocardial infarction, right
coronary artery stenting but untreated mid-​left anterior descending
artery occlusion presents to clinic with diminished exercise tolerance
but no chest pain. There is moderate reduction of tracer uptake in the
apex and apical anterior and inferior walls (arrows) on stress imaging.
Images acquired at rest show improvement in these areas but the
anterior wall and apex do not return to normal, indicating partial
(c) thickness myocardial damage (arrowheads).
ECG gating of the resting tomograms (z Video 19.4) shows mild
reduction of wall motion and thickening in the apical anterior wall
but normal regional function elsewhere.
provide enhanced risk stratification [58–60], the ultimate balance
of benefit, cost, and risks of such an approach in asymptomatic
patients remains controversial, particularly in the context of op-
timal lifestyle and pharmacological interventions for diabetes and
cardiovascular risk reduction.
Cost-​effectiveness
By quantifying the presence, extent, and severity of inducible is-
chaemia, MPS allows either conservative or invasive manage-
ment strategies to be recommended. Those with minor inducible
Fig. 27.10  Myocardial perfusion was evaluated
with 13N-​Ammonia PET during dipyridamole stress
in a 64-​year-​old man with familial dyslipidaemia
and typical angina. The images show short axis,
(c) vertical and horizontal long axis views of relative
myocardial perfusion during stress (upper rows)
and at rest (lower rows) (a) and polar plots of
quantitative myocardial perfusion using an absolute
scale in ml/​g/​min (b). Reversible stress-​induced
perfusion defects are present in the inferior and
inferolateral walls (RCA and possibly [left circumflex
artery, LCX] territories, arrow). Absolute perfusion
is homogeneous at rest but is abnormal in all three
coronary territories during stress (red box, b; LAD
1.87, RCA 1.43, LCx 1.67–​ml/​g/​min; normal value
>2.5 ml/​g/​min). Coronary angiography showed
three-​vessel disease (left coronary artery, (c) right
coronary artery, (d) The relative analysis did not
(d) miss the existence of CAD but it underestimated its
extent and severity.
412 CHAPTER 27   Nuc lear cardiol o gy and detecti on of c orona ry a rtery di sease

1.0 documenting cost-​effectiveness of SPECT MPS in patients pre-

0 vessels
senting with stable chest pain both at intermediate and high pre-
test likelihood of CAD and with or without known CAD [61–63]
Cumulative Hard Event-free Survival

0.9
0.8
0.7
0.6
0 10
Time (months)
Fig. 27.11  Cumulative hard event-​free survival in patients with known or
suspected CAD according to number of ischaemic vascular territories on
99mTc setsamibi MPS.
Reproduced from Sharir Tali et al. Incremental Prognostic Value of Post-​Stress Left
Ventricular Ejection Fraction and Volume by Gated Myocardial Perfusion Single Photon
Emission Computed Tomography. Circulation 100, 1035–​42 (1999) with permission from
Wolters Kluwer.
ischaemia may be safely managed conservatively, suggesting that
even a positive MPS need not lead to further investigation or inva-
sive treatment. An investigation strategy involving MPS, therefore,
ought to be more cost-​effective than one based on either sECG
alone or direct referral for ICA. This supposition was supported by
classical studies, performed both in Europe and the United States,
(E Fig. 27.14). Where sECG was used as the initial test, SPECT
1 vessel
MPS remained cost-​effective for further investigation of patients
2 vessels at intermediate or greater likelihood of CAD [64, 65] by redu-
cing costs by 30–​40% compared with an aggressive interventional
strategy [65]. This was particularly true in women, where stratifi-
cation of patients to ICA based on MPS results was associated with
3 vessels significant cost-​savings, regardless of pretest likelihood of disease
[66]. In the UK, MPS performed after sECG resulted in a 20–​25%
reduction in unnecessary ICA and had equal diagnostic accuracy
and cost for the identification of those requiring revascularization
compared with direct referral for ICA [67]. For preoperative as-
sessment of patients with chronic stable angina, MPS allowed
20 30
more cost-​effective assignment to ICA and revascularization or to
medical therapy compared with other strategies [15].
Analysis of temporal trends in the use of SPECT MPS in the
United States have shown a decrease since 2003 [68]. Nevertheless,
the same analysis showed that, in recent years, the percentage of
negative or low-​risk MPS results is increasing, corroborating the
impression that the prevalence of significant disease is falling.
In this clinical scenario and in the presence of multiple alterna-
tive diagnostic imaging modalities, cost is becoming a more and
more relevant factor in deciding the need for and modality of fur-
ther investigation. Thus comparative cost-​effectiveness studies of
imaging-​guided strategies in stable CAD have gained increasing
attention. However, the most recent economic analyses, based
on comparative effectiveness trials or computer simulation
models, provide contradictory results, with no imaging modality

(a) (b) P<0.0001

5 10
9.2
4.2
4 8
P<0.0001
Cardiac Death Rate (%/year)
Cardiac Event Rate (%/year)

2.9 2.9 5.7

3 2.7 6

2.3

2 4

1 0.8 2
0.5 0.96 0.92
0.3 0.35
0
0 0
Normal Mildly Moderately Severely Normal Mild to Severely
abnormal abnormal abnormal moderately abnormal
abnormal
Myocardial infections Cardiac death
EF>45% EF<45%

Fig. 27.12  (a) Rates of myocardial infarction and cardiac death according to severity of myocardial perfusion abnormalities. (b) Cardiac death rates in patients
with differing severities of myocardial perfusion abnormalities, separated according to left ventricular ejection fraction (EF). Those with EF <45% are at a
markedly higher risk of death when compared to those with normal left ventricular function.
Reproduced from Abidov, A. et al. Transient ischemic dilation ratio of the left ventricle is a significant predictor of future cardiac events in patients with otherwise normal myocardial
perfusion SPECT. J. Am. Coll. Cardiol. 42, 1818–​25 (2003) with permission from Elsevier.
 Sta b l e   C A D 413

Fig. 27.13  Prognosis defined by extent and severity of inducible

myocardial ischaemia. Stress imaging (a, c) demonstrates severe
reduction of counts in the apex and apical anteroseptum, the whole
(c) lateral wall and adjacent inferolateral segments and finally moderate
reduction of counts inferiorly and inferoseptally (arrows). Counts are
poorest at the apex and inferolaterally (asterisks). Images at rest (b, d)
show marked improvement in all areas, although the apex, inferior
and basal lateral and inferolateral walls do not return to normal,
indicating partial thickness myocardial damage (arrowheads). Of
note, the end-​diastolic volume after stress is significantly larger than
at rest (111 ml vs. 79 ml; transient ischaemic dilation (TID) ratio
(a) (b) 1.41). This transient left ventricular cavitary dilatation is a marker of
(d) significant three vessel coronary artery disease. The total amount
of ischaemia demonstrated in this study is extensive and severe and
suggests that the likelihood of future cardiac events is high.
EDV = end-​diastolic volume.

consistently emerging as superior to others, either overall or

£1,400 P<0.0001 within patient subgroups [68–70]. Nevertheless, they confirm
that SPECT MPS is more cost-​effective than exercise ECG or
£1253
direct referral to ICA in patients with intermediate likelihood of
£1,200 CAD, and that it improves clinical care beyond diagnosis by pro-
viding additional information on the location, extent, and severity
of myocardial ischaemia [70]. Results on the cost-​effectiveness of
£1,000
SPECT MPS over other non-​invasive tests, such as CTCA, stress
echocardiography, PET MPS, and cardiovascular magnetic reson-
P<0.006
£800 ance (CMR) remain conflicting. The CECaT trial demonstrated
£667 that SPECT MPS, stress echocardiography and stress CMR could
all be used to investigate patients with stable chest pain without
£600 £529
£490 adverse clinical outcomes or excess costs at 3 years, when com-
£460
£409 pared with a strategy led by ICA [71]. The same trial also demon-
£400 strated that, when compared with stress echo or stress CMR and
measured against an angiographic gold standard, SPECT MPS
was more likely to remain cost-​effective across a broad range of
£200 costs-​per-​quality-​adjusted life year [71]. Despite demonstration
of cost-​effectiveness of PET MPS in high-​throughput centres
£0
[72], the clinical utility of PET is still constrained by high upfront
1 2 3 4 Scint Non-scint cost and lower availability compared with SPECT.
Strategy

Fig. 27.14  Mean cost of diagnosis of coronary artery disease from
the Economics of Myocardial Perfusion Imaging in Europe (EMPIRE)
study. Four diagnostic strategies were employed: 1—​Stress
electrocardiography (sECG) followed by ICA; 2—​sECG followed by
myocardial perfusion scintigraphy (MPS) followed by ICA; 3—​MPS
followed by ICA; 4—​D irect referral to ICA. The most cost-​effective
strategy involved referral of patients with positive or equivocal sECG
to MPS with subsequent ICA only in those with evidence of inducible
ischaemia. The mean cost of diagnosis was significantly lower in centres
who were regular users of MPS (Scint) compared to those who referred
infrequently (Non-​s cint).
Reproduced from Shaw, L. J. et al. The economic consequences of available diagnostic
and prognostic strategies for the evaluation of stable angina patients: an observational
assessment of the value of precatheterization ischemia. Economics of Noninvasive
Diagnosis (END) Multicenter Study Group. J. Am. Coll. Cardiol. 33, 661–​9 (1999) with
permission from Elsevier.
Current guidelines
MPS is embedded in both European and US guidelines for the
management of stable CAD (E Table 27.2) [6, 8, 73]. MPS, stress
echocardiography, and stress CMR are considered equivalent
tests for the assessment of myocardial ischaemia, with availability
and expertise defining the choice of technique. Wide availability,
ease of administration, and prognostic value of exercise variables
means that sECG remains the initial stress test in many centres.
It retains a Class IIb diagnostic indication in the European guide-
lines in patients who can exercise well and who have an inter-
pretable ECG, but only if non-​ invasive functional testing is
unavailable [6]‌. It retains a class I indication in the US guidelines
for symptomatic patients with a normal baseline ECG who can
414 CHAPTER 27   Nuc lear cardiol o gy and detecti on of c orona ry a rtery di sease

Table 27.2  Selected 2019 European Society of Cardiology Guidelines for the use of functional imaging in the investigation of chronic coronary
syndromes

Indication Class Level of evidence

Non-​invasive functional imaging for myocardial ischaemia or coronary CTA is recommended as the initial Class I B
test to diagnose CAD in symptomatic patients in whom obstructive CAD cannot be excluded by clinical
assessment alone.
Functional imaging for myocardial ischaemia is recommended if coronary CTA has shown CAD of uncertain
functional significance or is not diagnostic.
Risk stratification, preferably using stress imaging or coronary CTA (if permitted by local expertise and
availability), or alternatively exercise stress ECG (if significant exercise can be performed and the ECG is
amenable to the identification of ischaemic changes), is recommended in patients with suspected or newly
diagnosed CAD.
If coronary CTA is available for event risk stratification, additional stress imaging should be performed before Class IIa B
the referral of a patient with few/​no symptoms for ICA.
CAD = coronary artery disease; CTA = computed tomography coronary angiography; ECG = electrocardiogram; ICA = invasive coronary angiography.
Reproduced from Knuuti J, Wijns W, Saraste A, et al. 2019 ESC Guidelines for the diagnosis and management of chronic coronary syndromes. Eur Heart J. 2020;41(3):407–​77.
doi:10.1093/​eurheartj/​ehz425 with permission from Oxford University Press.

exercise [8]. However, functional testing for ischaemia offers su-
perior diagnostic performance and is preferred to sECG as first
line test [6], particularly when resting ECG abnormalities, such
as left bundle branch block, pre-​excitation, left ventricular hyper-
trophy or drug effects, are likely to render the sECG uninterpret-
able [6]. MPS is most useful for the evaluation of symptomatic
patients with an intermediate pretest likelihood of obstructive
CAD and should be preferentially performed with exercise stress
when possible. Pharmacological stress is indicated for patients
who are unlikely to exercise adequately. In patients with inconclu-
sive results from another first test or with high pretest likelihood
of disease, MPS allows further stratification of risk in order to as-
sist management decisions [6]. Patients either without symptoms
or with symptoms and low pretest-​likelihood of obstructive CAD
are generally not recommended to undergo MPS. In those with
established but stable CAD, MPS is indicated for those in whom
symptoms develop (or persist) after revascularization.
Future directions
Hybrid imaging (PET or SPECT with multidetector X-​ray CT)
is conceptually attractive as it offers the possibility of assessing
coronary function and anatomy at the same sitting [74]. In recent
studies combining CTCA and qualitative or quantitative perfu-
sion imaging [75, 76], the addition of perfusion information to
the anatomical assessment provided by CTCA allowed identifica-
tion of patients at the highest risk. The techniques are covered in
a separate chapter of this textbook.
Acute coronary syndromes
Diagnosis
Acute coronary syndromes (ACS) comprise a spectrum from
unstable angina, through non-​ST elevation (NSTE-​ACS) [77] to
ST-​elevation MI (STEMI) [78]. The hallmark of ACS is athero-
sclerotic plaque rupture and intracoronary thrombosis. In those
with ST elevation and chest pain, primary PCI is the preferred
reperfusion strategy within 12 h of symptom onset, provided it
can be performed expeditiously [27, 77]. When primary PCI is
not an immediate option (i.e. >120 min from STEMI diagnosis),
fibrinolysis is indicated [78]. In patients without ST elevation,
clinical history and serial ECG assessment remain key for the
diagnosis of an acute coronary syndrome. However, differenti-
ation between unstable angina and NSTE-​ACS depends on the
presence of and dynamic change in circulating biomarkers of
myocardial necrosis, with high-​sensitive troponin assays now
embedded as the preferred choice in most algorithms [77].
Assuming a compatible history and ECG, patients with posi-
tive biomarkers have NSTE-​ ACS and invasive management,
including PCI if clinically appropriate and technically feasible, is
often the treatment of choice [27, 77]. Patients who present with
non-​specific symptoms, equivocal ECG changes and/​or normal
serial troponin measurements are a diagnostic challenge and the
majority are diagnosed ultimately with non-​cardiac chest pain.
However, in some patients, symptoms do relate to important
CAD, with a consequent increase in morbidity and mortality if
the ultimate diagnosis is delayed.
ESC Guidelines recommend, in patients with suspected ACS
but no recurrence of chest pain, normal ECG findings and normal
cardiac troponins (preferably high sensitivity), non-​ invasive
stress testing (preferably with imaging) for inducible ischaemia
as the preferred gatekeeper to invasive coronary assessment [77].
MPS is useful in these patients. Resting MPS, by detecting fixed
perfusion defects suggestive of myocardial necrosis, has a high
sensitivity for acute infarction, particularly if it is associated
with regional wall motion abnormalities on gated imaging [41].
If tracer injection occurs during chest pain, normal MPS rules
out an acute coronary syndrome and allows the patient to be dis-
charged [79]. On the other hand, an abnormal scan in patients
with atypical presentation is associated with a sevenfold increase
in the risk of cardiac events at 6 months [80]. Combined stress-​
rest imaging may further enhance assessment of ischaemia, while
a normal study is associated with excellent outcome [81, 82].

MPS is also useful after primary PCI to evaluate the functional
significance and need for treatment of intermediate non-​culprit
coronary artery stenoses. Lack of 24-​hour availability is the major
limitation for the utility of SPECT MPS in this scenario.
Prognosis
The role of MPS early after ACS is reflected in both European and
American guidelines [77, 78, 83]. Assessment of right ventricular
(RV) and LV function before and after hospital discharge in pa-
tients with ACS has a key prognostic role. Therefore, guidelines
recommend that biventricular function—​in particular LV ejec-
tion fraction (LVEF)—​is determined before hospital discharge in
all patients after STEMI and 6–​12 months after ACS in patients
with LVEF ≤40% at discharge [78]. While echocardiography is
the modality of choice, CMR or gated SPECT MPS are alterna-
tives in those cases where results are suboptimal or inconclusive.
MPS also allows risk stratification and guides the need for further
revascularization through identification of residual ischaemia
and viability in patients with multivessel disease in which only the
infarct-​related-​artery (IRA) lesion has been treated, or in patients
who have been admitted late after ACS. The timing and modality
of imaging (echocardiography, SPECT, CMR, or PET) often de-
pends on local availability and expertise. However, SPECT (used
in combination with exercise or pharmacological stress) is one
of the best validated and most widely available techniques; PET
is equally indicated but less widely available and more expensive
[78]. In patients without post-​infarction angina, complex ar-
rhythmias, or congestive heart failure, early SPECT MPS using
pharmacological stress allows prognostic assessment. It is su-
perior to sECG for risk stratification and can be performed safely
2–​4 days after acute MI [84].
As well as quantifying myocardial ischaemia, SPECT MPS al-
lows measurement of LVEF, an important prognostic predictor
of cardiac death after MI [85]. Early SPECT MPS allows the
prompt discharge of lower-​risk patients and appropriate referral
of those at higher risk, such as those with LVEF <35% or indu-
cible ischaemia in >50% of the remaining viable myocardium, for
ICA [86]. PET is a high-​resolution technique but its use is limited
by cost and availability. A randomized clinical trial using PET
imaging demonstrated that patients with a substantial amount of
dysfunctional but viable myocardium are likely to benefit from
myocardial revascularization and may show improvements in re-
gional and global contractile function, symptoms, exercise cap-
acity, and long-​term prognosis [86]. The association between
viability and improved survival after revascularization was also
demonstrated by meta-​analysis [87]. Hybrid cardiac PET-​MR
imaging has been recently used to quantify the myocardium at
risk in patients with reperfused STEMI patients using as predictor
of long-​term mortality and heart failure [88].
Cost-​effectiveness
There is some evidence that MPS in the setting of ACS may be
cost-​effective. For example, use of normal resting MPS alone
to exclude MI in patients with non-​diagnostic ECG changes
C on c lusi on 415
cost-​
effectively reduces unnecessary admissions irrespective
of gender, age, or risk factors for CAD [89]. This was also true
in patients with diabetes, a subpopulation considered to have
CAD-​equivalent status [90]. Importantly, discharge of these pa-
tients is safe [91, 92]. When used routinely in conjunction with
early exercise testing in the emergency department, median costs
were $1,843 (€1,400) lower and length of admission shorter [93].
Nonetheless, studies of the cost-​effectiveness of MPS in ACS have
largely originated in the United States and it can be difficult to ex-
trapolate this into other health economic settings. Furthermore,
the wider use of acute resting MPS in Europe is limited by local
availability and experience.
Guidelines
In the evaluation of patients with suspected NSTE-​ACS, the ESC
Guidelines recommend a non-​invasive stress test for inducible is-
chaemia (preferably with imaging such as MPS) in patients with
no recurrence of chest pain, normal ECG findings and normal
levels of cardiac troponin (preferably high sensitivity), before
deciding on an invasive strategy (Class I) [77]. In patients with
STEMI, the ESC Guidelines underline the importance of stress
imaging to stratify risk and guide revascularization through
identification of residual ischaemia or viability in patients with
multivessel disease in which only the IRA lesion has been treated,
or in patients who have been admitted late after ACS. SPECT or
PET receive a Class IIb indication to detect residual ischaemia
and myocardial viability, also based on local availability and ex-
pertise. SPECT (used in combination with exercise or pharmaco-
logical stress) is considered one of the best validated and widely
available technique; PET is equally indicated but less widely avail-
able and more expensive [78].
Future directions
In the future, diagnosis of patients with acute chest pain may
be undertaken through assessment of myocardial metabolism.
Under normal conditions, myocytes use fatty acids as the pri-
mary source of energy but during ischaemia cellular metab-
olism switches to glucose. After resolution of ischaemia there is
a delay in the return of metabolism to normal (up to 24 hours)
with continuation of glucose metabolism in preference to fatty
acids. This is known as ischaemic memory; abnormal uptake of
fatty acids during this time can be exploited by appropriately la-
belled radiotracers, the most common of which is iodine-​123
betamethyl-​p-​iodophenyl-​pentadecanoic acid (BMIPP). Several
studies have shown encouraging results and this could become
an attractive option for assessment of patients whose ischaemic
insult may have occurred hours before presentation.
Conclusion
MPS has proven value for the diagnosis and prognosis of both stable
CAD and ACS, and is additionally safe and cost-​effective in a wide
416 CHAPTER 27   Nuc lear cardiol o gy and detecti on of c orona ry a rtery di sease
variety of clinical settings. Experience with the technique can be
measured over decades and there is a large amount of evidence to
support its use. Although less widely available and relatively more
expensive, PET may be used to detect obstructive coronary disease
and it allows absolute quantification of myocardial perfusion and
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9 For additional multimedia materials please visit the online version of the book at M oxfordmedicine.com/esccvimaging3
RE F E RE N C E S 419
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Contents
Introduction  421
Technical considerations  421
Comprehensive delineation of non-​
obstructive and obstructive CAD with
PET/​CT  423
Atherosclerotic burden 423
Patient-Centered clinical applications of
myocardial perfusion PET/​CT in the
evaluation of CAD  424
Evaluation of patients with
suspected CAD  424
Evaluation of ischaemic burden in patients
with angiographic CAD  424
Evaluation of patients with stable CAD  426
Evaluation of symptomatic patients without
obstructive CAD  428
Evaluation of patients with prior
revascularization presenting with chest
pain  430
Conclusions  432
CHAPTER 28
PET-​CT and detection of
coronary artery disease
Marcelo F. Di Carli
Introduction
During the last two decades, we have witnessed a significant improvement in the pre-
vention and management of coronary artery disease (CAD) and its devastating conse-
quences. Despite these efforts, however, coronary heart disease and its sequelae remains
highly prevalent and it represents a healthcare burden in industrialized and developing
countries. This has resulted in a continued expansion and refinement of our noninvasive
imaging approaches to improve diagnosis and risk prediction. Positron emission tomog-
raphy (PET) is a powerful noninvasive imaging tool for phenotyping patients at risk or
with known CAD that has been evolving over the past 30 years. One of the key advan-
tages of PET over other imaging modalities used in the management of CAD is its unique
ability to quantify myocardial perfusion (in ml/​min/​g). In addition, PET scanners have
been largely converted to hybrid PET/​computed tomography (CT) devices, which in the
setting of CAD offer the potential for a comprehensive noninvasive evaluation of cor-
onary atherosclerotic burden, myocardial perfusion and left ventricular (LV) function.
This chapter will discuss current and potential future applications of myocardial perfu-
sion PET/​CT imaging in the evaluation and management of patients with suspected or
known CAD.
Technical considerations
As described earlier, all modern PET systems are now combined with a CT scanner into
a hybrid PET/​CT camera. Each component of the integrated system provides unique
quantitative information for the evaluation of patients with known or suspected CAD as
described next.
CT scan. Low-​dose CT scans (scout image or topogram) are used for positioning
patients in the scanner field of view. A low-​dose non-​gated CT scan covering the
heart region (transmission scan) is then used for correction of the in-​homogeneities
of radiotracer distribution in the PET images caused by overlapping soft tissue (e.g.
breast, diaphragm). This post-​processing step is known as attenuation correction and is
mandatory for cardiac PET imaging. In patients without known CAD, a prospectively
gated CT scan is acquired during inspiratory breath hold. This gated CT scan is used
to calculate a coronary artery calcium (CAC) score. Finally, depending on the type
of CT technology associated with the PET system, it may also be possible to obtain a
422 CHAPTER 28   PET- C T and det ect ion of c orona ry a rtery di sease

Focal disease LV function and volumes

Atherosclerosis burden Diffuse disease + CMD

Quantitative myocardial blood flow (mL/min/g)
and MFR
Rest Stress MFR
LAD 0.90 1.40 1.56
LCX 0.84 1.19 1.42
RCA 0.83 0.99 1.20
Global LV 0.86 1.21 1.41

Fig. 28.1  Comprehensive multiparametric cardiac PET/​CT imaging. This figure illustrates the main components of the cardiac PET/​CT examination,
namely: (1) myocardial perfusion images that allow to define the extent and severity of focal disease (a); (2) the ECG-​gated images that provide
measurements of the LV function and volumes (b); (3) non-​contrast CT scan that provides the extent and severity of coronary artery calcifications (c);
(4) the regional and global quantitative myocardial blood flow and flow reserve that helps define the presence of diffuse atherosclerosis and coronary
microvascular dysfunction.
LV = left ventricle; LAD = left anterior descending; LCX = left circumflex; RCA = right coronary artery.

coronary CT angiogram (CCTA) immediately following the as- Radiopharmaceuticals

sessment of myocardial perfusion.
E Table 28.1 lists the most common radiopharmaceuticals
PET scan. Due to the short physical half-​life of PET radio­
used with PET in clinical practice for the evaluation of myocar-
pharmaceuticals for the assessment of myocardial perfusion,
dial perfusion and detection of CAD. 15O-​water, 13N-​ammonia,
approximately the same dose is injected for both the rest and
and 82Rubidium have been in clinical use for quite some time.
stress myocardial perfusion imaging (MPI) studies. Injected 18
F-​Flurpiridaz is a new perfusion imaging agent with excel-
doses are adjusted according to the size of the patient and type
lent physiologic (high cellular extraction at high flow rates)
of PET data acquisition (i.e. 2-​D vs. 3-​D mode). List mode
and imaging (18Fluorine label) characteristics that is currently
imaging has become standard practice with modern PET
undergoing phase III evaluation. One additional advantage of
technology, which allows a comprehensive multidimensional
the 18Fluorine label is that it avoids the need for a generator
examination illustrated in E Figure 28.1. This includes the
and on-​site cyclotron, thereby reducing cost and increasing ac-
assessment of myocardial perfusion, LV ejection fraction (EF)
cess to PET MPI. In the phase II study, 18F-​Flurpiridaz showed
and volumes, calcified atherosclerotic burden, and quantita-
improved image quality and significantly better accuracy for
tive myocardial blood flow (MBF) and flow reserve (MFR) in
detecting angiographically obstructive CAD compared to
the same setting.
SPECT MPI [1, 2].

Table 28.1  PET radiopharmaceuticals for myocardial perfusion imaging

Radiopharmaceutical Production Uptake mechanism Physical half-​life Regulatory approval

15
O-​water On-​site cyclotron Freely diffusible ~2 min No
13
N-​ammonia On-​site cyclotron Metabolic trapping ~10 min Yes
82
Rubidium Generator Na/​K ATPase ~76 sec Yes
18
F-​Flurpiridaz Cyclotron Binding to mitochondrial complex 1 ~120 min No
 C o m preh ensive delineat ion of n on - ob stru cti ve a n d ob stru cti ve CA D w i t h   PET / C T
Comprehensive delineation of
non-​obstructive and obstructive
CAD with  PET/​CT
As outlined in E Figure 28.1, the integrated PET/​CT approach
provides access to a comprehensive list of quantitative imaging
markers that together provide powerful diagnostic and prog-
nostic assessments in patients with known or suspected CAD.
Atherosclerotic burden
Electrocardiographic (ECG)-​gated scanning for CAC offers a
reproducible, easy-​ to-​
perform method to reliably determine
whether coronary calcification is present or absent, without the
need of intravenous contrast administration. The extent and se-
verity of calcification, reflecting the burden of atherosclerosis in
the coronary arteries, can be quantified by validated scoring tech-
niques (e.g. Agatston score). A score of 0 indicates no coronary
calcification and portends very low risk of adverse cardiovascular
events, whereas a score ≥0 indicates the presence of mild, mod-
erate, or severe calcification and higher clinical risk [3]‌. The non-​
gated CT transmission scan used for attenuation correction of the
PET data may also be used to assess the extent of coronary cal-
cifications using semi-​quantitative visual analysis [4]. Given the
apparent clinical relevance of atherosclerotic burden assessment
in guiding intensification of preventive therapies [5, 6], a formal
CAC score or at least a semi-​quantitative assessment of CAC
should be assessed and reported in all patients without known
CAD undergoing myocardial perfusion PET/​ CT imaging. In
selected patients, it is also possible to use ECG-​gated CT imaging
to obtain high quality images of the coronary arteries after the
administration of intravenous contrast [7, 8], which allows visu-
alization of both calcified and non-​calcified plaques, as well as
estimation of the severity of coronary artery narrowing resulting
from those plaques.
Detection of focal coronary artery stenosis. The basic prin-
ciple of radionuclide MPI for detecting CAD is based on the
ability of a perfusion tracer to identify a transient regional per-
fusion deficit in a myocardial region subtended by a coronary
artery with a flow-​limiting stenosis. A reversible myocardial
perfusion defect is indicative of ischaemia, while a fixed perfu-
sion defect generally reflects scarred myocardium from prior
infarction. Generally, myocardial perfusion defects during
stress develop downstream epicardial stenoses with ≥50–​70%
luminal narrowing and become progressively more severe with
increasing degree of stenosis. It is noteworthy that coronary
stenosis of intermediate severity (e.g. 50–​90%) associate with
significant variability in the resulting maximal coronary blood
flow, which in turns affects the presence and/​or severity of re-
gional perfusion defects. The observed physiologic variability
between angiographic stenosis and flow is multifactorial [9]‌
and includes: (1) geometric factors of coronary lesions not ac-
counted for by a simple measure of minimal luminal diameter
423
or percent stenosis, including shape, eccentricity, and length;
(2) development of collateral blood flow; (3) presence of dif-
fuse coronary atherosclerosis and microvascular dysfunc-
tion, all consistent findings in autopsy studies of patients with
CAD [10].
Quantification of myocardial ischaemia. Regional myocar-
dial perfusion is usually assessed by semi-​quantitative visual
analysis of the rest and stress images [11]. The segmental scores
are then summed into global scores that reflect the total burden
of regional and global ischaemia and/​or scar. Objective quan-
titative image analysis is a helpful tool for a more accurate and
reproducible estimation of total defect size and severity and is
generally used in combination with the semi-​quantitative visual
analysis. The semi-​quantitative (visual) and quantitative scores
of ischaemia and scar are linearly related to the risk of adverse
CV events and are useful in guiding patient management, espe-
cially the need for revascularization, and for assessing response
to medical therapy. The presence of transient LV dilatation
during stress imaging (so-​called transient ischaemic dilatation
or TID) is an ancillary marker of risk that reflects extensive
subendocardial ischaemia. In the absence of perfusion defects,
it usually reflects subendocardial ischaemia from microvascular
dysfunction and it is commonly seen in patients with LV hyper-
trophy (e.g. aortic stenosis, uncontrolled hypertension, hyper-
trophic cardiomyopathy, and others). Similarly, the presence
of transient right ventricular uptake during stress along with a
drop in left ventricular ejection fraction (LVEF) post-​stress (a
sign of post-​ischaemic stunning) are also markers of multivessel
LV ischaemia.
Quantification of myocardial blood flow and coronary flow
reserve. MBF (in ml/​min/​g of myocardium) and myocardial flow
reserve (defined as the ratio between peak stress and rest MBF)
are important physiologic parameters that can be measured by
routine post-​ processing of myocardial perfusion PET images
[12]. These absolute measurements of tissue perfusion are ac-
curate and reproducible. Pathophysiologically, stress MBF and
MFR values provide a measure of the integrated effects of epicar-
dial coronary stenoses, diffuse atherosclerosis and vessel remod-
elling, and microvascular dysfunction on myocardial perfusion,
and, as such, the value obtained is a more sensitive and accurate
measure of myocardial ischaemia. In the setting of increased
oxygen demand, a reduced MFR can upset the supply-​demand
relationship and lead to myocardial ischaemia, subclinical LV
dysfunction (diastolic and systolic), symptoms, and death. As
discussed next, these measurements of MFR have important
diagnostic [7, 13–​16] and prognostic [17–​25] implications in the
evaluation and management [22, 25] of the patients with known
or suspected CAD.
Quantification of LV function and volumes. The acquisition of
ECG-​gated myocardial perfusion images allows quantification of
regional and global systolic function, and LV volumes. ECG-​gated
images with PET are typically collected at rest and during stress. A
drop in LVEF during stress testing can be helpful to identify high-​
risk patients with multivessel CAD [26].
424 CHAPTER 28   PET- C T and det ect ion of c orona ry a rtery di sease

As discussed earlier, one unique advantage of PET over SPECT

Patient-Centered clinical applications
of myocardial perfusion PET/​CT in
the evaluation of CAD
Evaluation of patients with suspected CAD
Case vignette #1: a 59-​year old man with a history of hyper-
tension, dyslipidaemia, obesity, and diabetes mellitus presented
with atypical chest pain and dyspnoea. His rest ECG was normal.
Given his cardiovascular risk factors, a vasodilator-​stress myo-
cardial perfusion PET was requested to rule out underlying
obstructive CAD.
The comprehensive cardiac PET/​CT examination is shown in
E Figure 28.2. The myocardial perfusion images demonstrate
normal regional myocardial perfusion (panel a). The ECG-​gated
images demonstrated a normal LVEF of 59% at rest that rose to
61% during stress with normal LV volumes (panel b). His CAC
score was zero (panel c). His stress MBF and MFR were normal
(panel d). These findings demonstrated no evidence of flow-​
limiting stenosis or CMD.
Recent meta-​analyses [27, 28] and a prospective European
multicentre study (Evaluation of Integrated CAD Imaging in
Ischemic Heart Disease—​EVINCI) [29] suggest that PET MPI
is one of the most accurate noninvasive techniques for detect­ing
obstructive angiographic stenosis. Furthermore, a recent meta-​
analysis using fractional flow reserve (FFR) rather than percent
angiographic stenosis as gold standard for flow-​limiting CAD,
demonstrated higher sensitivity, specificity, negative and posi-
tive predictive value for PET over SPECT MPI [30].
is that it allows routine quantification of MBF and flow reserve.
These quantitative measures of myocardial perfusion improve
the sensitivity and negative predictive value of PET for ruling
out high-​risk angiographic CAD [7, 13–​16]. In fact, the results
of the Prospective Comparison of Cardiac PET/​CT, SPECT/​CT
Perfusion Imaging and CT Coronary Angiography With Invasive
Coronary Angiography (PACIFIC) study confirmed the super-
iority of quantitative PET MPI for detection of flow-​limiting
CAD [31], including the combination of CCTA with CTFFR [32]
(E Fig. 28.3). In symptomatic patients without documentation
of angiographic stenosis, quantitative MBF and flow reserve pro-
vide incremental information that helps exclude or establish the
diagnosis of coronary microvascular dysfunction (CMD) as the
potential source of patients’ symptoms, which is especially im-
portant in high-​risk patient with cardiometabolic disease like case
vignette #1 [33].
Evaluation of ischaemic burden in patients
with angiographic CAD
Case vignette #2: A 63-​year old man with a history of hyperten-
sion and diabetes mellitus presented with exertional dyspnoea.
His rest ECG showed sinus bradycardia. A recent CCTA showed
extensive atherosclerosis. A vasodilator-​stress myocardial perfu-
sion PET was requested to evaluate flow-​limiting CAD.
The comprehensive cardiac PET/​CT examination is shown in
Figure 28.4. The PET images demonstrate normal regional myo-
cardial perfusion (panel a). The ECG-​gated images demonstrated
a borderline normal LVEF of 48% at rest that rose to 63% during

(a) (b)

stress LV function and volumes

rest • Rest LVEF: 59%

• Rest ESVI: 23 ml/m2
stress • Rest-stress LVEF: 61%
• Post-stress ESVI: 24 ml/m2
rest

(c) (d)
No evidence of CAC

Quantitative myocardial blood flow (mL/min/g)

and MFR
Rest Stress MFR
LAD 0.72 2.96 4.11
LCX 0.81 3.30 4.07
RCA 0.75 2.98 3.97
Global LV 0.75 3.08 4.05

Fig. 28.2  Comprehensive cardiac PET/​CT examination in a symptomatic patient with suspected CAD. See case vignette #1 text for description of the
imaging findings.
Patient-Centered clinical applications of myocardial perfusion PET/CT in the evaluation  of  CAD 425

Primary analysis (N = 157) Intention-to diagnose analysis (N = 208)

1 1
0.92 0.91 0.90
0.9 0.9
0.81 0.79
0.8 0.75 0.8 0.76
0.74
Area under the ROC curve 0.7 0.7

0.6 0.6

0.5 0.5

0.4 0.4

0.3 0.3

0.2 0.2

0.1 0.1

0 0
SPECT CCTA FFRCT PET SPECT CCTA FFRCT PET

Fig. 28.3  Comparative effectiveness of noninvasive imaging approaches for diagnosis of flow-​limiting CAD. The data reflects the per-​patient analysis.
Source data from Driessen RS, Danad I, Stuijfzand WJ, Raijmakers PG, Schumacher SP, van Diemen PA, Leipsic JA, Knuuti J, Underwood SR, van de Ven PM, van Rossum AC,
Taylor CA and Knaapen P. Comparison of Coronary Computed Tomography Angiography, Fractional Flow Reserve, and Perfusion Imaging for Ischemia Diagnosis. J Am Coll
Cardiol. 2019;73:161–​73.

stress with normal LV volumes (panel b). His CCTA shows ex-
tensive calcified and non-​calcified coronary plaque in the left
anterior descending artery (LAD) and left circumflex artery
(LCX) coronary arteries (panel c). His stress MBF was moder-
ately reduced in all coronary territories, but his MFR was normal
in all regions and globally (panel d). Together, these findings are
consistent with diffuse non-​obstructive atherosclerosis without
significant myocardial ischaemia, as reflected by the normal
perfusion images and MFR. The patient was placed on intensive
lipid lowering with high dose statin and optimization of blood
pressure control.
The goals of MPI in patients with known coronary atherosclerosis
are to quantify ischaemia and assess prognosis. This information
guides further diagnostic steps and therapeutic measures, espe-
cially the need for coronary angiography and revascularization.
The power of myocardial perfusion PET imaging for risk

(a) (b)

LV function and volumes

stress

• Rest LVEF: 48%

rest
• Rest ESVI: 32 ml/m2
• Post-stress LVEF: 63%
stress
• Post-stress ESVI: 25 ml/m2

rest

(c) (d)

Quantitative myocardial blood flow and MFR

LCX Rest Stress MFR
LAD 0.45 1.48 3.29
LCX 0.51 1.89 3.71
RCA 0.47 1.47 3.13
Global LV 0.47 1.58 3.36

LAD
Fig. 28.4  Comprehensive cardiac PET/​CT examination in a symptomatic patient with known angiographic CAD. See Case vignette #2 text for description of
the imaging findings.
426 CHAPTER 28   PET- C T and det ect ion of c orona ry a rtery di sease
Women (n = 2,904); 54 deaths
20.0% Model X2 = 47, p <0.0001.
Cumulative CAD mortality rate (%)
15.0%
10.0%
5.0%
0.0%
0.0 1.0 2.0 3.0
Fig. 28.5  Cumulative cardiac mortality rates by percentage of abnormal stress myocardium with Rubidiumb-​82 PET imaging. Stratified Cox model chi-​square:
154, P <0.0001.
Reproduced from Kay J, Dorbala S, Goyal A, Fazel R, Di Carli MF, Einstein AJ, Beanlands RS, Merhige ME, Williams BA, Veledar E, Chow BJ, Min JK, Berman DS, Shah S, Bellam N, Butler
J and Shaw LJ. Influence of Sex on Risk Stratification with Stress Myocardial Perfusion Rb-​82 Positron Emission Tomography: Results from the PET (Positron Emission Tomography)
Prognosis Multicenter Registry. Journal of the American College of Cardiology. 2013;62:1866–​76 with permission from Elsevier.
stratification is based on the fact that the major determinants of
prognosis in patients with CAD are readily available from gated
MPI. These include the amount of myocardial ischaemia and scar,
and measurements of LV volumes and LVEF. Single centre studies
and one multicentre registry support the value of PET MPI for risk
stratification (E Fig. 28.5) [34, 35]. Like with SPECT imaging,
these data indicate that risk increases with the extent and severity
of perfusion abnormalities, a concept that applies to all patient
demographics and types of clinical presentations.
Emerging data have consistently shown that the quantitative
flow data, especially MFR measurements by PET, can distinguish
patients at high risk for serious adverse events, including cardiac
death [17–​25, 36]. A reduced global MFR is independently as-
sociated with higher rates of cardiac and all-​cause mortality in
a large cohort of patients with and without diabetes mellitus
(DM) [19, 20]. Relatively preserved MFR identifies patients with
known or suspected CAD who have significantly lower risk of
cardiac death, regardless of traditional semi-​quantitative meas-
ures of stress-​induced ischaemia. Conversely, reduced MFR iden-
tifies patients at significantly higher risk of cardiac death, even
among those without objective evidence of ischaemia, probably
due to diffuse atherosclerosis and/​ or microvascular dysfunc-
tion. PET measures of MFR improved risk stratification beyond
comprehensive clinical assessment, LVEF and semi-​quantitative
measures of myocardial ischaemia and scar, and led to clinically
meaningful risk-​reclassification of ~50% of intermediate risk pa-
tients [20]. Importantly, diabetic patients without known CAD
and with impaired MFR experienced a rate of cardiac death com-
parable to, and possibly higher than, that for non-​diabetic pa-
tients with known CAD (E Fig. 28.6). These observations have
implications for the classification of DM as a CAD risk equivalent
Men (n = 3,133); 115 deaths
Model X2 = 71, p <0.0001.
≥20%
≥20%
1019.9%
1019.9%
59.9%
59.9%
0.14.9%
0.14.9%
0.0%
0.0%
4.0 5.0 0.0 1.0 2.0 3.0 4.0 5.0
Time to follow-up (in years)
[37]. Specifically, only among diabetics with impaired vascular
function is prognosis comparable to non-​diabetic patients with
known CAD. Thus, differing levels of vascular health among pre-
viously studied cohorts may account for inconsistencies in rela-
tive mortality rates of diabetics without CAD and non-​diabetics
with CAD [38–​40].
Furthermore, stress MBF and flow reserve measurements
provide robust complementary information that helps inform
risk and subsequent patient management. Stress MBF is a sensi-
tive marker of epicardial atherosclerosis (closely related to FFR)
whereas MFR provides a better measure of overall clinical risk
[21]. As shown in E Figure 28.7 [21], concordant abnormal
stress MBF and MFR identified the highest risk patients (car-
diac mortality: >3%/​yr.) whereas concordant normal results
identified the lowest risk patients (cardiac mortality: <0.5%/​
yr.). Discordantly low stress MBF (<1.8) with preserved MFR
(>2.0), as in case v­ ignette 2, identifies patients with epicardial
atherosclerosis that have a low risk of adverse events (<1%/​yr.)
in whom revascularization is unlikely to offer a prognostic ad-
vantage [22, 25].
Evaluation of patients with stable CAD
Case vignette #3: a 68-​year old woman with known stable CAD
with chronic total occlusion of the right coronary artery (RCA)
on prior coronary angiography, evaluated for exertional dyspnoea
and preoperative risk assessment for lung surgery. She had a his-
tory of controlled hypertension. Her rest ECG showed normal
sinus rhythm and left ventricular hypertrophy (LVH) with sec-
ondary repolarization abnormalities. Her medical therapy in-
cluded carvedilol, ASA, lisinopril, and atorvastatin.
Patient-Centered clinical applications of myocardial perfusion PET/CT in the evaluation  of  CAD 427

4% P = 0.015
N = 2423

Annualized cardiac mortality

CD = 122
3%
2.9% 2.8%
2%
2.0%

1%

P = 0.07 P = 0.33 P = 0.005 P = 0.65

0.3% 0.5%
0%
CAD+/DM+ CAD+/DM CAD/DM+ CAD/DM+ CAD/DM
(N = 606) (N = 569) CFR ≤1.6 CFR >1.6 NI MPI/EF
(N = 227) (N = 339) (N = 682)

*Adjusted for Duke score, ischaemia scar, rest LVEF, and early revascularization

Fig. 28.6  Annualized cardiac mortality among patients with diabetes mellitus (DM) or coronary artery disease (CAD). Adjusted cardiac mortality among
patients with CAD (i.e. history of coronary revascularization or myocardial infarction) without DM (orange), DM patients without CAD who have impaired
coronary flow reserve (red), DM patients without CAD who have preserved CFR (blue), and patients without DM or CAD with normal scans (no scar, ischaemia,
or left ventricular dysfunction; green) presented as annualized cardiac mortality rates. Data for patients with CAD and DM are also presented for comparison
(purple).
MPI = myocardial perfusion imaging; EF = ejection fraction; NI MPI = normal myocardial perfusion imaging; CD = cardiac death.
Reproduced from Murthy VL, Naya M, Foster CR, Gaber M, Hainer J, Klein J, Dorbala S, Blankstein R and Di Carli MF. Association between coronary vascular dysfunction and cardiac
mortality in patients with and without diabetes mellitus. Circulation. 2012;126:1858–​68 with permission from Wolters Kluwer.

Concordant Impairment Discordant with Impaired CFR Discordant with Preserved CFR Concordant Normal
High risk of CV Death (>3%/y) Intermediate risk of CV Death (1.3%/y) Low risk of CV Death (<1%/y) CV Death unlikely (<0.5%/y)

4 N = 4,029
CD = 392
FU = 5.6 yrs
Crude Annual CV Mortality (% per year)

4
p <0.001
3 3.5 3.3%
3
Coronary Flow Reserve

2.5 p = 0.04
2 2 1.7%
1.5
p = 0.01
1 0.9%
1
0.5 0.4%
0
Cardiovascular Death = Yes mMBF<1.8 mMBF≥1.8 mMBF<1.8 mMBF≥1.8
0 Cardiovascular Death = No CFR < 2 CFR ≥ 2.0
0 1 1.8 2 3 4
Maximal Myocardial Blood Flow, ml g–1 min–1

Fig. 28.7  Scatter plot of coronary flow reserve and maximal myocardial blood flow by cardiovascular
Death (left panel). Concordant and discordant impairment of coronary flow reserve and maximal myocardial blood flow identifies unique prognostic
phenotypes of patients. Coronary flow reserve <2 and maximal myocardial blood flow <1.8 ml⋅g‒1⋅min‒1 were defined as impaired. Annualized
cardiovascular mortality rates. Annualized CV mortality for the four groups based on concordant or discordant impairment of CFR and maximal MBF (right
panel). (a) Crude annualized CV mortality risk. (b) Adjusted annualized CV mortality risk after adjustment for age, sex, baseline CV risk factors, left ventricular
ejection fraction, amount of myocardial scar and ischaemia, revascularization after positron emission tomography scan, rate-​pressure product, and type of
radiotracer or stress agent.
CFR = coronary flow reserve; CV = cardiovascular; mMBF = maximal myocardial blood flow.
Reproduced from Gupta A, Taqueti VR, van de Hoef TP, Bajaj NS, Bravo PE, Murthy VL, Osborne MT, Seidelmann SB, Vita T, Bibbo CF, Harrington M, Hainer J, Rimoldi O, Dorbala S,
Bhatt DL, Blankstein R, Camici PG and Di Carli MF. Integrated Noninvasive Physiological Assessment of Coronary Circulatory Function and Impact on Cardiovascular Mortality in
Patients with Stable Coronary Artery Disease. Circulation. 2017;136:2325–​36 with permission from Wolters Kluwer.
428 CHAPTER 28   PET- C T and det ect ion of c orona ry a rtery di sease

(a) (b)

stress LV function and volumes

rest • Rest LVEF: 44%

• Rest ESVI: 57 ml/m2
stress • Post-stress LVEF: 39%
• Post-stress ESVI: 71 ml/m2
rest

stress rest reversibility

(c)

Quantitative myocardial blood flow (mL/min/g)

and MFR
Rest Stress MFR
LAD 0.72 1.21 1.68
LCX 0.81 1.21 1.49
RCA 0.68 1.00 1.47
Global LV 0.72 1.13 1.57

Fig. 28.8  Comprehensive cardiac PET/​CT examination in a symptomatic patient with stable CAD. See Case vignette #3 text for description of the
imaging findings.

The comprehensive cardiac PET/​CT examination is shown
in E Figure 28.8. The PET images demonstrate a moderately
large and severe perfusion defect throughout the inferior and
inferolateral walls that was reversible, consistent with myocar-
dial ischaemia involving 13% of the LV mass in the territory of
the occluded RCA (panel a). The ECG-​gated images demon-
strate a mildly reduced LVEF of 44% at rest that was reduced
during stress (panel b). Her stress MBF and MFR were both se-
verely reduced in all coronary territories and globally (panel c).
Together, these findings are consistent with significant stress-​
induced ischaemia in the territory of the known totally oc-
cluded RCA. Despite normal visual perfusion in the LAD and
LCX territories, however, the concordant severe reductions in
stress MBF and myocardial flow reserve (MFR) are consistent
with extensive multivessel obstructive CAD and placed the pa-
tient at high clinical risk. Follow-​up invasive coronary angiog-
raphy demonstrated ostial 70% left main lesion, 80% stenosis in
the proximal LCX and confirmed the chronic total occlusion of
the proximal RCA. The patient was subsequently referred for
coronary artery bypass surgery.
The concordant reduction in stress MBF and flow reserve
throughout the LV myocardium identifies a high likelihood of
obstructive CAD and, more importantly, very high clinical risk
(E Fig. 28.7) [21, 25]. The clinical risk information provided
by the quantitative flow data is incremental over that provided
by the conventional assessment of the extent of ischaemia and
scar and the LVEF [21]. More importantly, emerging data sug-
gest that identification of severely reduced MBF and flow reserve
throughout the LV myocardium may help select patients who
would benefit most from revascularization. Indeed, two sep-
arate single centre studies demonstrated a significant prognostic
benefit from revascularization only among patients with diffusely
reduced MBF and flow reserve (E Fig. 28.9).
Evaluation of symptomatic patients without
obstructive CAD
Case vignette #4: A 76-​year old woman with a history of non-​
obstructive atherosclerosis presented with dyspnoea. She had a
history of controlled hypertension and dyslipidaemia. A recent
CT coronary angiogram demonstrated extensive non-​obstructive
calcified and non-​calcified coronary plaques. Her rest ECG was
normal. Her medical therapy included atenolol, amlodipine, fur-
osemide, aspirin, rosuvastatin.
The comprehensive cardiac PET/​CT examination is shown
in E Figure 28.10. The PET images demonstrated regionally
normal myocardial perfusion on both the stress and rest images
(panel a). The ECG-​gated images demonstrated a normal LVEF
of 71% at rest with normal LV volumes that was essentially un-
changed during stress with normal LV volumes (panel b). Her CT
transmission scan showed extensive evidence of coronary artery
calcification (panel c). Her stress MBF and CFR were both mod-
erately reduced in all coronary territories and globally (panel d).
Together, these findings are consistent with moderate, diffuse cor-
onary vascular dysfunction, which in the absence of obstructive
CAD reflects non-​obstructive atherosclerosis and microvascular
dysfunction. These findings placed the patient at intermediate
risk for adverse cardiovascular events.
CMD is quite common in symptomatic patients with risk fac-
tors. The relative frequency and severity of CMD is similar in
women and men (E Fig. 28.11) [33], but numerically there is
a larger number of women with CMD than men. When present,
symptomatic patients with CMD have worse prognosis [33, 41].
Patient-Centered clinical applications of myocardial perfusion PET/CT in the evaluation  of  CAD 429

High global CFR Low global CFR

p = 0.001
12.5
11.52%

10.0
Adjusted Annualized
Event Rate (%) p = 0.22 7.38%
7.5
6.04%
5.0
3.83%
2.5 2.16%
p = 0.32 p = 0.48 p = 0.17 p = 0.006 0.88%
0.0
CFR High/ CFR High/ CFR High/ CFR Low/ CFR Low/ CFR Low/
No Revasc PCI CABG No Revasc PCI CABG
(n = 79) (n = 70) (n = 17) (n = 57) (n = 84) (n = 22)

p = 0.37

Fig. 28.9  Adjusted annualized rates of cardiovascular death and heart failure admission among patients referred for coronary angiography by coronary flow
reserve (CFR) and early revascularization (Revasc) strategy (coronary artery bypass grafting [CABG], percutaneous coronary intervention [PCI], or neither).
No difference in event rates was seen in patients with high CFR (orange, red, maroon), regardless of revascularization strategy pursued. In patients with low CFR,
those who underwent CABG (dark blue) had lower event rates than those who underwent PCI (light blue; P = 0.006) or no revascularization (green;
P = 0.001) and had event rates similar to those with high CFR who underwent CABG (maroon).
Annualized event rates were adjusted for pretest clinical score, left ventricular (LV) ejection fraction, LV ischaemia, and coronary artery disease prognostic index.
Reproduced from Taqueti VR, Hachamovitch R, Murthy VL, Naya M, Foster CR, Hainer J, Dorbala S, Blankstein R and Di Carli MF. Global coronary flow reserve is associated with
adverse cardiovascular events independently of luminal angiographic severity and modifies the effect of early revascularization. Circulation. 2015;131:19–​27 with permission
Wolters Kluwer.

Exercise stress testing for detection of myocardial ischaemia is a
Class I recommendation for patients with suspected CAD [42].
While a positive exercise stress test has been traditionally used
as a requirement for the diagnosis of CMD [43], recent studies
including women and men with chest pain and non-​obstructive
CAD found that a positive exercise stress test was neither sensitive
nor specific for CMD [44, 45]. Stress imaging tests, such as with
echocardiography or SPECT imaging, are frequently normal
but can occasionally show regional abnormalities that may not
follow typical vascular distributions. As such, conventional stress
testing with or without imaging is neither sensitive nor specific
for detecting CMD and thus has a limited role in its diagnosis.

(a) (b)

stress LV function and volumes

rest • Rest LVEF: 71%

• Rest ESVI: 10 ml/m2
stress • Post-stress LVEF: 73%
• Post-stress ESVI: 10 ml/m2
rest

(c) (d)
Extensive CAC

Quantitative myocardial blood flow (mL/min/g)

and MFR
Rest Stress MFR
LAD 0.91 1.57 1.73
LCX 0.92 1.53 1.66
RCA 0.83 1.46 1.76
Global LV 0.88 1.50 1.70

Fig. 28.10  Comprehensive cardiac PET/​CT examination in a symptomatic without obstructive CAD. See Case vignette #4 text for description of the
imaging findings.
430 CHAPTER 28   PET- C T and det ect ion of c orona ry a rtery di sease

F = 813 P(t-test) = 0.73

15 M = 405 P(equivalence) = 0.0005
N = 1,218

10

Percent
Female
Male
5
Female 46%
n = 813 54%
0
0 1 2 3 4 5

0 1 2 3 4 5
CFR > 2.0 CFR > 2.0
Coronary Flow Reserve

25%
P < 0.0001 (CFR)
P = 0.56 (gender) CFR < 2.0
20%

Male
MACE 15%
51% 49%
n = 405
10%
CFR ≥ 2.0
5%

0%
0 1 2 3
Years

Male Female

Fig. 28.11  Relative frequency of CMD in women and men (left panel). Distribution of coronary flow reserve by sex (top right panel). Histogram (top)
showing the distribution of coronary flow reserve for men (blue) and women (red). Areas of overlap are shown in purple. Fitted log-​normal distribution for
men (dashed blue line) and women (dashed red line) are also displayed. Similar data are also shown in box plots (bottom). Adjusted cumulative rate of major
adverse cardiac events by sex and coronary flow reserve (CFR). The data are adjusted for the modified Duke clinical risk score and rest left ventricular ejection
fraction (LVEF).
Reproduced from Murthy VL, Naya M, Taqueti VR, Foster CR, Gaber M, Hainer J, Dorbala S, Blankstein R, Rimoldi O, Camici PG and Di Carli MF. Effects of sex on coronary
microvascular dysfunction and cardiac outcomes. Circulation. 2014;129:2518–​27 with permission Wolters Kluwer.

Because the coronary microcirculation is beyond the reso-
lution of invasive or noninvasive coronary angiography, direct
interrogation of coronary microvascular function is necessary
to establish the diagnosis of CMD [43]. There are several non-
invasive and invasive approaches for the evaluation of coronary
vasomotor dysfunction [46], each with advantages and limita-
tions. Quantitative PET imaging is probably the most accurate
and reproducible noninvasive technique to interrogate coronary
microcirculatory function. It is important to recognize that dif-
fuse non-​obstructive atherosclerosis in the epicardial coronary
arteries is a common finding in the majority of symptomatic pa-
tients with CMD. Indeed, in studies involving patients with chest
pain and no obstructive CAD, nearly 70% to 80% of patients
showed evidence of diffuse non-​obstructive atherosclerosis by
intravascular ultrasound [47, 48] or coronary CT imaging [33].
The reduction of stress MBF and flow reserve, as observed in this
patient, results from the combined effects of altered coronary
fluid dynamics caused by a significant longitudinal pressure
gradient from diffuse atherosclerosis [49] and microcirculatory
dysfunction caused by endothelial-​and/​or smooth muscle-​cell
abnormalities [46], thereby affecting coronary blood flow and
myocardial perfusion [50] and contributing to myocardial is-
chaemia and symptoms. Such combination of abnormalities
affects both women and men [33] and, importantly, the asso-
ciation between extensive non-​obstructive atherosclerosis and
CMD increased clinical risk compared to either one alone [41,
51] (E Fig. 28.12). This highlights the important complemen-
tary role of delineating atherosclerotic burden by either quan-
tification of coronary artery calcifications and/​or contrast CT
angiography, as in case ­vignette 4. Given the extensive evidence
of non-​obstructive CAD in this patient, aggressive management
of atherosclerosis would be an important way of management
symptoms and reduce risk.
Evaluation of patients with prior
revascularization presenting with chest pain
Case vignette #5: A 56-​year-​
old man with known CAD and
prior percutaneous coronary intervention (PCI) presented with
Patient-Centered clinical applications of myocardial perfusion PET/CT in the evaluation  of  CAD 431

8
7.5
P = 0.24, CAC
7 P = 0.002, MFR

Adjusted annualized MACE (%)

6
5.2
5 4.8

4 3.6
3

2 1.8
1.4
1

0
CAC 0 CAC 1399 CAC ≥ 400
N= 214 188 163 197 53 86

MFR ≥ 2 MFR < 2

Fig. 28.12  Risk-​adjusted annualized rates of major adverse cardiac events (MACE) by myocardial flow reserve (MFR, below and above 2.0) and CAC score (0,
1 to 399, and ≥400) categories. MACE increased with increasing CAC and reduced MFR. At any level of CAC, MACE rates were consistently higher in those with
decreased MFR.
Reproduced from Naya M, Murthy VL, Foster CR, Gaber M, Klein J, Hainer J, Dorbala S, Blankstein R and Di Carli MF. Prognostic interplay of coronary artery calcification and
underlying vascular dysfunction in patients with suspected coronary artery disease. J Am Coll Cardiol. 2013;61:2098–​106 with permission from Elsevier.

atypical chest pain. He had a history of controlled hypertension,
obesity, and dyslipidaemia. His rest ECG showed non-​specific ST-​
T wave abnormalities. His medical therapy included carvedilol,
amlodipine, aspirin, and rosuvastatin.
The comprehensive cardiac PET/​CT examination is shown in
E Figure 28.13. The PET images demonstrate regionally normal
myocardial perfusion on both the stress and rest images (panel a).
The ECG-​gated images demonstrated a normal LVEF of 55% at
rest with normal LV volumes that increased to 59% during stress
with normal LV volumes (panel b). His stress MBF was severely
reduced but his MFR was preserved in all coronary territories and
globally (panel c). Together, these findings are consistent with dif-
fuse non-​obstructive atherosclerosis. These findings placed the
patient at low-​intermediate risk for adverse cardiovascular events.
Case vignette #6: an 86-​year old woman with known CAD
and prior coronary artery bypass grafting (CABG) presented
with dyspnoea and heart failure. She had a history of controlled
hypertension and dyslipidaemia. Her rest ECG showed atrial

(a) (b)

stress LV function and volumes

rest • Rest LVEF: 55%

• Rest ESVI: 25 ml/m2
stress • Post-stress LVEF: 59%
• Post-stress ESVI: 25 ml/m2
rest

stress rest reversibility

(c)

Quantitative myocardial blood flow (mL/min/g)

and MFR
Rest Stress MFR
LAD 0.65 1.31 2.02
LCX 0.66 1.50 2.27
RCA 0.64 1.35 2.11
Global LV 0.65 1.34 2.06

Fig. 28.13  Comprehensive cardiac PET/​CT examination in a symptomatic with CAD and prior revascularization via percutaneous coronary intervention (PCI).
See Case vignette #5 text for description of the imaging findings.
432 CHAPTER 28   PET- C T and det ect ion of c orona ry a rtery di sease

(a) (b)

stress LV function and volumes

rest • Rest LVEF: 50%

• Rest ESVI: 34 ml/m2
stress • Post-stress LVEF: 52%
• Post-stress ESVI: 31 ml/m2
rest

stress rest reversibility

(d)

Quantitative myocardial blood flow (ml/min/g)

and MFR
(c) Right heart catheterization Rest Stress MFR
LAD 0.98 1.47 1.50
LCX 1.02 1.34 1.31
mean WP V wave
RCA 0.89 1.16 1.30
Global LV 0.95 1.34 1.41

Fig. 28.14  Comprehensive cardiac PET/​CT examination in a symptomatic with CAD and prior revascularization via coronary artery bypass surgery (CABG). See
case vignette #6 text for description of the imaging findings.

fibrillation and LVH with secondary repolarization abnormal-
ities. Her medical therapy included metoprolol, amlodipine,
isordil, and Pravachol.
The comprehensive cardiac PET/​CT examination is shown in
E Figure 28.14. The PET images demonstrate a large perfusion
defect of severe intensity throughout the mid and basal inferior
and inferolateral walls, showing significant but not complete re-
versibility. By quantitative analysis, the magnitude of ischaemia
involves approximately 22% of the LV mass (panel a). The ECG-​
gated images demonstrate a normal LVEF of 50% at rest that
remained unchanged during stress, with mildly enlarged LV
volumes (panel b). Her stress MBF and flow reserve are severely
reduced in all coronary territories and globally (panel d). These
findings are consistent with a large area of prior non-​transmural
scar with significant stress-​ induced peri-​ infarct ischaemia
throughout the patent ductus arteriosus (PDA) and obtuse mar-
ginal branch (OM) territories. Of note, the perfusion defect in-
volves the posterior papillary muscle, suggesting that ischaemic
MR is a potential mechanism for her heart failure presentation
and confirmed by the tall V waves on her right heart catheter-
ization (panel c). The flow data is consistent with the presence of
diffuse atherosclerosis. However, the specific values are of limited
value in patients with CABG. Follow-​up coronary angiography
showed moderate left main disease (40%), 70% proximal LAD,
100% proximal LCX with extensive bridging and left to left col-
laterals, and 100% proximal RCA with left to left collaterals. Her
RCA and OM vein grafts were occluded, and the left internal
mammary artery (LIMA) graft to the diagonal branch was widely
patent.
These two cases illustrate the value of PET for delineating the ex-
tent and severity of ischaemia in patients with prior revascularization.
Specifically, the quantitative flow data is quite useful in the set-
ting of prior PCI [52], like in case ­vignette 5. The flow data in pa-
tients with prior CABG should be interpreted with more caution.
The limited available evidence suggest that quantitative flows post
CABG remain abnormal even after successful revascularization and
no symptoms of ischaemia [53]. This is likely related to the fact that
MBF is affected by diffuse atherosclerosis with extensive calcifica-
tion in the native epicardial coronary arteries and different vaso-
dilator response of both arterial and vein grafts.
Conclusions
Quantitative PET/​CT is a powerful tool to evaluate patients with
suspected of known CAD. The available evidence suggests that
the integration of quantitative MBF and atherosclerotic burden to
our traditional semi-​quantitative assessment of myocardial per-
fusion is critical to enhance diagnosis, risk prediction and, poten-
tially, for guiding management. While PET/​CT is effective across
the continuum of CAD risk, its incremental value compared to
other modalities is probably best in patients at intermediate-​high
clinical risk, especially in the growing segment of patients with
increased cardiometabolic risk (e.g. obese, prediabetes, DM,
chronic kidney disease). Future research should focus on the
comparative effectiveness of PET/​CT relative to other modal-
ities with respect to management and outcomes in patients with
intermediate-​high clinical risk.

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Contents
Calcium score  435
Coronary CT angiography (coronary
CTA)  436
Assessment coronary artery disease burden
and characteristics  438
Low-​attenuation plaques 438
Positive remodelling 439
Napkin-​ring  sign 439
Spotty calcium 439
Semi-​quantitative plaque burden assessment
and composite scores  439
Quantitative plaque assessment 440
Functional coronary artery disease
assessment  441
CT Myocardial perfusion imaging 441
CT-​based FFR assessment 441
Future directions  442
Radiomics 442
Pericoronary adipose tissue
characterization 443
CHAPTER 29
MDCT and detection of
coronary artery disease
Stephan Achenbach
and Pál Maurovich-​Horvat
Calcium score
Calcification is a marker of advanced atherosclerosis [1]‌. Therefore, coronary artery
calcium (CAC) is a highly specific feature of coronary atherosclerosis and it is one of
the most thoroughly studied tests in cardiovascular medicine [2]. CAC provides a sum-
mary measure of atherosclerotic disease, the severity of CAC correlates to atherosclerotic
plaque burden and it reflects the cumulative lifetime effect of cardiovascular risk factors
(E Fig. 29.1).
It has been demonstrated by early histopathological investigations and subsequent in
vivo intracoronary imaging studies that CAC quantification is an excellent measure of
atherosclerotic plaque burden. With the introduction of electron-​beam computed tom-
ography (EBCT) and electrocardiographic (ECG) gating, precise quantification of CAC
became feasible. Based on EBCT images acquired with a tube voltage of 130 kVp and
a reconstructed slice thickness of 3 mm, the first CAC score was proposed by Arthur
Agatston and Warren Janowitz in 1990. Conceptually, the so-​called Agatston score is
a summed score of all coronary calcified lesions, where each lesion is quantified using
its area and maximum density. EBCT is no longer available and for modern MDCT
scanners, methods have been created that report an ‘Agatston score’ after compensating
for the use of 120 KVp and, typically, 2.5-​mm slice thickness.
Following observations based on single-​centre and clinical registry studies, large
population-​based observational studies with long-​term follow-​up were launched in
the United States, Germany, and the Netherlands in the late 1990s and early 2000s. All
these large-​scale investigations have produced consistent, reproducible, and robust data
showing a strong association between CT-​derived CAC quantification (Agatston scoring)
and major cardiovascular outcomes in asymptomatic individuals [2]‌. A CAC score >300
Agatston units is associated with a fourfold increase, and a score >1,000 Agatston units is
associated with a tenfold increase of the risk for future cardiovascular events as compared
to individuals without any coronary calcification (‘zero CAC score’). A calcium score
of zero is associated with an excellent long-​term prognosis (<1% annual cardiovascular
mortality rate for up to 15 years in asymptomatic and otherwise low-​or intermediate-​
risk patients), which led to the introduction of ‘the power of zero’ concept [3]. In line with
these strong prognostic data, a recently published large-​scale registry study of asymp-
tomatic individuals demonstrated that in retrospective analysis, statin therapy was as-
sociated with reduced risk of cardiovascular events in patients with CAC, but not in
patients with zero CAC. The number needed to treat to prevent 1 initial cardiovascular
event was ranging from 100 to 12 patients in the population with CAC 1–​100 and CAC
>100, respectively, to prevent 1 cardiovascular outcome over 10 years [4]. The blood lipid
436 CHAPTER 29   MD C T and detection of c orona ry a rtery di sease
Input: traditional risk factors
Age, years
0 10 20 30
Input: burden of disease
Imaging paradigm
Fig. 29.1  The illustration of score based and imaging-​based risk assessment strategies.
CVD = cardiovascular disease.
guideline released in 2018 and the primary prevention guideline
released in 2019 by the American Heart Association (AHA) and
the American College of Cardiology (ACC) refer to CAC scan-
ning as a helpful tool to guide preventive interventions in indi-
viduals with intermediate predicted risk (≥7.5% to <20%) by the
pooled cohort equation or for select adults with borderline (5% to
<7.5%) predicted risk. In these groups, CAC measurement can re-
classify risk upward (particularly if coronary artery calcium score
is ≥100 Agatston units) or downward (if coronary artery calcium
is zero) in a significant proportion of individuals [5, 6].
Coronary CT angiography
(coronary CTA)
Coronary CTA permits to accurately rule out obstructive coronary
artery disease (CAD). This has repeatedly been demonstrated by
multicentre trials with independent core laboratory evaluations
and meta-​analyses. Throughout, these studies demonstrated nega-
tive predictive values of 97–​99% to rule out obstructive CAD in
comparison with invasive coronary angiography (ICA). However,
the positive predictive values to identify obstructive CAD were
generally lower (64–​86%), usually due to overestimation of the de-
gree of luminal narrowing. Importantly, the somewhat lower speci-
ficity and positive predictive value do not limit the clinical value of
coronary CTA. If used as a ‘gate keeper’ to cardiac catheterization in
patients considered for ICA, it is the negative predictive value that
counts. In addition, a recent meta-​analysis has shown that a nega-
tive coronary CTA test result confidently rules out significant CAD
in nearly all patients independently of their pretest probability
Less accurate
prediction of incident events
Risk score
paradigm
CVD risk factors
40 50 60 70 80 90
Atherosclerosis
Disease Acute clinical event
More accurate
prediction of incident events
(E Fig. 29.2) [7]‌. Because of these test characteristics and the fa-
vourable cost effectiveness of coronary CTA, the British National
Institute for Health and Care Excellence (NICE) recommends cor-
onary CTA as the first-​line test in patients with suspected stable
CAD and atypical or typical chest pain.
However, coronary CTA provides valuable information be-
yond the assessment of the grade of coronary artery stenosis
as it can directly visualize the coronary atherosclerotic plaques
(E Fig. 29.3). Two recent large randomized-​controlled clinical
trials, the PROMISE (Prospective Multicenter Imaging Study for
Evaluation of Chest Pain) conducted in North America, and the
SCOT-​HEART (Scottish Computed Tomography of the Heart)
trial, completed in Scotland, demonstrated the safe and appro-
priate addition of coronary CTA to standard of care. In addition,
the SCOT-​HEART trial showed that during a 5-​year median
follow-​up the implementation of coronary CTA in addition to
the standard of care was associated with a 41% reduction in the
combined endpoint of cardiac death or myocardial infarction
as compared to standard care alone (2.3% vs. 3.9%, P = 0.004).
The significant reduction in myocardial infarction in the cor-
onary CTA arm as compared to the ‘standard of care’ arm (2.1%
vs. 3.5%, HR 0.60, 95% CI 0.41–​0.87) suggests that CT-​guided
changes in patient management can improve clinical outcomes.
Importantly, with continuous technical developments, the ra-
diation exposure of coronary CTA has significantly decreased
during the past decade. A recent survey showed that the average
contemporary radiation exposure of coronary CTA is 195 mGy ×
cm corresponding to effective doses between 2.7 mSv and 5.1 mSv
(depending on the conversion factor), which is 78% lower than in
a similar survey performed in 2007 [8]‌.
 C orona ry CT a n g i o g r a phy ( c orona ry   C TA ) 437

(a) Test Pretest probability of ICA-significant CAD (b) Test Pretest probability of FFR-significant CAD
results 0% 50% 100% results 0% 50% 100%

+ +
Stress ECG ICA
− −

+ +
CCTA CCTA
− −

+ +
PET PET
− −

Stress + Stress +
CMR − CMR −

Stress + +
Echocardiography SPECT
− −

+ 15% 85%
SPECT
−

15% 85%
Pretest probability range where test
can rule-in CAD (Post-test probability will rise above 85%)
Pretest probability range where test
can rule-out CAD (Post-test probability will drop below 15%)

Fig. 29.2  Ranges of clinical pretest probability in which each single-​positive test will confidently rule-​in (in orange) the presence of significant coronary artery
disease or, conversely a negative test will confidently rule-​out (in green) based on the likelihood ratio values of the test. (a) The ranges when the reference
standard is visually significant stenosis in invasive coronary angiography and (b) when abnormal fractional flow reserve is the reference standard are shown.
The crosshairs mark the mean value and the gradient-​coloured areas contain their 95% confidence intervals. The results are based on the criteria that disease is
confidently ruled-​out when the post-​test probability is <15% and ruled-​in when it is >85%.
Reproduced from Knuuti J, Ballo H, Juarez-​Orozco LE, et al. The performance of non-​invasive tests to rule-​in and rule-​out significant coronary artery stenosis in patients with stable
angina: a meta-​analysis focused on post-​test disease probability. Eur Heart J. 2018;39(35):3322–​30. doi:10.1093/​eurheartj/​ehy267 with permission from Oxford University Press.

(a) (b)

Fig. 29.3  A coronary CT

angiography (a) and invasive
coronary angiography (b) of a 42-​
year-​old female patient with atypical
chest pain. The curved multiplanar
reconstruction demonstrates
severe stenosis of the proximal left
anterior descending artery (LAD)
caused by a non-​calcified plaque
(yellow arrow, a). The severe LAD
stenosis was confirmed by invasive
coronary angiography (yellow arrow,
b). LAD: left anterior descending
coronary artery
438 CHAPTER 29   MD C T and detection of c orona ry a rtery di sease

plaques and plaques with predominantly fibrous components is

Assessment coronary artery disease desirable for prediction of acute events. Conventionally, coronary
burden and characteristics CTA classifies plaques according degree of calcified components,
for example by differentiating between calcified, partially calci-
Current diagnostic strategies predominantly focus on the detec- fied, and non-​calcified plaques (E Fig. 29.4). The further classi-
tion of myocardial ischaemia and coronary luminal narrowing, fication of non-​calcified plaques into lipid­rich and fibrous lesions
but not on the detection and characterization of coronary ath- by CT remains challenging. Studies comparing coronary CTA
erosclerotic plaque, even though the majority of acute coronary with invasive imaging techniques demonstrated that low CT at-
events originate from sites with non-​obstructive atheroscler- tenuation is a surrogate for lipid-​rich content and correlates with
otic lesions. Therefore, the characterization and quantification the presence of necrotic core and fibrofatty tissue. In histogram
of atherosclerotic plaques might provide important prognostic analyses of intraplaque CT attenuation, lipid­rich plaques have a
information. High-​risk coronary atherosclerotic plaques—​often higher percentage of voxels with low Hounsfield unit (HU) values
termed ‘vulnerable plaques’—​ have distinct characteristics. as compared to plaques of predominantly fibrous composition.
Histopathological studies showed that plaques prone to rup- Despite the differences in mean CT attenuation between fibrous
ture harbour certain key histological characteristics, including plaques and lipid­rich plaques, almost all investigators have con-
a thin fibrous cap (<65 mm), positive remodelling, a large nec- cluded that the reliable subclassification of non-​calcified plaques
rotic core, inflammation, microcalcification, angiogenesis, and is currently not feasible due to the substantial overlap of between
plaque haemorrhage [3]‌. Most commonly, acute coronary syn- the HU values. However, several studies have shown that low at-
dromes (ACS) are caused by acute plaque rupture, which ex- tenuation plaques, usually defined by an average attenuation <30
poses the thrombogenic, tissue factor-​rich lipid core to the HU are associated with future ACS and may correlate to the risk
circulating blood. The slow progression of CAD and the charac- of future acute coronary events. Important to note that the HU
teristic morphologic features of high-​risk lesions provide an op- values of coronary plaques are influenced by several factors, such
portunity for invasive and non-​invasive cardiovascular imaging
to identify these plaques before the acute coronary event occurs.
Moreover, the majority of clinically manifest acute coronary (a) (b) (c)
events are caused by atherosclerotic plaques located in the prox-
imal portions of the main coronary arteries, where the vessel
diameter is largest, and coronary CTA has the highest image
quality and accuracy for plaque detection. With modern CT
scanners, the detection and quantification of certain high-​risk
plaque features may therefore be feasible.
Prospective data have suggested that coronary atheroscler-
osis is a dynamic process, and most plaques demonstrating
high-​risk characteristics either stabilize or rupture subclinically
rather than causing an acute event. Importantly, vulnerable
plaques rarely exist in isolation and can serve as a marker of
patients with advanced and metabolically active CAD [3]‌. In
addition, pathological studies have taught us that that multiple
subclinical coronary plaque ruptures and thrombotic events are
present at the time of fatal myocardial infarction. These obser-
vations support the notion of pancoronary vulnerability and
have generated interest in the quantification of total atheroscler-
otic plaque burden on one hand and the simultaneous detec-
tion of vulnerable plaques on the other. Higher plaque burden
translates into higher probability to develop high-​risk plaques
and acute events. On the other hand, the detection of high-​risk
plaques may indicate a more advanced atherosclerotic process.
Therefore, the comprehensive assessment of plaque burden and
high-​risk plaque features may provide a means of identifying
vulnerable patients [3]. Fig. 29.4  The panels illustrate various atherosclerotic plaque types as
depicted by coronary CTA. The dashed lines show the location of the plaque
Low-​attenuation plaques cross-​sections. The orange lines indicate the outer vessel wall, whereas the
lumen is indicated by the yellow lines. Panel (a) shows calcified plaque, panel
Atherosclerotic lesions leading to ACS often have a large lipid-​rich (b) partially calcified (predominantly non-​calcified) plaque, and panel (c)
necrotic core; therefore, the CT differentiation between lipid-​rich shows non-​calcified plaque.
 Assessment c orona ry a rtery di sease bu rden a n d cha r ac t e ri st i c s
as the concentration of adjacent intraluminal iodinated contrast
agent, plaque size, image noise, tube voltage, slice thickness, and
the reconstruction filter.
Positive remodelling
Pathological studies have shown that rupture prone plaques, even
with a large plaque volume, might not cause significant luminal
narrowing, owing to the effect of ‘positive remodelling’. Positive
remodelling describes the compensatory enlargement of the
vessel wall that occurs at the site of the atherosclerotic lesion as
plaque size increases, resulting in the preservation of luminal area.
Positive remodelling is an active process and it is associated with
local inflammation and a large necrotic core. Coronary CTA is
a well-​suited imaging modality to non-​invasively measure vessel
wall dimensions and hence assess remodelling. The ‘remodelling
index’ is calculated as the vessel cross-​sectional area at the site of
maximal stenosis divided by the average of proximal and distal
reference segments cross-​sectional areas. A remodelling index of
≥1.1 has been suggested to define ‘positive remodelling’ assessed
by coronary CTA. Positive remodelling and low attenuation carry
strong prognostic information to predict acute coronary events,
which has been demonstrated by a prospective clinical study
with 27 ± 10 months follow-​up (positive remodelling and/​or low
plaque attenuation was an independent predictor of ACS with a
HR 22.8; 95% CI 6.9–​75.2; P <0.001) [9]‌.
Napkin-​ring  sign
Pathological studies have demonstrated that only fibrous cap
thickness (OR 0.35; P <0.05), and necrotic core size (OR 2.0;
P <0.02) are independent predictors of plaque rupture in cul-
prit versus non-​culprit thin cap fibroatheromas (TCFAs) with
similar degrees of luminal stenosis. Hierarchical importance
analysis of plaque features that are accessible by non­invasive
imaging revealed that the size of the necrotic core and the pres-
ence of macrophage infiltration are the two best discriminators
between vulnerable and stable plaques. In addition, it has been
shown that a large necrotic core cross­sectional area (>3.5 mm2)
is a hallmark feature of high-​risk lesions. Therefore, the detec-
tion of large necrotic cores, with dimensions above the detection
threshold of coronary CTA may be an important marker of vul-
nerability. The so-​called napkin-​ring sign (NRS) is a qualitative
plaque feature and can be identified in cross-​sectional recon-
structions of vessel segments with non-​calcified plaque by the
presence of two features: a central area of low CT attenuation
that is apparently in contact with the lumen; and ring­like higher
attenuation plaque tissue surrounding this central area. Based
on histological observations, the NRS is a marker of large cen-
trally located necrotic core or lipid-​rich plaque tissue. The spe-
cificity of the NRS to identify advanced coronary atherosclerotic
plaques with large lipid pool and TCFA is excellent (98.9% and
94.1%, respectively), while the sensitivity is relatively low (24%).
A recent meta-​analysis showed that presence of the NRS was
strongly associated with future cardiac events (HR, 5.06; 95%
CI, 3.23–​7.94; P <0.001) [10].
439
Spotty calcium
Although most acute plaque ruptures in individuals with sudden
cardiac death histologically contain some degree of calcifica-
tion, the connection between calcification and plaque instability
remains controversial. Importantly, two­ thirds of all ruptured
plaques show only microcalcification, which is not detectable by
CT. Nevertheless, coronary CTA has excellent sensitivity to iden-
tify larger calcifications. Spotty calcification is defined as a <3 mm
calcified plaque component with a >130 HU density surrounded
by non-​ calcified plaque tissue. According to multiple cross­
sectional studies in patients with ACS and stable CAD, spotty
calcification was associated with ACS culprit lesions. However,
results vary widely, which highlight the current uncertainty in
the relationship between spotty calcification and plaque rup-
ture. Further improvements in CT technology will be required
to permit the detection of microcalcifications, suggested to be a
frequent feature in unstable angina.
Semi-​quantitative plaque burden assessment
and composite scores
Several studies, such as the Clinical Outcomes Utilizing
Revascularization and Aggressive Drug Evaluation (COURAGE)
trial have shown that plaque burden assessment may be more im-
portant than ischaemic myocardial burden for predicting major
adverse outcomes. Furthermore, prospective clinical studies
demonstrated that patients with extensive CAD (>4 coronary
segments involved) have a higher rate of cardiovascular events,
as compared to patients with non-​extensive disease. Even among
patients with obstructive CAD, greater extent of non-​obstructive
plaque is associated with higher event rate [11]. Due to the strong
prognostic value associated with simple plaque quantity metrics,
several scoring systems have been proposed to describe plaque
burden. The most widely used CTA-​based score systems are the
segment stenosis score (SSS) and the segment involvement score
(SIS). The SSS is calculated by grading all coronary segments as:
0, no plaque; 1, <50% stenosis; 2, 50–​69% stenosis; 3, ≥70% sten-
osis, whereas the SIS is a simple metric of the number of segments
carrying any detectable coronary atherosclerotic plaque. However,
these scores suffer from inherent limitations as they assume that
plaque burden is additive, meaning that adding one plaque to al-
ready 1 diseased segment or 10 diseased segments has the same
effect [12]. Furthermore, SSS and SIS discard all anatomical in-
formation, thus for example they assume that a severe stenosis
in the proximal segment of the left anterior descending coronary
artery has the same effect as a severe stenosis in the second obtuse
marginal branch. Due to these limitations, more comprehensive
risk scores that integrate clinical risk factors, high-​risk plaque fea-
tures, plaque quantity and distribution have been proposed and
validated in clinical studies.
The COMFIRM risk score is a combination of clinical risk fac-
tors and selected CTA imaging markers, such as the number of
proximal coronary segments containing plaques with stenosis
greater than 50%, and the number of proximal segments with
440 CHAPTER 29   MD C T and detection of c orona ry a rtery di sease

partially calcified or calcified plaques. Adding these two additional
parameters caused 32% of all patients to be reclassified, 22% to a
lower risk category and 10% to a higher risk category [13]. Overall,
the combined risk score outperformed all clinical scores and sig-
nificantly improved prediction of all-​cause mortality.
In the Leaman score, obstructions are weighted based on their
degree of stenosis, location, and coronary dominance to reflect
the concept that proximal segments are associated with larger
areas of supplied myocardium. In addition, the Leaman score
considers plaque composition and uses a weighting factor of 1.5
for non-​calcified and partially calcified plaques, while calcified
plaques receive a weighting factor of one [14]. In a single-​centre
prospective registry, the Leaman score displayed a higher hazard
ratio than both SSS or SIS to predict adverse cardiac events [15].
Based on the multicentre CONFIRM registry data, the inves-
tigators have explored the utility of machine learning (ML) to
further improve coronary CTA-​based risk stratification. A study
performed using the CT data sets of 8,844 individuals demon-
strated that a ML based algorithm that utilizes only the standard
16 coronary segment stenosis and plaque composition informa-
tion derived from coronary CTA had greater prognostic accuracy
than current coronary CTA integrated risk scores [16]. Similarly,
to these findings, another CONFIRM-​based analysis showed that
using ML for clinical and coronary CTA data integration can pre-
dict 5-​year all-​cause mortality significantly better than existing
clinical or coronary CTA metrics alone [17].
Quantitative plaque assessment
Coronary CT data sets with their submillimetre isotropic spatial
resolution permit the quantitative assessment of plaque compo-
nents and total plaque burden either manually or, optimally, with
automated software tools (E Fig. 29.5). The reproducibility of
automated quantification software tools for plaque burden has
been demonstrated to be excellent, with an intraclass correlation

Fig. 29.5  Coronary CTA-​based atherosclerotic plaque characterization and quantification using an automated software tool. The upper panels demonstrate
atherosclerotic plaque cross-​sections at various locations with and without colour overlay. The colour overlay is derived with adaptive HU threshold setting.
Plaque components with low CT densities are shown in red (lipid-​rich components), intermediate-​density NCP shown in light green, and high-​density NCP is
dark green (fibrotic components), whereas calcified plaque components are white. The middle panel shows the coronary artery in ‘stretched’ view. The orange
lines indicate the outer vessel border, the yellow lines show the lumen. The graph in the lower panel illustrates the areas of different plaque components in
relation to the distance from the coronary artery ostium. The colour coding is the same as for the plaque cross-​sections in the upper row.
CTA = computed tomography angiography; HU = Hounsfield unit; NCP = non-​calcified plaque.
 Fu n cti ona l c orona ry a rtery di sease as se s sm e n t
(ICC) value of 0.88 (95% CI 0.74–​0.95). The accuracy of automated
coronary plaque quantification by coronary CTA has successfully
been validated against greyscale intravascular ultrasound (IVUS)
and virtual histology IVUS. Importantly, automated plaque quan-
tification software tools have poor interplatform reproducibility
so that identical software should be used for serial or comparative
plaque assessment.
Longitudinal clinical investigations have demonstrated a strong
prognostic value of coronary CTA derived plaque volume for
acute coronary events. Total plaque volume provided additional
prognostic value for ACS over both clinical risk factors and trad-
itional CT reading (including calcium score, SSS, lesion severity,
and number of segments with non-​calcified plaque). Individuals
who developed ACS had a higher total plaque volume (median 94
mm3 versus 29 mm3; P <0.001) and total NCP volume (28 mm3
versus 4 mm3; P <0.001) at baseline compared to individuals who
did not develop ACS [18].
In line with these results a recently published prospective ob-
servational registry of patients who underwent repeated coronary
CTA (>2 years) demonstrated the incremental value of quanti-
tative plaque assessment to predict adverse cardiovascular out-
comes. This study showed that both cross-​sectional and serial
plaque volume assessment provides strong prognostic value to
identify patients who suffered adverse cardiovascular event [19].
In addition the study demonstrated that statins were associ-
ated with slower progression of overall coronary atherosclerotic
plaque volume, with increased plaque calcification and reduction
of high-​risk plaque features [20].
Mounting evidence suggest that the direct quantification of
atherosclerotic plaque burden in addition to conventional as-
sessment of CAD is beneficial for improving risk stratification of
CAD. In the near future, coronary CTA may serve as an imaging
tool not only to risk stratify patient but also to assess response to
antiatherosclerotic therapy. Furthermore, ML and deep learning
techniques may further simplify and improve the diagnostic ac-
curacy and efficiency of coronary CTA-​based plaque assessment.
Functional coronary artery disease
assessment
The mismatch between coronary artery stenosis severity and
ischaemia is well known. It is one of the reasons why coronary
CTA can very accurately rule out, but cannot as reliably rule-​in
haemodynamically relevant lesions. Different methods have been
introduced to overcome this limitation and to combine anatomic
with functional information. The two main and most robust ap-
proaches to add functional dimension to coronary CTA imaging
are the CT-​based simulation of fractional flow reserve (FFR) and
CT perfusion imaging (CTP). It has been demonstrated by nu-
merous investigations that these techniques are complementary
to coronary CTA and improve its diagnostic performance by
increasing positive predictive value and specificity and conse-
quently reducing the need for downstream testing.
441
CT Myocardial perfusion imaging
Myocardial perfusion imaging is based on the principle that there
is a direct relationship between the amount of iodinated contrast
material in the myocardium and myocardial blood flow. Regional
differences in myocardial attenuation can occur at any given mo-
ment in time due to coronary stenosis, longer contrast arrival
pathways in cases of previous bypass surgery or collaterals, micro-
vascular disease, or differences in capillary density as in between
normal myocardium and densely scarred tissue. The resulting
areas of hypoattenuation reflect perfusion defects [21]. Modern
CT scanners offer myocardial perfusion imaging by using either
shuttle mode or wide detector panel to cover the whole volume of
the left ventricle. Myocardial perfusion imaging using cardiac CT
is comparable to stress echocardiography, SPECT, or perfusion
MRI, albeit it is still not widely adopted despite the encouraging
early results. Possible reasons include a relatively high associ-
ated radiation exposure and lack of widely available expertise.
A growing body of evidence supports the use of CT perfusion
(CTP) in patients with intermediate stenoses for ischaemia de-
tection (E Fig. 29.6). Using static CTP, a single CT data set is
obtained during the estimated upslope or peak contrast enhance-
ment during rest and stress, and myocardial attenuation maps are
generated for visual or semi-​quantitative assessment. Another,
technically more challenging approach is dynamic CTP, which al-
lows for the quantification of myocardial blood flow using tissue
attenuation curves. Perfusion imaging can be especially useful
in patients with heavily calcified coronaries or in patients after
revascularization. It has been shown that both static and dynamic
CTP in combination with coronary CTA has a higher diagnostic
performance as compared to coronary CTA alone to identify
haemodynamically relevant CAD.
CT-​based FFR assessment
The application of computational fluid dynamics (CFD) to cor-
onary luminal models derived from CTA datasets permits
simulation of coronary blood flow and pressure, and hence the
non-​invasive derivation of FFR values (FFR-​CT; E Fig. 29.6).
FFR-​CT calculations are based on conventionally acquired cor-
onary CTA images; the do require excellent image quality.
Three prospective multicentre trials have evaluated the diag-
nostic performance of FFR-​CT (HeartFlow, Inc., Redwood City,
CA) using invasive FFR measurement as the reference standard
[22–​24]. The most recent study (NXT trial—​Analysis of Coronary
Blood Flow Using CT Angiography: Next Steps) showed an ex-
cellent correlation with invasively measured FFR. The area under
the receiver operator curve (AUC) for per-​patient analysis was
0.90 (95% CI: 0.87–​0.94) and per-​vessel analysis was 0.93 (95%
CI: 0.91–​0.95). Importantly, the diagnostic performance of FFR-​
CT remained robust in presence of coronary calcification, motion
artefact, and reduced signal-​to-​noise ratio where coronary CTA
would in general underperform. Beyond the improvement of diag-
nostic performance, it has been showed that FFR-​CT significantly
alters downstream patient management by decreasing the rate of
false positive coronary CTA findings and therefore decreasing
442 CHAPTER 29   MD C T and detection of c orona ry a rtery di sease

(a) (b) (d) (f) (h)

(c) (e) (g) (i)

Fig. 29.6  Panels (a), (b), and (c) show coronary CTA images with curved multiplanar reconstruction. The right coronary artery (RCA) and LAD have no visible
atherosclerotic plaques (a and b). The LCx shows a moderate stenosis (yellow arrows on c). Stress myocardial CT perfusion images in long (d) and short (e) show
perfusion defect in the basal segments of the inferolateral wall. However, the FFR-​CT is normal in all segments (e and f). In this case the perfusion images proved
to be false positive most probably due to beam hardening artefact. The invasive coronary angiography images (h and i) confirm the FFR-​CT findings.
CTA = computed; FFR-​CT = fractional flow reserve computed tomography; LAD = left anterior descending artery; LCx = left circumflex artery; RCA = right coronary artery.
Courtesy of Dr. Gianluca Pontone, Milan, Italy.

the rate of unnecessary invasive angiographies. According to the
results of the international, multicentre ADVANCE (Assessing
Diagnostic Value of Non-​invasive FFR-​CT in Coronary Care)
Registry almost 70% of subjects, had a change in management
following review of FFR-​CT results and importantly the majority
of subjects who underwent ICA following FFR-​CT ≤0.80 under-
went revascularization. Furthermore, during short-​term follow-​
up (90 days), while adverse events were rare, they were higher in
patients with FFR-​CT ≤0.80 (hazard ratio 14.7 for death/​MI) and
no adverse events were reported in patients with FFR-​CT >0.80
[25, 26]. The utility of FFR-​CT in patients with complex CAD was
further demonstrated by the SYNTAX III REVOLUTION trial.
Separate heart teams composed of an interventional cardiologist,
a cardiac surgeon, and a radiologist were randomized to assess the
CAD with either coronary CTA or conventional angiography in
patients with de novo left main or three-​vessel coronary artery
disease. Each heart team, blinded for the other imaging modality,
quantified the anatomical complexity of the CAD according to
the SYNTAX score and integrated clinical information using the
SYNTAX score II to recommend treatment: coronary artery by-
pass grafting or percutaneous coronary intervention. Agreement
concerning treatment decision between coronary CTA and con-
ventional angiography was high (Cohen’s kappa 0.82) and the heart
teams agreed on which segments should be revascularized in 80%
of cases. The use of FFR-​CT changed the treatment decision in 7%
of patients. These observations are suggesting the potential feasi-
bility of a treatment decision-​making and planning based solely on
this non-​invasive imaging modality and clinical information [27].
The FFR-​CT algorithm used in aforementioned studies re-
quires substantial computational power and is performed off-​site
using a supercomputer. Recently, reduced-​order CFD models and
ML based algorithms have shortened the computational burden,
facilitating on-​site assessment using regular desktop computer
workstations. They have demonstrated similar diagnostic per-
formance as the original FFR-​CT algorithm [28–​31].
Future directions
Radiomics
The large, high-​resolution data sets of modern imaging tech-
niques contain information on disease characteristics that are
impossible to appreciate by the human eye. Radiomics provides
quantitative radiographic phenotyping through feature extrac-
tion from image datasets. Radiomic analysis is the process of
extracting numerous quantitative features from a given region
of interest to create large data sets in which each abnormality
is described by hundreds or even thousands of parameters [32].
From these parameters, data mining is used to explore and es-
tablish new correlations between the radiomic and clinical data.
The central hypothesis of radiomics is that distinctive imaging
algorithms quantify the state of diseases, and thereby provide
valuable information for personalized medicine. Radiomics has
emerged from oncology, but can be applied in other medical do-
mains in which a disease is imaged [33]. It has recently been
demonstrated that radiomic analysis of coronary CTA data sets
 Fu tu re di re c t i on s 443

(a) (b) (c)

Fig. 29.7  Panel (a) shows a left anterior descending coronary artery in curved multiplanar reconstruction, the partially calcified plaque is highlighted with a
yellow rectangle. For radiomic analysis, voxels containing plaque are extracted from the image (b). Large number (usually more than thousand) of descriptors
of heterogeneity and spatial complexity are calculated to create big data databases, which are analysed using novel analytic techniques, such as machine
learning (c).
Reproduced from Nicol ED, Norgaard BL, Blanke P, et al. The Future of Cardiovascular Computed Tomography: Advanced Analytics and Clinical Insights. JACC Cardiovasc Imaging.
2019;12(6):1058–​72. doi:10.1016/​j.jcmg.2018.11.037 with permission from Elsevier.

is feasible in spite of the small and complex three-​dimensional
plaque structures that are imaged [34]. The study demonstrated
a large number of radiomic features are different between plaque
with versus without NRS and radiomic data exhibit excellent
discriminatory value (E Fig. 29.7). A subsequent investiga-
tion of patients, who underwent multimodality imaging (IVUS,
OCT, NaF-​PET and coronary CTA) demonstrated that using en-
gineered radiomic features it is feasible to identify plaque which
show high-​risk features in invasive imaging techniques and
plaques that show radionuclide uptake [35]. These encouraging
results signal the transition from qualitative to quantitative
imaging, which a prerequisite of precision disease phenotyping
in the era of personalized medicine.
Pericoronary adipose tissue characterization
The body´s adipose tissue is no longer viewed simply as a passive
energy-​storing depot. A growing body of evidence suggests that
it may be a relevant component and regulator of cardiovascular
health with a wide range of endocrine and paracrine effects. The
epicardial fat depot, also named ‘pericoronary adipose tissue’
(PCAT) is a distinct compartment with close proximity to the
vascular wall. Several large-​scale epidemiological studies have
demonstrated a strong association between pericoronary adi-
pose tissue volume and CAD, CAD progression, and adverse
cardiovascular outcome. Studies attempting to quantify PCAT
showed that PCAT volume is associated to plaque burden in-
dependent of overall obesity or total epicardial adipose tissue
volume [36]. On one hand it is assumed that mediators released
from epicardial fat may influence the vessel wall and contribute
to the development and progression of atherosclerosis. In add-
ition, however, coronary atherosclerosis may in turn impact
the characteristics of the surrounding adipose tissue. In fact, it
has been shown that locally released inflammatory mediators
and/​or oxidation products from a diseased coronary vessel can
directly modify the phenotype of perivascular adipocytes [37].
Therefore, PCAT imaging may provide important information
regarding coronary atherosclerotic disease activity and ultim-
ately improve cardiovascular risk stratification. A new coronary
CTA-​based technique has been developed to analyse the PCAT
compartment’s function a ‘sensor’ of coronary inflammation
and vascular disease [38]. The gradient in CT-​measured attenu-
ation of PCAT (fat attenuation index, FAI) on routinely acquired
coronary CTA datasets correlates strongly with the gradient in
adipocyte size and lipid content. Signals released from the in-
flamed coronary artery diffuse to the PCAT, inhibiting local
adipogenesis hence the change in cell size and lipid content.
In addition, the study demonstrated that pericoronary FAI is
significantly increased around the coronary vessels of patients
with CAD compared with healthy controls, as well as around
the culprit lesions versus stable lesions of patients with acute
444 CHAPTER 29   MD C T and detection of c orona ry a rtery di sease
myocardial infarction [38]. The prognostic value of this novel
imaging biomarker was investigated in the Cardiovascular RISk
Prediction using Computed Tomography (CRISP-​CT) study in
two large and different real-​life prospective cohorts of patients
undergoing clinically indicated coronary CTA in Europe and
the USA. The study demonstrated a strong prognostic value
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Contents
Introduction  447
Detection of ischaemia by CMR  447
Indications for ischaemia detection
by CMR  447
Dobutamine-​CMR  450
Introduction  448
Stress agents  448
Dobutamine-​CMR protocol  448
Imaging technique  448
Diagnostic criteria  449
Diagnostic performance  449
Functional assessment of viable
myocardium  449
Prognostic value of dobutamine-​CMR  450
Limitations  452
Conclusions  452
Myocardial perfusion-​CMR  452
Introduction  452
Perfusion-​CMR techniques  452
Perfusion-​CMR protocols for the detection
of CAD  452
Reading and image display  455
Diagnostic criteria  455
Diagnostic performance  456
Safety of perfusion—​CMR  457
Prognostic value of perfusion-​CMR  457
Cost-​effectiveness of ischaemia detection
by CMR  459
Limitations  460
Future developments  460
Conclusion  460
CHAPTER 30
CMR and detection of
coronary artery disease
Eike Nagel, Juerg Schwitter, and Sven Plein
Introduction
Cardiovascular magnetic resonance (CMR) imaging plays a major role in the diagnosis
and assessment of coronary artery disease (CAD). This chapter will focus on the diag-
nosis of ischaemia by CMR with brief reference to viability assessment, which is covered
in detail elsewhere. Coronary angiography by CMR will not be discussed in this chapter
as it is only recommended for delineation of the course of coronary artery anomalies [1]‌.
Detection of ischaemia by CMR
CMR offers two principal methods for the detection of myocardial ischaemia. The first
method, dobutamine-​CMR, allows a direct assessment of ischaemia through the assess-
ment of inducible wall motion abnormalities. The second method, myocardial perfusion-​
CMR, relies on the detection of myocardial perfusion defects during vasodilator-​induced
hyperaemia. While both methods are used to detect flow-​limiting coronary artery sten-
osis, they are based on fundamentally different concepts and therefore have different
strengths and limitations. As described in the ischaemic cascade, a decrease in myo-
cardial perfusion represents the first of several events in the progression of myocardial
ischaemia, followed by metabolic changes, wall motion abnormalities, and eventually
electrocardiographic (ECG) changes and anginal pain. Perfusion imaging, therefore, de-
tects the first pathological step in the ischaemic cascade making it theoretically the most
sensitive method for the detection of flow-​limiting coronary stenosis. Importantly, per-
fusion imaging can detect maldistribution of myocardial blood during vasodilator stress
flow which may not necessarily provoke ischaemia, while wall motion abnormalities, as
induced by dobutamine stress, only occur in the presence of ischaemia. Consequently,
wall motion abnormalities are less sensitive, but more specific for the detection of cor-
onary artery stenosis than perfusion imaging [2]‌. In practice, vasodilator perfusion-​CMR
is much more commonly used than dobutamine-​stress CMR, owing largely to its better
safety profile, speed of imaging, and the combination with late gadolinium enhancement
for scar detection. The choice of a stress method is, however, also governed by patient-​
specific factors, as well as operator preference.
Indications for ischaemia detection by CMR
The main indication for the use of dobutamine or perfusion-​CMR is the detection of
significant CAD in patients with intermediate pretest likelihood. Current US guide-
lines still focus primarily on stress echocardiography and SPECT for this patient group
448 CHAPTER 30   C MR and det ect ion of c orona ry a rtery di sease

[3]‌, despite the growing evidence for CMR and strong support
in appropriateness scenarios [1]. In the current ESC guidelines Dobutamine Stress
CMR, SPECT, PET and stress-​echo are ranked as interchange-
able [4]. A further indication for dobutamine or perfusion-​CMR
10 micrograms/kg
is the detection and quantification of ischaemia in patients with body weight/minute
3 LAX, 3 SAX
Cine Imaging
intermediate stenoses by luminography (CT or invasive coronary for 3 minutes
angiography) [1]. Given that the severity of a luminal narrowing no
is only weakly related to the amount of blood flow reduction

New WMA in ≥2 segments?

Target heart rate reached?
20 micrograms/kg

Untolerable symptoms?
distal to it, functional testing provides important additional in- 3 LAX, 3 SAX
body weight/minute
Cine Imaging
formation to luminography especially regarding the indication for 3 minutes
for revascularization as well as strong predictive value for future no
cardiac events. The results of the COURAGE and FAME trials 30 micrograms/kg
3 LAX, 3 SAX
have highlighted the importance of functional testing and further body weight/minute
Cine Imaging
underline the need for adequate ischaemia testing to optimize for 3 minutes
outcome [5, 6]. Accordingly, only confirmed ischaemia is a Class no
1A indication for revascularization [7]. Despite this evidence, 40 micrograms/kg
3 LAX, 3 SAX
such testing remains underused in clinical practice and only 45% body weight/minute
Cine Imaging
of patients underwent functional assessment of ischaemia before for 3 minutes

revascularization in the United States [8]. no

yes
40 micrograms/kg
body weight/minute + 3 LAX, 3 SAX End of
up to 2 mg atropine for Cine Imaging protocol
Dobutamine-​CMR 3 minutes

Fig. 30.1  Time sequence of high-​dose dobutamine-​atropine stress

Introduction cardiovascular magnetic resonance.
The principles of dobutamine-​CMR are identical to dobutamine-​ Reproduced with permission from https://​www.cardiac-​imaging.org/​links-​to-​
stress echocardiography. Dobutamine-​ CMR assesses regional resources.html.

wall motion from cine CMR images acquired at rest and during
incremental doses of intravenously administered dobutamine.
Acquisition typically uses steady-​ state free-​
precession (SSFP)
cine imaging methods, which provide excellent visualization of
the endocardial and epicardial borders, allowing reliable assess-
ment of wall motion and wall thickening. Real-​time image ac-
quisition can also be used if required for example in patients with
poor breath-​holding [9]‌and cine imaging can be combined with
strain analysis, which may increase the sensitivity of the analysis.
One benefit of CMR over stress echocardiography is that image
quality is independent of acquisition windows and body habitus.
Stress agents
Most commonly, pharmacological stress agents are used for the
detection of inducible wall motion abnormalities, although exer-
cise stress is in principle feasible in CMR with the use of supine
cycle ergometers or treadmill exercise in the MRI scanner room
[10]. The most commonly used stress agent is dobutamine, which
exerts positively inotropic and chronotropic effects. Vasodilator
(adenosine/​dipyridamole) stress has been suggested for the in-
duction of ischaemic wall motion abnormalities but has signifi-
cantly lower diagnostic accuracy for the detection of epicardial
coronary stenosis, both with CMR and echocardiography [2]‌.
Dobutamine-​CMR protocol
The pharmacological stress protocol for CMR follows the
standard dobutamine/​atropine regimen as used in stress echo-
cardiography (E Fig. 30.1). The set-​up for a dobutamine-​CMR
study includes infusion pumps for the stress agent, blood pressure
and heart monitoring and interaction with the patient to ascer-
tain symptoms (E Fig. 30.2). Resting cine images are acquired in
standard imaging planes (typically apical, mid, and basal short-​
axis view, four-​chamber, two-​chamber, and three-​chamber view)
for baseline comparison. Dobutamine is then infused intraven-
ously at 3-​minute intervals at doses of 10, 20, 30, and 40 μg/​kg/​
min, and imaging is repeated in all views at each stress level. If the
target heart rate (age predicted submaximal heart rate (220 –​age)
× 0.85) is not reached at the maximal dobutamine dose, atropine
is applied in 0.25 mg fractions up to a maximum of 2 mg and
imaging is repeated once the required heart rate has been reached
(see E Fig. 30.1 for a flow chart).
During the pharmacological stress procedure the exam-
iner evaluates the CMR cine images for the presence of new
or worsening wall motion abnormalities in-​line at every stress
level. Termination criteria are identical to those of dobutamine-​
stress echocardiography and include the detection of new wall
motion abnormalities in at least two segments or heart rhythm
changes [11].
Imaging technique
For data acquisition, balanced SSFP sequences in combination
with parallel image acquisition and retrospective ECG gating
are typically used. During short breath-​holds, cine loops of
>25 phases/​cardiac cycle are acquired, with an in-​plane spatial
resolution usually between 1.5–​2 mm × 1.5–​2 mm and a slice

Fig. 30.2  Clinical 3 Tesla whole body MR tomograph (Skyra, Siemens, Erlangen, Germany). (a) Blood pressure monitoring system. (b) Dual head infusion pump
used for contrast agent injection and saline flush, can be steered from outside. (c) In room ECG display. The same trace is visible on the operator console outside
the scanner room. D = Infusion pump for adenosine or dobutamine. For regadenoson no pump is required.
Reproduced with permission from www.cardiac-​imaging.org.
thickness of 8–​10 mm. Alternative methods include the acquisi-
tion of strain-​encoded images (e.g. SENC) [12, 13].
Diagnostic criteria
Standard assessment of wall motion and wall motion abnor-
malities is usually performed visually for all 17 segments using
a synchronized display of the different dobutamine-​dose levels
(E Figs. 30.3 and 30.4). First, image quality is graded as good,
acceptable, or bad, and the number of diagnostic segments is re-
ported. Segmental wall motion and thickening are classified as
normokinetic, hypokinetic, akinetic, or dyskinetic. A decrease
or no change in wall motion or systolic wall thickening during
increasing dobutamine stages are regarded as pathological
findings.
Diagnostic performance
A meta-​ analysis of studies using wall motion imaging with
CMR to identify angiographically defined significant cor-
onary stenosis showed a sensitivity of 83% with a specificity of
86% for all stressors—​dobutamine, exercise (1 study only), or
dipyridamole—​as well as 85% sensitivity (95% CI 82–​90%) and
86% specificity (95% CI 81–​90%) for dobutamine and exercise
only [14]. Diagnostic accuracy was found to be gender inde-
pendent [15], even though responses of longitudinal function
and aortic stiffness to dobutamine stress are different in men and
women [16]. Other studies have suggested that the diagnostic ac-
curacy (and prognostic value) of dobutamine-​stress CMR may be
improved by the use of strain imaging (e.g. SENC) [12, 13] or
D obu ta m i n e -C M R 449
feature tracking analysis of cine CMR images [17]. Dobutamine-​
stress CMR has high interobserver reproducibility, as shown in a
multicentre read of 150 patients in six centres [18]. While adding
perfusion to dobutamine wall motion assessment is possible, only
high-​resolution techniques seem to improve overall diagnostic
accuracy due to a higher sensitivity [19].
In older single-​centre studies dobutamine-​ stress CMR had
higher diagnostic accuracy than dobutamine-​stress echocardiog-
raphy for the detection of inducible wall motion abnormalities
in patients with suspected CAD [20], in patients with wall mo-
tion abnormalities at rest [21], and in patients not well suited for
second harmonic echocardiography [22] (E Table 30.1). The
superiority of dobutamine-​stress CMR in these studies was at-
tributed primarily to the consistently high endocardial border
visualization with CMR and the gain in diagnostic accuracy
was mainly seen in those patients with inadequate acoustic win-
dows or limited echocardiographic image quality despite the use
of second harmonic imaging [23]. However, no comparisons of
dobutamine-​stress CMR using SSFP imaging with contemporan-
eous echocardiography methods or contrast-​echocardiography
have been published.
Functional assessment of viable myocardium
In addition to the assessment of ischaemia, dobutamine-​stress
CMR allows an assessment of myocardial viability, for example
after myocardial infarction or in chronic CAD (hibernation).
At low dose of 10–​20 μg/​kg/​min, dobutamine has mostly posi-
tively inotropic properties and increases the contractility of viable
450 CHAPTER 30   C MR and det ect ion of c orona ry a rtery di sease

(a) Rest 10 μg 20 μg Max (b) Rest 10 μg 20 μg Max

End-diastole

End-diastole
End-systole

End-systole
End-diastole

End-diastole
End-systole

End-systole

Fig. 30.3  (a) Cine images of the DSMR examination (apical short-​axis and four-​chamber view) in a patient with single-​vessel disease of the left anterior
descending artery (LAD). The four readers showed perfect agreement regarding newly developed wall motion abnormalities in the anterior and anteroseptal
segment and the apex (segment 17). (b) Cine images of the DSMR examination (apical short-​axis and four-​chamber view) in a patient with triple-​vessel disease
(significant stenoses of the first diagonal branch, proximal left circumflex, and distal right coronary artery (RCA)). The four readers detected newly developed
wall motion abnormalities in the lateral wall (apical and equatorial segments). The development of a mitral regurgitation jet due to ischaemic papillary muscle
dysfunction is depicted as well.
Reproduced from Paetsch I, Jahnke C, Ferrari VA, et al. Determination of interobserver variability for identifying inducible left ventricular wall motion abnormalities during
dobutamine stress magnetic resonance imaging. Eur Heart J. 2006;27(12):1459–​64. doi:10.1093/​eurheartj/​ehi883 with permission from Oxford University Press.

myocardium. Hibernating myocardium will typically show a ‘bi-
phasic response’ with a wall motion abnormality at rest, improve-
ment at low dose, and deterioration at high-​dose dobutamine.
Studies comparing low-​dose dobutamine and late gadolinium
enhancement imaging for predicting functional recovery after
revascularization have shown inconsistent results, with one study
suggesting superiority of low-​dose dobutamine in particular in seg-
ments with non-​transmural scar [24], while another study reported
opposite findings in patients with severely reduced left ventricular
(LV) function [25]. Differences in the study populations in these
small single-​centre studies may have caused these different re-
sults. Other studies have reported on the combination of low-​dose
dobutamine and late gadolinium enhancement (LGE) CMR [26].
For a detailed discussion of viability imaging we refer to [27].
patients with negative dobutamine-​CMR testing (2% over 2 years
for patients with LVEF >40% and 0% over 2 years for patients with
LVEF ≥60%). Jahnke et al. [29] reported a follow-​up of 513 pa-
tients with known or suspected CAD for a median duration of
2.3 years. A normal dobutamine-​CMR study resulted in a cumu-
lative event rate (death or myocardial infarction) of 1.2%, 2.6%,
and 3.3% in the first 3 years, whereas patients with an abnormal
dobutamine-​CMR had a significantly higher event rate (7.3%,
10.3%, and 18.8% in the first 3 years). More recently, Kelle et al.
reported the outcomes of a two-​centre cohort of 3,138 patients
examined with dobutamine-​CMR and followed over more than 3
years. They found a 0.6% annual event rate (myocardial infarction
or cardiac death) in patients with a negative test. In patients with
inducible wall motion abnormalities, prognosis was normalized
by early revascularization (within 3 months of the stress test) [30].

Prognostic value of dobutamine-​CMR Safety of dobutamine-​stress CMR

Several single-​centre studies have been presented on the prog-
nostic value of dobutamine-​ CMR. Hundley et al. [28] found
that the presence of inducible wall motion abnormalities during
dobutamine-​CMR identifies patients at risk of myocardial in-
farction and cardiac death independently of the presence of trad-
itional risk factors for CAD. A low cardiac event rate was found in
A report on the safety of high-​dose dobutamine-​stress CMR
in 1,000 consecutive patients showed a safety profile similar to
dobutamine-​stress echocardiography: one patient suffered sus-
tained ventricular tachycardia with successful conversion; no
cases of death or myocardial infarction occurred. The patients
included in this study reflect current clinical practice with an
 D obu ta m i n e -C M R 451

4-chamber Mid-ventricular short-axis

ED ES ED ES
Rest
20 μg
40 μg

Fig. 30.4  Four-​chamber and mid-​ventricular short-​axis views at rest, and at intermediate-​and peak-​dose dobutamine stress (steady-​state free-​precession
technique). Both end-​diastolic (ED) and end-​systolic (ES) frames are shown. Note the development of mid-​lateral akinesia (arrows) at peak dobutamine stress. In
this patient, invasive coronary angiography demonstrated a left circumflex coronary artery stenosis.
Reproduced from Wahl A et al., Safety and feasibility of high-​dose dobutamine-​atropine stress cardiovascular magnetic resonance for diagnosis of myocardial ischaemia: Experience in
1000 consecutive cases. Eur Heart J 2004; 25: 1230–​6, by permission of Oxford University Press.

Table 30.1  Diagnostic accuracy of dobutamine stress wall motion studies. Only studies performed in more than 100 patients and using SSFP
or applying a newer imaging techniques or specific subgroup are shown

Author Year Journal # Characteristics sens spec Comment/​specific subgroup

Dobutamine stress
Hundley et al. [22] 1999 Circulation 41 Suspected CAD 83 83 Poor acoustic windows on TTE
Nagel et al. [20] 1999 Circulation 172 Suspected CAD 86 86 Superior to dobutamine-​stress echo
Schalla et al. [9]‌ 2002 Radiology 220 Suspected CAD 81 83 Real-​time imaging technique
Paetsch et al. [2]‌ 2004 Circulation 79 Suspected or known CAD 89 81 Superior to perfusion imaging
Wahl [21] 2004 Radiology 160 Wall motion abnormalities 89 84 Patients with WMA at rest
Paetsch et al. [18] 2006 EHJ 150 Suspected CAD 78 88 Multicentre read
Korosoglou [12] 2010 JACC CVI 80 Suspected or known CAD 98 91 By addition of SENC
Gebker et al. [19] 2012 Int J Cardiol 78 Suspected or known CAD 92 83 Dobutamine-​stress perfusion
81 87 wall motion in the same population
452 CHAPTER 30   C MR and det ect ion of c orona ry a rtery di sease
intermediate pretest likelihood and more than 50% positive
findings [31]. A prospective registry of 554 patients undergoing
dobutamine-​CMR confirmed these findings with two patients
suffering significant complications, one sustained ventricular
tachycardia and one sustained atrial fibrillation [32].
Limitations
Dobutamine-​CMR has several limitations, most of which are
similar to dobutamine-​stress echocardiography:
◆ Because the test is stopped when a diagnostic wall motion ab-
normality occurs, only the haemodynamically leading stenosis
may be detected and multivessel CAD may be missed.
◆ Up to now, no multicentre studies on dobutamine-​CMR have been
performed. This might be less important for dobutamine-​CMR
than for other techniques, e.g. perfusion-​CMR, since the data ac-
quisition is highly standardized and robust, and the variability of
data interpretation has been assessed in a multicentre read with
good interobserver variability [18]. However, a multicentre trial
would enhance the evidence for this technique.
Conclusions
Dobutamine-​CMR provides prognostically relevant information
in patients with suspected CAD and can be used for functional
assessment of viable myocardium. Dobutamine-​CMR has at least
comparable diagnostic accuracy to stress echocardiography and
strong prognostic relevance.
Myocardial perfusion-​CMR
Introduction
While dobutamine-​ CMR directly visualizes functional con-
sequences of ischaemia, i.e. impaired systolic thickening,
perfusion-​CMR utilizes a contrast medium (CM) to probe myo-
cardial perfusion and myocardial perfusion reserve, usually
during pharmacologically induced hyperaemia. The most com-
monly used perfusion-​CMR method is T1-​weighted, dynamic
first-​pass contrast enhanced imaging with a gadolinium-​based
CM. This method has been validated in preclinical studies and
a large number of clinical single-​centre and multicentre studies
(E Tables 30.2 and 30.3), and has become an integral part of the
work-​up of patients with known or suspected CAD. Perfusion-​
CMR is typically combined with cine CMR imaging and scar
imaging with LGE CMR for a comprehensive assessment of
CAD [33, 34]. When clinically indicated, viability assessment by
low-​dose dobutamine-​CMR may be added [24].
This chapter will not address the perfusion techniques BOLD
(blood-​oxygen level dependent imaging) and arterial spin label-
ling, which measure perfusion with endogenous contrast.
Perfusion-​CMR techniques
In first-​pass perfusion-​CMR, the first passage of the CM through
the myocardium is visualized and higher CM concentrations
result in brighter signal intensities. To achieve this, a conventional
Gd-​based CM is injected into a peripheral vein, usually in the
forearm, via a power injector at a dose of 0.075–​0.10 mmol/​kg
[11], but the use of higher doses of up to 0.15 mmol/​kg has been
shown to be feasible [35].
Simultaneously to the CM injection, the CMR acquisition is
started to acquire the perfusion data. Motion artefacts are minim-
ized by ECG-​triggering (to ‘eliminate’ cardiac contraction) and by
breath-​holding (to ‘eliminate’ respiratory motion). Alternatively,
motion compensation methods are now available on many
scanners, which allow data acquisition during free breathing [36].
To detect myocardial ischaemia, imaging is performed during
hyperaemia, most commonly induced by an intravenous infu-
sion of adenosine at a standard dose of 140 μg/​kg body weight/​
min over 3–​5 min. It is recommended to increase the dose up to
210 μg/​kg body weight/​min if there is insufficient haemodynamic
(heart rate increase by at least 10 bpm and/​or blood pressure drop
by >10 mmHg) or symptomatic response [37] (see E Fig. 30.5.
for a flow chart). The selective A2a receptor agonist regadenoson
can be used as an alternative to adenosine. It has the advantage of
being injected as a single bolus injection of 0.4 mg and of having a
more favourable side effect profile. Dipyridamole remains used in
some centres. For all vasodilators, abstinence from caffeine for 24
hours prior to the test is advised to achieve full vasodilatation, as
caffeine is a competitive agonist of adenosine receptors. A typical
example of a perfusion-​CMR study is given in E Fig. 30.6.
To obtain meaningful first-​pass information, the LV myocardium
must be covered with several short-​axis slices at every other, or
preferably every heartbeat, its spatial resolution must be adequate
to differentiate transmural perfusion differences in the LV wall,
and its sensitivity to the CM must yield a several-​fold increase in
signal vs. baseline during first-​pass (recommended 250–​300%)
[38]. Following from these requirements, the typical features of a
perfusion-​CMR pulse sequence are [11]:
◆ Saturation–​recovery technique (i.e. a 90° preparation pulse for
each slice).
◆ Short read-​out (≤150 ms).
◆ Coverage of the heart in at least 3 slices/​every 1–​2 heart beats.
◆ In-​plane spatial resolution of <3 mm.
These requirements are typically met by fast-​gradient echo-​pulse
sequences with hybrid-​echoplanar read-​outs, parallel imaging
techniques, or by a combination with temporo-​spatial acceler-
ation strategies [39, 40]. Many alternative acquisition and accel-
eration methods have been proposed and are reviewed in [41] as
well as in [42].
Perfusion-​CMR protocols for the
detection of CAD
All CMR perfusion protocols in CAD aim at the detection of
inducible ischaemia. The detection of scar with LGE is usually
added and scar tissue is not regarded as ischaemic (even if it shows
a perfusion defect during first-​pass perfusion as scar tissue is ex-
pected to be non-​reactive to vasodilators). In principle, detection
 M yo ca rdia l perf usi on -C M R 453

Table 30.2  Studies comparing perfusion-​CMR with invasive angiography (only studies with >100 patients and adenosine stress were included)

N Comment Diameter Patient-​based results

stenosis
Sensitivity Specificity Accuracy
Single-​centre studies
Gebker [81] 101 90 71 84
Merkle [82] 228 >70% 93 86 91
>50% 96 72 88
Klem [66] 136 Women ≥70 84 88 87
Bernhardt [83] 477 ≥70 Suspected CAD: 94 Suspected CAD: 94 –​
Previous PCI: 91 Previous PCI: 90
Previous CABG: 79 Previous CABG: 77
Manka [84] 146 3D perfusion-​CMR ≥50 92 74 83
Greenwood [55] 752 Superior sensitivity and similar specificity ≥70% 86 (82–​90) 83 (79–​87) AUC 0.89
compared to SPECT
Greenwood [67] 235 Subanalysis of women. Superior sensitivity ≥70% 89 83 AUC 0.90
and similar specificity compared to SPECT.
Merkle [85] 256 ≥50% 91 82 89
Pilz [86] 171 ≥70% 96 83 92
Multicentre studies
Schwitter [53] 241 18 centres, CMR superior to ungated SPECT ≥50 –​ –​ AUC 0.86
(AUC 0.86 vs. 0.67, P <0.013)
Schwitter [54] 515 33 centres, CMR superior to gated SPECT ≥50 –​ –​ AUC 0.75
(AUC 0.75 vs. 0.69, P <0.02)
CMR superior to SPECT in men (P = 0.004)
and women (P = 0.03)
Schwitter [87] 515 33 centres, at a given sensitivity/​specificity ≥50% 75 (69–​80) 59 (52–​65) –​
point, superior sensitivity, and inferior
specificity compared to SPECT
Meta-​analyses
Jaarsma [88] 2,937 Various stressors ≥50% 89 (88–​91) 76 (73–​78) 86
Kiaos [89] Various stressors ≥50% 82 75 –​
1.5 Tesla ≥50% 90 79 –​
3 Tesla ≥70% 86 77 –​
1.5 Tesla ≥70% 91 74 –​
3 Tesla

Table 30.3  Studies comparing perfusion-​CMR with fractional flow reserve (FFR). (only studies with >100 patients and adenosine stress were included)

N Comment Reference FFR Patient-​based results

Sensitivity Specificity Accuracy
Watkins [90] 101 <0.75 95 (87–​99) 91 (72–​99) 94
Manka [91] 120 3D technique <0.75 90 (80–​96) 82 (69–​92) 87
Bettencourt [92] 103 <0.80 89 (76–​96) 88 (77–​95) 88
Ebersberger [93] 116 ≤0.80 85 (70–​94) 87 (77–​94) 86
Groothuis [63] 192 ≤0.75 85 (65–​96) 82 (71–​91) 83
Layland [94] 106 ≤0.80 86 95
Multicentre
Manka [65] 155 3D technique <0.8 85 91
Meta-​analyses
Li [95] 650 ≤0.75 or 0.80 90 (86–​93) 87 (82–​90)
Takx [96] 798 <0.75 89 (86–​92) 87 (83–​90) 88
Kiaos [89] 90 85
454 CHAPTER 30   C MR and det ect ion of c orona ry a rtery di sease

(a) (b)
Adenosine Stress

140 micrograms/kg body weight/minute for 2 minutes

(c)
Heart rate increase by >10bpm or blood pressure drop by >10mmHg?

no yes

(d) (e)
170 micrograms/kg body weight/
Wait until minute 3
minute for maximal 2 minutes

Heart rate increase by >10 bpm or

blood pressure drop by >10 mmHg? yes
(f)
no
Perform
Perfusion
210 micrograms/kg body weight/
minute for maximal 2 minutes
yes Imaging
(g) (h)
Heart rate increase by >10bpm or
blood pressure drop by >10 mmHg?

no

(i)
End of stress protocol

Fig. 30.5  Time sequence of adenosine stress cardiovascular magnetic

resonance. In patients with severe symptoms imaging is performed without
increasing the dose even if no haemodynamic change is observed. (j)
Reproduced with permission from https://​w ww.cardiac-​imaging.org/​links-​to-​
resources.html.

of CAD can be achieved by a stress-​only protocol. If a perfusion

abnormality is present during hyperaemia, an LGE acquisition
is added to differentiate whether the perfusion deficit is located
in viable myocardium or in scar. Perfusion deficits found in vi-
able myocardium are regarded as inducible ischaemia. If such
areas represent a substantial amount of myocardium, typically
exceeding 1 of 16 segments [43] or 10–​12% of the overall myo-
cardial mass [44], the ischaemic burden is considered to being
prognostically significant [7]‌and revascularization may be in-
dicated. This stress-​only perfusion-​CMR/​LGE protocol matches
the principle of the scintigraphic approach, where ischaemic
territories are detected on the stress study and the rest injection
study visualizes scar tissue through re-​distribution of the radio-​
tracer. A more detailed description of these concepts is available
elsewhere [45].
In clinical practice, rest perfusion is often added routinely to
the CMR study in patients with CAD, however there is increasing
evidence that this is not required on a routine basis, which may
save time and reduce the total dose of contrast agent [46, 47]
(E Fig. 30.6). The rest study may help to exclude artefacts when
they are found in both stress and rest images, and can thus be
Fig. 30.6  Perfusion-​CMR, late gadolinium enhancement, and invasive
angiography from a 67-​year-​old participant in the MR-​INFORM trial. The
patient has a stenosis of the circumflex artery (j) as well as a significant
perfusion defect during adenosine hyperaemia in the corresponding territory
in the basal (g) and mid-​short-​axis view (d). There is no defect in the apical
slice at stress (a) or in any slice at rest (c, f, i). There is no corresponding late
gadolinium enhancement (b, e, h). The perfusion defect fulfils three criteria
for positivity: it is visible on two adjacent slices, it covers more than 60°
circumference (d), and it covers more than 50% slice thickness (g).
Reproduced with permission from the MR-​INFORM investigators.
discriminated from inducible ischaemia, which occurs at stress
only. A stress/​rest protocol can also be used for the calculation of
the myocardial perfusion reserve (MPR), which follows the con-
cept applied by PET imaging. These various perfusion-​CMR strat-
egies (involving various pulse sequences, CM doses, protocols)
 M yo ca rdia l perf usi on -C M R 455

have consequences with respect to the reading and analysis and
post-​processing of the data. As such, it is important to keep the
technical parameters of the local perfusion sequence consistent
and carefully assess the consequences of any change.
Reading and image display
The acquisition of adequate perfusion data requires a high-​end
scanner, operator skills, and patient cooperation with respect to
both the cessation of medication and caffeine intake, as well as
breath-​holding during first-​pass, unless free-​breathing methods
with motion compensation are used. When reading the per-
fusion data, images need to be checked for artefacts. The most
common artefact is the subendocardial dark-​rim artefact, caused
primarily by susceptibility effects, which can be challenging to
differentiate from a true perfusion defect. This type of artefact
is a consistent feature of a given pulse sequence and can be min-
imized by optimizing the pulse sequence and shimming of the
magnet, increasing the in-​plane spatial resolution of the perfu-
sion pulse sequence, and administration of a correct CM dose
for the pulse sequence used. Dark-​rim artefacts also typically
occur before CM arrival in the myocardium, usually allowing
differentiation from true perfusion defects. In addition, it is im-
portant to window the images in a way that the brightest blood
signal of the bolus is nearly white (but not overspilling) and the
myocardium is nearly black (but with some remaining signal).
Since dark-​rim artefacts become darker during the arrival of
the contrast agent, this is an important differentiation from is-
chaemia (which remains unchanged or mildly increases signal).
Other possible artefacts are extensive motion during first-​pass,
extrasystoles, or ECG mis-​triggering during first-​pass, ghosting,
and wrap-​around artefacts, and can usually be readily identified
by an experienced observer. Even with an appropriate set-​up,
some CMR perfusion studies have inadequate quality. While this
was reported as high as 10–​15% in early large multicentre trials
[35] this has been less of a problem in more recent trials [48]. The
influence of data quality on diagnostic performance is illustrated
in E Figure 30.7.
In clinical practice, perfusion-​CMR studies are usually analysed
visually, by reviewing stress and LGE data side-​by-​side, some
readers add rest perfusion into the same view. E Figure 30.8
shows the various levels for data analysis and addresses the issue
of observer-​interference with the data. Recently, fully in-​line ana-
lysis methods on a pixel basis have been proposed for automated
quantitative myocardial perfusion estimation [49]. Validation in
animal models and in patients against the clinical reference tests
Fractional Flow Reserve and PET have shown promising results
[50, 51]. The integration of these quantitative perfusion maps into
clinical practice and their combination with visual assessment of
perfusion remain to be established.
Diagnostic criteria
Perfusion abnormalities are typically evaluated in a 16-​segment
model of the LV (excluding the apical segment 17). In each seg-
ment the inflow of CM during hyperaemic conditions is assessed
as reduced, if the signal at peak effect of the CM bolus is reduced
(dark-​grey) or delayed in the subendocardial layer in comparison
to either the subepicardial layer of the same segment and/​or in
comparison to non-​ affected segments (in case of transmural
perfusion deficits) [52–​55]. The 16 segments can be further div-
ided into a subendocardial and subepicardial portion to yield 32

(a) Slices with minimal motion (b) All slices and all
and artefact score <4 artefact scores
1 1

0.75 0.75
Sensitivity

Sensitivity

0.50 0.50

0.25 0.25

P < 0.05 D1 vs D2 and D3

0 0
0 0.25 0.5 0.75 1 0 0.25 0.5 0.75 1
1-specificity 1-specificity

D1: 0.57 ± 0.12 D1: 0.57 ± 0.12

D2: 0.91 ± 0.07 D2: 0.72 ± 0.10
D3: 0.86 ± 0.08 D3: 0.80 ± 0.09

Fig. 30.7  Receiver operating characteristic (ROC) curves of MR upslope data are shown for the detection of coronary artery disease (≥50% diameter stenosis in
≥1 vessel by quantitative coronary angiography). MR upslope data from the subendocardial layer are highly reliable in the detection of disease when analysis is
restricted to the three slices with minimal motion and the patients with adequate image quality. Numbers within the plots represent area under the ROC curve
± standard error for doses 1, 2, and 3 (= D1, D2, D3, respectively). AUC of dose 2 for the entire data (all slices, all quality scores, (b) was worst (P <0.05 vs. dose 2
in (a)). A dose of 0.05 mmol/​kg (= D1) performed inadequately in all analyses. D1 = 0.05 mmol/kg; D2 = 0.10 mmol/kg; D3 = 0.15 mmol/kg.
Reproduced from Giang TH, Nanz D, Coulden R, et al. Detection of coronary artery disease by magnetic resonance myocardial perfusion imaging with various contrast medium
doses: first European multi-​centre experience. Eur Heart J. 2004;25(18):1657–​65. doi:10.1016/​j.ehj.2004.06.037 with permission from Oxford University Press.
456 CHAPTER 30   C MR and det ect ion of c orona ry a rtery di sease
Data analysis
Fig. 30.8  Schematic for perfusion data analysis. MTT: mean
transit time.
segments. Additional criteria indicative for true hypoperfusion
vs. artefacts are subendocardial signal reduction persisting longer
than the CM first-​pass through the LV cavity, signal reduction in
several slices and neighbouring regions, and absence of breathing
motion and triggering artefacts during CM first-​pass [53, 54].
The perfusion defects should be described as subendocardial or
transmural.
Perfusion abnormalities must be assessed in relation to the
presence of scar tissue as detected by LGE. If hypoperfusion is
detected in viable (LGE-​negative) tissue, these segments are re-
ported as ‘ischaemic’ segments, whereas ‘perfusion abnormalities’
in scar (i.e. LGE-​positive) tissue are reported as scar tissue. Since
accumulation of CM in scarred tissue begins immediately after
the contrast passage in the stress study, resting scans frequently
do not show perfusion abnormalities in these segments.
When applying quantitative measures to detect ischaemia, a
frequently used measure is the upslope of the signal–​intensity–​
time profiles of the contrast passage [35, 38, 56–​58]. This method
has shown adequate reproducibility [35, 59, 60] but thresholds de-
pend on the perfusion method and contrast regime used. In one
study, segmental upslope values of 1.75 standard deviations below
the mean of healthy subendomyocardium yielded good sensitiv-
ities and specificities to detect ≥50% diameter coronary stenoses
of 83–​87% and 75–​85%, respectively [35, 61]. Other parameters,
such as time-​to-​peak, time-​to-​start, or peak signal intensity, are
less robust and accurate, and should not be used [62]. Fully quan-
titative analysis methods, which estimate absolute myocardial
blood flow in mg/​ml/​min, have been developed and are expected
to make their way into clinical practice in the near future.
Diagnostic performance
There is a large and continuously increasing body of evidence on
the high diagnostic accuracy of perfusion-​CMR in comparison to
invasive angiography as well as fractional flow reserve (FFR). The
main landmark studies are listed next, a summary of the main
studies with detailed characteristics can be found in [42]. Results
from studies with ≥100 patients versus invasive angiography and
versus FFR are shown in E Tables 30.2 and 30.3.
The largest study of perfusion-​CMR versus invasive angiog-
raphy is the single-​centre CE-​MARC study [55], which prospect-
ively included 628 patients with suspected CAD who underwent
perfusion-​CMR as part of a multiparametric CMR study, gated
SPECT, and invasive coronary angiography. CMR showed
Linked to
perfusion: Semi-automatic
Visual read Parameters:
- Upslope
- MTT Automatic
Quantitative - ect.
evaluation
Absolute Semi-automatic
perfusion:
Unit: ml/min/g Automatic
a sensitivity of 87% and a specificity of 83% to detect stenoses
≥50% on quantitative coronary angiography (QCA) with an AUC
of 0.89 for all patients and 0.91 in the multivessel disease popu-
lation. SPECT resulted in a sensitivity of 67%, specificity of 83%
and AUC of 0.74.
The largest study of perfusion-​CMR versus FFR has been re-
ported by Groothuis et al. [63] in 192 patients using an FFR ≤0.75
as the reference standard. A sensitivity of 85% with a specificity
of 82% was reached.
The largest multicentre studies using invasive angiography as
the reference standard is the MR-​IMPACT I [53] (18 centres) and
II [64] (33 centres) comparing perfusion-​CMR vs. ungated and
gated SPECT, respectively, with both studies showing larger AUC
with perfusion-​CMR for the detection of CAD (>50% diameter
stenosis on X-​ray coronary angiography) vs. SPECT. In 465 pa-
tients MR-​IMPACT II yielded a sensitivity of 67% and a specifi-
city of 61% for CMR at a predefined sensitivity/​specificity point
with an AUC of 0.75 for all patients and 0.80 in the multivessel
disease population [54]. SPECT resulted in a sensitivity of 59%,
specificity of 72% and a statistically inferior AUC of 0.65 (for
gated SPECT vs. the perfusion-​CMR technique [54]).
The largest multicentre study using FFR as the reference
standard has been published by Manka et al. [65] and reported on
155 patients. An FFR of <0.8 was regarded as significant yielding
a sensitivity of 85% with a specificity of 91% for perfusion-​CMR.
Meta-​analyses show sensitivities from 88 to 91% with
specificities of 73–​78% vs. invasive angiography and 86–​92%/​83–​
90% versus FFR. Importantly, similarly high diagnostic accuracy
has also been reported in specific subgroups such as females [54,
66, 67], post bypass surgery [68] or in patients with multivessel
disease [54].
In general, diagnostic accuracy and especially specificity are
higher when using FFR rather than invasive angiography as the
reference standard.
More recently the CE-​MARC II study [48, 69] was published
demonstrating in a prospective multicentre setting, that perfu-
sion imaging (by CMR or SPECT) significantly reduces the rate
of negative invasive angiographies, thus providing the potential to
save costs and invasive procedures. The international, randomized
controlled clinical-​effectiveness MR-​INFORM trial [70] demon-
strated in 918 patients with stable chest pain and intermediate
to high pretest likelihood for CAD that non-​invasive perfusion
imaging with CMR can guide further management as effectively

as invasive angiography supported by pressure measurements
in the coronary arteries (FFR). Patients were randomized into a
non-​invasive arm guided by stress perfusion-​CMR or an invasive
arm guided by angiography and FFR. In the CMR-​informed arm
only 40.5% required an invasive angiography despite the inter-
mediate to high pretest likelihood and less patients than in the
FFR-​informed arm were revascularized (MR guided: 35.7% vs. in-
vasively guided: 45.0%, p = 0.005). The occurrence of angina pec-
toris (50.8% vs. 56.2%, P = 0.21) or major cardiac events (death,
myocardial infarction, target vessel revascularization) (3.56% vs.
3.72%, HR: –​2.68–​2.36 P = ns) was identical by perfusion-​CMR
or invasively guided therapy. These important studies may allow
changing clinical practice as the current invasive strategy can be
safely replaced by a short, non-​invasive imaging test in patients
with stable angina and intermediate to high pretest likelihood
for CAD.
Safety of perfusion—​CMR
In the European CMR registry an excellent safety profile of
perfusion-​CMR was recorded with 0.01% severe complications in
18,840 patients [71]. No death and no myocardial infarction oc-
curred. In this context, it is important to recognize that CMR is
not associated to any exposure to ionizing radiation.
Prognostic value of perfusion-​CMR
A normal perfusion-​CMR test predicts a low event rate. In
the largest meta-​analysis so far [72] of 11,636 patients with an
average follow-​up time of 32 months the event rates for cardio-
vascular death or myocardial infarction were 0.3 ± 0.3% and
0.4 ± 0.3% in case of a negative CMR study (0.8 ± 0.7% for the
combined endpoint of cardiovascular death or myocardial in-
farction). In case of a positive stress CMR event rates were 2.8
± 1.6%, 2.6 ± 2% and 4.9 ± 3.1% (P <0.0001 for all) resulting
in hazard ratios of 7.7, 6.96, and 6.5. Similar prognostic values
were observed for men and women with annual MACE (death or
new acute MI) rate of 0.3% and 1.1% in men and women with a
normal perfusion-​CMR study, and 15.1% and 10.8%, in patients
with a positive perfusion-​CMR test (difference between men and
women not significant) [73]. In a large single-​centre cohort, 1,152
patients with stable angina and known CAD (34% with a history
of MI and 50% with a history of revascularizations) or with stable
angina but without known CAD underwent perfusion-​CMR for
ischaemia detection [74]. MACE were as low as 1.0%/​year in pa-
tients without ischaemia on perfusion-​CMR over a follow-​up
period of 4.2 years, whereas MACE were 3.9%/​year in patients
positive on perfusion-​CMR. The 5-​year outcome analysis of the
CE-​MARC [75] study demonstrated very low and similar annual
event rates for negative CMR or SPECT studies (2% vs. 2.8%)
whereas a positive study resulted in 5.0% and 4.2% events. CMR
had a stronger influence on any model predicting outcome than
SPECT. These data of prospective studies match well with the out-
come data of perfusion-​CMR as observed in the large European
Cardiovascular Magnetic Resonance (EuroCMR) registry, which
M yo ca rdia l perf usi on -C M R 457
prospectively collected data on patients with suspected CAD in
18 countries since 2008 [76]. In 3,647 patients, deaths (cardiac
death and death of unknown origin) and non-​fatal myocardial
infarction occurred in 0.8% and 1.2% per year in the patients
with normal and ischaemic perfusion-​CMR, respectively [77].
A general problem of all current outcome studies is the poten-
tial influence of the test itself on the therapeutic work-​up. Most
studies censored patients who received a revascularization based
on a positive stress test within the first three months, however,
a remaining influence cannot be fully excluded. In the patients
with positive ischaemia on perfusion-​CMR, a trend to lower
event rates is observed over the past years, with a very low event
rate of 1.2% per year finally occurring in the latest EuroCMR
data [77], most likely indicating that revascularizations are in-
creasingly performed when perfusion-​CMR detects ischaemia.
In this regard, it is important to know the threshold for is-
chaemia burden, which indicates the need for revascularization.
This question was addressed in a large high risk cohort of 1,024
patients (previous infarction and previous revascularizations in
42% and 45%, respectively) with a follow-​up of 2.5 years [43].
No ischaemia or low ischaemic burden of one segment (of the
16-​segment model) was associated with an excellent prognosis
for cardiac death and non-​fatal myocardial infarction of 0.4%
per year versus 3.9% per year, if two or more segments were
ischaemic. Following that study in a smaller cohort of 395 pa-
tients followed over 460 days’ data on the amount of ischaemia,
as assessed visually and by quantitative perfusion-​CMR data
were reported [78]. Prognostic value of visual quantification of
ischaemia (number of ischaemic segments) and using quanti-
tative perfusion data was similar indicating that novel quanti-
tative perfusion-​CMR techniques show potential for outcome
prognostication. For absolute perfusion-​CMR data, this study
applied a dual bolus approach (a very small prebolus is used to
provide the input function), which is rather challenging to use in
clinical routine. Thus, standardization on these technical aspects
is needed. In order to apply the cut-​off value for significant is-
chaemia of at least two ischaemic segments, it is important to
apply the reading criteria of perfusion-​CMR studies as provided
in the literature [43, 79]. Novel quantitative perfusion-​CMR
approaches measuring perfusion in absolute units are at the
horizon and may facilitate perfusion assessment further in the
near future. In general, larger ischaemic defects confer a worse
prognosis, the additional presence of scar detected by LGE fur-
ther increases the event rate [43].
The high diagnostic accuracy, strong outcome data and the
consistent performance at the upper end of the diagnostic ac-
curacy when compared to other imaging techniques in combin-
ation with large numbers and strong prognostic data suggests that
perfusion-​CMR is a first line tool in the work-​up of suspected
and known CAD. Accordingly, CMR and, in particular, ischaemia
detection by CMR, is recommended at the same level as other
imaging techniques, such as stress-​echo or stress SPECT, for the
work-​up of heart failure patients in the most recent guidelines of
the European Society of Cardiology [80] (E Table 30.4).
458 CHAPTER 30   C MR and det ect ion of c orona ry a rtery di sease

Table 30.4  Prospective outcome studies using vasodilator (adenosine) stress CMR in patients with known or suspected coronary artery
disease. Follow-​up (FU) is expressed in months. HRs are expressed as absolute values (positive test versus negative test) followed by 95% CI.
All analyses are adjusted/​multivariable

N and FU Comment Endpoint Event rate for CV death/​ CMR outcomes (HR)
MI (%/​year)
CMR –​ CMR +
Single-​centre studies
Jahnke [29]  = 513
N CV death /​MI 0.7 6.2 MRP+ 10.57*
FU = 27.6 (2.86–​39.1)
Steel [97]  = 254
N CV death /​MI 1.9 21.0 MRP+ and LGE+ –​
FU = 17
MRP+ 8.61#
(3.85–​19.29)
Coelho-​Filho [73]  = 405
N CV death /​MI 1.1 15.1 MRP+ and LGE+ –​
FU = 30
MRP+ (Ischaemia 1.11&
score) (1.03–​1.19)
women 1.49#
(1.31–​1.69)
men 1.17#
(1.09–​1.25)
Krittaya-​phong [98]  = 1232
N CV death/​MI 0.5 5.0 MRP+ 6.24*
FU = 39 (2.7–​14.44)
LGE+ 3.64*†
(1.95–​6.78)
CV death/​MI/​UA/​HF –​ –​ MRP+ 2.92*
(1.86–​4.6)
LGE+ 3.76*†
(2.58–​5.48)
Bertaso [99]  = 362
N CV death /​MI 2.2 3.6 MRP+ and LGE+ –​
FU = 22
Buckert [74]  = 1229
N CV death /​MI/​stroke 0.9 3.2 MRP+ and LGE+ 3.21#
FU = 50 (2.06–​5.00)
Shah(100)  = 255
N Obesity (BMI > 35), CV death/​MI 0.3 10.8 MRP+ and LGE+ –​
FU = 25 adenosine, and
MRP+ 7.5+
regadenoson
(2.0–​28.0)
1.5 T and 3 T
Abbasi [101]  = 364
N Regadenoson, 3 T CV death/​MI 0.6 3.2 MRP+ 6.95§
FU = 23
CV death/​MI, late –​ 2.59&
coronary revascularization (1.30–​5.18)
(>90 days), ventricular
arrhythmia
hospitalization for
UA or HF
Pontone [102]  = 793
N Dipyridamole CV death/​MI 1.8 5.8 MRP+ –​
FU = 27
MRP+ and stress 2.61&
AWM (1.27–​5.38)
Greenwood [75]  = 752
N CV death, acute coronary MRP+ 2.77#
FU = 60 syndrome, unscheduled SPECT+ (1.85–​4.16)
revascularization, or 1.63§
hospital admission for any (1.11–​2.39)
CV cause
 M yo ca rdia l perf usi on -C M R 459

Table 30.4 Continued

N and FU Comment Endpoint Event rate for CV death/​ CMR outcomes (HR)
MI (%/​year)
CMR –​ CMR +
Vincenti [43]  = 1024
N 1.5 T and 3 T Cardiac death/​MI/​ 1.4 9.7 MRP+ and LGE+ –​
FU = 30 late revascularization
MRP ≥2 segments 8.35*
(>90 days)
(5.3–​13.2)
LGE+ 1.66§
(1.0–​2.7)
Sec. endpoint: cardiac 0.4 3.9 MRP+ and LGE+ –​
death/​MI
Greenwood [103]  = 1202
N 3-​parallel groups, MACE CMR vs. NICE 1.37
FU = 12 randomized clinical (0.52–​3.57)
trial
CMR vs. SPECT 0.95
(0.46–​1.95)
Nagel, MR-​INFORM N = 918 Randomized MACE CMR vs. FFR 0.85
comparative (–​0.43–​1.69)
effectiveness trial of
CMR vs. FFR guided
management
Meta-​analysis
Lipinski [72] = 11636
N Perfusion-​CMR and MI –​ –​ –​ 7.7#
FU = 32 DSMR (3.28–​18.23)
CV death 6.96#
(4.13–​11.74)
CV death/​MI 6.5#
(4.41–​9.58)
Prospective EuroCMR Registry
Bruder et al. [104]  = 3647
N Observational CV death/​MI 0.8 1.3 MRP+ and LGE+ –​
FU = 12 prospective registry
MACE = major cardiac event; CV = cardiovascular; DSMR = dobutamine stress magnetic resonance; MI = myocardial infarction; MRP = MR perfusion; LGE = late gadolinium
enhancement; HF = heart failure; BMI = body mass index, HR = hazard ratio, ischaemia score (32-​segment model) = HR per segment ischaemic.
#
<0;0001; *<0.001; + <0.005; &<0.01; §<0.05.

Cost-​effectiveness of ischaemia
detection by CMR
In a prospective substudy of the European CMR registry, patients
with suspected CAD underwent ischaemia testing by CMR. Costs
were calculated for the initial CMR examination and for invasive
X-​ray coronary angiography for patients positive for ischaemia
on perfusion-​CMR. In addition, costs for revascularizations and
management of complications of CAD were taken into account
[105]. These costs were compared with a hypothetical invasive
strategy to detect CAD, either as a combination of invasive X-​ray
coronary angiography with FFR (indicating revascularization if
FFR ≤0.80) or as an invasive coronary angiography only (indi-
cating revascularization for stenoses ≥50%). Of the 3,647 pa-
tients studied, revascularizations were performed in 6.2 %, 4.5 %,
and 12.9 % of all patients, patients with atypical chest pain (n =
1,786), and typical angina (n = 582), respectively. Compared with
the coronary angiography + FFR approach, the CMR strategy
led to cost savings in the healthcare systems of Germany, United
Kingdom, Switzerland, and US of 14%, 34%, 27%, and 24%, re-
spectively [105]. The coronary angiography-​ only strategy re-
sulted in considerably more revascularizations and cost-​savings
for the CMR strategy were as high as 59%, 52%, 61%, and 71%
for the German, United Kingdom, Swiss, and US healthcare sys-
tems, respectively. A cost-​effectiveness analysis of the CE-​MARC
data compared eight different diagnostic algorithms to detect
CAD (applying stress-​ ECG, CMR, scintigraphy, and invasive
coronary angiography in various combinations) [106]. Only the
two strategies all including CMR were cost-​effective in this ana-
lysis [106]. A similar cost-​effectiveness analysis based on the
EuroCMR registry data was performed for the Swiss healthcare
system and demonstrated the strategy stress-​ECG inconclusive
→ CMR-​positive → coronary angiography as dominant (lowest
costs with highest quality adjusted life-​years gained) [107]. The
costs to detect and treat ischaemia were assessed in 600 consecu-
tive symptomatic revascularized patients who were randomly as-
signed to perfusion-​CMR or anatomical cardiac CT. In the CT
460 CHAPTER 30   C MR and det ect ion of c orona ry a rtery di sease
arm, there were 48% more invasive coronary angiographies, 46%
more revascularizations and more MACE (death and myocar-
dial infarction: 10% vs. 5%), while costs in the CMR arm were
25% lower (all differences statistically significant) [108]. Another
study assessed the cost-​effectiveness of CMR in the emergency
department and demonstrated cost savings of approximately
35% over a 1-​year follow-​up when patients with suspected acute
coronary syndrome (no ST elevations, normal initial troponin)
were referred to CMR, compared with routine in-​hospital work-​
up [109]. This cost-​saving was obtained without a difference in
clinical outcome in the two patient groups and was explained
mainly by the facts that (1) hospitalization could be avoided in
approximately 80% of the CMR group, and (2) after discharge, i.e.
during the 1-​year follow-​up, costs continued to decrease in the
CMR group.
Limitations
A major general limitation of CMR today remains its re-
stricted availability. Recent and future evidence on cost-effect-
iveness of CMR should help to improve these financial aspects
in the near future. Most modern PM and ICD devices are now
MR-conditional and patients can safely undergo CMR [110–
115]. CMR stress studies have a number of specific contraindi-
cations, as given in E Box 30.1. Additional possible limitations
may be the lack of full coverage for perfusion studies (the true
apex is usually not visualized) even though this has not been
limiting diagnostic accuracy and artefacts as discussed earlier
which are especially important for less experienced observers.
Future developments
Perfusion-​CMR is still a demanding technique, and with an
increasing request for such studies, the need for well-​trained car-
diac imagers will also increase and with it the need for ongoing
standardization of training [116] and of CMR applications.
Generally accepted protocols are available and will be updated
as the technique progresses [11]. Technically, recent years have
seen a trend towards higher-​resolution perfusion-​CMR [52] and
quantitative perfusion mapping. One study of 100 patients has
suggested that high-​resolution CMR may improve the overall
diagnostic performance of the method further [117]. High-​
resolution perfusion-​CMR may also prove beneficial for (semi)-​
automatic analysis of perfusion data, which would consequently
improve post-​processing reproducibility (E Fig. 30.9). First
fully automated software approaches based on the transmural
gradient are becoming available [118]. When exploiting the
very fast temporospatial acceleration strategies that have also
allowed high-​resolution perfusion-​CMR [40, 52], it has also be-
come possible to acquire 3D perfusion data covering the entire
heart at every heartbeat. Methods for 3D perfusion-​CMR have
been proposed at 1.5 T [91] and 3 T [84] with promising initial
results. Future multicentre trials are warranted to evaluate the
robustness of these accelerated 3D techniques and to show su-
periority with respect to diagnostic and prognostic performance
Box 30.1  Specific contraindications for stress CMR
Contraindications for dobutamine-​CMR
Severe arterial hypertension (>220/​120 mmHg)
◆
Unstable angina pectoris
◆
Acute myocardial infarction
◆
Severe aortic stenosis (AVA <1 cm2)
◆
Hypertrophic obstructive CMP with severe obstruction
◆
Acute perimyocarditis or endocarditis
◆
Glaucoma
◆
Contraindications for perfusion-​CMR
Contraindications for adenosine or dipyridamole infusion
◆
second and third degree AV-​block, trifascicular block, severe
asthma, and severe chronic obstructive pulmonary disease
Allergy against vasodilator
◆
Severe allergy against MR contrast medium
◆
versus ‘conventional’ 2D perfusion-​CMR. Myocardial perfusion
can also be measured by monitoring hyperpolarized 13C-​CM
during first-​pass and first clinical studies are reported [119].
This technique is able not only to provide quantitative perfusion
data, but also to assess the metabolites of the injected CM (e.g.
lactate produced of injected 13C-​pyruvate) and thus, can probe
ischaemia on a molecular level.
Gd-​chelates (primarily linear compounds) can cause
nephrogenic systemic fibrosis (NSF) in patients with severe renal
impairment. Approximately 335 cases of NSF were reported
until November 2009 out of a total of approximately 200 Mio.
administrations{Luechinger:ww}. Linear agents have also been
related to some brain accumulation of unknown significance and
have been withdrawn from the European market. Cyclic contrast
agents can be given in all patients [120].
Conclusions
Perfusion-​CMR has matured to a reliable technique for the
assessment of CAD. It detects and excludes CAD with a high
diagnostic performance. There is also increasing evidence from
single-​centre studies and the European CMR registry for the
high prognostic value of ischaemia detection by perfusion-​
CMR and a normal CMR study in patients with or without
known CAD predicts a rate for MACE of 0.3–​1%/​year. In add-
ition, European CMR registry data suggest substantial cost
savings when using CMR for the work-​up of patients with
suspected CAD. Since CMR lacks radiation exposure of pa-
tients, repetitive examinations can be safely performed, even in
women of lower age. Accordingly, the evidence is now robust to
recommend perfusion-​CMR for the work-​up of patients with
suspected or known CAD, as well as for patients with heart
failure, in particular when combined with an assessment of
contractile function and viability.

(a) CMR
Stress
Rest
Base Mid
Fig. 30.9  Fully quantitative cardiovascular magnetic resonance myocardial perfusion ready for clinical use: a comparison between cardiovascular magnetic
resonance imaging and positron emission tomography.
Reproduced from Engblom H, Xue H, Akil S, et al. Fully quantitative cardiovascular magnetic resonance myocardial perfusion ready for clinical use: a comparison between
cardiovascular magnetic resonance imaging and positron emission tomography. J Cardiovasc Magn Reson. 2017;19(1):78. Published 2017 Oct 19. doi:10.1186/​s12968-​017-​0388-​9
(http://​creativecommons.org/​licenses/​by/​4.0/​) with permission from Springer Nature.
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Contents
Introduction  467
Pathophysiology  467
Coronary artery imaging and the vulnerable
plaque  468
Computed tomography coronary
angiography  468
Computed tomography coronary
angiography: vulnerable plaque
characteristics  469
Computed tomography coronary
angiography: evidence for clinical use  470
Computed tomography: other methods of
plaque assessment  471
Computed tomography coronary
angiography: future directions  471
Cardiovascular magnetic resonance  471
Cardiovascular magnetic resonance:
advantages and disadvantages  471
Cardiovascular magnetic resonance:
vulnerable plaque  472
Cardiovascular magnetic resonance and
angiography: evidence for clinical use  472
Cardiovascular magnetic resonance: future
directions  472
Positron emission tomography  473
Positron emission tomography:
18
F-​fluorodeoxyglucose  473
Positron emission tomography: 18F-​sodium
fluoride  474
Positron emission tomography: other
radiotracers  474
Conclusions  475
CHAPTER 31
Non-​invasive imaging
of the vulnerable
atherosclerotic plaque
Rong Bing, David E. Newby, Jagat Narula, and
Marc R. Dweck
Introduction
Cardiovascular disease remains the leading cause of death globally despite advances in
medical therapy and risk stratification; ischaemic heart disease was responsible for an
estimated 9.5 million deaths in 2016 [1]‌. To address this ongoing global burden of mor-
bidity and mortality, there is a need for more sophisticated methods of diagnosis and
prognostication, above and beyond clinical risk scores alone.
The majority of myocardial infarction occurs due to ruptured atherosclerotic plaque,
leading to acute thrombosis and coronary occlusion. For decades, the concept of the
vulnerable plaque—​plaques prone to rupture or thrombotic complications—​has been
central to our understanding of the pathophysiology of acute coronary syndromes [2–​4].
More recently, there has been a shift towards identifying the vulnerable patient through
assessment of total atherosclerotic disease burden, in recognition of the fact that most
plaque rupture events do not lead to clinical events [5, 6]. Moreover, demonstrating a
strong causal link between vulnerable plaques and clinical events has previously proven
difficult due to limitations in available invasive and non-​invasive imaging modalities.
However, we now have an array of imaging techniques that hold great potential for the
advancement of vulnerable plaque imaging. These modalities are the subject of state-​of-​
the-​art clinical research, aiming to develop the role of atherosclerotic plaque imaging in
modern clinical practice and ultimately to improve patient outcomes.
Pathophysiology
Although an in-​depth exploration of the pathology of the atherosclerotic coronary plaque
is beyond the scope of this chapter, an understanding of plaque biology is required to ap-
preciate the rationale behind plaque imaging.
Atherosclerosis is a chronic, inflammatory disease that spans decades [7]‌. Endothelial
damage within the arterial lumen is the precursor to atherosclerosis. The process can
begin early in life, particularly in regions of low shear stress such as bifurcations, with
adaptive intimal thickening due to accumulation of vascular smooth muscle cells.
Circulating lipoproteins infiltrate across the endothelium and deposit in the intima
where they are bound by an extracellular proteoglycan-​rich matrix. Lipid deposition is
opposed by macrophage uptake and reverse cholesterol transport, although this response
is limited by local inflammation due to lipoprotein oxidation and cellular apoptosis.
Smooth muscle cells express cellular adhesion molecules that promote migration and
differentiation of circulating monocytes, enhancing the local inflammatory response.
468 CHAPTER 31   N on - i nvasive imaging of t he vu l n er a b l e athero s cl eroti c  pl aqu e

Fibrous cap
Plaque rupture

Lumen Circulating monocyte Thrombus

VSMCs
Microcalcification
Endothelial cell

Calcific
Intima Lipid/
Foam cell nodule
Activated
necrotic core
macrophage
Media Apoptotic
macrophage
Neovascularisation
Adventia and IPH

Positive remodelling

Fig. 31.1  Pathophysiology of the vulnerable plaque. Schematic of the vulnerable plaque and imaging targets. Circulating monocytes migrate into early intimal
thickening where they phagocytose lipid, becoming foam cells and activated macrophages detectable on PET (18F-​FDG, 68Ga-​DOTATATE). Enlargement of the
lipid core is visualized as a low-​density lesion on CTCA and a high-​intensity signal on T1-​weighted MRCA. Positive vascular remodelling can also be detected
on CTCA and MRCA. A necrotic core develops with microvesicles arising from apoptotic macrophages and vascular smooth muscle cells (VSMCs), leading to
superficial microcalcifications detectable on PET (18F-​NaF) before coalescing into more stable calcific nodules detectable on CT.
PET = positron emission tomography; FDG = fluorodeoxyglucose; NaF = sodium fluoride.
Reproduced from Adamson PD, Dweck MR, Newby DE. The vulnerable atherosclerotic plaque: in vivo identification and potential therapeutic avenues. Heart. 2015;101(21):1755–​66.
doi:10.1136/​heartjnl-​2014-​307099 with permission from  BMJ.

Macrophage phagocytosis of lipid results in foam cells, with pro- that myocardial infarction is often due to plaque rupture in non-​
gressive accumulation resulting in the formation of a lipid core obstructive lesions [2, 9, 10].
and ultimately the genesis of the necrotic core that is a central From the original post-​mortem histopathological studies of
constituent of the vulnerable plaque (E Fig. 31.1). patients with myocardial infarction and plaque rupture, invasive
Plaque rupture remains the most common form of plaque de- plaque interrogation has progressed from modalities such as angi-
stabilization [3]‌, with disruption of the fibrous cap exposing the ography and intravascular ultrasound (IVUS) to more modern
highly thrombogenic necrotic core. Thin-​cap fibroatheromas are modalities such as optical coherence tomography and near-​
the prototypical vulnerable plaque and have several hallmark infrared spectroscopy. Meanwhile, non-​ invasive imaging has
histological and intravascular imaging characteristics, including developed in parallel. Next we will discuss each of the currently
a large lipid-​rich necrotic core, macrophage infiltration, a thin utilized non-​invasive techniques for the assessment of vulnerable
fibrous cap (<55–​85 μm) and superficial microcalcification [3]. plaque in the coronary arteries: computed tomography coronary
These findings provide potential targets for cardiac imaging, angiography (CTCA), cardiovascular magnetic resonance (CMR)
forming the basis of in vivo identification of the vulnerable and positron emission tomography (PET) (E Table 31.1).
plaque [8]. Importantly, the complexities of vascular inflamma-
tion, atherogenesis and plaque destabilization are yet to be fully
understood [6]. Computed tomography coronary
angiography
Coronary artery imaging and the Current computed tomography (CT) scanners have largely over-
come the inherent difficulties of coronary artery imaging, allowing
vulnerable plaque the acquisition of high temporal and spatial resolution datasets
The goal of coronary artery imaging in general is twofold—​ within a very short period of time (single breath-​hold). Modern
diagnosis and prognosis. Vulnerable plaque imaging offers an prospectively-​gated protocols have resulted in a dramatic reduc-
appealing method of prognostication and forms the basis of a tion in radiation dose [11], with typical radiation doses under
breadth of exciting research currently underway. This is particu- 3–​5 mSv. Diagnostic image quality is now achievable in the vast
larly relevant given the extensive body of evidence demonstrating majority of patients referred for CTCA. The main impediment to
 C o m pu ted to mo g r a phy c orona ry a n g i o g r a ph y 469

Table 31.1  Current modalities for non-​invasive vulnerable plaque scanners have also demonstrated superior discrimination of pa-
imaging tients with suspected acute coronary syndrome when comparing
CTCA to IVUS using assessments of high-​risk plaque [23].
CTCA MRCA PET
There are several hallmark CTCA findings of vulnerable plaque:
Spatial resolution (μm) 300–​600 500–​1,000 5,000–​7,000 low-​attenuation plaque, positive remodelling, spotty calcification,
Radiation 3–​5 mSv Nil 3–​5 mSv and the napkin-​ring sign (E Fig. 31.2). These distinctive plaque
Protocol time (min.) 15–​20 60 120–​180 characteristics reflect histopathological changes that are features
(scan time 30) of plaque vulnerability. Early studies utilizing CTCA confirmed a
Macrocalcification +++ ++ -​ close association between thin-​cap fibroatheroma detected inva-
Microcalcification -​ -​ +++ sively using IVUS and optical coherence tomography and typical
CTCA findings [24–​26]. Extensive observational data have dem-
Lipid core +++ +++ -​
onstrated the prognostic value of these findings with regards to
Positive remodelling +++ ++ -​
future acute coronary syndrome and plaque rupture events [27–​
Thrombus + ++ -​ 30]. Various thresholds and definitions have been studied. Low-​
Inflammation -​ -​ +++ attenuation plaque is accepted to include plaque <30 Hounsfield
units (HU), while positive remodelling, measured by dividing
the maximum vessel diameter by the reference vessel diameter, is
obtaining satisfactory image quality remains elevated heart rates, commonly defined as a remodelling index >1.1 [14]. Spotty cal-
while dense calcification or stents can result in blooming artefacts cification describes a pattern of plaque disease associated with
that reduce the ability to assess lumen calibre and plaque charac- other high-​risk features, first noted on IVUS where only small
teristics. Consequently, use of CTCA in the modern era still re- calcium deposits exist within a <90-​degree arc, and subsequently
lies on suitable patient selection and preparation. International described on CTCA [31–​33]. The napkin-​ring sign describes the
guidelines on the performance, acquisition, interpretation, and finding of a low-​attenuation plaque core with a rim of higher at-
reporting of CTCA scans have been established in an attempt to tenuation. This pattern of plaque is relatively uncommon but is
provide a standardized and reproducible method for real-​world also a particularly strong independent predictor of future acute
clinical practice—​particularly relevant given the escalating up- coronary syndromes, being additive to low-​attenuation plaque
take and integration of CTCA into clinical pathways [12–​14]. and positive remodelling [34, 35].
CTCA has been used predominantly to diagnose obstructive The prognostic value of combining anatomy and plaque char-
coronary artery disease in patients with suspected angina due acteristics has been investigated. It is being proposed that the
to its outstanding sensitivity, with CT identifying up to twice CTA-​verified high-​risk plaques are more likely to result in adverse
as many plaques as invasive coronary angiography [15] while events if they are significantly stenotic [29]. Importance of plaque
offering a negative predictive value in some cohorts of patients progression has also been demonstrated on the serial scans; the
without known coronary artery disease approaching 100% [16]. CT-​verified vulnerable plaques that undergo interval progression
Furthermore, CTCA compares favourably with IVUS, the refer- are at substantially higher risk of adverse events [29]. The CT-​
ence standard for many years, for the detection and quantification adapted Leaman score has been proposed, combining the simple
of atherosclerotic plaque [17, 18]. The spatial resolution of cur- parameters of plaque location (accounting for dominance), type
rent CTCA scanners now facilitates the non-​invasive assessment of plaque (calcified, non-​calcified or mixed), and degree of sten-
of plaque composition—​providing quite different information osis (<50% or ≥50%) to provide a total score for each patient. A
from assessments of luminal stenosis alone and potentially incre- cut-​off of >5 has been validated as an independent predictor of
mental prognostic information [19]. myocardial infarction and all-​cause mortality in retrospective
registry cohorts [36, 37].
Computed tomography coronary angiography: More recently, interest in the contribution of vascular and
vulnerable plaque characteristics systemic inflammation to atherosclerosis has been re-​ignited.
CTCA is able to visualize intramural and extramural plaque char- Investigators from the CRISP CT study have described a novel
acteristics in addition to luminal changes. The IVUS-​based high-​ marker of risk: the perivascular fat attenuation index [38].
risk plaque characteristics can be appropriately identified by the Signalling from inflamed coronary arteries diffuse to the perivas-
extent of tissue attenuation on CT angiography [20]. Plaques are cular adipose tissue and inhibit adipogenesis which results in a
broadly described as calcified, partially calcified, or non-​calcified change to a more aqueous composition (higher attenuation, i.e.
based on visual assessment of plaque attenuation compared to less negative HU). Using a threshold of –​70 HU, high attenuation
luminal blood pool and epicardial fat or connective tissue [20]. perivascular fat around the proximal left anterior descending ar-
Large-​scale, non-​randomized contemporary data have consist- tery and right coronary artery was a strong predictor of all-​cause
ently demonstrated the prognostic power of CTCA-​defined high-​ (hazard ratio [HR] 5.62, 95% confidence interval [CI] 2.90–​10.88)
risk plaque for predicting plaque rupture and acute coronary and cardiovascular (HR 3.69, 95% CI 2.26–​6.02) mortality. This
syndromes [21, 22]. Contemporary analyses with modern CT is of particular relevance given a recent randomized controlled
470 CHAPTER 31   N on - i nvasive imaging of t he vu l n er a b l e athero s cl eroti c  pl aqu e
Fig. 31.2  Computed tomography coronary angiography
plaque features. Hallmarks of vulnerable plaque on
computed tomography coronary angiography. (a) Positive
remodelling: a vessel diameter (longer line) >10% the mean
diameter of the segments proximal (shorter line) and distal
to the lesion. (b) Low-​attenuation plaque: <30 Hounsfield
units (arrow). (c) Spotty calcification: focal calcification <3
mm in maximum diameter (arrow). (d) Napkin ring sign:
central low-​attenuation plaque (arrow) with an enhancing
rim of high attenuation.
Reproduced from Williams MC, Moss AJ, Dweck M, et al. Coronary
Artery Plaque Characteristics Associated with Adverse Outcomes
in the SCOT-​HEART Study. J Am Coll Cardiol. 2019;73(3):291–​301.
doi:10.1016/​j.jacc.2018.10.066 (http://​creativecommons.org/​licenses/​
by/​4.0/​) with permission from Elsevier.
trial which demonstrated a reduction in cardiovascular events
with the interleukin-​1 beta inhibitor, canakinumab, highlighting
inflammation as a potential therapeutic target for cardiovascular
disease prevention [39].
Computed tomography coronary angiography:
evidence for clinical use
Although multiple studies have assessed CTCA in suspected
stable coronary heart disease, only two randomized controlled
trials large enough to assess outcomes have been published. The
Scottish Computed Tomography of the Heart (SCOT-​HEART)
trial (n = 4,146) compared CTCA to routine care in stable pa-
tients with suspected angina. The primary outcome was cer-
tainty of angina due to coronary artery disease at 6 weeks, while
a prespecified secondary analysis was death from coronary heart
disease or non-​fatal myocardial infarction at 5 years. Stress elec-
trocardiography was performed in 85% of all patients, with add-
itional stress imaging performed in 10% of the standard care arm
due to continuing diagnostic uncertainty. The trial met both out-
comes. CTCA improved diagnostic certainty and led to more ap-
propriate use of invasive angiography and preventative therapies
[40, 41]. At 5 years, the combined endpoint was reduced in the
CTCA arm (2.3% vs. 3.9%, HR 0.59, 95% CI 0.41–​0.84), prin-
cipally driven by a reduction in non-​fatal myocardial infarction
(2.1% vs. 3.5%, HR 0.60, 95% CI 0.41–​0.87) [42].
The Prospective Multicenter Imaging Study for Evaluation of
Chest Pain (PROMISE) trial (n = 10,003) compared CTCA with
functional testing in symptomatic outpatients without diagnosed
(a) (b)
(c) (d)
coronary artery disease in whom physicians believed non-​urgent,
non-​invasive testing for suspected coronary artery disease was
required [43]. The primary end point was death, myocardial
infarction (MI), hospitalization for unstable angina, or major
procedural complication. In the functional testing arm, 89.8%
underwent either nuclear stress imaging or stress echocardiog-
raphy. At a mean follow-​up of 25 months, there was no difference
in the primary outcome between groups (HR 1.04, 95% CI 0.83-​
1.29). However, at 12 months the risk of death or non-​fatal MI
was lower in the CTCA group (HR 0.66, 95% CI 0.44–​1.00). There
was also a reduction in the rate of normal coronary arteries or
non-​obstructive disease found on subsequent invasive coronary
angiography in the CTCA arm.
Subsequent analyses from both trials add further weight to the
prognostic value of CTCA assessment of vulnerable plaque. In
SCOT-​HEART, 608 (34%) patients had at least one adverse plaque
feature, the presence of which conferred a threefold higher risk of
coronary heart disease death or non-​fatal MI (HR 3.01, 95% CI
1.61–​5.63) [19]. This finding, however, was not independent of
the coronary artery calcium score. Indeed, in patients who under-
went CTCA and met the combined endpoint, approximately half
did not have obstructive coronary artery disease. This highlights
the importance of total disease burden and plaque characteris-
tics, rather than obstructive disease alone, as a prognostic marker
[44]. In PROMISE, 676 (15%) patients had high-​risk plaque
which again conferred a higher risk of major adverse events after
adjustment for significant stenoses and atherosclerotic cardiovas-
cular disease risk score (HR 1.72, 95% confidence interval [CI]

1.89–​3.93) [45]. Again, over a half of patients with major adverse
events had non-​obstructive coronary artery disease on the CTCA.
To date, there is no randomized controlled trial directly ad-
dressing the question of whether mandated intervention based on
CTCA findings improves patient outcomes, although preventa-
tive medications were recommended in SCOT-​HEART based on
CTCA findings. Observational data from the CONFIRM registry
demonstrated that in patients with suspected symptomatic cor-
onary artery disease, there was an association between reduced
mortality and revascularization in high-​risk disease—​obstructive
proximal disease or multivessel disease—​ when compared to
medical therapy (HR 0.31, 95% CI 0.18–​0.54) [46, 47]. These data
are subject to confounding but highlight the further need for ran-
domized controlled data.
Computed tomography: other methods of
plaque assessment
Coronary artery calcium scoring is a widely available technique
that is easily performed, requires no iodinated contrast, and util-
izes low doses of radiation (<1.5 mSv). Although only calcified
plaques are detected (lesions of at least 1 mm2 and >130 HU) and
other characteristics such as lesion severity and plaque morph-
ology cannot be assessed, coronary artery calcium scoring does
offer a reasonable approximation of total plaque burden. As such,
its use focuses on the identification of the vulnerable patient ra-
ther than the vulnerable plaque. A number of studies have dem-
onstrated the incremental prognostic value of coronary artery
calcium scoring when used in conjunction with clinical risk score
[48–​51]. In the absence of large-​scale randomized data, however,
coronary artery calcium scoring is not a routine risk stratifica-
tion tool, but rather an adjuvant technique of risk assessment in
selected patients.
The current era of interventional cardiology has seen a dra-
matic shift towards the use of coronary physiology in the car-
diac catheterization laboratory [52]. As a result, there has been
major interest in reproducing coronary physiologic assessments,
typically fractional flow reserve (FFR), with CTCA. While CT-​
FFR does not directly image vulnerable plaque, there does ap-
pear to be a correlation between the presence of high-​risk plaque
and ischaemia as defined by CT-​FFR [53–​56]. This needs fur-
ther prospective clinical study to determine whether it has
incremental value.
Computed tomography coronary angiography:
future directions
The available data confirm the clinical utility of standard CTCA
in patients with suspected angina. Indeed, the latest National
Institute of Health and Clinical Excellence Clinical Guideline
95 update on chest pain recommends CTCA as the first-​line in-
vestigation for the evaluation of stable patients with suspected
symptomatic coronary artery disease [57]. Although there are
robust data supporting the prognostic implications of high-​risk
plaque, future research is needed to examine the clinical applica-
tion of using CTCA to identify high-​risk plaque—​and high-​risk
Ca rdi ovas cu l a r m ag n eti c re s ona n c e 471
patients—​in clinical practice. There are no current data demon-
strating the added prognostic value of plaque morphology as-
sessment over and above total plaque burden [19, 44], which is
simpler and quicker to perform. Overall, the future of CTCA is
bright and presents an exciting field for future research, with the
potential to combine stenosis quantification, plaque quantifica-
tion, plaque characterization, and coronary physiology measure-
ments within a single non-​invasive modality.
Cardiovascular magnetic resonance
Improvements in scanner technology and software have led to
a surge in CMR use for a broad range of cardiovascular condi-
tions, supported by a robust and growing evidence base. The
multiparametric approach of CMR is unique in the field of
cross-​sectional cardiovascular imaging, providing a breadth of
information—​ for example, anatomy, function, perfusion, and
viability—​unmatched by any other single imaging modality. This
has driven the pursuit of CMR as a ‘one-​stop shop’ for cardio-
vascular assessment. A variety of protocols can be applied with
different pulse sequences to provide the requisite information.
Contrast agents, typically gadolinium-​based, are often adminis-
tered and allow interrogation of the extracellular matrix but are
not mandatory for other assessments such as myocardial na-
tive T1 and angiography. Plaque characterization is based upon
the plaque appearance and signal intensity on different contrast
weightings (e.g. T1-​weighted, T2-​weighted). Calcification, which
does not contain free water or triglycerides, appears dark on CMR
(c.f. atherosclerosis which contains a larger amount of free water).
Plaque composition—​such as fibrous or haemorrhagic tissue—​
will further affect the signal intensity, thus facilitating analysis.
However, magnetic resonance coronary angiography (MRCA)
and the assessment of plaque characteristics is a field that has yet
to establish a clear clinical role despite more than two decades of
research [58–​60].
Cardiovascular magnetic resonance:
advantages and disadvantages
MRCA has a number of advantages over CTCA.
The patient is not exposed to ionizing radiation. The coronary
artery lumen can be assessed even in the presence of heavy cal-
cification, while exogenous contrast agents are not mandatory
due to the high T2/​T1 ratio of blood during sequences such as
steady-​state free precession with appropriate fat-​saturation. There
are, however, several disadvantages. Compared to CT, scan times
are longer, while spatial and temporal resolution are inferior,
meaning that only sizeable proximal and mid-​vessel coronary ar-
tery segments can be readily visualized [61]. In addition, sensi-
tivity of MRCA for the detection and quantification of coronary
calcification and atheroma is poorer than CT. This is in contrast
to larger vessels such as the carotid artery where much of the prior
histological validation and clinical research has been focused. The
presence of metal material such as stents may preclude accurate
472 CHAPTER 31   N on - i nvasive imaging of t he vu l n er a b l e athero s cl eroti c  pl aqu e
image analysis due to imaging artefact. As a consequence, MRCA
is currently used in a limited clinical capacity only, largely for the
assessment of anomalous coronary arteries.
Cardiovascular magnetic resonance:
vulnerable plaque
One benefit of CMR that has maintained a research interest in
MRCA is its ability to characterize tissue and plaque, particu-
larly given the established association between adverse carotid
plaque features on MRI and future cerebrovascular events [62].
Small-​scale studies comparing CMR plaque visualization to
CTCA and invasive angiography [63] were followed by system-
atic evaluations of high-​intensity coronary artery plaque detected
by non-​contrast T1 weighted (black blood) imaging. This tech-
nique quantifies plaque-​to-​myocardium signal intensity ratio and
correlates with CTCA findings of positive remodelling and low
density, IVUS findings of positive remodelling and ultrasound at-
tenuation, and a slow-​flow phenomenon after intervention [64,
65]. Invasive angioscopy has also demonstrated higher rates of
thrombus in high-​ intensity plaques compared to non-​ high-​
intensity plaques [66]. Furthermore, it is possible to further dif-
ferentiate the region of high-​intensity signal which may provide
insight into the underlying pathology. Intramural high-​intensity
signal correlates with macrophage accumulation and the absence
of calcium, whereas intraluminal high-​intensity signal correlates
with thrombus and intimal vasculature on optical coherence tom-
ography [67]. In patients with stable angina or silent ischaemia
scheduled for percutaneous intervention, high-​intensity plaque is
associated with healed plaque rupture (odds ratio [OR] 9.32, 95%
CI 4.05–​22.71), and lipid-​rich plaque (OR 4.38, 95% CI 1.08–​
29.77) [68]. Intraplaque haemorrhage, another marker of plaque
vulnerability, has a robust body of data establishing its major role
as a determinant of carotid plaque instability [69], but has yet to
be confirmed as a main driver for high-​intensity coronary plaque.
The Coronary Atherosclerosis T1-​weighted CHaracterization
with integrated anatomical reference (CATCH) sequence was
developed to overcome the limitations associated with MRCA
and plaque characterization, such as low spatial resolution and
long scan times. CATCH provides 3-​dimensional whole-​heart
coverage, high spatial resolution and simultaneously acquired
T1-​weighted black blood images and anatomical reference im-
ages (E Fig. 31.3a–​b) [70]. Although this sequence is sup-
ported by histological validation of high-​ intensity plaque on
T1-​weighted imaging in the carotid artery due to methaemo-
globin in intraplaque haemorrhage [71, 72], a similar correl-
ation in the coronary artery has yet to be confirmed. Of interest,
the AQUAMARINE pilot study demonstrated a reduction in
plaque-​to-​myocardium signal intensity ratio after statin therapy
in patients with coronary artery disease, while the signal inten-
sity ratio in a retrospectively propensity-​matched control group
that did not receive statin therapy increased after 12 months
[73]. However, the mechanisms driving this reduction in high-​
intensity plaque in are not certain, although are likely to be due to
a reduction in lipid volume.
MRCA modalities focused on anatomical imaging may also
be fused with other imaging modalities such as PET, providing
hybrid imaging of vulnerable plaque (E Fig. 31.3c–​e), which will
be discussed next.
Cardiovascular magnetic resonance and
angiography: evidence for clinical use
Although multiple small studies have investigated the use of
MRCA for the identification of coronary artery disease, the diag-
nostic accuracy compared to invasive angiography is variable,
and best when limited to analysis of the proximal vessels [74].
CTCA consistently outperforms MRCA [75, 76]. There are few
data describing the clinical utility of coronary plaque character-
ization with MRI. A small study has reported a prognostic role
for high-​intensity plaque as an independent predictor of coronary
events [77], in keeping with carotid artery imaging and histology
studies [78]. Two studies have also demonstrated an association
with periprocedural myocardial injury after intervention [65, 79].
There is a clear need for further data exploring the impact of vul-
nerable plaque imaging using CMR and clinical outcomes.
Cardiovascular magnetic resonance: future
directions
Given the appealing advantages of magnetic resonance imaging,
ongoing research into the field remains at the frontier of cardio-
vascular imaging. Advances in scanner technology and software
have permitted the introduction of new sequences optimized for
the coronary artery, while targeted contrast agents, novel in both
their development and their target, are being developed.
Ultrasmall superparamagnetic iron oxide (USPIO) particles to
target inflammation, exploiting their uptake by macrophages and
powerful T2* effect which results in signal hypointensity of tis-
sues where there is active macrophage infiltration. Uptake is in-
creased in culprit carotid plaques post-​stroke and asymptomatic
carotid stenoses when compared to non-​culprit or healthy con-
trol vessels [80, 81]. Furthermore, similar to the high-​intensity
T1-​weighted coronary findings in the AQUAMARINE study,
treatment with statin therapy has been shown to reduce carotid
USPIO uptake [82]. The use of USPIOs in coronary arteries is yet
to be explored.
Elastin, which is abundant in the arterial media and increased
in atherosclerosis, is another novel imaging target, with elastin-​
specific contrast media showing promise in preclinical studies of
plaque progression and regression [83]. Tropoelastin, the soluble
precursor to elastin, demonstrates a high sensitivity and specifi-
city for identifying rupture-​prone plaque in animal models [84].
THI0567-​targeted liposomal-​Gd binds with high affinity to in-
tegrin α4β1agent, a key component in the recruitment of inflam-
matory cells to atherosclerotic plaque, with preclinical results
demonstrating enhancement in areas of macrophage and mono-
cyte accumulation [85].
Ultimately, despite the exciting potential of this field, MRCA
and vulnerable coronary plaque imaging using CMR currently
lacks the robust body of data that underpins the use of CTCA and
 P o si tron em i s si on to mo g r a ph y 473

(a) (b) (c)

(d) (e) (f)

Fig. 31.3  Magnetic resonance imaging and coronary plaque characterization. (a, b) Coronary Atherosclerosis T1-​weighted CHaracterization with integrated
anatomical reference (CATCH). Coronary angiography of a patient who presented late with a completed inferior myocardial infarction shows an occluded mid-​
right coronary artery (a, arrow). T1-​weighted magnetic resonance coronary angiogram shows a focal high-​intensity signal corresponding with the lesions (b,
arrow). Subsequent percutaneous intervention was successful (c), a large thrombus load was extracted.
(c, d) Non-​contrast ECG-​gated image-​navigator (iNAV)-​based motion-​corrected proprietary sequence with 100% respiratory scan efficiency combined with 18F-​
sodium fluoride positron emission tomography [118]. Invasive angiography demonstrated a culprit proximal left anterior descending artery lesion in a patient
with an acute coronary syndrome (d, arrow). PET-​MR demonstrated focal 18F-​sodium fluoride uptake in the lesion, co-​registered with magnetic resonance
angiography (d and e, arrows).

nuclear imaging, and as such the modality resides largely within
the realm of research.
Positron emission tomography
PET is a molecular nuclear imaging technique that utilizes tar-
geted probes bound to radioactive isotopes. After intravenous
injection of the tracer, the radioisotope distributes to different tis-
sues according to the carrier molecule and emits a positron which
collides with a free electron, resulting in annihilation of both par-
ticles and the emission of two photons in opposing directions.
These photons strike the encircling detector and are identified
as coincident events, providing electronic collimation. Although
PET has been studied since the 1950s [86], coronary imaging has
long been beyond the capabilities of PET due to limitations of
spatial resolution, partial volumizing effects, and cardiac motion.
The development of hybrid PET-​CT and PET-​MR imaging has
led to a major interest in non-​invasive molecular imaging of ath-
erosclerosis due to the ability to co-​register the PET signal with
gated, high-​resolution anatomical CT or MR images. Although
still early in its development, the prospect of clinical coronary
PET imaging is now taking shape, potentially providing a unique
molecular insight into coronary pathology that is unavailable
with any other imaging modality.
In principle, PET is able to measure the activity of any patho-
logical process, depending on the availability of a targeted
radiotracer. The radiotracer may be developed using a bespoke
design specifically targeting a critical key step in the process of
interest—​for example, glucose metabolism in malignant cells with
high metabolic activity. Radiotracers have largely been developed
for cancer tracking but given the decades of histopathologic re-
search into the atherosclerosis, there is a strong basis for mo-
lecular imaging of the vulnerable plaque. Coronary PET imaging
research has largely focused on 18F-​fluorodeoxyglucose (18F-​FDG)
and 18F-​sodium fluoride (18F-​NaF), although other novel and se-
lectively targeted tracers are under investigation.
Positron emission tomography:
18
F-​fluorodeoxyglucose
Inflammation is a key component of atherosclerosis plaque pro-
gression and rupture. 18F-​FDG is a glucose analogue that has a
predilection for tissues with high metabolic activity due to uptake
474 CHAPTER 31   N on - i nvasive imaging of t he vu l n er a b l e athero s cl eroti c  pl aqu e
by the glucose transporter protein system. 18F-​FDG is converted
to 18F-​FDG-​6-​phosphate within cells and this metabolite cannot
undergo glycolysis, leading to intracellular accumulation. First
used clinically in 1976 to assess glucose metabolism in the brain,
18
F-​FDG is widely used in oncology and was first applied clinic-
ally for atherosclerosis imaging in the carotid artery in 2002 [87].
Subsequently a number of studies have demonstrated 18F-​FDG
uptake in a variety of vascular beds, including the coronary ar-
teries, and shown correlation with the presence of atherosclerosis,
as well as general cardiovascular risk factors, the Framingham
Risk Score, and biomarkers of inflammation [88]. Features of
plaque vulnerability in carotid and femoral vessels correlate with
18
F-​FDG uptake [89, 90]. Recent retrospective data in asymptom-
atic patients without coronary artery disease undergoing 18F-​FDG
PET-​CT for other reasons demonstrated an independent asso-
ciation between aortic 18F-​FDG PET signal and coronary heart
disease events, over and above the Framingham Risk Score [91],
while a prospective study in patients with stable angina or MI
demonstrated that the presence and extent of MI was associated
with increased aortic inflammation [92].
The main limitation with 18F-​FDG imaging of coronary plaque
is its avid myocardial uptake due to high glucose transport in
cardiomyocytes. While this provides an excellent assessment of
myocardial viability, the signal from adjacent coronary plaque
is obscured. This limitation has yet to be overcome consist-
ently, despite patient preparation with a very low-​carbohydrate,
high-​fat diet on the preceding day, followed by an overnight fast
(exploiting the switching of the myocytes to free fatty acid me-
tabolism when glucose availability is limited). Small studies have
examined the role of 18F-​FDG in coronary imaging [93–​96] with
varying success. Thus, 18F-​FDG has not seen a significant uptake
for detailed assessment of coronary plaque.
Positron emission tomography: 18F-​sodium
fluoride
The current understanding of calcification in plaque goes be-
yond the association between macrocalcification and cardio-
vascular events, incorporating the concept of pathogenic, active
calcium microprecipitation in the early stages of atherosclerosis
[97]. Microcalcification is thought to represent an early adaptive
response to local cell necrosis and inflammation. In contrast to
large, macroscopic deposits of calcium that stabilize plaque and
may reduce the potential for future rupture—​leading to stable
atherosclerotic plaques—​ it has also been hypothesized that
microcalcification within a thin fibrous cap acts to destabilize the
plaque and increase the chance of rupture [98]. Hydroxyapatite is
a key component in the early stage of vascular microcalcification.
18
F-​NaF is a radiotracer that has seen extensive use in oncology
for the detection of bony metastases for over 40 years and has
recently become a radiopharmaceutical of interest in cardiovas-
cular imaging [99, 100]. It binds avidly to hydroxyapatite and was
subsequently noted to accumulate in areas of arterial wall plaque.
Derlin et al. first raised the potential for using 18F-​NaF PET-​
CT to identify arterial plaque by retrospectively co-​localizing
regions of uptake with CT evidence of calcification that were
distinct from 18F-​FDG uptake [101]. These findings were sup-
ported by prospective studies in the arterial vasculature [102,
103]. Subsequent research demonstrated excellent interobserver
repeatability of coronary arterial 18F-​NaF imaging and a strong
correlation with atherosclerosis and coronary calcium score
[104], while histological validation in carotid plaque rupture con-
firmed an association between 18F-​NaF uptake and active calci-
fication, macrophage infiltration, apoptosis, and necrosis [96].
Interestingly, in the former study [104], 41% of patients with cal-
cium score >1,000 Agatston units demonstrated no 18F-​NaF up-
take. A proposed mechanism relates to the preferential binding
of 18F-​NaF to regions of active microcalcification and calcium
metabolism where the surface area of hydroxyapatite is high
[100], in contrast to areas of established macrocalcification where
the available surface area is low. The latter occurs in established
plaques that are stabilized by a thick cap of macrocalcification,
in keeping with the hypothesis that 18F-​NaF activity is associated
with vulnerable, rather than quiescent, atherosclerotic plaque.
The first clinical study to examine the role of 18F-​NaF in iden-
tifying ruptured and high-​risk coronary plaque demonstrated
higher tissue-​to-​background ratios in culprit lesions (median
1.66 [interquartile range (IQR) 1.40–​2.25] vs. 1.24 [IQR 1.06–​
1.38]) [96] (E Fig. 31.4). In stable patients, lesions with higher
tissue-​to-​background ratio were associated with a higher remod-
elling index, more microcalcification, and a higher prevalence of
necrotic cores on IVUS. These findings were supported by a sub-
sequent study of patients with ST-​elevation MI, utilizing 18F-​NaF
PET-​CT after an initial PET-​MR scan [105]. A recent prospective
study also showed that the presence of high-​risk plaque as as-
sessed by CTCA predicted higher 18F-​NaF tissue-​to-​background
ratios [106]. Similar clinical associations have been demonstrated
between high-​ risk/​ruptured carotid plaque and neurological
events [107], as well as abdominal aortic aneurysm growth rate
and future repair or rupture [108]. The largest multicentre ob-
servational trial of 18F-​NaF is currently underway, examining the
prognostic significance of 18F-​NaF as a marker of plaque vulner-
ability in patients with recent MI (NCT02278211).
Positron emission tomography: other
radiotracers
At present, 18F-​NaF is the most developed radiotracer for vulner-
able plaque imaging, with a number of studies optimizing the ac-
quisition and reproducibility of 18F-​NaF PET-​CT imaging of the
coronary arteries [109–​111]. However, multiple other radiotracers
have been investigated for use in atherosclerosis imaging, targeting
inflammation and macrophage activation (68Ga-​ DOTATATE,
18
F-​fluorocholine, 11C-​PK11195), apoptosis (Annexin V), hyp-
oxia (18F-​fluoromisonidazole), and angiogenesis (18F-​fluciclatide)
[112, 113]. Of these tracers, only 68Ga-​DOTATATE has been
tested clinically with regards to coronary plaque imaging. This
radiotracer binds to somatostatin receptor subtype 2 on the sur-
face of activated proinflammatory M1 macrophages, with recent
clinical data demonstrating superior differentiation between
 C on c lusi on s 475

(a) (b) (c)

(d) (e) (f)

Fig. 31.4  18F-​sodium fluoride and 18F-​fluorodeoxyglucose uptake in patients with myocardial infarction and stable angina.
Top row: Patient with acute ST-​segment elevation myocardial infarction with proximal occlusion (a, red arrow) of the left anterior descending artery on invasive
coronary angiography and intense focal 18F-​NaF uptake at the culprit plaque (b, red arrow) on PET-​CT, with no corresponding 18F-​FDG uptake (c, red arrow).
There is 18F-​FDG myocardial uptake overlapping the coronary artery (yellow arrow) and also uptake within the oesophagus (blue arrow).
Bottom row: Patient with anterior non-​ST-​segment elevation myocardial infarction with culprit (d, red arrow; left anterior descending artery) and bystander non-​
culprit (d, white arrow; circumflex artery) lesions on invasive coronary angiography that were both stented. Only the culprit lesion had increased 18F-​NaF uptake
on PET-​CT (e) after percutaneous coronary intervention. Corresponding 18F-​FDG PET-​CT (f) showing no uptake in either lesion. There is intense 18F-​FDG uptake
within the ascending aorta.
NaF = sodium fluoride; FDG = fluorodeoxyglucose; PET-​CT = positron emission tomography-​computed tomography.
Reproduced from Joshi NV, Vesey AT, Williams MC, Shah AS, Calvert PA, Craighead FH, et al. 18F-​fluoride positron emission tomography for identification of ruptured and high-​risk
coronary atherosclerotic plaques: a prospective clinical trial. Lancet. 2014;383(9918):705–​13 (https://​creativecommons.org/​licenses/​by/​3.0/​) with permission from Elsevier.

culprit and non-​culprit coronary plaque and also high-​risk and
lower-​risk coronary lesions compared to 18F-​FDG [114]. Finally,
an alternative target is the activated platelet, with the novel 18F-​
GP1 tracer demonstrating promise in identification of venous
and arterial thromboembolic disease [115, 116].
Further investigation of these and other novel radiotracers is
required before comment on their clinical utility can be made,
but the future of molecular imaging of vulnerable plaque appears
promising.
Conclusions
After decades of research, imaging the vulnerable coronary
plaque and identifying vulnerable patients remains an area of
intense interest. With advances in technology and the advent
of sophisticated and novel imaging techniques, the potential
for precise and comprehensive lesion-​and patient-​b ased as-
sessments is greater than ever. Ultimately, although the prog-
nostic significance of vulnerable plaque is well described, no
non-​invasive imaging modality of plaque morphology assess-
ment has demonstrated incremental prognostic value beyond
total plaque burden. The true benchmark for any imaging
modality is the ability to improve outcomes through the iden-
tification of patients that require preventative therapies. To
date, conventional CTCA remains the only imaging modality
that has demonstrated clinical benefit in a randomized con-
trolled trial; non-​invasive vulnerable plaque imaging is yet to
develop a robust body of evidence supporting routine clinical
application.
476 CHAPTER 31   N on - i nvasive imaging of t he vu l n er a b l e athero s cl eroti c  pl aqu e
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Contents
Summary  481
Introduction  481
Anatomy and pathophysiology of coronary
microcirculation  482
Assessment of microvascular physiology
and dysfunction  482
Coronary flow reserve  482
Microvascular spasm  484
Type 1 dysfunction  484
Type 2 dysfunction  487
Type 3 dysfunction  488
Type 4 dysfunction  488
Future perspectives  490
Conclusion  490
CHAPTER 32
Imaging of microvascular
disease
Paolo G. Camici and Ornella Rimoldi
Summary
In the past two decades it has become evident that in several clinical conditions either
abnormal structure or impairments in the function of the coronary microcirculation or
their combination may interfere with the control of myocardial blood flow and contribute
to the pathogenesis of myocardial ischaemia. In this chapter we discuss the different non-​
invasive imaging techniques that can be used to assess coronary microvascular dysfunc-
tion, their respective benefits, disadvantages, and prognostic significance.
Introduction
The clinical observation that inadequate perfusion and ‘unmistakable’ anginal symptoms
could occur in the absence of detectable stenosis of the epicardial coronary arteries dates
back to the sixties when selective coronary angiography became available [1]‌. Twenty
years later Cannon and Epstein proposed the term microvascular angina to categorize
patients with normal coronary arteriograms and evidence of myocardial ischaemia
caused by dysfunction of the coronary microvasculature. The epicardial arteries are the
proximal segment of the coronary circulation, however, the largest volume of blood in
the coronary arterial system resides in the microcirculation.
The paradigm of obstructive coronary artery disease (CAD) as the main source of
symptoms in chronic stable angina and acute coronary syndromes (ACS) has guided
diagnostic strategies for the past 50 years. Only more recently, in the 2013 ESC guidelines
[2]‌, it was recognized that abnormalities in microvascular and endothelial function con-
tribute to ischaemia, predominantly in women.
Coronary microvascular dysfunction (CMD) occurs also in many cardiomyop-
athies: primary and secondary left ventricular hypertrophy and dilated cardiomyop-
athy. Patients who, after successful percutaneous or surgical revascularization, report
persistence of symptoms and evidence of demand ischaemia, could find a possible ex-
planation in CMD.
Over the decades, measurement technologies have been refined to allow understanding
of regulation of coronary blood flow and relentless effort has been made to improve both
the spatial and temporal resolution of imaging techniques in the clinical setting.
In the experimental setting, intravital microscopy of the subepicardial microcircula-
tion in isolated heart with multiphoton microscopy allows visualization of the coronary
microcirculation. The spatial resolution of the most advanced computed tomography
(CT) angiography scanner is 230 μm, and therefore, imaging of the microcirculation in
482 CHAPTER 32   Im aging of microvascu l ar di sease
vivo in humans is not feasible. CMD, independently of the under-
lying mechanism, results in the impairment of the mechanisms
regulating normal coronary physiology. This will, eventually, im-
pair the ability of the circulation to match myocardial perfusion
to changes in myocardial oxygen demand. Thus, the study of the
microcirculation in humans is based on its functional aspects.
Anatomy and pathophysiology of
coronary microcirculation
The coronary microcirculation comprises three compartments,
small arteries, arterioles, and capillaries, with different functions
and regulatory mechanisms and whose anatomic borders cannot
be clearly delineated in vivo (E Fig. 32.1). Intramyocardial
small arteries have more than three layers of smooth muscle in
the media compared to arterioles that have one to three smooth
muscle layers. The segments of the microcirculation show dif-
ferent histological features: (1) wall/​ lumen ratio is inversely
proportional to luminal diameter (0.04 in large epicardial ar-
teries and 0.13 in arterioles); (2) amount of collagen in the tu-
nica media, small arteries and arterioles have the least; (3) quality
and density of autonomic innervation; arterioles lack parasympa-
thetic (vasodilatory) innervation [3]‌. Intramyocardial arterioles,
the site responsible for autoregulatory adjustments of coronary
resistance, more than by their diameter, are classified according
to their function (E Fig. 32.1). Each segment is governed by
distinct regulatory mechanisms: shear stress, changes in driving
pressure (myogenic regulation), metabolites (E Fig. 32.1) [4].
The arteriolar vasodilator response to increases in work of con-
tracting myocytes during exercise is driven by changes in muscle
metabolism, myogenic control, and endothelial-​based control
(shear stress) [4, 5].
Under resting conditions, oxygen extraction from the arterial
blood is close to 70%, and therefore a rise in myocardial oxygen
demand can only be met by an appropriate increase in coronary
blood flow (CBF). Myocardial ischaemia ensues when myocar-
dial metabolic demands are not met by a parallel increase of CBF.
Impairment of blood supply is due to anatomic and/​or functional
abnormalities in all and each of the segments of the coronary cir-
culation. Extravascular factors, such as decreased diastolic time
and elevated interstitial pressure hampering vasomotion of the
microcirculation, can also contribute to the development of myo-
cardial ischaemia [4]‌.
Myocardial ischaemia, equivalent to an obstructive epicardial
stenosis, despite apparently normal coronary arteriograms, can
be caused by CMD limiting the increase of CBF in response to
an increased myocardial oxygen demand [6]‌or by microvascular
spasm [7].
The pathogenic mechanisms of CMD are listed in E Table
32.1. The individual weight of these mechanisms can vary be-
tween different clinical pictures, although several of them may
coexist in the same condition.
Increase of wall/​lumen ratio due to smooth muscle hyper-
trophy and increased collagen deposition, with variable degrees
of intimal thickening and perivascular fibrosis have been consist-
ently documented in patients with hypertrophic cardiomyopathy
(HCM) and those with arterial hypertension or heart failure with
preserved ejection fraction (HFpEF) [8–​10]. A common feature
in patients with systemic hypertension and those with HCM is
the diffuse nature of microvascular remodelling, which is ex-
tended to the whole left ventricle [11]. Structural alterations of
intramural coronary arterioles have been demonstrated in other
myocardial diseases including amyloidosis [12]. CMD may re-
sult from a combination of disrupted functional mechanisms
leading to either impaired dilatation or increased constriction
of the microvessels (E Fig. 32.2). Impaired vasodilatation may
be due to abnormalities in endothelium-​dependent mechanisms
(diabetes, obesity, smoking, hypercholesterolemia) as well as to
endothelial-​independent mechanisms (nitrate resistance due to
reduced production of cyclic guanosine monophosphate) [13].
Coronary constriction limited to the microvasculature may con-
tribute to myocardial ischaemia in the absence of changes in the
diameter of epicardial coronary arteries. Capillaries and venules
are a substantial component of the coronary microcirculation,
and both can undergo structural and functional abnormalities
(i.e. capillary rarefaction in left ventricular (LV) hypertrophy or
microembolization during revascularization procedures) which
can contribute to the development of myocardial ischaemia.
Assessment of microvascular
physiology and dysfunction
Coronary flow reserve
In the clinical setting, microvascular function can only be as-
sessed indirectly through measurements of coronary (i.e. volu-
metric flow, ml/​min) or myocardial (i.e. tissue perfusion, ml/​min
per gram of tissue) blood flow (MBF) and coronary flow reserve
(CFR, the ratio of hyperaemic to baseline blood flow) in response
to different vasoactive stimuli. CFR is an integrated measure of
flow through both the large epicardial arteries and the microcir-
culation. In the absence of lesions on the conduit epicardial ar-
teries, a reduced CFR is an established marker of CMD [4, 14, 15].
The co-​existence of obstructive disease, both focal and diffuse, of
the epicardial arteries and CMD is a common finding in clinical
practice and discrimination between the effects and interaction of
these two components on myocardial perfusion is challenging and
requires multimodality imaging. CFR reduction in patients with
CMD usually is diffuse and does not follow the territory of dis-
tribution of the main coronary arteries as seen in patients with
obstructive CAD. The functional response of the microcircula-
tion can be influenced by several factors such as: increased heart
rate and reduced diastolic time, driving blood pressure and LV
inotropism which need to be accounted for when assessing micro-
vascular function [16, 17]. CFR is a simple and powerful index,
 Assessm en t of m i crovas cu l a r physi ol o g y a n d dysf un c t i on 483

(a) Epicardium
Type III Type I Type II
Epicardial artery

Transmural artery

Microcirculation

Intramyocardial
pressure Endocardium

Papillary muscles
Trabeculae

LV cavity

(b) MICROCIRCULATION

metabolites

ΔQ ΔP

epicardial arteries small arteries large arterioles arterioles

>500 μm <500150 μm <15080 μm <80 μm

100

Autoregulation
Shear
Neuro-humoral
Metabolic
MICROCIRCULATION
% of Total resistance

Myogenic

Shear
Neuro-humoral Myogenic
Metabolic Metabolic
Myogenic Neuro- Metabolic
humoral Myogenic
Shear Neuro-humoral
0 Shear
Aorta 500 μm 150 μm 100 μm Capillaries

Fig. 32.1  (a) Branching patterns of the epicardial coronary arteries: type 1 multiple early intramural branches, type 2 directed to the subendocardium and
papillary muscles. Type 3 short branches that supply mainly the subepicardial myocardium. Transition to microcirculation corresponds to a diameter of <500
μm. On the left progressive increase of intramyocardial pressure from the epicardium to the subendocardium.
(b) Small arteries are more responsive to shear stress and flow-​dependent dilatation. Large arterioles’ diameter changes in response to intravascular pressure and
are the main site of autoregulation. Arterioles are mainly responsible for the metabolic regulation; they vasodilate in response to an increase of concentration of
metabolites. Small arteries account for 20% and arterioles for 40% of vascular resistance.
Q = coronary blood flow; P = coronary pressure.
Reproduced from Chronic Coronary Artery Disease Eds. James de Lemos and Torbjørn Omland; Chapter 5. Elsevier 2017 ISBN: 9780323428804 with permission from Elsevier.
484 CHAPTER 32   Im aging of microvascu l ar di sease
Table 32.1  Classification of coronary microvascular dysfunction
Type Clinical setting
1 Coronary microvascular dysfunction in Risk factors
the absence of myocardial diseases and Microvascular angina
obstructive CAD
2 Myocardial or heart valve disease in the Hypertrophic and dilated cardiomyopathy
absence of obstructive CAD Anderson–​Fabry’s disease, amyloidosis
myocarditis, aortic stenosis
3 In patients with concomitant obstructive Stable angina
CAD Acute coronary syndrome
4 Iatrogenic Following PCI, CABG, and heart transplant
Abbreviations: CAD = coronary artery diseases; SMC = smooth muscle cells; PCI = percutaneous coronary intervention; CABG = coronary artery bypass graft; CMD = coronary
microvascular dysfunction.
but it cannot fully depict the complex interactions among the
various segments of the coronary circulation. Resting flow, hyper-
aemic flow, and haemodynamic conditions during the scanning
session, all contribute to defining the full range of pathophysio-
logical changes. CFR is a ratio, thus factors that influence either
the numerator or the denominator may affect its calculation (E
Fig. 32.3). A low CFR value does not necessarily reflect a reduction
of hyperaemic flow, but it can be due to an abnormally elevated
resting flow in the face of a normal hyperaemic flow. Similarly, a
normal CFR can be misleading as it can result from a significant
reduction in both resting and hyperaemic flow. This problem can
be overcome, at least in part, by normalizing resting flow for the
external cardiac workload, which is generally estimated using the
rate–​pressure product. Although a single cut-​off value of CFR
(e.g. ≤2.5) below which microvascular function is deemed ab-
normal is generally accepted clinically, it must be pointed out that,
in normal humans, CFR varies according to age and gender [18,
19]. Therefore, it is essential to compare CFR data in patients with
those obtained in age-​and sex-​matched normal subjects.
Angina can be caused by subendocardial hypoperfusion during
effort or vasodilator stress. In the absence of lesions in epicardial
arteries, a region with a slightly reduced hyperaemic flow and
CFR in parallel with symptoms and electrocardiographic (ECG)
changes can raise the suspicion of subendocardial ischaemia [15].
A correct measurement of CFR requires abolition of coronary
vasomotor tone and maximal vasodilatation. Intravenous admin-
istration of endothelium-​independent vasodilators (adenosine, di-
pyridamole, regadenoson) induce near-​maximal vasodilatation. The
relatively short half-​life of these compounds and rapid regression of
the side effects make these stressors practical and safe allowing, if
necessary, repetition of the test during the same session [20].
Under certain circumstances, maximum MBF measured during
vasodilator stress can be more informative than CFR. In fact, it has
been demonstrated that in patients with primitive cardiomyop-
athies the severity of impairment of MBF measured during dipyr-
idamole stress is superior to CFR to assess the severity of CMD and
predicting major adverse cardiac events at follow-​up [21].
Cold pressure testing (CPT) has been used in combin-
ation with positron emission tomography (PET) to assess
Mechanisms of CMD
Endothelial dysfunction, vascular SMC dysfunction,
vascular remodelling, and capillary rarefaction
As in type 1, plus compression by increased
Intramyocardial pressure or oedema, reduced
diastolic perfusion, perivascular fibrosis
Endothelial dysfunction, vascular SMC dysfunction,
microembolization, extramural compression
Reperfusion injury, microembolization, and
transplant vasculopathy
endothelium-​dependent coronary vasodilator function [22, 23].
CPT is performed immersing one hand of the patient in iced
water for 90–​120 seconds. The pain generated by cold stimulation
increases blood pressure and heart rate, which, in turn, induce
flow-​mediated dilatation. CPT can be used to unmask abnormal-
ities of endothelial function when pharmacological vasodilata-
tion is still preserved [22].
Microvascular spasm
Patients with non-​obstructive CAD and symptoms may have a
normal CFR. In the presence of risk factors including positive
family history for CAD, diabetes, dyslipidaemia, hypertension
and smoking the possibility of microvascular spasm has to be
ruled out [6]‌. Intracoronary injection of acetylcholine at incre-
mental doses over a period of 3 min each, is considered the gold
standard for the assessment of endothelial function and coronary
spasm [24]. Spasm may involve both the epicardial arteries and
microcirculation. Therefore, in order to diagnose microvascular
spasm in isolation, the response to ACh should be carefully ana-
lysed to exclude epicardial spasm. The development of symptoms
and ischaemic ECG changes, in the absence of epicardial spasm,
is indicative of CMD due to microvascular spasm. In patients
with non-​diagnostic acetylcholine-​test, results for microvascular
spasm, transient metabolic alterations, coronary sinus lactate
production, or low oxygen saturation can equally suggest CMD.
Standardized drug administration protocol and experienced op-
erators guarantee the safety of the test [25]. In patients with an-
gina undergoing acetylcholine testing, Ong et al. showed that ≈1
out of 4 patients had microvascular spasm. Myocardial perfusion
abnormalities can be associated with abnormal myocardial con-
tractility and less frequently with elevation of high-​sensitivity car-
diac troponin concentrations [26].
Type 1 dysfunction
Type 1 hallmarks are structural or functional alterations of the cor-
onary microvasculature [16]. Adverse remodelling of intramural
coronary arterioles results from smooth muscle hypertrophy and
 T y pe 1 dysf un c t i on 485

CORONARY MICROCIRCULATION

Arteriole
Capillaries

FUNCTIONAL MECHANISMS
STRUCTURAL MECHANISMS
Adverse arteriolar remodeling Microvascular spasm

• Increased medial wall thickness

• Intimal thickening
• Reduced wall/lumen ratio
Intravascular plugging
Perivascular fibrosis Abnormal vasodilation

Capillary rarefaction

Microvessel
unable to dilate
Endothelial dysfunction
MYOCARDIAL FACTORS AFFECTING and/or VSMC dysfunction
MICROVASCULAR FUNCTION
Occlusive CAD
Left ventricular hypertrophy
Reduced diastolic time
Calcium overload
Amyloidosis
Coronary spasm Increased intramyocardial pressure
Increased intracavitary pressure
Tissue oedema

Fig. 32.2  The role of coronary microvascular dysfunction in the pathogenesis of ischaemic heart disease. Ischaemia can result from several mechanisms,
including obstructive atheromatous plaques in the epicardial coronary arteries, coronary artery spasm, and coronary microvascular dysfunction (CMD).
CMD can lead to myocardial ischaemia by impairing the ability of the coronary circulation to increase coronary blood flow in response to an increased
myocardial oxygen demand. CMD can result from an abnormal vasodilator response of the microvasculature, adverse remodelling of the vessel wall, increased
intramyocardial pressure compressing the intramural microvessels, or microvascular spasm. The adverse remodelling of intramural coronary arterioles is
characterized by medial wall thickening, mainly owing to smooth muscle hypertrophy and increased collagen deposition, with variable degrees of intimal
thickening. Coronary microvascular dysfunction can result from a variable combination of abnormal vasodilatation (both endothelium-​dependent and
endothelium-​independent mechanisms) and undue vasoconstriction.
VSMC = vascular smooth muscle cell.
Reproduced from Kaski JC, Crea F, Gersh BJ, Camici PG. Reappraisal of Ischemic Heart Disease. Circulation. 2018;138(14):1463–​80. doi:10.1161/​CIRCULATIONAHA.118.031373 with
permission from Wolters Kluwer.

increased collagen deposition, with variable degrees of intimal
thickening and a reduced wall/​lumen ratio. Adverse remodelling
of the microcirculation leads to progressive reductions in CFR;
at variance with flow-​limiting lesions of the epicardial arteries,
the impairment of CFR is not limited to the distribution terri-
tories of the main coronary arteries rather appearing as patchy,
or diffuse, to the whole left ventricle. Impairment of CFR due
to endothelium-​dependent mechanisms is frequently associated
with diabetes mellitus, obesity, smoking, and other cardiovas-
cular risk factors), endothelial-​independent mechanisms, or both
[10, 22, 27–​29]. Inflammation is an important cause of CMD in
chronic inflammatory rheumatic diseases: rheumatoid arthritis,
486 CHAPTER 32   Im aging of microvascu l ar di sease
• Age
• Scar/Fibrosis
• Drugs
• Caffeine
•
•
Scar/Fibrosis
Drugs
• Vessel anatomic
Fig. 32.3  Factors affecting myocardial remodelling
blood flow (MBF) and coronary flow reserve
• Increased vascular tone
(CFR). The same CFR value can result either
• Increased extravascular
from low resting MBF and blunted increase compression/resistance
in hyperaemic MBF during vasodilator
• Endothelial dysfunction
stress or increased resting MBF and normal
• Systemic inflammation
hyperaemic flow.
systemic lupus erythematosus, and systemic sclerosis. CMD con-
tributes to the development of myocardial ischaemia and adverse
cardiovascular events in the absence of epicardial lesions [30].
The feasibility of transthoracic Doppler echocardiography
(TTDE) on the left anterior descending coronary artery is high,
reaching more than 90% with an experienced operator [31], and
nearly 100% with the use of intravenous contrast agents [32].
The performance is less satisfactory in the posterior descending
and the circumflex arteries due to inherent anatomical and tech-
nical limitations including the poor resolution of the lateral wall
[33]. While TTDE is low cost and highly feasible, intra-​and
interobserver variability is still a concern, particularly when per-
forming sequential recordings to assess disease progression or ef-
fects of therapy [34, 35].
PET is at present the gold standard to assess type 1 micro-
vascular dysfunction as it can interrogate the whole left ventricle
providing absolute MBF (ml/​min/​g) and CFR. The procedures
have been refined over the past 20 years and provide accurate
and reproducible quantification of regional MBF in humans [17,
36, 37]. The precision and test–​retest variability of quantitative
myocardial perfusion have been well validated and there are ex-
tensive data in normal volunteers for various tracers [17, 38–​40].
Absence of CAD can be confirmed in the same session by the
simultaneous acquisition of CT coronary angiography (CCTA)
with hybrid CT/​PET scanners [41].
CMD develops in parallel with the increasing severity of glu-
cose intolerance and a blunted hyperaemic flow in response to
vasodilators has been documented in patients with diabetes [42]
and metabolic syndrome [43]. More recently, Murthy et al. dem-
onstrated that assessment of CFR can provide an incremental risk
stratification. Diabetic patients without CAD with a CFR below
1.6 have event rates comparable to those of patients with prior
CAD, conversely diabetics with preserved CFR have event rates
comparable to non-​diabetics [44].
Reductions of hyperaemic blood flow and CFR have been re-
ported in asymptomatic subjects with dyslipidaemia [45, 46] or
obesity [47, 48]. Smoking releases free radicals and pro-​oxidant
factors damaging the endothelium [49]. These detrimental ef-
fects, which cause a reduction of CFR, have to be taken into con-
sideration when studying apparently healthy individuals who are
• Increased oxygen
Rest Rest consumption
MBF = 0.45 MBF = 1.5 • Gender
• Anaemia
Stress Stress
MBF = 1.12 MBF = 3.75
CFR = 2.5
heavy smokers [50–​52]. Using a co-​twin control design in an ele-
gant study Rooks et al. [53] measured CFR: the smoking twin had
a higher resting MBF and a lower hyperaemic MBF compared to
the non-​smoker twin.
The impairment of CFR in systemic hypertension can be due to
both higher resting and/​or reduced hyperaemic MBF [54]. The in-
crease of resting MBF could be explained by the increased oxygen
demand due to high systolic blood pressure. The reduction of
vasodilator response is caused by a number of factors, mainly if
left ventricular hypertrophy is present [9]; among these the re-
modelling of the arteriolar wall, high intracavitary pressure, func-
tional capillary rarefaction and reduced lusitropic function [55].
In addition, in severe long lasting hypertension, chronic kidney
disease increases circulating angiogenesis and NO inhibitors
damaging cardiac endothelial cells and promoting endothelial to
mesenchymal transition, thus resulting in increased cardiac inter-
stitial fibrosis and capillary rarefaction [56]. Cardiac mortality
in patients with impaired vasodilatation in the absence of overt
evidence of myocardial ischaemia was 5.9% vs. 1.1% per year for
those with relatively preserved CFR, thus adding incremental car-
diovascular risk in patients with renal impairment [57].
Cardiovascular magnetic resonance (CMR) [4, 58] has a great
potential to investigate large populations with risk factors in com-
bination with tissue characterization. The possibility to detect
subendocardial scar, which can be a determinant of a reduced CFR,
scarcely recognized with other imaging techniques, is an advan-
tage of this rapidly evolving technique. Reproducibility has been
tested in normal subjects with satisfactory results [59], although,
to date, few quantitative studies have been carried out in patients
with type 1 microvascular dysfunction. The multiethnic study of
atherosclerosis (MESA) reported the results of fully quantitative
myocardial perfusion and CFR in 222 subjects [60]. CFR ranged
from 1.18 to 5.24 and was significantly lower among male par-
ticipants, the elderly, and those with concomitant hypertension,
fasting hyperglycaemia, higher total, and low-​density lipopro-
tein (LDL) cholesterol. Hyperaemic MBF and CFR were inversely
associated with the predicted absolute cardiovascular risk, esti-
mated from the Framingham equation. The use of stress CMR
perfusion could prove particularly useful in women. A cohort of
a hundred women with symptoms of myocardial ischaemia and
 T y pe 2 dysf un c t i on 487

no obstructive CAD has been studied in the NHLBI-​sponsored
WISE study (Women’s Ischaemia Syndrome Evaluation). Semi-​
quantitative MBF assessment was predictive of adverse events in
the presence of risk factors [61]. This study hints at the predictive
value of globally reduced perfusion in combination with multiple
cardiovascular risk factors in women. Liu et al. have proposed a
new technique, without gadolinium contrast medium for detec-
tion of CMD [62]. Myocardial territories downstream obstructed
epicardial arteries showed elevated resting T1 relaxation times,
which remained virtually unchanged during adenosine stress. By
contrast, myocardial territories with CMD defined invasively by
an invasive index of microvascular resistance value ≥25, down-
stream coronary arteries with lesions < 50%, had normal resting
T1, and a blunted, but detectable stress T1 response compared
with normal.
Type 2 dysfunction
Type 2 dysfunction encompasses primitive and secondary disease
of the myocardium as well as valve abnormalities. In heart failure
with preserved ejection fraction (HFpEF), similarly to hyperten-
sion, several factors contribute to CMD including (E Fig. 32.4):
coexisting cardiovascular risk factors, endothelial dysfunction,
vascular smooth muscle cell hyperactivity to vasoconstrictor
stimuli, a systemic pro-​inflammatory state, vascular remodelling,
and fibrosis, vascular rarefaction, and increased extravascular
pressure due to increased myocardial interstitial fibrosis and stiff-
ness [10, 63]. PET investigations with 82Rb confirmed a reduction
of CFR in HFpEF that was more pronounced than in hypertensive
controls as well as normotensive controls, both without symptoms
of heart failure [64]. Taqueti et al. reported that in symptomatic
patients without flow-​limiting epicardial CAD, impaired CFR was
associated with diastolic dysfunction and Major Cardiovascular
Adverse Events (MACE) including HFpEF hospitalization. A
global CFR<2 was associated with impaired diastolic function (E/​
e’ >15), and a fivefold increase of adjusted risk for HFpEF hospi-
talization [65]. At present, there are no large studies with CMR to
investigate CMD in HFpEF. Overall, these findings suggest that
CMD has a central role in the development of the ‘clinical pheno-
type’ of HFpEF which shares many features with that of older pa-
tients with coronary microvascular dysfunctions (E Fig. 32.4)
[66, 67]. The multicentre, prospective study PROMIS, measured
left anterior descending artery (LAD) Doppler flow signals and
CFR together with reactive hyperaemic change in digital blood
flow after arm occlusion in HFpEF patients. The authors found
that CMD was highly prevalent (75%) in HFpEF patients and was
associated with NTproBNP levels, systemic endothelial dysfunc-
tion, and cardiac dysfunction [68].
The abnormal structure of intramural coronary arteries, with
markedly thickened wall and narrowed lumen, plays a causal role
in inducing diffuse impairment of coronary microvascular func-
tion and ischaemia in patients with hypertrophic cardiomyopathy
(HCM). CMD in HCM patients has been extensively studied
using different imaging techniques [9, 69–​72]. SPECT imaging
has shown fixed and/​or reversible defects and stress-​induced
transient cavity dilatation, suggestive of diffuse subendocardial
ischaemia [71]. SPECT imaging is widely available although it
provides only a semi-​quantitative evaluation of relative changes
in perfusion and cannot be used to quantify absolute MBF. Severe
impairment of microvascular function and myocardial fibrosis
are significantly more prevalent among HCM patients with sarco-
mere gene mutations, compared to those who are genotype-​
negative [70, 71]. PET studies have highlighted that resting MBF
is comparable with normal control subjects, whereas hyperaemic
blood flow is significantly blunted, often <2 ml/​min/​g, reflecting
an inability to match increased demand. Flow abnormalities are
more pronounced in the subendocardium [73] and usually hyper-
aemic flow is lower in the hypertrophied ventricular septum, al-
though, a blunted vasodilator response can be present in the
non-​hypertrophied portions of the LV wall leading in the long
term to adverse LV remodelling and systolic dysfunction [70].

Cardiovascular risk factors:

Endothelial
Hypertension
dysfunction
Obesity
Diffuse non obstructive
Diabetes
atherosclerotic lesions
Insulin resistance

CMD
Oxidative
stress Fig. 32.4  Cardiovascular risk factors induce systemic
ISCHAEMIA
ROS inflammation, evident from elevated plasma levels
NO of inflammatory biomarkers. Chronic inflammation
affects several organs: kidney, skeletal muscle, lungs,
HFpEF myocardium. Myocardial remodelling and dysfunction
begin with microvascular endothelial dysfunction.
Mytochondrial dysfunction Inflammation results in presence of reactive oxygen
Systemic inflammation
Interstitial Fibrosis species (ROS) and reduced nitric oxide (NO)
Multiorgan involvement
LV RV hypertrophy availability favouring CMD.
Decreased O2 availability
Impaired diastolic function CMD = coronary microvascular disease; HFpEF = heart failure
with preserved ejection fraction.
488 CHAPTER 32   Im aging of microvascu l ar di sease
These observations taken together suggest a primary and diffuse
impairment of coronary microvascular function in HCM [73–​75]
which has been demonstrated to be an independent predictor of
cardiac death in the long term [69].
CMR studies investigating both quantitative perfusion and
tissue injury with late gadolinium enhancement reported marked
hypoperfusion in the subendocardial layer without tissue in-
jury [72]. In patients with severe microvascular dysfunction [76]
hyperaemic flow fell significantly from resting values; the mean
stress MBF of these patients was 1.05 ml/​g/​min which is in line
with the value previously reported by Cecchi et al. as the threshold
best predictive of future risk [69].
In aortic stenosis CMD [77, 78] is mainly due to increased
intramyocardial pressure caused by raised extravascular com-
pressive forces without vascular remodelling. The demand of
the hypertrophied myocardium was met by an increased base-
line MBF in a PET study [77]. Conversely, CFR was severely re-
duced both in the subepicardium and the subendocardium and
was inversely correlated with valve orifice area and diastolic time
[77]. Similar results were reported 15 years later with CMR and
semi-​quantitative myocardial perfusion reserve index (MPRI).
Interestingly among the patients with severe aortic stenosis,
MPRI was much lower in patients complaining of angina than in
the asymptomatic group [79].
In the past few years imaging techniques gained a central role
in the quantitative assessment of microvascular dysfunction in
patients suffering from infiltrative cardiomyopathies [80]. Using
contrast echocardiography, stress-​induced wall motion abnormal-
ities can be elicited in absence of obstructive CAD [81]. Dorbala
and colleagues [82] using 13NH3 quantified MBF, CFR, and min-
imal coronary vascular resistance in a cohort of symptomatic
patients with amyloidosis who showed significantly reduced
MBF both at rest and during hyperaemia with a lower CFR, irre-
spective of the LV mass or amyloidosis subtype. In Fabry’s disease
globotriaosylceramide deposits are diffuse to both cardiac tissue
and vasculature resulting in significant reduction of hyperaemic
MBF and CFR [83]. Tomberli et al. [84] investigated the role of
gender and LV hypertrophy with 13NH3 and observed a mean 60%
reduction in hyperaemic MBF, irrespective of LV hypertrophy,
gender, and phenotype. In sarcoidosis the effects of inflammatory
cytokines, TNF-​α and oxidative species contribute to endothelium-​
mediated functional CMD [85]. The loss of vasodilatory capacity
is diffuse and can precede the myocardial structural alterations,
and it could be envisaged as a warning of the lethal progression of
the cardiac involvement and a prognostic factor [86].
Type 3 dysfunction
CMD often coexists with epicardial CAD, causing or aggravating
myocardial ischaemia and providing additional prognostic value
[87]. The coexistence of CMD with diffuse or focal atheroscler-
osis in affected patients is nowadays supported by considerable
evidence derived from both invasive [88, 89] and non-​invasive
imaging studies [15, 90, 91, 92].
In the past few years the concept of ischaemia (INOCA) and
myocardial infarction (MINOCA) with non-​obstructive lesions
(i.e. stenosis <50% luminal diameter) of the epicardial coronary
arteries has gained attention, these patients show evidence of is-
chaemia and/​or reduced CFR at PET [27, 92, 93]. Modern imaging
tools can identify the co-​existence of non-​obstructive epicardial
lesions combined with CMD. A combined invasive and non-​
invasive assessment can provide a more accurate characterization
of the composition of the plaques in comparison with coronary
angiography. Intravascular ultrasound, optical coherence tomog-
raphy, or computed tomography angiography together with global
and segmental CFR can encompass the entire spectrum of dif-
ferent severity of atherosclerosis and CMD and the relative clinical
risk of their combination as proposed by Taqueti and Di Carli [14].
Notwithstanding the fact that women and men are equally
likely to have CMD as a manifestation of preclinical coronary ath-
erosclerosis [92], the assessment of epicardial arteries and micro-
circulatory function is particularly relevant in women who have
less incidence of overt CAD and in whom adverse prognosis is
more dependent on severely impaired CFR than presence of ob-
structive epicardial lesions [94].
It is not uncommon to find a reduced CFR in regions sub-
tended by arteries with a flow-​limiting stenosis and in re-
mote regions subtended by non-​diseased arteries suggesting
that CMD and CAD can both contribute to the development
of ischaemia in the same patient. The crucial role of CMD in
patients with CAD has been demonstrated by PET studies
showing that the inclusion of CFR in risk prediction models
resulted in net re-​classification of risk of major adverse events
at follow-​up [91, 95]. Taqueti et al. [90] by means of myocar-
dial perfusion PET and invasive coronary angiography, showed
that global CFR was only weakly associated with the extent and
severity of angiographic lesions. Conversely, a low CFR was
strongly and independently associated with MACE and pa-
tients with a low CFR appeared to have a superior benefit from
surgical revascularization. Similar conclusions were drawn
in 4,313 patients with known or suspected CAD, assessed by
TTDE. In this cohort a CFR ≤2 and inducible wall motion ab-
normalities on stress echocardiography were independent pre-
dictors of mortality [96].
The role of CMR in stable CAD is at present limited to the de-
tection of ischaemia [28, 97], measurement of CFR is technically
feasible but has not yet impacted on clinical practice [29, 98].
Computed tomography myocardial perfusion (CTP) has the
potential to improve the diagnostic accuracy of CTCA [99], a
pilot study has demonstrated that CT attenuation density has a
fair correlation with PET MBF. CT perfusion could identify sig-
nificant CAD as defined by fractional flow reserve (FFR) with a
radiation dose a total CT protocol of 8.98 mSv [100].
Type 4 dysfunction
Myocardial reperfusion in STEMI may be followed by CMD as
a consequence of endothelial swelling, microvascular spasm,
 T y pe 4 dysf un c t i on 489

Anginal symptoms and myocardial ischaemia (stress ECG, SPECT, echo, cardiac MRI)

Coronary angiogram (Invasive or CCTA) showing

normal coronary arteries or non obstructive CAD

Assess non-invasively CFR

CFR < 2.5 CFR ≥ 2.5

Microvascular angina Invasive Acetylcholine test

No or <90% diameter reduction >90% diameter reduction

No reduction of diameter
Symptoms
Ischaemic ECG changes
No symptoms Symptoms
No ECG changes Ischaemic ECG changes
Lactate production

Consider false positive

Epicardial coronary
Microvascular spasm test for ischaemia
Investigate other causes artery spasm

Fig. 32.5  Algorithm to diagnose microvascular angina and microvascular spasm in patients with angina and documented myocardial ischaemia. Once the
patients have had a coronary angiogram showing no obstructive coronary artery disease, the task for the specialist imager is to document whether these
subjects have a reduced coronary flow reserve and possibly to identify functional and structural mechanisms that can be responsible for coronary microvascular
dysfunction and myocardial ischaemia.
CFR = coronary flow reserve; CCTA = coronary computed tomography angiography.

external compression, and distal embolization by thrombus debris
resulting in coronary microvascular obstruction (MVO) [101],
thus preventing complete reperfusion of the ischaemic region, i.e.
the no reflow phenomenon [102]. CMR is the elective technique
to detect MVO [103, 104], late gadolinium enhancement (LGE)
allows volumetric quantification of MVO, which can be assessed
within a few minutes after contrast administration. Areas of MVO
will appear as a hypointense area within the hyperintense infarcted
myocardium. CMR-​MVO has been reported to be an independent
predictor of clinical outcome, alone or adjusted for other factors
such as infarct size and LVEF [105–​107]. More recently, an insight
into the relationship between microvascular function and severity
of ischaemic injury has been provided by a CMR study quanti-
fying resting MBF, LGE, and MVO. Acutely after reperfusion and
at 6 months, resting MBF corrected for the rate pressure product
was strongly associated with the extent of LGE [108].
Persistent angina after PCI can affect ≈20% to 50% of patients
at 1-​year follow-​up [109], however, when the revascularization
procedure is guided by fractional flow reserve the rate of residual
chest pain after PCI is significantly lower [110]. The mechan-
isms of angina after a successful PCI involves both structural
and functional mechanisms. Structural causes include in-​stent
restenosis, stent thrombosis, progression of atherosclerotic dis-
ease in other epicardial arteries, diffuse non-​obstructive lesions.
Vasomotor abnormalities of epicardial coronary arteries or CMD
can cause functional impairment. CMD has been demonstrated
post PCI both invasively, with ACh test [24], and non-​invasively
with TTDE where CFR was significantly reduced at 6-​month
follow-​up only in patients with myocardial ischaemia on exercise
stress testing [111].
Cardiac allograft vasculopathy (CAV) is a major cause of death
5 years after heart transplant. Endothelial dysfunction, resulting
from inflammatory injury, predisposes to thrombosis, undue
vasoconstriction, and vascular smooth muscle proliferation. At
variance with atherosclerosis, the whole length of the coronary
vessels is usually affected and, in some patients, only the small
intramyocardial branches are involved [112]. Non-​invasive per-
fusion assessment for post-​heart transplant CAV surveillance
could reduce the need for invasive angiography and represent a
surrogate marker for adverse clinical outcomes in the absence of
angiographically evident CAV. PET assessments of myocardial
perfusion in transplanted patients found that decreased global
490 CHAPTER 32   Im aging of microvascu l ar di sease
CFR was the most significant predictor of MACE and correlated
with the severity of CAV as assessed with coronary angiography
[113–​116]. Blunting of MPRI and diastolic strain rates were ob-
served at CMR and were associated with histological evidence
of reduced microvessel lumen to wall thickness ratio and capil-
lary rarefaction [117]. The absence of radiation makes CMR and
TTDE [118] the techniques of choice in children.
Future perspectives
E Figure 32.5 is a proposal for a diagnostic flowchart for the diag-
nosis of microvascular angina. It is foreseeable that in the future
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 SECTION 6

Heart failure

33 Evaluation of systolic LV function and LV mechanics  497

Rainer Hoffmann and Frank A. Flachskampf
34 Evaluation of left ventricular diastolic function  507
Bogdan A. Popescu, Carmen C. Beladan, and Maurizio Galderisi†
35 Imaging of the right heart  519
Lawrence Rudski, Petros Nihoyannopoulos, and Sarah Blissett
36 Assessment of viability  545
Luc A. Pierard, Paola Gargiulo, Pasquale Perrone-​Filardi, Bernhard Gerber, and
Joseph B. Selvanayagam
37 Imaging cardiac innervation  565
Albert Flotats and Ignasi Carrió
38 Cardiac resynchronization therapy: Selection of candidates  577
Victoria Delgado and Jens-​Uwe Voigt
39 Cardiac resynchronization therapy: Optimization and follow-​up  587
Marta Sitges and Erwan Donal
40 Echocardiography evaluation in extracorporeal support  599
Susanna Price and Alessia Gambaro
41 Cardiac imaging in cardio-​oncology  613
Riccardo Asteggiano, Patrizio Lancellotti, Maurizio Galderisi†, Stephane Ederhy, and Marie Moonen

Contents
Summary  497
Introduction  497
Parameters of systolic function  498
Imaging for diagnosis, guidance of treatment,
and follow-​up in heart failure  502
Comparison of strengths and weaknesses of
different modalities and techniques  503
CHAPTER 33
Evaluation of systolic LV
function and LV mechanics
Rainer Hoffmann and Frank A. Flachskampf
Summary
Analysis of systolic left ventricular (LV) function is the most frequent indication to per-
form echocardiography and an integral part of cardiac magnetic resonance (CMR) or
radionuclide studies. Visual estimation of LV function may be supplemented by quan-
titative analysis of two-​dimensional (2D) images to obtain parameters of global func-
tion. Contrast administration has been demonstrated to enhance the reproducibility of
2D echocardiography based analysis of LV function and should be applied in cases of
impaired endocardial border definition. 2D echocardiography of the left ventricle re-
sults in underestimation of end-​systolic and end-​diastolic LV volumes compared to
CMR. Three-​dimensional (3D) echocardiography is associated with significantly less LV
volume underestimation and a high accuracy in the analysis of ejection fraction. Analysis
of regional LV function is mainly based on subjective visual assessment, which is limited
by significant interobserver variability. Tissue Doppler and speckle-​tracking echocardi-
ography have become validated methods for quantitative analysis of global and regional
LV function. Similarly, tagging, SENC, and feature tracking are modalities to quantify
regional LV function based on CMR.
Echocardiography should be used as primary technique to assess systolic LV function
as it is cheapest, widely available, and can be applied without the use of ionizing radi-
ation or nephrotoxic contrast material. CMR has become the gold standard technique for
quantification of LV function and may be applied if other information achievable best by
CMR is required. Similarly, nuclear techniques should be applied to assess LV function
only if simultaneous assessment of myocardial perfusion is requested.
Introduction
Chronic heart failure has developed into a major cause for hospitalization and mortality.
The severity of LV systolic dysfunction is a strong predictor of clinical outcome for a
wide range of cardiovascular diseases. Thus, the analysis of global LV function allows
prediction of clinical outcome and is a major driver of treatment decisions. Different
imaging modalities allow analysis of global as well as regional LV function in clinical
practice. Analysis of systolic LV function and its potential impairment is the most fre-
quent indication to perform echocardiography and an integral part of CMR or radio-
nuclide studies. This chapter describes the commonly evaluated parameters to describe
global and regional LV function, describes currently applied imaging modalities, specific
498 CHAPTER 33   Evaluat ion of systolic LV f u n cti on a n d LV m echa n i cs
Table 33.1  Normal values of the left ventricle
Women Men
LV diastol. diameter (cm) 3.8–​5.2 4.2–​5.8
LV systol. diameter (cm) 2.2–​3.5 2.5–​4.0
LV diastol. volume (ml) 46–​106 62–​150
2 2D echocardiography volumes should be determined using the
LV diastol. volume/​BSA (ml/​m ) 29–​61 34–​74
LV systol. volume (ml) 14–​42 21–​61
LV systol. volume/​BSA (ml/​m2) 8–​24 11–​31
Ejection fraction (%) 54–​74 52–​72
indications for the analysis of systolic function in clinical practice
and provides an assessment of advantages and disadvantages of
the different imaging modalities.
Parameters of systolic function
Systolic LV function may be characterized by a number of param-
eters. Usually, what is meant is ‘pump function’ which is typic-
ally measured by ejection fraction or stroke volume. Note that
these parameters are heavily dependent on preload and afterload
of the left ventricle, as well as myocardial contractility. This is
also true for not volume-​based parameters such as longitudinal
strain and strain rate, tissue velocities, and apico-​basal displace-
ment of the annular plane. Truly load-​independent parameters
of pure myocardial contractility do not exist in the clinical arena.
Volumes and pump function may be evaluated based on 2D or
3D imaging techniques. Considering echocardiographic imaging,
visual assessment of global and regional contraction is the basis
of LV function analysis. It may be supplemented by quantita-
tive analysis of volume changes during the cardiac cycle. Using
2D imaging, LV function is evaluated best from multiple tomo-
graphic planes, typically including parasternal long-​axis, para-
sternal short-​axis, apical four-​chamber, apical two-​chamber, and
apical long-​axis views. Systole for these purposes is defined as
the interval of the cardiac cycle lasting from mitral valve closure
(end diastole, the time point of largest LV volume) to aortic valve
closure (end systole, the time point of smallest LV volume). Left
ventricular diameters as well as ejection fraction and related vol-
umes are the parameters normally determined to describe global
systolic LV function.
LV dimensions and volumes
The normal shape of the left ventricle is that of a truncated el-
lipsoid with two short axes of similar length and a long axis from
base to apex. Analysis of left ventricular dimensions should con-
sider gender and body surface area of the patient [1]‌. E Table
33.1 displays normal values for LV diameters, volumes and func-
tion determined by 2D echocardiography as given in the ASE/​
EACVI recommendations 2015 [1].
Global systolic function
The classic parameter of global systolic function is the ejection
fraction (EF), calculated from the end-​diastolic (LVEDV) and
end-​systolic (LVESV) volumes of the left ventricle (EF = [LVEDV –​
LVESV]/​LVEDV). It relates the mechanical output of the left
LV in systole, the stroke volume, to the maximal volume at end
diastole. The volumes provide clues to increased LV preload (in-
creased end-​diastolic volume) as well as increased afterload or im-
paired myocardial contractility (increased end-​systolic volume).
modified Simpson´s rule applied monoplane on the apical four-​
chamber view or biplane on the apical four-​and two-​chamber
view. Typical difficulties in the analysis of these parameters using
2D echocardiography relate to a foreshortening of the apical
views as the true apex is not visualized. This results in underesti-
mation of systolic and diastolic volumes, while the analysis of EF
is less affected. 3D echocardiography has been shown to result
in significantly less underestimation of LV volumes and high ac-
curacy in the analysis of EF compared to measurements obtained
by magnetic resonance imaging [2]‌. Another difficulty of current
2D echocardiographic techniques is insufficient endocardial con-
tour definition, in particular using apical views, resulting in inac-
curacies with regard to analysis of LV volumes. Administration
of contrast agents may improve the accuracy in the analysis of
volumes and EF [3].
Doppler echocardiography allows determination of global LV
systolic function based on the calculation of stroke volume and
cardiac output. Using Doppler and 2D echo data, stroke volume
is calculated as cross-​sectional area (CSA) of flow times the
velocity-​time integral (VTI) of flow through that area: SV = CSA
× VTI. However, the method is limited by potential inaccuracies
related to the multiple measurements required to calculate the
stroke volume.
Myocardial deformation analysis provides further param-
eters of global LV function. As different points of the deformable
myocardium move at different velocities, this results in de-
formation. Strain is the ratio of the difference between the final
length (L) and the initial length (L0) to that of the initial length
(L–​L0/​L0), in percent. For more details, see the corresponding
section in this book. Echocardiographic myocardial deformation
imaging from apical views is used to define the global longitu-
dinal strain (GLS). It describes the relative length change of the
LV myocardium between end diastole and end systole (MLs-​
MLd/​MLd) and is a parameter of global LV function. This par-
ameter is obtained by speckle-​tracking analysis using the three
standard apical views thus accounting for function within all LV
segments. The GLS is recommended as a reliable and reprodu-
cible index of global LV systolic function in the ASE/​EACVI
2015 guidelines [1]‌. GLS correlates modestly with LV EF, but
represents different information and may be abnormal in con-
ditions with a preserved EF, for example in aortic stenosis or
amyloidosis, where LV hypertrophy leads to small ventricular
volumes, preserving EF in spite of a small generated stroke
volume and typically heavily impaired longitudinal (apico-​basal)
systolic contraction. Importantly, GLS seems to provide better
discrimination of prognosis when LV function is only mildly re-
duced. As a consequence, it is able to detect small decrements of
LV function which are not identifiable by EF, thus providing a

more sensitive tool to detect incipient, often subclinical LV dys-
function at early stages of diseases [4].
A peak GLS in the range of approximately –​20% can be ex-
pected in a healthy person. A GLS ≥–​12% was found to be equiva-
lent to an EF ≤35% for the prediction of prognosis. However, the
addition of GLS to clinical variables caused a greater increment in
prognostic power for mortality than left ventricular ejection frac-
tion (LVEF) in a study on 546 patients [5]‌. GLS is recommended
for follow-​up studies in oncology patients on chemotherapy to
detect early and discrete changes in systolic LV function. Changes
in GLS have been reported to predict subsequent decrease in
LVEF. A relative reduction of GLS of >15% relative percent, i.e. for
example a decrease from 20 to 16%, from baseline is considered
abnormal and a marker of early LV subclinical dysfunction [6].
Note, these are relative percentages, i.e. a decrease of GLS from
20% to 16% would be a >15 (relative) % decrease. Increasingly,
GLS is also used in valvular heart disease to characterize incipient
myocardial depression in patients with preserved EF, for example
in left-​sided regurgitant lesions and in aortic stenosis.
A further unique characteristic of GLS is that it reflects to a de-
gree also diastolic function and is decreased, often quite substan-
tially in patients with heart failure with preserved EF [7, 8]. In these
patients, GLS is inversely associated with impaired prognosis.
Although regional strain measurements are currently not re-
commended for assessing regional systolic LV function, such
measurements can be helpful to corroborate or refute visual ana-
lysis. In some instances, subtle changes may be demonstrable on
strain analysis which are not detectable by visual analysis, for
example post-​systolic shortening, which is regional longitudinal
myocardial shortening occurring after aortic valve closure. While
a minor degree of post-​systolic shortening can occur in normal
segments, values >20% of the total shortening indicate myocar-
dial disease, for example ischaemia or scar formation. Normal
values for regional strain measurements have not been estab-
lished, not least due to the known manufacturer-​dependency of
such measurements [1]‌.
Myocardial deformation imaging is normally performed con-
sidering the ventricular wall as having only one layer. In addition,
a layer specific deformation imaging has been proposed. This re-
lates to the understanding that there are different LV myocardial
layers which contribute to LV deformation and function. There
is right-​handed helical myofiber geometry in the subendocardial
region which gradually changes into a left-​ handed helical
myofiber geometry in the subepicardium. This might lead to
more pronounced longitudinal strain in the endocardial layer and
more pronounced circumferential strain in the epicardial layer.
Analysis tools which allow assessment of strain for three different
layers within the myocardium from the endocardium to epicar-
dium have become available. Within a segment, higher strains
are usually recorded from the subendocardium than from the
subepicardium. It has been proposed that a layer specific analysis
may be of interest in cases with endocardial ischaemia or necrosis
such as in ischaemic heart disease affecting only the endocardial
layer as the most vulnerable and most sensitive layer of myocar-
dial disease. However, whether echocardiographic resolution is
I n t roduc t i on 499
high enough to allow a reasonable assessment of strain in three
different layers and if these have indeed separable functional
characterics has been debated.
The helical structure of the heart muscle results in a wringing
motion during the cardiac cycle, with counterclockwise rotation
of the apex and clockwise rotation of the base during ejection
considering the LV long axis, when evaluated from the apical
perspective. Myocardial twist as the consequence of opposing
apical and basal rotation occurs during systole while myocardial
untwist occurs during diastole and contributes to diastolic func-
tion. Myocardial deformation imaging allows the measurement
of myocardial rotation over time at the different levels of the left
ventricle from base to apex as well as the analysis of the twisting
and untwisting mechanics [9]‌. However, standards for measuring
and interpreting rotation, torsion, and twist are lacking.
2D speckle-​tracking imaging has the intrinsic limitation of 2D
imaging, in particular the foreshortening of the LV which affects
the accuracy of quantification. Furthermore, speckles may not re-
main within the 2D imaging plane and the assumption that they
can be tracked throughout the cardiac cycle may not always be
valid considering the complex 3D motion of the heart. 3D speckle-​
tracking echocardiography, which allows speckle-​tracking within
3D data sets has become available [10]. It has been shown to allow
LV volume measurements [11]. While lower frame rates are a sig-
nificant limitation of 3D image acquisition, the ability to analyse
the entire LV from a single volume of data obtained from one
transducer position is a significant advantage.
Regional systolic function
Regional function abnormalities are most frequently due to cor-
onary artery disease causing either myocardial infarction, acute
ischaemia, myocardial stunning, or hibernation. Dilated cardio-
myopathy and myocarditis are less frequent causes. The ventricle
is divided into segments for the assessment of regional LV func-
tion. To allow standardized communication between imaging
modalities, the left ventricle is commonly evaluated considering
a 17-​ segment model. In this 17-​ segment model, which is re-
commended for assessment of myocardial perfusion, the apex
is divided into five segments, a septal, inferior, lateral, and an-
terior segment as well as an ‘apical cap’, which is defined as the
myocardium beyond the end of the LV cavity. A 16-​ segment
model without the ‘apical cap’ as well as an 18-​segment model are
also used. Note that the ‘apical cap’, which has no border with the
LV cavity, is a convention derived from nuclear imaging which in
echocardiography has no real counterpart. The 16-​segment model
is recommended for echocardiographic wall motion analysis
(E Fig. 33.1), because endocardial excursion and thickening of the
tip of the apex are imperceptible. Regional systolic function is char-
acterized by wall thickening and endocardial inward motion with
the focus on wall thickening. In clinical practice regional function
is evaluated visually considering the following qualitative score:
◆ Normokinesia: normal thickening and normal inward motion
◆ Hypokinesia: reduced but not absent thickening and inward
motion
500 CHAPTER 33   Evaluat ion of systolic LV f u n cti on a n d LV m echa n i cs

Anteroseptal
segment mid basal

Posterior mid basal

segment

apical apical
apical apical
mid mid
mid
mid basal
basal
basal basal

Fig. 33.1  Sixteen-​segment model of the left ventricle according to Septal Lateral Inferior Anterior
the American Society of Echocardiography. The perfusion areas of segment segment segment segment
the LAD (left anterior descending artery) and the joint territory of
the RCA (right coronary artery) and LCX (left circumflex artery) are LAD LCx RCA
indicated.

◆ Akinesia: absent thickening and inward motion speckles are tracked from image to image thereby allowing the de-
◆ Dyskinesia: systolic outward motion of the ventricular wall termination of tissue movement vectors (E Fig. 33.3). Tracking
of two different speckles allows the determination of strain be-
Visually assessed regional LV systolic function can be semi-​
tween the two myocardial speckle points. Deformation parameters
quantified by the wall motion score index, which is often used
obtained from speckle-​tracking echocardiography are less affected
in stress echocardiography. For this dimensionless number,
by these limitations. Radial, circumferential as well as longitudinal
wall motion in each segment is assigned a number (score): 1 for
strain parameters can be derived (E Fig. 33.4). However, strain and
normokinesia, 2 for hypokinesia, 3 for akinesia, 4 for dyskinesia,
strain rate data obtained by speckle-​tracking echocardiography may
and 0 for ‘not seen’. The sum of all scores, divided by the number
be affected by artefacts and noise, in particular in case of impaired
of segments (typically, a 16-​segment model is used) gives the wall
image quality. Furthermore, there is considerable intervendor
motion score index, which is 1 in a completely normally con-
measurement variability. Thus, although definitions for a common
tracting ventricle and becomes numerically larger if regional wall
standard for 2D speckle-​tracking echocardiography have been for-
motion abnormalities are present.
mulated in a consensus document of the EACVI/​ASE/​Industry Task
Visual qualitative analysis of regional function on native 2D
Force [15], no reference values for GLS or regional strain data have
echocardiography has been found to be observer dependent with
currently been defined.
only moderate to fair interobserver agreement. A special dif-
Tagging, SENC, and the recently introduced feature tracking
ficulty relates to segments with poor visibility in which there is
are modalities to quantify regional LV function based on CMR.
pronounced insecurity of the observers on the correct analysis of
Feature tracking is an image post-​processing technique similar,
function. Application of left heart contrast agents enhances visi-
but not identical to echocardiographic speckle-​tracking which al-
bility of endocardial systolic motion and thereby improves ac-
lows to estimate longitudinal (e.g., GLS) and other strains.
curacy of function analysis as well as agreement between different
An additional indication for regional function analysis has
observers on regional function analysis [12] (E Fig. 33.2). Due
been the definition of dyssynchrony in LV function affecting in
to its superb image quality CMR is known to allow high quality
particular patients with significantly impaired LV function and
assessment of LV function; however, quality is significantly im-
left bundle branch block. For this purpose, myocardial strain
paired in the presence of arrhythmia, e.g. atrial fibrillation.
or velocity curves obtained by deformation imaging or regional
Several approaches for quantification of regional and global
volume curves either from three apical views using 2D echo
myocardial systolic function have been suggested. Myocardial
imaging or by 3D echocardiography are compared between dif-
deformation imaging based either on (I) tissue Doppler velocity
ferent LV segments.
analysis or on (II) speckle tracking within 2D or 3D echocardio-
grams are currently the preferred modalities for quantification using
Other derived indexes of systolic function
echocardiography [13, 14] (E Fig. 33.3). Tissue Doppler analysis
obtained from an apical view allows definition of peak systolic vel- In addition to conventional parameters to describe global LV
ocities in the longitudinal direction. These velocities are echo angle function several other indexes have been suggested recently:
dependent, increase from apex to base and are affected by myocar- ◆ The longitudinal shortening of the left ventricle contributes
dial tethering. In speckle-​tracking echocardiography myocardial significantly to the ejection. Mitral annular plane systolic
 I n t roduc t i on 501

OnR vs. OffR1/2 OffR1 vs 2 OnR vs. OffR1/2 OffR1 vs. 2 OnR vs. OffR1/2 OffR1 vs 2 OnR vs. OffR1/2 OffR1 vs 2
Kappa

1.0

0.8

0.6

0.4

0.2

0.0
0.41 0.56 0.43 0.77 Mean
(0.300.52) (0.450.66) (0.280.58) (0.690.85) Kappa-Value
(95% Cl)

Fig. 33.2  Interobserver agreement between three readers on cineventriculography, magnetic resonance imaging, echocardiography without and with contrast
enhancement.

excursion (MAPSE) which measures the lateral mitral annular
movement toward the apex during LV systole is a surrogate of
the left ventricular longitudinal function. A high correlation
between the long-​axis amplitude of the mitral annulus mo-
tion determined in apical views and the EF has been shown.
This parameter is measurable in nearly all patients regardless
of image quality, making it attractive for a rough assessment of
global function.
◆
of LV contractility (normal >1,000 mmHg/​s). To determine this
parameter the time interval between a regurgitant velocity of
1 m/​s (equivalent to a ventriculoatrial pressure difference of 4
mmHg) and 3 m/​s (equivalent to a ventriculoatrial pressure dif-
ference of 36 mmHg) is defined (E Fig. 33.5). Although theor-
etically attractive, this parameter has many shortcomings and is
rarely used in clinical practice.
The myocardial performance index (MPI or Tei-​index) pro-

◆ Based on the analysis of the continuous-wave Doppler signal
of mitral insufficiency the increase in early systolic pressure in-
crease (dP/​dt) can be calculated. Although this analysis is not
based on the absolute LV pressure but a pressure difference be-
tween left ventricle and atrium, it provides a global parameter
1 2
◆ Strain rate, the temporal derivative of strain (in 1/​s), is a the-
y
2 oretically attractive parameter of LV systolic function which
Δy
2D Vector
x
Δx
Fig. 33.3  Speckle tracking for myocardial deformation imaging. Myocardial
speckles are tracked from image to image thereby allowing the determination
of a myocardial movement vector.
vides a parameter of systolic and diastolic function [16]. It is
based on the analysis of the Doppler mitral inflow and the aortic
outflow signal to determine the time interval between the end
of mitral inflow from a first cardiac cycle and the start of mitral
inflow from the next cardiac cycle (A) as well as the duration
of the ejection period (B). The MPI is calculated as A–​B/​B
(E Fig. 33.6). Myocardial diseases prolong the isovolumetric
contraction and relaxation time. Thus, the MPI which is nor-
mally <0.49 increases. This parameter has been mainly used in
the paediatric cardiology arena
has been well validated experimentally, with relatively good
correlation with invasive measures of contractility. It can be
obtained both from tissue Doppler signals and from speckle-​
tracking analysis, in the longitudinal, circumferential, or ra-
dial direction of strain. However, the signal is very noisy when
acquired by tissue Doppler and undersampled when acquired
502 CHAPTER 33   Evaluat ion of systolic LV f u n cti on a n d LV m echa n i cs

Fig. 33.4  Speckle-​tracking image showing

circumferential strain of a patient with akinesia
of the posterior wall. The blue zone of the left
ventricular wall in the left picture corresponds to
the blue line in the graph on the right, showing
distinctly lower and later peaking longitudinal
shortening.

by speckle-​tracking, so that it is not currently used in clinical
practice.
Imaging for diagnosis, guidance of treatment,
and follow-​up in heart failure
In clinical practice, cardiac imaging provides very important
supplementary information to those obtained from the clin-
ical scenario in guiding the therapeutic management of patients
with congestive heart failure. Cardiac imaging allows the diag-
nosis of systolic and diastolic dysfunction, both in patients with
overt heart failure and in those with asymptomatic LV dysfunc-
tion. In the overt heart failure management, an individualized
echocardiography-​ guided strategy that monitors the haemo-
dynamic profile can evaluate the therapeutic effects much better
than a conventional clinically oriented strategy. When echocar-
diography has been used to guide pharmacologic therapy proto-
cols in patients with heart failure and LV systolic dysfunction,
mortality, and hospitalization has been reduced. Cardiac imaging
(mainly echocardiography) is able to identify, besides to overt
heart failure, a substantial number of subjects in the commu-
nity with asymptomatic LV dysfunction, mostly due to hyper-
tensive cardiomyopathy and silent coronary artery disease [17,
18]. It acts progressively, often beginning with asymptomatic LV
dysfunction and culminates in the overt congestive heart failure

pLV-pLA t1= 4 mmHg

pLV-pLA t2= 36 mmHg

Δt = 60 msec

dp/dt = 36  4 mmHg/ 60ms

Fig. 33.5  Calculation of left ventricular pressure rise dP/​dt
from the mitral regurgitant jet. dp/dt = 533 mmHg/sec (abnormally low)

a–b
MPI =
b on 2D echocardiography. In contrast, 3D echocardiography has
a and interobserver variability of real-​time 3D echocardiography
mitral inflow mitral inflow
ICT = (a–b) – IRT ICT b IRT
ET
Tei-index a – b (ICT + IRT) ICT IRT >0.55 bad prognosis
b
=
ET
=
ET
+
ET <0.55 good prognosis
Fig. 33.6  Schematic drawing demonstrating the myocardial performance
index (MPI) from mitral inflow and left ventricular outflow profile.
(CHF) with symptoms and signs from fluid overload and poor
end-​organ perfusion. The early identification of the subgroup of
patients who can deteriorate is essential to establish the appro-
priate therapy. In patients identified to have asymptomatic LV
dysfunction, a reduction of the progression rate to symptomatic
heart failure with angiotensin-​converting enzyme (ACE) inhibi-
tors and beta-​blocker therapy has been demonstrated in large
scale clinical trials.
Furthermore, cardiac imaging can guide therapy also in pa-
tients with clinical syndrome of congestive heart failure and pre-
served systolic function, implying that abnormal LV diastolic
function is the mechanism responsible for producing congestive
symptoms. Recent guidelines recommend performing a cardiac
imaging test (preferring echocardiography as screening test) in all
patients with suspected congestive heart failure [19]. In these pa-
tients cardiac imaging is essential in the diagnosis of heart failure
with preserved EF and of its aetiology (ischaemia, remodelling,
dyssynchrony, etc).
Most data related to the application of myocardial deformation
or strain imaging relate to longitudinal deformation.
Myocardial deformation imaging increased the sensitivity in
the detection of subclinical myocardial disease or involvement
for instance hypertensive heart disease, amyloidosis, diabetes. It
helps to distinguish constrictive pericarditis vs. restrictive car-
diomyopathy. It has been used to assess myocardial fibrosis and
determine myocardial viability as well as to detect myocardial
ischaemia.
LV systolic and diastolic volume as well as EF are the conven-
tional quantitative parameters to determine LV function during
follow-​up studies of therapeutic interventions. Subjective visual
assessment of LV EF is effective for single assessments but in-
sufficiently reliable for sequential analysis. Conventional echo-
cardiographic parameters based on 2D echocardiography have
also been shown to have limited test-​retest reproducibility. Major
limiting factors are poor image quality, geometric issues related
to volume calculations, and the performance of off-​axis cuts. In
a study on 50 patients test-​retest correlation of LV EF was found
I n t roduc t i on 503
to be only moderate (r = 0.66) using quantitative analysis based
been proven to have high test-​retest correlation (r = 0.92). Intra-​
derived LV volumes and EF have also been shown to be only in
the range of 5.1–​7.6%. Thus, using 3D echocardiography intra-​
and interobserver variability in the analysis of LV function can
be similar to that obtained with magnetic resonance imaging
[20–​22]. Newer parameters such as left atrial size and tissue
Doppler imaging parameters have also been described for serial
clinical testing of LV function. However, they have demonstrated
high variability. Thus, these parameters are not recommended
for sequential LV assessment. Considering the high intra-​and
interobserver agreement as well as the low test-​retest variation
for 3D echocardiographic analysis of LV function parameters,
3D echocardiography should be considered if accurate echocar-
diographic analysis of LV function during follow-​up studies is
required.
In oncology patients on chemotherapy GLS is recommended
for follow-​up studies in addition to the left ventricular EF to de-
tect early and discrete changes in systolic LV function.
Comparison of strengths and weaknesses of
different modalities and techniques
When a clinician has to choose the best imaging technique to
evaluate left and right ventricular function, she has to take into
account the availability and accuracy of different imaging tech-
niques in calculating the exact function, the eventual presence
of contraindications and to balance advantages and limitations
in that particular subset of patients. The availability of a par-
ticular imaging technique is often the first reason for the se-
lection, especially in patients with limited mobility, while the
absence of ionizing radiations is important in young patients
and in those who need frequent re-​evaluations of ventricular
function. The knowledge of the characteristics, advantages, and
limitations of different imaging techniques, summarized in E
Table 33.2, will guide the clinician to the right patient diag-
nostic management.
Echocardiography
Due to its portability and immediate availability, 2D echocar-
diography is considered the technique of first choice (and very
often the single one utilized) to assess regional and global LV
function, as well as other cardiac pathology, such as valve dis-
ease, cardiomyopathies, pericardial effusion, etc. Its features
are also fundamental in all the uses in the emergency depart-
ment and in the intensive care unit for the ancillary anatomic
information. In a limited number of patients with unsatisfactory
acoustic windows intravenous echo-​contrast administration can
improve the wall motion and cardiac chamber volume analysis.
Echocardiography has the highest temporal resolution among all
imaging techniques and, with good image quality, spatial reso-
lution is similar to computed tomography. It does not expose the
patient to radiation and is highly cost-​effective.
504 CHAPTER 33   Evaluat ion of systolic LV f u n cti on a n d LV m echa n i cs

Table 33.2  Characteristics, advantages, and limitations of different imaging techniques

Echocardiography Cardiac magnetic Nuclear radionuclide Nuclear ECG-​gated

resonance (CMR) angiography (RNA) SPECT imaging
Operator skill (acquisition Important in acquisition and Important in evaluation Mostly operator Important in evaluation
and evaluation) evaluation independent
Reproducibility Dependent on acoustic window; Excellent in global function, High High
excellent with contrast good in regional
Spatial and temporal resolution High Highest spatial resolution Intermediate Limited with extensive
perfusion defects
Perfusion Investigational with contrast Optimal resolution (also –​ Largest data at rest and
viability) stress (also for viability)
Regional systolic thickening Largest data in literature Includes different layers –​ Possible
analysis (tagging, SENC, and
feature tracking)
Function during stress Optimal Optimal (expensive) Feasible Feasible
Diastolic dysfunction Optimal Untwisting study (tagging) Quantitative LV filling –​
Three-​dimensional analysis Novel technique Optimal No –​
Ancillary structural info Excellent Excellent Limited No
LV hypertrophy and mass Very good Excellent No No
RV function assessment Good (estimate) Optimal Accurate (direct) No
Safety (ionizing radiation /​ Safe Contrast (limited toxicity) Ionizing radiation Ionizing radiation
contrast media)
Portability and availability Optimal Limited Limited Limited
Cost Lowest High Low Low
Peculiar characteristics Most useful and convenient as Proximal coronary arteries Large literature data for Simultaneous info on
first /​unique technique visualization function follow-​up perfusion and function
Other limitations Claustrophobia. No metallic
objects

Analysis of regional wall motion is mainly based on subjective
visual assessment. This qualitative analysis is limited by signifi-
cant interobserver variability. Administration of left heart contrast
agents can improve endocardial border definition and thereby
increases the observer’s ability to define regional LV function.
Using contrast-​enhanced echocardiography, high interobserver
agreement, and accuracy in the definition of regional wall motion
could be demonstrated which is comparable to CMR.
Echocardiography is quick and useful for estimation of right
ventricular (RV) function, although quantitation is limited due
to the complicated geometry of the right ventricle. 3D recon-
struction of right ventricular volumes is limited by needing good
image quality. Furthermore, echocardiography allows to esti-
mate left ventricular mass and to assess left ventricular diastolic
function.
The calculation of the EF and volumes is very accurate, es-
pecially when using echo-​contrast and 3D echocardiography,
although it is highly operator dependent and the automatic
analysis of these parameters is still suboptimal. Furthermore,
echocardiography may be considered as the most useful single
technique in the cardiac imaging scenario when analysing the
cost/​effectiveness  ratio.
Cardiac magnetic resonance imaging (CMR)
CMR has recently become the clinical gold standard for quan-
titation of left and right ventricular volumes and mass, thanks
to its three-​dimensional nature. The ventricles are imaged with
steady-​state, free-​precession cine images, which are then evalu-
ated as stacks of short-​axis slices (thickness, 6–​10 mm) after tra-
cing endocardial and epicardial contours.
Analysis of global and regional function of left and right ven-
tricle is very precise, due to good spatial resolution even in obese
patients (E Fig. 33.7), and operator-​independent imaging acqui-
sition. However, the evaluation of the data obtained with CMR
remains operator-​dependent.
CMR can further supply other information such as myocardial
perfusion (evaluated with gadolinium contrast) and some degree
of tissue characterization. Myocardial deformation can also be
evaluated by CMR. It does not involve radiation and is generally
safe, if contraindications such as non-​compatible implanted de-
vices (e.g. pacemakers) or contrast application in patients with
renal failure are observed.
Similar to echocardiography, but with an increased spatial
resolution, CMR supplies ancillary anatomic information on
ventricles and other cardiac and paracardiac structures that can

Fig. 33.7  Four-​chamber view of the left ventricle obtained by cardiac
magnetic resonance.
be fundamental for a complete clinical diagnosis. It can be very
useful also in the diagnosis of complex congenital heart disease.
Concerning the study of diastolic function, thanks to the ro-
tational and translational motion of the ventricle, which can be
evaluated with CMR tagging, the untwisting motion can be cal-
culated in its time and direction and allows an estimation of the
diastolic properties of the LV.
Nuclear techniques and LV function: ECG-​gated
equilibrium radionuclide ventriculography (RVG),
and ECG-​gated single-​photon emission computed
tomography (SPECT)
RVG (or ‘MUGA’, multigated radionuclide angiography) uses
intravenously injected radiolabelled red blood cells to assess
left and right ventricular volumes by generating, via a gamma-​
camera, a composite planar image set from many heart beats. The
expression ‘equilibrium’ indicates that these are studies done after
the initial bolus has ‘equilibrated’ in the whole blood volume, dif-
ferentiating it from ‘first pass’ techniques, which are rarely used
nowadays. RVG techniques determine the changes in radio-
nuclide counts in the left and right ventricles over the cardiac
cycle generating time intensity curves. Subsequently, ventricular
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RE F E RE N C E S 505
volumes can be obtained by comparison of the above counts with
the counts in a blood sample of known volume. This relates to
the great advantage of RVG, the high accuracy and reproduci-
bility in calculation of volumes and EF, which has been used in
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fusion SPECT allows simultaneous assessment of regional wall
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according to the same examination protocol, to avoid introducing
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tween different nuclear techniques nor with values obtained from
echocardiography or CMR. The major advantages of this tech-
nique are those related to perfusion imaging, such as the study
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myocardium, the presence of stress induced perfusion defects.
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formation imaging. Eur Heart J Cardiovasc Imaging 2015; 16: 1–​11.
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time three-​dimensional echocardiography versus cardiac magnetic
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21. Jenkins C, Bricknell K, Hanekom L, Marwick TH. Reproducibility
and accuracy of echocardiographic measurements of left ventricular
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Contents
Summary  507
Introduction  507
Left ventricular diastolic function:
physiology  507
Invasive evaluation of diastolic
function  508
Echocardiographic assessment of left
ventricular diastolic function  509
Echocardiographic indices of relaxation,
restoring forces, and compliance  509
Echocardiographic assessment of LV filling
pressure  510
Left atrium size and left ventricular
diastolic function  512
Evaluation of left atrial function  512
Algorithms for the diagnosis of left
ventricular diastolic dysfunction and
estimation of filling pressure  513
Other imaging techniques for the
assessment of diastolic function  516
Specific groups of patients  516
Atrial fibrillation  516
Hypertrophic cardiomyopathy  516
Constrictive pericarditis  516
Future perspectives  517
CHAPTER 34
Evaluation of left ventricular
diastolic function
Bogdan A. Popescu, Carmen C. Beladan, and
Maurizio Galderisi†
Summary
Left ventricular diastolic dysfunction (LVDD) is a key player in the pathophysi-
ology of heart failure and it has prognostic implications even in the preclinical stage.
Echocardiography is the first-​line imaging modality used for the clinical evaluation of
LV diastolic function. A large number of echocardiographic parameters have been tested
and validated against invasive measurements of diastolic function, each of them having
potential limitations.
The updated 2016 American Society of Echocardiography (ASE)/​European Association
of Cardiovascular Imaging (EACVI) recommendations proposed a comprehensive inte-
grated approach aiming to make the assessment of LV diastolic function easier and ac-
curate for daily clinical practice.
Introduction
The assessment of LV diastolic function is an important component of the standard
evaluation of cardiac function by imaging. It plays an essential role in the management
and risk stratification of patients with symptoms and signs of heart failure (HF), both
with preserved and with reduced ejection fraction (EF), and it was found to be an inde-
pendent predictor of cardiovascular events even in the preclinical stage.
From a practical standpoint, LV diastolic function assessment is particularly useful
in evaluating patients with dyspnoea and suspected or confirmed HF. In this setting,
imaging measures of LVDD are used to make the diagnosis of HF with preserved EF
(HFPEF) [1]‌. Moreover, non-​invasive estimates of LV filling pressure (LVFP) can be
used to determine the haemodynamic status, provide prognostic information, and guide
therapy in patients with HF, irrespective of left ventricular ejection fraction (LVEF).
Left ventricular diastolic function: physiology
Diastole is the part of the cardiac cycle beginning with aortic valve closure and ending at
mitral valve closure. It is conventionally divided into four phases: isovolumic relaxation,
rapid filling, diastasis (with slow filling), and filling during atrial contraction. In normal
hearts most of the LV filling occurs during the rapid filling period [2]‌. With impaired LV
†
  In beloved memory of our great friend Professor Maurizio Galderisi.
508 CHAPTER 34   Evaluat ion of lef t vent ric u l a r diastol i c fu n cti on

relaxation, filling progressively shifts to the later part of diastole
and, therefore, the left atrial (LA) contribution to cardiac output
increases. A normal diastolic function implies the ability of the
LV to fill adequately in order to provide a normal stroke volume at
normal filling pressure, both at rest and during exercise.
The separation of the cardiac cycle in two distinct phases—​
systole and diastole—​is just a theoretical framework, as the two
are interlinked. Thus, myocardial relaxation starts already in sys-
tole, before aortic valve closure, mediated by actin-​myosin inter-
actions responsible for both early diastolic events and ventricular
contraction  [3]‌.
Release of the potential energy stored in compressible LV elem-
ents (e.g. collagen, titin) during systolic twist promotes subsequent
elastic recoil and untwisting [4]‌. Ventricular untwisting precedes
diastolic lengthening and expansion of myocardial fibres, being
responsible for the early diastolic base-​to-​apex pressure gradients
and for diastolic suction [5]. In normal hearts a brisk untwisting
leads to a rapid decrease in early diastolic LV pressure and to mi-
tral valve opening with rapid filling [5]. Blood flows into the LV
until the pressure equalizes between the left chambers resulting
in diastasis. The final component of ventricular filling occurs with
LA contraction. The atrial contribution to LV filling may increase
from about 20% in young, healthy individuals with strong LV suc-
tion, to about 40% in elderly subjects with alterations of LV relax-
ation and compliance [6].
Increased LV contractility and smaller end-​systolic volume
determine stronger recoil and more rapid early diastolic filling.
Since ‘restoring’ forces and recoil depend on the magnitude and
duration of the previous twist, systolic performance influences
diastolic filling with each cardiac cycle [4, 5]. Thus, the con-
cept of diastolic dysfunction preceding systolic dysfunction was
questioned and replaced with the more likely hypothesis that LV
systolic and diastolic dysfunction usually coexist. Therefore, sev-
eral systolic function parameters are currently considered when
assessing diastolic function.[7]‌.
In conclusion, LVDD is usually the result of abnormal LV re-
laxation with or without reduced restoring forces (responsible for
early diastolic suction), and increased LV chamber stiffness [7]‌.
Invasive evaluation of diastolic
function
Definitive assessment of diastolic function requires invasive
measurements to assess parameters such as the relaxation time
constant (tau), LV diastolic pressures, and ventricular stiffness.
The term LV filling pressure can refer to LV pressures during
the different phases of diastole such as mean pulmonary capil-
lary wedge pressure (PCWP), mean LA pressure (LAP), LV pre-​A
pressure (before atrial contraction), mean LV diastolic pressure,
and LV end-​diastolic pressure (LVEDP). Although these pres-
sures correlate with each other, there are important pathophysio-
logic differences between them. (see E Fig. 34.1) [7]‌. These
differences need to be acknowledged when assessing different
Doppler parameters and analysing their significance.
In the clinical setting, the LVFP most often measured invasively
are LVEDP, obtained by left heart catheterization, and PCWP (an
indirect estimate of mean LAP), obtained by right heart cath-
eterization. Notably, increased LVFP represents the main deter-
minant of symptoms and prognosis in patients with HF. Filling
pressures are considered elevated when the mean PCWP is >12
mmHg or when the LVEDP is >16 mmHg [8]‌. Because these

LV LA LV + LA

LV A-wave
LV LV
A-wave
V-wave
V A
LV A-wave LA Mean LAP LA
LV EDP

LV pre-A X
LV RFW

LVmin Y
Fig. 34.1  (Left) LV diastolic pressures recording. Arrows point to LV minimal pressure (min), LV rapid filling wave (RFW), LV pre-​A pressure (pre-​A), A wave
rise with atrial contraction and end-​diastolic pressure (EDP). (Middle) LAP recording showing ‘V’ and ‘A’ waves marked along with Y and X descent. (Right)
Simultaneous LV and LAP recording showing early and late transmitral pressure gradients. Notice that LA ‘A wave’ pressure precedes the late diastolic rise (LV A
wave) in LV pressure.
Reproduced from Nagueh SF, Smiseth OA, Appleton CP, et al. Recommendations for the Evaluation of Left Ventricular Diastolic Function by Echocardiography: An Update from
the American Society of Echocardiography and the European Association of Cardiovascular Imaging. J Am Soc Echocardiogr. 2016;29(4):277–​314. doi:10.1016/​j.echo.2016.01.011 with
permission from Elsevier.
 E ch o cardio graph ic indices of rel ax ati on , restori n g forces , a n d c o m pl ia n c e
invasive measurements are impractical for daily routine, atten-
tion has been directed towards noninvasive methods. However,
catheterization remains the gold standard whenever non-​invasive
measurements are inconclusive [9].
Echocardiographic assessment of left
ventricular diastolic function
Echocardiography is the first-​line method used to assess LV dia-
stolic function in practice, being widely available, noninvasive,
and cost-​effective. In addition, echocardiography allows a com-
prehensive overview of LV morphology and function, LA size
and function, pulmonary pressures, the right ventricle, and the
pericardium. However, echo can only provide indirect evidence
of the pathophysiological hallmarks of LVDD as it allows deter-
mination of velocities and time intervals, but not of intracavitary
pressures.
The evaluation of LV diastolic function should always be placed
in the clinical context of the examined patient. Thus, the assess-
ment should start by noting the clinical information relevant to
LVDD and HF (e.g. history of hypertension, coronary artery dis-
ease, diabetes), and by identifying specific settings which may
change the way LV diastolic function is evaluated (e.g. atrial fib-
rillation, mitral valve disease, conduction abnormalities/​pacing
rhythm, etc.).
The echocardiographic evaluation of diastolic function should
start by looking at relevant structural changes, such as the pres-
ence of LV hypertrophy and that of LA dilatation. These changes
increase the likelihood of LVDD and are more ‘stable’ parameters
than Doppler echo parameters which may change very fast.
A large number of echocardiographic parameters have been
tested and validated for their correlation with the main invasive
LV pressure
LA pressure
Relaxation Compliance
E/A ratio. EDT, IVRT A dur-Ar dur
FPV, e’, Se, SRe E/e’, LAVi
Fig. 34.2  Diagram emphasizing the interplay between LV diastolic
components and their main echo correlates.
509
diastolic function parameters. Given the complexity of diastole
in itself and the many factors that influence each echo parameter,
none of these parameters should be used in isolation to describe
LV diastolic function.
The key principle is to apply a comprehensive, integrated algo-
rithm, combining structural and functional information related
to various diastolic properties and interpreting them in the rele-
vant clinical context.
Echocardiographic indices of
relaxation, restoring forces, and
compliance
For individual patient management it is useful to discern whether
the main factor responsible for diastolic dysfunction is abnormal
relaxation or decreased compliance. This can be achieved by sep-
arately assessing indicators of abnormal LV relaxation and indica-
tors of decreased compliance (see E Fig. 34.2).
Delayed LV relaxation and loss of restoring forces lead to de-
creased velocities of LV lengthening and untwisting and slower
LV pressure decay during isovolumic relaxation [10].
Transmitral Doppler flow velocities and filling patterns may
be used to evaluate LV relaxation and restoring forces. In young,
healthy individuals the peak E velocity exceeds that of the A vel-
ocity (E/​A ratio >1) since most of LV filling occurs during the
rapid filling phase. With abnormal relaxation, a reduction in the
early diastolic transmitral pressure gradient occurs leading to an
‘impaired relaxation’ pattern (E/​A ratio <1), with prolongation
of the isovolumic relaxation time (IVRT) and the E wave decel-
eration time (EDT>200 ms) (see E Fig. 34.3a) [10]. However,
a delayed relaxation filling pattern is commonly seen after
the age of 60 years in otherwise healthy subjects, therefore age
should always be considered when evaluating diastolic function
parameters [11].
With further progression of diastolic dysfunction, the E/​A ratio
will increase (due to the compensatory increase in LAP to pre-
serve cardiac output), leading to a pseudonormal filling pattern
with ‘normalized’ transmitral E/​A ratio, IVRT, and EDT (see E
Fig. 34.3b), and in the more advanced disease stage to a restrictive
filling pattern (E/​A>2, short IVRT and short EDT) (see E Fig.
34.3c). Therefore, the transmitral filling pattern may not reflect
by itself the degree of LVFP, and additional parameters are needed
for an adequate evaluation.
The mitral annulus early diastolic velocity e’, measured by
pulsed-​wave tissue Doppler imaging, reflects the velocity of myo-
cardial motion in early diastole and is significantly related to
the time constant of LV relaxation (τ). It is a key parameter of
diastolic function since it reflects both relaxation and restoring
forces [12]. Slower LV relaxation is associated with a lower e’
velocity, and there is a continuous decline of e’ values with the
progression of LVDD. Thus, whereas the E/​A ratio of the mitral
inflow exhibits a biphasic, U-​shaped relationship with advancing
degrees of LVDD, the e’ velocity decreases progressively, as it is
510 CHAPTER 34   Evaluat ion of lef t vent ric u l a r diastol i c fu n cti on

(a) (c)

Fig. 34.3  Transmitral Doppler A

E A
flow pattern. Abnormal relaxation
is associated with a reduction in the
early transmitral velocity (E) and
a compensatory increase in the A
wave with a reduction in the E/​A
ratio along with prolongation of the
deceleration time of E. This filling
pattern is named impaired relaxation (b) (d)
(3A). A compensatory rise in LAP,
which serves to maintain LV filling,
leads to a pseudonormal filling pattern
A
with normal transmitral E/​A ratio (3B).
With severely elevated filling pressures, E
further increase in E wave velocity E
leads to a restrictive filling pattern with A
increased E/​A ratio, short EDT and
IVRT (3C). Further signs of elevated
LAP include the occurrence of a
mid-​diastolic transmitral L wave (3D)
(yellow arrow).

less affected by the progressive increase in LVFP [13]. Therefore,
patients with pseudonormal filling typically present with an asso-
ciated reduction in e’. Furthermore, with delayed LV relaxation,
e’ onset and peak, which normally occur close to the onset and
peak of the E wave, are delayed, leading to less dependence of e’
on LAP [10, 14].
LV early diastolic strain rate and LV untwisting velocity provide
similar diagnostic information as e’ (reflecting both LV relaxation
and restoring forces) and can be derived from speckle-​tracking-​
based strain imaging. However, due to methodological chal-
lenges, their assessment is not recommended for routine clinical
use at the present time [7]‌.
In conclusion, abnormal early diastolic function due to im-
paired relaxation and loss of restoring forces can be detected non-​
invasively in clinical routine practice even if there is no method
that differentiates between these two mechanisms. In HF, both
processes are affected and responsible for slowing of LV pressure
fall and elevation of minimal LV diastolic pressure.
LV diastolic compliance represents the relationship between
the change in volume and the change in pressure in diastole. It
is determined by intrinsic myocardial compliance and extrinsic
factors that are mainly represented by pericardial restraint and
right ventricle-​LV interactions. Therefore, changes in LV chamber
compliance do not necessarily mirror changes in myocardial
elastic properties.
Reduced LV diastolic compliance is associated with a short
IVRT and short EDT, particularly in patients with a restrictive
filling pattern [10, 15].
Reduction in LV chamber compliance is also suggested by re-
duced amplitude and time duration of the mitral A wave and is
typically combined with increased amplitude and duration of the
pulmonary vein Ar wave [16–​18].
Echocardiographic assessment of LV
filling pressure
The ultimate consequence of diastolic dysfunction is an increase
in LVFP which represents the final common pathway for HF, re-
gardless of aetiology. In the early stages of LVDD, the patient is
asymptomatic at rest and LVFP is normal. With further alter-
ations of LV diastolic function, LVEDP increases, while mean
LAP may initially remain normal.
Abnormal end-​diastolic Doppler signals may help to identify
patients with elevated LVEDP. The increase in LVEDP leads to
a decrease in late diastolic transmitral pressure gradient with re-
duced peak A velocity and duration, decreased fraction of LV
filling due to LA contraction, and shortened mitral A DT. Mitral
annulus late diastolic velocity a’ is also reduced in patients with
elevated LVEDP [19]. Moreover, the duration of flow reversal into
the pulmonary veins exceeds the duration of antegrade flow into
the LV, and a reverse pulmonary venous A >30 ms longer than the
antegrade mitral A is a good indicator of elevated LVEDP, irre-
spective of LVEF and age [9, 17, 18] (see E Fig. 34.4).
LA systolic dysfunction, atrial fibrillation/​flutter/​tachycardia
or atrioventricular block make the use of late diastolic Doppler
signals unavailable or unreliable for drawing conclusions
about LVEDP.
In patients with advanced LVDD, dyspnoea with exercise re-
flects increased mean LA pressure (LAP). In these patients the
 Echo ca rdi o g r a phi c as ses sm en t of LV fi l l i n g pre s sure
(a) (b)
mitral valve opens at a high pressure, the early diastolic filling
becomes more dominant despite the impaired myocardial relax-
ation and IVRT gets shortened. Thus, an increased transmitral E/​
A ratio (≥ 2) with short EDT in patients with myocardial disease
is associated with increased LVFP [20, 21]. Another consequence
of increased mean LAP is a higher pulmonary vein–​LAP gradient
during diastole than during systole, leading to a lower systolic to
diastolic (S/​D) velocity ratio of the pulmonary venous flow [22].
However, the load and age dependency of IVRT, peak E vel-
ocity, E/​A ratio, EDT, S/​D ratio limit their use as predictors of
invasively measured LVFP.
The reduction in preload that occurs during the Valsalva
manoeuvre provides a method of distinguishing normal from
pseudonormal filling [23] (see E Fig. 34.5). The Valsalva man-
oeuvre can also unmask the presence of elevated LVEDP in pa-
tients with severely impaired relaxation and E/​A<1 at baseline
(commonly interpreted as having normal LVEDP) [24]. However,
this manoeuvre is not easily performed properly and cannot be
applied in critically ill or intubated patients [7]‌.
The mitral E/​e’ ratio is very often used to assess LVFP. It has the
advantage of adjusting the mitral E velocity (increased in both
young healthy subjects and in patients with advanced LVDD and
elevated LAP) for LV relaxation (e’ decreases only in patients with
Fig. 34.5  PW-​Doppler mitral flow. The Valsalva manoeuvre allows unmasking of an impaired relaxation pattern in a patient with pseudonormalization. A
decrease of >50% in the E/​A ratio is highly specific for increased LVEDP.
511
Fig. 34.4  Pulsed-​wave Doppler flow
patterns. The duration of flow reversal
into the pulmonary veins (Ar dur)
(4A) exceeds the duration of the
transmitral flow A wave (A dur) (4B)
with a time difference in the duration
of pulmonary vein Ar and mitral A
of 55 ms, suggesting elevated left
ventricular end-​diastolic pressure.
LVDD) and, therefore, it better reflects the LVFP. An average E/​e’
>14 is highly specific for elevated LVFP, regardless of patient’s age,
and it provides convincing evidence of LVDD [25]. When E/​e’ is
<8, LAP is usually normal. When E/​e’ is between 8 and 15, other
parameters or methods are necessary to estimate LVFP.
While E/​e’ is specific, it is a less sensitive indicator of increased
LVFP. Many patients with increased LVFP have an E/​e’ <14, espe-
cially when LVEF is preserved. Clinical settings in which the E/​
e’ ratio is a less reliable measure of increased LVFP include mitral
valve disease, surgical ring, or prosthetic mitral valve, more than
mild mitral annulus calcification, left bundle branch block, ven-
tricular pacing, pericardial disease, and normal hearts [9]‌.
Other echocardiographic signs of elevated LAP include the oc-
currence of a transmitral L wave (see E Fig. 34.3d), which is a
consequence of increased gradient during mid-​diastole due to de-
layed and prolonged LV relaxation with continuing forward pul-
monary venous flow into late diastole, indicating that the blood
is ‘pushed’ through the mitral valve rather than ‘pulled’ into the
LV [10, 23].
Increased pulmonary artery systolic pressure (PASP) can also
be used to identify patients with increased LVFP [7]‌. In the ab-
sence of pulmonary disease, increased PASP suggests elevated
LAP [7].
512 CHAPTER 34   Evaluat ion of lef t vent ric u l a r diastol i c fu n cti on
Fig. 34.6  Measurement of left atrial
strain components by speckle-​tracking
echocardiography with the zero strain
reference at end diastole.
LASr, calculated as difference between
onset of filling and end-diastole, LASct,
calculated as difference between end-
diastole and onset of atrial filling.
Left atrium size and left ventricular
diastolic function
In the absence of other causes (e.g. mitral valve disease, atrial
fibrillation) LA enlargement is an important feature for the
diagnosis of LVDD since it often reflects chronic, long-​term ele-
vation of LAP. LA volume indexed to body surface area (LAVi)
is the current metric recommended to assess LA size, with a
value of 34 ml/​m2 used as the upper limit of the normal range
and also as the reference value for diastolic function and LVFP
assessment [7, 26].
While in grade I LVDD, LA volume is usually still normal, the
atrial cavity dilates with increasing severity of LVDD, as LA pres-
sures increase. The strong association between LA volume and
the severity of LVDD in patients without alternative causes for LA
dilatation was shown to be independent of LVEF, age, gender, or
cardiovascular risk score [27].
Therefore, LA dilatation has been proposed as one of the main
components of the algorithms recommended for the diagnosis of
LVDD and increased LVFP [7]‌.
Evaluation of left atrial function
The non-​invasive approach to assess LA function is very im-
portant for identifying LVDD and LVFP increase. LAP is strongly
related to LA size and function and therefore a long-​standing in-
crease in LAP will be reflected by changes in both LA size and
function. Many studies have suggested that LA functional meas-
urements may be superior to LA size measurements in various
aspects and may provide clinical information even when the LA
is not dilated [28].
LASr
LASct
Left atrial function can be explored by several methods:
◆ Pulsed-​wave (PW) Doppler at mitral inflow, assessing the atrial
contribution (A velocity) to overall LV filling;
◆ PW-​Doppler at pulmonary venous flow, assessing the atrial re-
verse velocity (Ar);
◆ PW tissue Doppler at the mitral annulus, a’ velocity (septal or
lateral);
◆ Speckle-​tracking echocardiography, allowing the quantifica-
tion of LA strain (see E Fig. 34.6).
LA longitudinal strain is a promising parameter to assess LV
diastolic function. Given that tissue Doppler strain is cumber-
some and time consuming, 2D speckle-​tracking strain is now
increasingly more utilized. Recent observational studies have
shown a significant inverse correlation between LA peak lon-
gitudinal strain and invasively measured LVFP, mainly PCWP
[29]. The relation between LA strain and LVFP appears to be
stronger in patients with HF and reduced EF than in patients
with normal EF. The assessment of LA reservoir function by
LA peak strain provides prognostic information independent
of LA volume and LV longitudinal function in HF with reduced
EF [30].
In a study of 329 healthy subjects normal LA reservoir strain
was 45.5 ± 11.4% with the lowest cut-​off value of 23% [31]. By ap-
plying this cut-​off value in a cohort of 377 patients with LVDD, LA
strain was found to be reduced in 23% of patients with a normal
LAVi and in 27% of those with a normal LA emptying fraction
[31]. Similar findings were reported in patients with hypertension
and/​or diabetes, who had reduced LA strain despite a normal LA
volume [32].
Noteworthy, LA peak strain had better agreement with the in-
vasively measured pre-​A pressure compared to the guidelines’ al-
gorithm in a validation cohort of 50 patients [33].
 Diag n o si s of l eft ven tri cu l a r diastol i c dysf un c t i on
In patients with normal LV EF
1-Average E/e’ >14
2-Septal e’ velocity <7 cm/s or
Lateral e’ velocity <10cm/s
3-TR velocity >2.8 m/s
4-LA volume index >34 ml/m2
<50% 50%
positive positive
Normal diastolic
Indeterminate
function
However, the proper measurement of LA strain needs to be
well standardized [34]. The need to define normal reference
values and validated cut-​off values for different clinical settings,
and the intervendor variability represent limitations for using
LA strain on a larger scale in daily practice. Therefore, current
recommendations do not include determination of LA strain
in the algorithms proposed to evaluate LVDD and the level
of LVFP.
LA function assessment could play a role especially in the set-
ting of borderline LVDD assessment (i.e. indeterminate readings)
[35]. There are many areas of uncertainty regarding the progres-
sion from asymptomatic LVDD to HFPEF. As the LA is an im-
portant compensatory mechanism in the initial stages of LVDD
contributing to a preserved cardiac output in this setting, LA
dysfunction/​progressive failure could represent the key factor
leading from LVDD to HFPEF.
Algorithms for the diagnosis of left
ventricular diastolic dysfunction and
estimation of filling pressure
The 2009 recommendations for diastolic function assessment,
including a large number of echocardiographic parameters, were
perceived as too complex [36]. In 2016, the ASE and EACVI pro-
posed a simplified approach to foster the use of the recommenda-
tions in daily clinical practice.
According to this approach, the evaluation of LV diastolic func-
tion should always start by assessing the presence of clinical risk
factors known for their association with LVDD, by searching for
the presence of cardiac structural abnormalities (e.g. wall mo-
tion abnormalities, LV hypertrophy, LA dilatation, etc.), and by
estimating LVEF.
If clinical and 2D-​echo findings are not indicative of cardiac
disease and LVEF is >50%, four key parameters are proposed for
513
>50%
positive Fig. 34.7  Algorithm for diagnosis of LV diastolic
dysfunction in subjects with normal LVEF.
Reproduced from Nagueh SF, Smiseth OA, Appleton CP, et al.
Recommendations for the Evaluation of Left Ventricular Diastolic
Function by Echocardiography: An Update from the American
Diastolic Society of Echocardiography and the European Association of
dysfunction Cardiovascular Imaging. J Am Soc Echocardiogr. 2016;29(4):277–​314.
doi:10.1016/​j.echo.2016.01.011 with permission from Elsevier.
the diagnosis of LVDD: e’, the E/​e’ ratio, LAVi, and the tricuspid
regurgitation velocity.
The following cut-​off values are proposed: mean E/​e’ >14,
septal e’ <7 or lateral e’ <10, peak tricuspid regurgitation velocity
>2.8 m/​s, LAVi >34 ml/​m2. Diastolic dysfunction is diagnosed if
>50% of these criteria are met, diastolic function is interpreted
as normal if <50% of values meet the criteria, while the study is
inconclusive if half of the parameters are normal and half are ab-
normal [7]‌(see E Fig. 34.7).
In patients with structural heart abnormalities, known is-
chaemic heart disease, or abnormal LV systolic function (LVEF
<50%) LVDD is assumed to be present and therefore the echocar-
diography examination should focus in this setting on the assess-
ment of LVFP [7]‌.
In this regard, the first step is to examine the mitral inflow pat-
tern and identify the two groups where additional data beyond
mitral inflow are usually not needed:
◆ patients with mitral inflow E/​A ratio <0.8 and a peak E vel-
ocity ≤50 cm/​s are diagnosed with grade I LVDD (i.e. normal
mean LAP);
◆ patients with mitral inflow E/​A ratio ≥2 (except for the setting
of recent cardioversion of atrial fibrillation or flutter to sinus
rhythm) are diagnosed with grade III LVDD (i.e. elevated
mean LAP).
If the E/​A is ≤0.8 with an E velocity of >50 cm/​s, or the E/​A is
between 0.8 and 2, the recommendation is to use of E/​e’, peak tri-
cuspid regurgitation velocity, and LAVi to determine whether the
LVFP is elevated or not.
If all or two of these three parameters are abnormal, a diagnosis
of grade II LVDD is made (i.e. elevated LAP). Conversely, if all or
two of these three parameters are normal, the LVFP is most likely
normal and grade I LVDD is diagnosed.
If only two of the three parameters can be satisfactorily as-
sessed, both have to be normal for the diagnosis of grade I
LVDD, or both have to be abnormal for the diagnosis of grade
514 CHAPTER 34   Evaluat ion of lef t vent ric u l a r diastol i c fu n cti on

II LVDD. If just one of the two available parameters is abnormal,
LVFP cannot be determined and additional parameters should
be used (see E Fig. 34.8).
It is important to note that the recommendations suggest cau-
tion about using this algorithm to estimate mean LAP in circum-
stances such as: more than moderate MR, mitral stenosis of any
severity, prosthetic mitral valves, and annuloplasty rings, mod-
erate to severe mitral annular calcification, hypertrophic cardio-
myopathy, pericardial constriction, atrial fibrillation, and atrial
flutter, left bundle branch block, right ventricular or biventricular
pacing, and LV assist devices.
Alternative approaches for estimating LVFP in a number of
these disorders are discussed in greater detail in the ASE/​EACVI
recommendation paper [7]‌.
In patients with dyspnoea on exertion and preserved LVEF,
echocardiographic diagnosis of grade I LVDD with normal
resting LAP should not exclude reduced diastolic reserve with ex-
ercise and cardiac dyspnoea.
Diastolic stress testing is recommended in patients with grade
1 LVDD (normal mean LAP) at rest. There is little utility in per-
forming the test in patients who have normal results on resting
two-​dimensional studies and normal annular e′ velocities, as
there is little likelihood they will have exercise-​induced LVDD.
Similarly, there is no indication to perform a diastolic stress test
in patients with Doppler findings consistent with increased LAP
already evident at rest [7]‌.
Exercise echocardiography is preferred to pharmacological
stress echocardiography as a diastolic stress test since it is safer
and provides further insight on functional status. During the test,
changes in E and e’ velocities, E/​e’ ratio, and pulmonary artery
pressure should be assessed [7]‌. In healthy subjects, both E and
e’ velocities increase and so the E/​e’ ratio remains virtually un-
changed as LVFP remains within normal limits during exertion.
In patients with HFPEF, in the presence of LV hypertrophy
and small ventricular volumes, the increase in LAP during stress
increases the E velocity, while the e’ velocity is reduced both at
rest and during stress. As a consequence, the E/​e’ ratio increases
during stress. A cut-​off value of E/​e’ ratio >13 during exercise was
associated with an increased LVEDP >15 mmHg, while an E/​e’
ratio ≥10 at stress was the best predictor of reduced exercise cap-
acity (≤7 METS) [37]. A systolic pulmonary artery pressure ≥45
mmHg during exercise identified patients with HFPEF in another
study [38].
The current recommendations suggest that diastolic stress
testing should be performed by measuring mitral E, septal an-
nular e′, and tricuspid regurgitation peak velocities at baseline,
during each stage including peak exercise, and during recovery.
In patients with normal diastolic reserve, increased transmitral
flow (E velocity) with exercise is accompanied by an increase in e’,
as relaxation improves during exercise. Thus, the E/​average e′ (or
septal e′) ratio remains <10 and tricuspid regurgitation velocity
remains ≤2.8 m/​sec. The test is considered definitely abnormal
indicating LVDD when all of the following three conditions are
met: average E/​e’ >14 or septal E/​e’ >15, tricuspid regurgitation
peak velocity >2.8 m/​sec, and septal e’ velocity <7 cm/​sec during
exercise (see E Fig. 34.9).
Unless all three criteria are met, the test should be considered
non-​diagnostic  [7]‌.

Mitral Inflow

E/A ≤ 0.8 + E > 50 cm/s

or
E/A ≤ 0.8 + E ≤ 50 cm/s E/A > 0.8  <2 E/A ≥ 2

3 criteria to be evaluated

1-Average E/e’ > 14

2 of 3 or 3 of 3 2 of 3 or 3 of 3
2-TR velocity > 2.8 m/s
Negative Positive
3-LA Vol. index > 34 ml/m2
Fig. 34.8  Algorithm for estimation
of LV filling pressures and grading LV
diastolic function in patients with When only 2 criteria are available
depressed LVEFs and patients with 1 positive and
2 negative 2 positive
myocardial disease and normal LVEF 1 negative
after consideration of clinical and
other 2D data.
Reproduced from Nagueh SF, Smiseth OA, Normal LAP Cannot determine ↑ LAP ↑ LAP
Appleton CP, et al. Recommendations Grade I diastolic LAP and diastolic Grade II diastolic Grade III diastolic
for the Evaluation of Left Ventricular dysfunction dysfunction dysfunction dysfunction
Diastolic Function by Echocardiography: grade*
An Update from the American Society
of Echocardiography and the European If Symptomatic
Association of Cardiovascular Imaging.
J Am Soc Echocardiogr. 2016;29(4):277–​ Consider CAD, or
314. doi:10.1016/​j.echo.2016.01.011 with proceed to diastolic
permission from Elsevier. stress test
 Diag n o si s of l eft ven tri cu l a r diastol i c dysf un c t i on
Resting
E/e’ = 11
Exercise
E/e’ = 18
Recovery
E/e’ = 15
The evaluation of LV diastolic function may be challenging in
elderly subjects due to age-​related changes in LV structure and
function (i.e. delayed LV relaxation, increased LV stiffness) or
presence of comorbidities (e.g. ischaemic heart disease, hyperten-
sion) usually associated with reduction of E and e’ velocities, or
the E/​A ratio.
Therefore, filling patterns in the elderly might resemble those
observed in mild diastolic dysfunction in younger patients [7]‌.
However, the probability of an E/​e’ >14 is extremely low in the
presence of a normal diastolic function. Similarly, a significant re-
sponse of the transmitral Doppler flow pattern to Valsalva man-
oeuvre (>50% decrease in the E/​A ratio) or an increased duration
of the pulmonary vein Ar versus transmitral A duration are elem-
ents indicating the presence of increased LVEDP. The presence
of pulmonary hypertension in the absence of primary causes
(precapillary pulmonary hypertension) is another feature sug-
gesting LVDD at any age.
Other features suggesting the presence of LVDD are LA dilata-
tion (in the absence of atrial arrhythmias or mitral valve disease),
and pathological LV hypertrophy.
The diagnosis of LVDD is of particular clinical relevance in pa-
tients with HFPEF since diastolic dysfunction is part of the diag-
nostic algorithm in this setting. On the other hand, numerous
studies have demonstrated that despite a normal global systolic
function, these patients exhibit LV longitudinal systolic dys-
function reflected by reduced systolic displacement of the mitral
515
Fig. 34.9  Diastolic stress testing
performed in a 70 y/​o woman with
dyspnoea and fatigue with moderate
exertion, severe HTN (requiring four
classes of drugs), and dyslipidaemia.
Resting 2D-​echocardiography revealed
left ventricular hypertrophy, left atrial
dilatation, and normal left ventricular
ejection fraction. PW-​Doppler resting
echocardiography showed E = 78
cm/​s, E/​A = 0.64, e’sep = 6.7 cm/​s, E/​
e’sep = 11, VmaxTR = 2.4 m/​s. Diastolic
stress testing revealed an increase
in E/​e’ ratio to 18 with septal e’ <7
cm/​s and VmaxTR>2.8 cm/​s during
stress, suggesting increased LVFP with
exercise and the diagnosis of HFPEF
was made.
annulus by M-​mode (MAPSE), reduced systolic velocity (s’) of
the mitral annulus by pulsed-​wave tissue Doppler, or by reduced
global longitudinal strain (GLS) assessed by speckle-​ tracking
echocardiography.
Considering the close relationship demonstrated between sys-
tolic and diastolic events, it was suggested that in cases where
diastolic function evaluation is inconclusive, the presence of lon-
gitudinal systolic dysfunction may be an additional argument
for LVDD.
The newly proposed algorithms [7]‌have been validated by sub-
sequent studies as being fairly accurate. Two recent multicentre
studies have directly assessed the accuracy of the proposed algo-
rithms against invasive measurements of LVFP.
The EACVI Euro-​Filling study [39] evaluated 159 patients with
simultaneous echo and LV end-​diastolic pressure measurements
and concluded that the 2016 algorithm is fairly reliable, with
an area under the curve of 0.78 for the prediction of increased
LVEDP [40].
Andersen et al. have studied 450 patients using either PCWP
or LV pre-​A pressure and found an overall accuracy of 87% of
the 2016 algorithm in estimating invasively measured LVFP [41].
These results show that the 2016 recommendations are clinic-
ally useful and superior to the previous ones, but there is still need
for further validation and refinements.
At the same time, the limitations of these classification schemes
built by experts and based on the same conventional parameters
516 CHAPTER 34   Evaluat ion of lef t vent ric u l a r diastol i c fu n cti on
with their well-​known drawbacks, call for different approaches to
be tested.
Other imaging techniques for the
assessment of diastolic function
Several cardiac magnetic resonance (CMR) techniques have been
tested for their ability to assess LV diastolic function.
Due to its accuracy and reproducibility steady state free pre-
cession (SSFP) cine CMR is regarded as the reference standard
for morphological assessment of LV chamber and estimation of
LV volumes, mass and LVEF [42]. Conditions associated with LV
hypertrophy and LVDD, such as apical variants of hypertrophic
cardiomyopathies which are sometimes difficult to assess by
transthoracic echocardiogram (TTE), can be identified by CMR.
Late gadolinium enhancement (LGE)-​CMR can be used to
non-​invasively assess the extent and location of myocardial fi-
brosis (due to different cardiac diseases) which is relevant to
understand the pathophysiology of diastole. Increased tissue col-
lagen deposition alters the main determinants of diastolic func-
tion impairing relaxation, diastolic recoil, and passive stiffness
irrespective of LVEF. A gradient of LVDD severity, paralleled by
the extent of myocardial fibrosis (assessed by LGE-​CMR) has been
demonstrated [43]. Moreover, in patients with echocardiographic
parameters or biomarkers which are borderline for LVDD, tissue
characterization by CMR may reveal the presence of myocardial
disease and confirm the existence of LVDD.
Assessment of global and regional contractile LV function
(myocardial strain and strain rate, twisting, and untwisting) can
be performed by CMR tagging [44]. More recently, with CMR
feature of tissue tracking, derivation of such parameters is readily
possible from routine SSFP cine images.
With phase-​contrast CMR, transmitral and pulmonary vein
flow assessment is feasible, as well as measurements of myocardial
tissue velocities. The CMR derived E/​e’ ratio has demonstrated
good agreement with invasive measurements of LVFP [45].
Despite its advantages (demonstrated particularly in patients with
poor acoustic windows) the routine use of CMR in clinical practice
for LV diastolic function assessment is hampered by lower temporal
resolution, increased cost, and limited availability. Furthermore,
some patients may not be able to undergo a CMR examination, be-
cause of implanted metallic devices, claustrophobia, or the inability
to maintain a supine position for a long time.
Specific groups of patients
Atrial fibrillation
In patients with atrial fibrillation (AF) the non-​invasive assess-
ment of LV diastolic function is substantially limited by several
factors including absence of organized atrial activity, cycle length
variability, and the common finding of LA enlargement which
can be due to AF itself, independent on LVFP increase.
Accordingly, it is important to average the measurements
chosen on several cardiac cycles and match RR intervals for them.
The 2016 recommendations [7]‌suggest using velocities and time
intervals from 10 consecutive cardiac cycles, or to average meas-
urements from three non-​consecutive beats with cycle lengths
within 10–​20% of the average heart rate. Moreover, since patients
with increased LVFP show lower beat-​to-​beat variation, the vari-
ability of mitral inflow pattern with the RR cycle length should be
carefully assessed.
The following measurements can be used to predict increased
LVFP in patients with AF:
◆ E velocity DT (≤160 msec) in the presence of reduced LVEF;
◆ peak acceleration rate of mitral E velocity (≥1.900 cm/​sec2)
◆ IVRT (≤65 msec)
◆ Deceleration time of pulmonary venous diastolic flow velocity
D (<220 msec)
◆ E/​e’ ratio (≥11)
The time interval between the onset of mitral E and annular e’
velocities can also be considered to detect a delay in annular e’ vel-
ocity, which has demonstrated to be predictive of elevated LVFP.
Hypertrophic cardiomyopathy
In hypertrophic cardiomyopathy (HCM) different combinations
of abnormal LV relaxation and LVFP can occur. Accordingly, in-
dividual measurements have rather poor correlations with LVFP
because of phenotype variability, differences in both LV mass
and myocardial fibre disarray, and presence of LV outflow tract
obstruction.
The comprehensive approach suggested by current recom-
mendations [7]‌includes average E/​e’ ratio (>14), LAVi (>34 ml/​m2),
pulmonary vein Ar duration—​transmitral A duration (Ar-​A) ≥
30 msec, and colour wave (CW) Doppler-​derived TR jet peak
velocity (>2.8 m/​sec).
When more than 50% of these measurements are abnormal,
grade II LVDD and increased LVFP are present, while grade I
LVDD and normal LVFP can be attributed when less than 50%
of these measurements are abnormal. When 50% of the measure-
ments are normal and 50% are abnormal LVFP is interpreted as
inconclusive. In the presence of a clear restrictive filling pattern
and reduced e’ velocity (septal e’ <7 cm/​sec and lateral e’<10 cm/​
sec), grade III LVDD is diagnosed.
This approach can be considered valid even in patients with
significant left ventricular outflow tract (LVOT) obstruction,
whereas only Ar–​A difference and TR jet velocity should be
taken into account in the presence of moderate to severe mitral
regurgitation.
Recent studies have demonstrated the association of LV systolic
and diastolic strain rate, as well as of LV twisting and untwisting
with diastolic function in HCM [46].
Constrictive pericarditis
Left ventricular diastolic function should be assessed to differen-
tiate constrictive pericarditis from restrictive cardiomyopathies, a

differential diagnosis difficult to make on clinical grounds alone,
and very important from a therapeutic standpoint. Important
distinctive parameters between constriction and restriction have
been reported [47].
In constrictive pericarditis the E/​A ratio is >0.8, and septal e’
velocity is usually >8 cm/​sec. In restrictive cardiomyopathies the
E/​A ratio is usually higher (>2.5), EDT and IVRT are shortened
(<150 msec and <50 msec, respectively), while mitral annular e’
velocity is reduced (<6 cm/​sec).
An E/​ e’ ratio >15, pulmonary venous systolic fraction
<40% and LAVi >48 ml/​m 2 are ancillary findings in favour of
restriction. When septal e’ velocity is in the grey zone (range
= 6–​8 cm/​s ec), a lateral e’ velocity lower than the septal e’ vel-
ocity (‘annulus reversus’) and hepatic vein respiratory end-​
diastolic reversal velocity/​forward flow velocity ratio ≥0.8
are consistent with constriction. The E/​e’ ratio should not be
used to estimate LVFP in patients with constrictive pericar-
ditis. Similar to tissue Doppler-​d erived myocardial velocities,
the ratio of LV lateral longitudinal strain to septal longitu-
dinal strain is ≥1 in restrictive cardiomyopathy and <1 in
constrictive pericarditis, in relation with a lower deformation
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Contents
Introduction  519
Right ventricular anatomy and
physiology  519
Chamber size and wall thickness  520
Right atrial size with echocardiography  521
Right atrial size with MRI  521
Right ventricle size with
echocardiography  521
RV linear dimensions  522
RV outflow  522
RV area  522
RV volume  523
Right ventricle size with MRI  524
Right ventricular hypertrophy with
echocardiography  524
Right ventricular hypertrophy with MRI  524
Right ventricular function  526
Assessment of RV systolic function with
echocardiography  526
Assessment of RV diastolic function with
echocardiography  529
Right ventricular function and tissue
characterization with MRI  530
Right heart and pulmonary artery
haemodynamics  532
Estimation of right atrial pressure with
echocardiography  532
Estimation of pulmonary artery systolic
pressure with echocardiography  533
Haemodynamic assessment with MRI  534
Conditions associated with right ventricular
pathology  534
Conditions associated with RV volume
overload  534
Cardiomyopathic conditions associated with
RV pathology  538
Future directions  539
Summary and recommendations  539
CHAPTER 35
Imaging of the right heart
Lawrence Rudski, Petros Nihoyannopoulos,
and Sarah Blissett
Introduction
The right ventricle has lost its designation as the ‘forgotten ventricle’ over the past decade.
Clinicians recognize its prognostic significance in a wide array of disease processes and
imagers are now providing an assessment of right ventricular size and function in most
studies. Despite this recognition, imaging the right heart presents numerous challenges
to the imager. The shape of the chamber, the unique structure, and its coupling to the
pulmonary circulation mandate a different approach to its evaluation as compared to the
left ventricle. Imaging may be done by several modalities, each with their own strengths
and limitations but even more so than with the left ventricle (LV), the findings must be
interpreted in the context of loading conditions and clinical setting.
This chapter will focus on the two main right heart imaging modalities—​echocardiography
and cardiac magnetic resonance imaging (MRI) derived. Echocardiography remains the
most commonly used technique to assess right heart chamber size and function as well as
right heart-​pulmonary artery haemodynamics, owing to its wide availability, non-​invasive
nature, and low cost. These advantages are balanced by the challenges posed by the in-
ability to adequately image all integral parts of the right heart in standard imaging planes,
and the numerous methods required to attempt to compensate for this limitation. Three-​
dimensional echocardiography partially overcomes this as well but technical challenges
in images quality and lack of feasibility still make echocardiography suboptimal in some
circumstances. Cardiac MRI is viewed as the non-​invasive reference standard in its assess-
ment of right heart chamber size and function, but it too has several technical limitations
related to cardiac motion and imaging planes, as well as a reliance principally on ejection
fraction—​a load-​dependent measure—​in the evaluation of systolic function. In the end, an
integrative approach with either modality or both, is often required to provide the clinician
with the relevant information to help guide management.
Right ventricular anatomy and physiology
The right heart should be thought of as an interrelated complex of structures that work
together to receive and eject blood so that it can be oxygenated and carried to the left
heart. As such, all components must be evaluated. The inferior vena cava (IVC) and su-
perior vena cava (SVC) drain into the right artery (RA), which receives blood, allows
for its transit, and actively ejects blood into the RV during atrial contraction. The tri-
cuspid valve is more apically positioned than its left-​sided counterpart—​the mitral valve.
While usually comprised of three leaflets, there are far more anatomic variants seen of the
520 CHAPTER 35   Im aging of th e righ t  h eart
tricuspid leaflets, the papillary muscles, and chordae. The TV per-
mits unidirectional flow and its dysfunction must be accounted
for when assessing right heart chambers and function. The right
ventricle, covered next, is the main pumping chamber and ejects
via the right ventricular outflow tract (RVOT) through the pul-
monic valve into the main pulmonary artery (PA) and beyond.
The RV is anteriorly positioned in the chest immediately behind
the sternum and is oriented leftward [1]‌. Anatomically, its inferior
portion extends to a position just adjacent to the apex, which is
usually formed by the LV. Due to its position, both transthoracic
and transoesophageal imaging modalities have difficulty imaging
the RV, while MRI and computed tomography (CT) can over-
come these limitations. Standard echocardiographic imaging
planes project the LV accounting for far more of the cardiac apex,
such that when the RV appears to be ‘apex-​forming’ by echo it is
assumed to be significantly enlarged.
The right ventricle is often thought to be loosely divided into
three regions, the inflow portion, the body, and the outflow
tract. Embryologically, however, the RV really has two distinct
regions, the body (including the inflow region) which is de-
rived principally from the first cell field, and the outflow tract,
derived from conotruncal cushion with important contribu-
tions during the second cell field migration [2]‌. Unlike the LV
which approximates a prolated ellipse, the RV shape cannot be
easily modelled by geometric shapes. It loosely resembles a flat-
tened pyramid, with a curved base that wraps around the LV via
the interventricular septum. The RVOT extends off this pyramid.
As a result of this complex shape, echocardiographic imaging in
any two-​dimensional plane cannot adequately represent the true
RV form. Three-​dimensional image acquisition and reconstruc-
tion improves this limitation with more accurate representations
of shape and size. Cardiac MRI, by its nature, can image in any
plane, and can reconstruct the RV in a manner that closely resem-
bles its true morphology.
The RV myocardium is much thinner than that of the LV.
Despite the RV being slightly larger than the LV in terms of
volume, the RV mass is significantly smaller than the LV mass.
The endocardial surface of the RV, excluding the infundibulum,
is more trabeculated, which presents additional challenges to the
imager when tracing chamber contours. In addition, the RV has
two layers of muscle fibres—​a circumferential one that provides
an inwards bellows function and a longitudinal one that provides
the ‘piston-​like’ base to apex shortening. The RV does not contain
a well-​defined spiral muscle layer as seen in the LV [3]‌.
The RV is linked to the LV via the interventricular septum as
well as via the circumferential fibres that become more oblique at
the apex. This linkage is recognized as abnormal septal motion
in a number of clinical scenarios such as electrical conduction
abnormalities, volume, or pressure-​load states and pericardial
diseases. This interdependence and abnormal motion is usually
maladaptive but in rare situations adaptive (e.g. severe free-​wall
hypokinesis with marked paradoxical septal motion) [4]‌.
Finally, the RV is perfused principally by the right coronary ar-
tery via the acute marginal branches and the posterior descending
artery branch. Because the RV generates lower intracavitary pres-
sures, the transmural pressure gradient across the myocardium
permits for flow in both systole and diastole, with diastole still
being predominant. Under certain pathologic conditions, such as
pulmonary arterial hypertension (PAH), this advantage is elimin-
ated, with high intracavitary pressures at a time when perfusion is
most needed to supply a hypertrophied myocardium.
Chamber size and wall thickness
Two-​dimensional echocardiography and cardiac MRI provide
vastly different approaches to assess chamber size and wall thick-
ness with echocardiography relying on numerous simplifications
and assumptions due to the limited imaging planes.
When echocardiography is used to assess the RV, single views
are taken to represent larger areas of the RV and the interpreter
is left to ‘mentally’ stitch together measures taken from diverse
views. Linear dimensions are measured including base-​, mid-​,
and length determination [5]‌. The most commonly used view
to assess RV size is the apical four-​chamber view, and more spe-
cifically a ‘RV-​focused’ view. Additional evaluation may include
the RVOT from the parasternal long axis. Due to limitations
of 2D echo, a visual comparison of the relative sizes of the RV
and LV is employed to help gauge if the RV is dilated whereby
the RV should be less than three-​fourths of the LV in the apical
four-​chamber  view.
MRI relies far more on quantitation using either short-​axis
stack or four-​chamber stack to measure RV volumes in systole
and diastole, which are then indexed to body surface area (BSA).
Three-​dimensional echocardiography uses similar methodology
and provides similar information, with current generation soft-
ware being more automated, but suffers from a lack or feasibility
for routine use and not optimal correlation with MRI-​derived
volumes.
The Recommendations for Cardiac Chamber Quantification
by Echocardiography in Adults by the European Association
of Cardiovascular Imaging (EACVI) and American Society of
Echocardiography (ASE) is the established reference document
to assess the RV using echocardiography [6]‌. When developing
reference limits, an abnormal measurement was defined as >2 SD
above the mean value in healthy subjects. Most measurements are
not indexed to BSA or gender-​specific. This is a significant limita-
tion of current guidelines. Three-​dimensionally derived volumes
benefit from studies with larger numbers of patients and accord-
ingly can provide indexed RV volumes[7].
Assessment of right-​sided chamber size and function using
MRI is informed by the Society of Cardiac Magnetic Resonance
protocols for image acquisition [8]‌and by the 2019 EACVI Expert
Consensus Paper [9]. The gender-​specific, indexed normative
values and cut-​offs of severity provided in the Expert Consensus
Paper are predominantly based on a systematic review and meta-​
analysis [10]. The cut-​offs for severity for RA and RV volumes
were established by statistical methods: abnormal was defined

as > 2 SD above the mean value in healthy subjects with further
cut-​offs defined as follows: mildly abnormal up to 3 SD, moder-
ately abnormal up to 4 SD and severely abnormal >4 SD above the
mean in healthy subjects. Cut-​offs for severity of right ventricular
ejection fraction (RVEF) were established by statistical methods
and expert consensus. The authors [9] acknowledge further revi-
sions are anticipated, ideally also specific for age and race, once
more population studies have been published.
Right atrial size with echocardiography
The right atrium sits antero-​superiorly in the chest and is in the
far field when imaged from the standard apical four-​chamber
window. It is somewhat spherical but major and minor axes are
rarely identical. Measurement of RA size may yield prognostic
clues in diseases such as PAH and assist in determining right-​
sided filling pressures. The RA can be measured in a variety of
methods by transthoracic echocardiography (TTE)—​all of which
are from the apical four-​chamber. Linear minor and major-​axis
dimensions are not recommended. RA area was previously pro-
moted but the most recent EACVI-​ASE recommendations pro-
pose an estimation of volume from a single-​plane Simpson’s
(method of discs) or area-​length measurement [6]‌(E Fig. 35.1)
Care must be taken to cut across the plane of the annulus and
trace down along the interatrial septum and back around the su-
perior RA aspect, returning to the annulus. An unindexed area
exceeding 18 cm2 is likely dilated. A single-​plane volume estima-
tion assumes that dimensions into the Z-​plane are similar, which
is rarely the case. Mean indexed RA volume for males is 25 ± 7
ml/​m2 and 21 ± 6 ml/​m2 for females. Considering reference limits
being 2 SD above the mean, cut-​offs are 39 ml/​m2 for males and
33 ml/​m2 for females. The SD is quite large, providing a high
upper reference limit. There may be cases wherein the RA volume
is within the reference limit but may still be pathologically large.
Three-​dimensional estimation of RA volume can be performed
using standard 3D software and has been prognostic in PAH.
There are no large studies of RA volume in normals to estab-
lish reference values. Echocardiography underestimates volumes
Fig. 35.1  Single-​plane Simpson’s method to estimate RA volume measured
at end-​systole in the apical four-​chamber view.
Cha m b er si z e a n d wa l l t h i c k n e s s 521
when compared with MRI [11]. A dilated RA usually suggests ele-
vated right-​sided pressures, though may be seen due to electrical
remodelling as in atrial fibrillation.
Right atrial size with MRI
RA size can be measured using linear dimensions, area, or vol-
umes at end-​systole. The 2019 EACVI Expert Consensus Paper
recommends using the biplane method to calculate RA volumes
by contouring the RA in the four-​chamber and RV two-​chamber
views. RA volumes can also be obtained by the Simpson’s method
and 3D modelling, where the RA is contoured in the short-​axis
stack of steady-​state free-​precession (SSFP) images, however, are
limited in availability at present time. In the area and the single-​
plane methods, the RA is contoured in the four-​chamber view.
The right atrial appendage is included in the RA volume whereas
the SVC and IVC are excluded. As seen in E Table 35.1, norma-
tive values provided in the 2019 EACVI Expert Consensus Paper
[9]‌vary by technique used. They are based on single-​study data,
highlighting that the values may be further informed by future
studies.
Right ventricle size with echocardiography
Basic imaging planes
In order to overcome the complexities of chamber shape, multiple
tomographic imaging planes are necessary to visualize the entire
RV [12] (E Fig. 35.2).
Parasternal long-​axis  view: The anterior RV wall and RVOT
are visualized in this view. This view can identify RV dilation as
the RV should be approximately 1/​3 the diameter of the LV in this
view, albeit the entire RV is not visualized in this view.
Parasternal long-​axis view of RV inflow: From this view, the
RV inflow is visualized. The anterior and inferior walls of the RV
are imaged. The RV apex is not often visualized within the sector
window.
Parasternal short-​axis of basal RV: This view visualizes the RV
inflow, the basal anterior RV wall and the RVOT. Measurements
of the RVOT can be made from this view.
Parasternal short-​ axis view of the left ventricle at mid-​
papillary muscle level: The RV is seen wrapping around the LV
with its typical crescent shape. This is an important view to assess
the ventricular interdependence. Normally the LV appears cir-
cular throughout the cardiac cycle. In case of RV volume overload,
Table 35.1  Right atrial maximal volume and area reference ranges
Reference Mildly Moderately Severely
range abnormal abnormal abnormal
RA area/​BSA 8–​16 17–​18 19–​20 >20
4ch (cm2/​m2)*
RA volume/​BSA 18–​90 91–​108 109–​126 >126
(ml/​m2)**
*in adults aged 20–​80 years.
**obtained using the biplane method in adults aged 25–​73 years.
522 CHAPTER 35   Im aging of th e righ t  h eart
Fig. 35.2  Echocardiographic views that image the right ventricle.
Reproduced from Rudski LG, Lai WW, Afilalo J, et al. Guidelines for the echocardiographic assessment of the right heart in adults: a report from the American Society of
Echocardiography endorsed by the European Association of Echocardiography, a registered branch of the European Society of Cardiology, and the Canadian Society of
Echocardiography. J Am Soc Echocardiogr. 2010;23(7):685–​788. doi:10.1016/​j.echo.2010.05.010 with permission from Elsevier.
the ventricular septum will become flat in diastole. In case of RV
pressure overload the septum will flatten during systole.
Apical four-​chamber  view: Care should be taken to include the
true LV apex just under the artefact of the transducer position and
to avoid foreshortening of the apex. The lateral wall of the RV is
visualized in this view. Although this view was previously is used
to measure RV linear dimensions, the measurements are highly
variable dependent on probe rotation. As a result of this variability,
the RV-​focused view (next) was defined and recommended.
RV-​focused apical four-​chamber  view: The aim of this view is
to ensure that the RV chamber size is maximized, such that the
imaging plane is cutting through the largest short-​axis dimension
of the RV chamber (E Fig. 35.3). This is performed by probe
rotation counterclockwise from the apical four-​chamber view,
enhancing the imaging of the lateral RV wall which is not often
seen from the apical four-​chamber view. Linear dimensions of the
right ventricle can be made from this view.
Subcostal images: The lateral RV wall is visualized in this view.
This view can be used to assess the RV free-​wall thickness as it lies
perpendicular to the image plane. This view is not ideal to measure
the RV size as it is often foreshortened through probe angulation.
RV linear dimensions
The RV linear dimensions are measured at end diastole from the
RV-​focused four-​chamber apical view and parasternal long and
short-​axis views (E Table 35.2, Fig. 35.4a, b). The RV inflow
tract view and subcostal view are not usually used to measure
RV size but can give a visual assessment when correctly imaged.
Normal measurements have been established and have been
included in the American and European guidelines [5, 6, 12] for
disease diagnosis [13–​15]. The RV annular dimension has been
proposed to guide concomitant tricuspid valve repair at the
time of other cardiac surgery, with an upper limit of 40 mm or
21 mm/​m2[16].
RV outflow
The RV outflow tract can be measured in the parasternal long and
short-​axis views (E Fig. 35.4c, d). The proximal portion is visu-
alized in the parasternal long-​axis view [6]‌with the upper normal
limit of 35 mm. This measure is often used when imaging for sus-
pected arrhythmogenic cardiomyopathy.
The distal RVOT is visualized in the parasternal short-​axis view
at the basal RV, with values <27 mm being within normal limits.
RV area
The RV area can be measured in both diastole and systole and has
been used as a measure of both RV size and RV function. Normal
RV end-​diastolic area indexed to BSA ranges from 5 to 12.6 cm2/​
m2 in males and 4.5 to 11.5 cm2/​m2 in females. The RV area can be
used to calculate the fractional area change (FAC) (see next). Poor
 Cha m b er si z e a n d wa l l t h i c k n e s s 523

(a) (b)

RV 3

ral
LV

Late
RA 2
LA
LV
1* RV
RV modified apical 4-chamber

LV
Lateral

Septal
RV Leaflet

LA
RA
Ant.
Leaflet

RV focused apical 4-chamber

Lateral

LV
RV

RA LA
RVD1 = 59 mm RVD1 = 57 mm RVD1 = 55 mm
Apical 4-chamber
Fig. 35.3  (a) Three imaging planes of the RV. The middle panel depicts the RV-​focused view. (b) Linear dimensions superimposed on 3D data sets
demonstrating the variations in RV linear dimensions depending on the orientation of the apical image obtained.
Reproduced from Lang RM, Badano LP, Mor-​Avi V, et al. Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of
Echocardiography and the European Association of Cardiovascular Imaging. J Am Soc Echocardiogr. 2015;28(1):1–​39.e14. doi:10.1016/​j.echo.2014.10.003 with permission from Elsevier.

visualization of the RV endocardium can limit accurate measure-
ment of RV area. Endocardial border detection can be improved
with the use of intravenous injection of second-​generation con-
trast ultrasound agents [17].
RV volume
Because of the crescent shape of the RV, volumes are difficult
to assess using cross-​sectional imaging and are rarely measured
in routine clinical practice. One method used to assess RV vol-
umes was the area-​length based on the modified pyramidal or
ellipsoid model. This method however excludes the RV outflow
tract and so underestimates the overall volumes. As a result, as-
sessing RV volumes with two-​dimensional echocardiography is
not recommended.
Recent developments in three-​dimensional (3D) echocardiog-
raphy has made the estimation of RV volume feasible with good
correlation to those of cardiac MRI [18]. Temporal resolution has
improved with newer systems achieving higher frame rates and
better image quality. In patients with severe RV dilation, volumes
may be underestimated by 3D echo as compared to cardiovascular
magnetic resonance (CMR) because of the inability to incorp-
orate the entire RV apex within the sector [18]. Foreshortening is
not an issue in 3D echocardiography as long as the entire volume
is included in the data set.
There are now commercially available systems that allow for
relatively easy processing and analysis of RV volumes. From the
modified RV apical four-​chamber view, the 3D data set of the
RV full volume is acquired using ECG-​gating during 4–​7 con-
secutive beats. Sequential pyramidal subvolumes of the RV are
acquired and stitched to form the full volume. In one large study,
calculation of RV volumes using 3D echocardiography was feas-
ible in 94% of individuals [7]‌, however most users do not find
the feasibility as high, and there remains a significant learning
curve. Other systems now use the modified four-​chamber and
outflow tract views and by marking the hinge points of the apex,
tricuspid annulus, and the outflow tract calculates the RV vol-
umes in a semiautomated way. Recently, single-​beat acquisition
of large pyramidal volumes has become feasible, although at the
cost of lower spatial and temporal resolution. These technological
advances have made RV volumes measurements more feasible
and faster [19]. E Figure 35.5 is an example of a normal RV in
end diastole showing the endocardial contour with the thin green
line. On the left at different levels using a dedicated commercially
available software (TomTec Imaging Systems, 4D-​RV analysis,
Unterschleissheim, Germany).
The 2015 EACVI/​ASE consensus document [6]‌recommends
3D volumes indexed to body surface area and sex in laboratories
with suitable equipment and expertise. Upper reference limits for
end-​diastolic volume are 87 ml/​m2 for males and 74 ml/​m2 in fe-
males and end-​systolic volume is 44 ml/​m2 for males and 36 ml/​m2
for females. Additional values are available stratified by age as well.
Females have smaller indexed volumes and a higher ejection
524 CHAPTER 35   Im aging of th e righ t  h eart

Table 35.2  RV dimensions Analysis is performed by contouring the RV endocardium

on each slice to obtain end-​diastolic (RVEDV) and end-​systolic
Parameter Mean value Normal limit
(RVEDV) volumes (E Fig. 35.6). The contours can be manually
(95%CI) (95%CI)
traced or generated by semi-​automatic contouring software. The
RV basal diameter (mm) 33 41 end-​diastolic frame is the frame with the largest RV volume be-
RV mid-​diameter (mm) 27 35 fore the tricuspid valve closes. The end-​systolic frame is the frame
RV longitudinal diameter (mm) 71 83 with the smallest RV volume before the tricuspid valve opens.
RVOT PLAX diameter (mm) 25 30 Attention must be paid to contour only the blood volume within
the tricuspid valve to pulmonary valve. Cross-​referencing with or-
RVOT proximal diameter (mm) 28 35
thogonal views is used to determine the planes of the tricuspid and
RVOT distal diameter (mm) 22 27
pulmonary valves. Including or excluding the trabeculations and
RV wall thickness (mm) 3 5 papillary muscles affects the volumes, therefore normative values
RVOT EDA (cm2) are provided for each condition. Including the trabeculations and
  Overall 17 25 papillary muscles as part of the RV volumes increases reproduci-
  Men 17 24
bility of manual contouring [20–​22].
The short-​axis stack is most commonly used to measure RV
  Women 14 20
volume. The four-​chamber stack can better delineate the exact
2 2
RV EDA indexed to BSA (cm /​m ) planes of the tricuspid and pulmonary valves, however, has more
  Overall 9.8 13.7 partial volume effects than short-​axis stacks. The four-​chamber
  Men 8.8 12.6 stack is most useful in patients with congenital heart disease,
  Women 8.0 11.5 where it can be challenging to determine the exact plane of the
2
valves.
RV ESA(cm )
Using short-​axis stacks in patients without congenital heart
  Overall 9 14 disease, the interstudy variability was 6% for RVEDVi and 14%
  Men 9 15 for RVESVi [23].
  Women 7 11 Gender-​specific, indexed normative values for RV volumes
RV ESA indexed to BSA (cm /​m ) 2 2 have proposed in the 2019 EACVI Expert Consensus Paper
(E Table 35.3). In all but one of the studies pooled to estab-
  Overall 5.6 8.8
lish these normative values, RV trabeculations and papillary
  Men 4.7 7.4 muscles were included as part of the RV volumes. Notably, RV
  Women 4.0 6.4 volumes are larger in males as compared to females.
RV EDV indexed to BSA (ml/​m ) 2
RV size can also be compared to the LV size to determine if the
  Overall 64 86 RV is relatively enlarged. The RV/​LV end-​diastolic volume ratio
can be used to quantitatively assess for relative RV enlargement in
  Men 61 87
patients with normal RVEDV, with values >1.27 suggesting rela-
  Women 53 74
tive RV enlargement [24].
2
RV ESV indexed to BSA (ml/​m )
  Overall 26 40 Right ventricular hypertrophy with
  Men 27 44 echocardiography
  Women 22 36 Wall thickness is measured in the subcostal view at end diastole
RVOT = right ventricular outflow tract; EDA = end-​diastolic area; ESA = end-​systolic
from 2D or M-​mode images [6]‌. The measurement should be
area; ESV = end-​systolic volume; EDV = end-​diastolic volume. made distal to the tricuspid annulus, approximately at the level
of the tip of the anterior tricuspid valve leaflet when it is open.
Trabeculae, papillary muscles, and epicardial fat should be ex-
fraction, and in both sexes, RV volumes decrease with age (–​5 ml/​ cluded. Zoomed in images with focus on the mid-​RV wall can
decade diastolic and –​3 ml/​decade systolic) [6]. improve endocardial visualization. Normal wall thickness is
approximately 3 mm. A wall thickness of greater than 5 mm is
Right ventricle size with MRI abnormal. This measurement is not highly specific for right ven-
MRI can overcome some of the challenges encountered with the tricular hypertrophy because the RV free wall could be imaged
echocardiographic assessment of the RV because slices or stacks obliquely on the subcostal view.
of images can be acquired from any plane. Furthermore, imaging
the entire RV allows for measurement of RV volumes and RVEF Right ventricular hypertrophy with MRI
without relying on geometric assumptions. Right ventricular mass can be measured by contouring the RV
RV volume can be measured from short-​axis or four-​chamber myocardium on a short-​axis stack of SSFP images. There is no con-
of SSFP cine images (E Fig. 35.6). sensus as to whether the mass should be measured at end diastole
 Cha m b er si z e a n d wa l l t h i c k n e s s 525

(a) (b) Fig. 35.4  (a, b) RV linear dimensions

measured in RV-​focused apical
four-​chamber view at end diastole.
(c) RVOT dimension as measured
from the parasternal long axis at end
diastole. (d) RVOT dimension as
measured in the parasternal short axis
at the basal RV at end diastole.
Reproduced from Rudski LG, Lai
WW, Afilalo J, et al. Guidelines for the
echocardiographic assessment of the
right heart in adults: a report from the
American Society of Echocardiography
endorsed by the European Association of
Echocardiography, a registered branch of
the European Society of Cardiology, and
the Canadian Society of Echocardiography.
J Am Soc Echocardiogr. 2010;23(7):685–​
(c) (d) 788. doi:10.1016/​j.echo.2010.05.010 with
permission from Elsevier.

(a) (b)

Fig. 35.5  Patient with pulmonary arterial hypertension demonstrating the automated RV endocardial contour delineation (a) after identification of the
RV inflow, outflow, and RV apex. (b) RV reconstruction showing the enlarged RV in diastole (wireframe) and in systole (green) with the respective volume
calculations. RVEDV 200 ml, RVESV 137 ml, RV EF 31%.
526 CHAPTER 35   Im aging of th e righ t  h eart

Fig. 35.6  Manual RV end-​diastolic (left) and end-​systolic (right) contours in yellow as measured in the short-​axis stack.

or end systole. There is limited data to establish cut-​offs for normal
values, with values of 13–​29 g/​m2 being normal for males and
12–​28 g/​m2 for females in a single study (E Table 35.3) [9, 25].
Right ventricular function
Assessment of RV systolic function with
echocardiography
Estimation of RV systolic function is at least as challenging as es-
timation of RV size. In addition to the anatomic and geometric
challenges that the RV imposes, there are other considerations
including differences in RV myocardial structure and function,
exquisite sensitivity to afterload, and even ventricular inter-
dependence via a shared septum as well as the shared pericardial
sac. Just as in the setting of mitral regurgitation and its impact
on LV function, so too should the severity of tricuspid regurgi-
tation (TR) be considered when assessing RV systolic function.
Each one of these interacting features must be considered, if not
quantitated, in order to adequately assess RV systolic function.
The RV contracts in a base to apex movement, as well as an in-
ward motion of the free wall towards the septum. Estimation of
RV systolic function can be done using global and regional meas-
ures, with each of these being measurable using different param-
eters. Regional measures include tricuspid annular plane systolic
excursion (TAPSE), velocity of annular motion by tissue Doppler
(S’) and RV free wall strain. The global measures include RVEF
by 3D imaging, RV strain, right-​sided index of myocardial per-
formance (RIMP), RV dp/​dt and to a lesser extent, FAC. The more
commonly used of the above measures are presented in more de-
tail (E Fig. 35.7).
Tricuspid annular plane systolic excursion (TAPSE)
TAPSE is a measure of longitudinal motion of the RV annulus.
It is measured in the apical four-​chamber view by placing the
M-​ mode cursor through the lateral tricuspid valve annulus
(E Fig. 35.7a). The TAPSE represents the distance that the an-
nulus has travelled between the beginning and the end of systole.
Larger values represent greater RV annular function. In normal
subjects, there is a good correlation between TAPSE and other
parameters of RV function [26, 27].
Since TAPSE reflects annular RV motion it may not accurately
quantify global RV function. As noted above, the RV has both
a base to apex piston-​like motion, as well as an inward bellows
motion driving the free wall inwards towards the septum. The re-
mainder of the RV could be dysfunctional with preserved annular
motion as is seen commonly in PAH, or the TAPSE could be di-
minished despite relatively normal global RV function (as is seen
post-​cardiac surgery). Another limitation of TAPSE is that the
measurement is angle-​dependent; incorrect measurements may
be made if the cursor is not parallel to the longitudinal motion of
the annular RV.

Table 35.3  Normal values for right ventricular dimension and function in adults aged 20–​68 years

Female Male
Opposite Normal Mildly Moderately Severely Opposite Normal Mildly Moderately Severely
abnormal abnormal abnormal abnormal abnormal abnormal
RVEDVi (ml/​m2) <48 48–​112 113–​128 129–​144 >144 <61 61–​121 122–​136 137–​151 >151
RVESVi (ml/​m2) <12 12–​52 53–​62 63–​72 >72 <19 19–​59 60–​69 70–​79 >79
RVEF (%) >71 51–​71 41–​51 30–​40 <30 >72 52–​72 41–​52 30–​40 <30
2
RV Mass/​BSA (g/​m ) <12 12–​28 29–​32 33–​36 >36 <13 13–​29 30–​33 34–​37 >37
Opposite: values outside the normal range but in the opposite direction of typical pathology, e.g. smaller RVEDV and higher ejection fraction.

(a)
(b)
(c)
Fig. 35.7  Parameters to assess regional (a) Tricuspid annular plane systolic excursion; (b) tricuspid annular velocity S and global (c) 2D RV free wall strain
longitudinal strain; (d) fractional area change RV function.
Despite these limitations, due to its simplicity and repro-
ducibility, TAPSE is a recommended measure to help distin-
guish the presence of RV systolic dysfunction. The EACVI/​ASE
chamber quantification recommendations provide a lower value
of 17 mm.
In patients with precapillary pulmonary hypertension, TAPSE
has been shown to correlate with MRI-​derived RV ejection frac-
tion and predict long-​term mortality [28, 29]. In patients pre-
senting with inferior myocardial infarction, a reduced TAPSE
was an indicator of RV infarction even when no RV regional wall
motion abnormalities could be identified [30]. Up to 50% of pa-
tients with chronic left-​sided heart failure were found to have a
reduced TAPSE, which was associated with a significant increase
in long-​term mortality [31, 32]. Finally, in patients undergoing
transcatheter aortic valve replacement, abnormal TAPSE, as well
Ri g ht ven tri cu l a r f un c t i on 527
(d)
as abnormal S’ and FAC (see next), were independent risk factors
for post-​procedural mortality [33].
Tricuspid annular velocity (S’)
S’ measures the longitudinal velocity of the RV annulus during sys-
tole. It is measured in the apical four-​chamber view by placing the
tissue Doppler sample volume on the lateral tricuspid valve annulus
and activating the pulsed Doppler function. The peak systolic vel-
ocity is measured, ensuring that one does not measure the earlier
peak isovolumetric contraction velocity waveform (E Fig. 35.7b).
An abnormal value is <9.5 cm/​s with greater values reflecting greater
annular RV systolic function [6]‌. Both pulsed tissue Doppler and
colour-​coded tissue Doppler can be used to measure S’, although the
colour-​coded method yields mean velocities that are usually slightly
lower since colour Doppler is a reflection of mean velocities.
528 CHAPTER 35   Im aging of th e righ t  h eart
As a Doppler-​derived measurement, S’ is an angle-​dependent
measurement. In addition, since only the basal velocity is meas-
ured and since only longitudinal velocity is measured, it may not
reflect global RV function in the setting of disease.
Like TAPSE, S’ appears to have prognostic value in a variety of
clinical situations. S’ has been shown to correlate well with MRI
RV ejection fraction [34, 35] and demonstrates prognostic value
in patients with pulmonary hypertension [36, 37] inferior myo-
cardial infarction [38–​40].
Fractional area change (FAC)
FAC is the percent change in RV area from diastole to systole, a
two-​dimensional surrogate for ejection fraction, and thereby re-
flects the systolic function of the inflow and apical portions of the
RV. FAC is not limited to one type of motion, but rather encom-
passes longitudinal shortening as well as radial motion and thick-
ening as well as the contribution of the interventricular septum. It
is measured in the apical four-​chamber view by manually tracing
the contour of the RV at end diastole (when the RV cavity is at its
largest) and at end-​systole (when the RV cavity is at its smallest).
The FAC is calculated as follows:
 (end - diastolic RV area − end -systolic RV area ) 
FAC =   × 100
 end - diastolic RV area  Lower values indicate superior function since the healthy RV
The normal reference limit (E Table 35.2) for FAC is ≥35% [6]‌.
The primary challenge and main limitation of FAC is the accurate
identification and tracing of the true RV endocardial border (com-
pacted myocardium) rather than the prominent trabeculations
and muscle bands (E Fig. 35.7d). This, as well as variability in
acquisition of the apical four-​chamber view make reproducibility
suboptimal.
Clinically, FAC has been demonstrated to be a strong inde-
pendent predictor of all-​cause mortality in patients with acute
myocardial infarction and left-​ ventricular dysfunction, with
a FAC <35% carrying an adjusted hazard ratio of 3.56 [41, 42].
Fractional area change is also included as the sole 2D echocardio-
graphic parameter of RV function in the ARVC Task Force cri-
teria list with a FAC ≤33% as a major criterion and 34–​40% as a
minor criterion [15].
Fig. 35.8  Pulsed Doppler and continuous wave Doppler methods for measuring the myocardial performance index.
FAC appears to be an excellent compromise between effi-
ciency of use and global representation of RV systolic function.
Compared to other two-​dimensional measures of RV systolic
function such as TAPSE and S’, FAC was found to correlate best
with the reference standard of MRI-​derived RVEF (r = 0.80) [43].
Myocardial performance index (MPI)
MPI, also referred to as RIMP or right ventricular Tei index, reflects
both the systolic and early diastolic function of the RV [44]. Contrary
to the TAPSE, S’, and FAC, the MPI is based on time intervals and
is independent of chamber geometry and contraction pattern. The
MPI was once thought to also be independent of loading conditions,
although this has been subsequently proven to be false [45].
The MPI is derived by calculating the ratio of isovolumetric
time over ejection time as follows:
MPI
isovolumetric relaxation time + isovolumetric
contraction time
=
ejection time
   (tricuspid closure-​to-opening time – ejection time)
=
ejection time
should theoretically spend a lower relative proportion of time in
an isovolumetric contraction and relaxation state and a greater
proportion ejecting blood.
The MPI can be measured by pulsed-​or tissue-​Doppler imaging
(E Fig. 35.8). The time intervals being measured are often diffi-
cult to delineate, and small variations can lead to substantial dif-
ferences in the final calculated value [5]‌.
Pulsed Doppler method: The ejection time is derived from the
pulsed-​wave Doppler tracing of the distal RVOT; the tricuspid-​
closure-​opening time is derived from the pulsed-​wave Doppler
tracing of the tricuspid inflow (time from end of the A wave to the
onset of the following E wave) or the continuous wave Doppler
tracing of the TR jet; and the total isovolumetric time is derived
from the difference between the tricuspid-​closure-​opening time
and the ejection time (E Fig. 35.8). The normal reference limit
for the pulsed Doppler MPI is ≤0.43.

Tissue Doppler method—​The ejection time, tricuspid-​closure-​
opening time, and total isovolumetric time are all derived from
the pulsed tissue Doppler tracing of the lateral tricuspid annulus
(E Fig. 35.8). The normal reference limit for the tissue Doppler
MPI is ≤0.54. This method has the distinct advantage of being
measured from a single acquisition in a single heartbeat.
The MPI is often affected before other functional parameters so
it is a sensitive parameter to evaluate subclinical or early RV dys-
function. Since MPI is non-​geometric in nature and relies solely
on time intervals to derive a measure of RV function, it is useful
to evaluate an RV which is oddly shaped or poorly visualized.
Abnormal RV MPI has been linked to adverse outcomes in sev-
eral disease states [46–​49] and has been used to predict response
to therapy in patients with PAH and or chronic thromboembolic
disease [50, 51]. In patients scheduled to undergo coronary artery
bypass or aortic valve replacement surgery, abnormal RV MPI is
an independent risk factor for postoperative mortality and major
morbidity [52–​54].
3D RVEF
RVEF is derived from RV volumes by the following equation:
(RVEDV –​RVESV) /​RVEDV. As with the LVEF, RVEF is not a
direct measure of contractility as it is affected by preload, afterload
including parameters such as pulmonary vascular resistance and
TR. RVEF values were derived from the same studies used to de-
fine RV volumes and this method has been validated against MRI
with close correlation of ejection fraction (EF) despite consistent
underestimation of volumes [55, 56]. Current software used to
define RV volumes as described above will automatically derive
RVEF. Recently investigators have demonstrated the utility of
3D RVEF to predict death and major cardiac adverse events in a
broad range of cardiac conditions, with performance superior to
left-​sided parameters [57]. The 2015 EACVI/​ASE consensus docu-
ment recommends 3D-​derived RVEF in laboratories with suitable
equipment and expertise. The lower reference limit is 45%, based
on meta-​analysis of multiple studies [6]‌. RVEF tends to be higher
in females because of smaller volumes. The RVEF increases in the
elderly as RV volumes decrease with age. Thus, echo laboratories
may choose to report sex-​based and age-​based values [7].
Strain imaging
Deformation imaging represents a novel and more accurate
method for the assessment of global and regional myocardial
function. Stain imaging measures the percentage of active de-
formation of a myocardial segment relative to its original length
or thickness. Different equations can be used to calculate strain
but, the most used in echocardiography is the Lagrangian strain
(SL) equation in which the end-​systolic length of a myocardial
segment (L) is compared to the initial length [the end-​diastolic
length (L0)], and is defined as:
L − L0
SL = 100 (%) ;
L0 *
Strain can be computed taking a myocardial segment of length
L along any specified direction. When this segment is taken
Ri g ht ven tri cu l a r f un c t i on 529
along the longitudinal direction it gives the longitudinal strain
(LS). During myocardial base to apex contraction the tissue seg-
ments becomes smaller and therefore the strain has a negative
value, while when the segment relaxes, the strain has a positive
value. Strain rate reflects the instantaneous deformation in strain
over time.
While Doppler-​derived strain can be measured, its numerous
limitations in terms of reproducibility and angle dependence makes
it not feasible for routine clinical use. Instead, 2D-​speckle-​tracking
echocardiography, a greyscale-​based technique that is effectively
angle-​independent, permits for a more comprehensive assessment
of myocardial deformation. The myocardial speckles can be tracked
throughout the cardiac cycle. The displacement of this speckled pat-
tern is considered to follow myocardial movement and a change
between speckles represents myocardial deformation (strain). The
higher the frame rate the better the tracking of the speckles.
Practically, peak RV free wall longitudinal strain (FWLS) is
measured from the apical four-​chamber view (E Fig. 35.7c).
The RV free wall shortens in systole. Consequently, values of RV
FWLS are negative. RV FWLS values are typically slightly higher
than peak LV global LS, and generally >20% in absolute values
[5, 6]. Muraru et al., using General Electric (GE) ultrasound
machines and software found the overall RV FWLS in a normal
population to be –​30.5 ± 3.9% with the lower limit of normal to
be –​23.3% [58]. For males it was 29.3 ± 3.4% with a lower limit
of –​22.5% and for females –​31.6 ± 4.0% with a lower limit –​23.3%.
The EACVI/​ASE consensus statement used meta-​analyses from
several studies to support their recommendation for a lower ref-
erence limit of >–​20% to be abnormal [6]‌. The majority of data in-
cluded in this meta-​analysis was from a single ultrasound system
manufacturer (GE). It should be noted that these values may vary
with different ultrasound machines and software versions and
should be standardized to individual laboratories.
There is now a large body of evidence demonstrating the clin-
ical value of speckle tracking to assess regional and global RV sys-
tolic function in a number of clinical settings including congestive
heart failure [59], acute pulmonary embolism [60], pulmonary
hypertension [61], ischaemic heart disease [62], and infiltrative
cardiomyopathy [63] among others.
Limitations of 2D speckle-​tracking strain include the required
high frame rate (40–​80 fps) and drop out of the RV free wall with
myocardium motion. The use of recently developed 3D speckle-​
tracking strain imaging holds great promise for further quantifi-
cation of RV function. Unlike 2D imaging, speckles remain visible
within the pyramidal volume scan throughout the cardiac cycle.
Consequently, despite lower frame rates than two-​dimensional
speckle-​tracking, 3D imaging ultrasound speckles can be tracked
in 3D space without the risk of being lost out of plane as they re-
main within the 3D field of view.
Assessment of RV diastolic function with
echocardiography
Assessment of RV diastolic function has not attracted much
attention and is usually limited to the assessment of RV
530 CHAPTER 35   Im aging of th e righ t  h eart
systolic pressures, right atrial size and diameter, and collaps-
ibility of the IVC. From pulsed-​wave Doppler recordings of
the tricuspid inflow in the apical four-​chamber view, the RV
diastolic function can be assessed in a similar way to that
of the LV. The peak early (E) and late (A) diastolic veloci-
ties and the deceleration time of the E wave can be measured.
Care must be taken to measure at held unforced expiration
and average between 3 and 5 beats. Severe TR and/​or atrial
fibrillation will hinder the assessment of diastolic function.
The tricuspid E/​e’ ratio, RA area or volume appear promising
and have attracted interest in recent studies, although more
studies are needed. The EACVI/​ASE consensus document
provides an algorithm to evaluate diastolic function to be
used when clinically relevant [6]‌.
Right ventricular function and tissue
characterization with MRI
RV systolic function
RV function can be assessed qualitatively and quantitatively
using multiple views. SSFP cines obtained in the four-​chamber
view and short-​axis stack as well as RV-​specific views (RV inflow-​
outflow and RVOT views) are analysed to identify regional or
global wall motion abnormalities (E Fig. 35.9). In patients with
(a)
(c)
Fig. 35.9  Views to assess RV
function: (a) four-​chamber view;
(b) short-​axis view; (c) RV-​inflow-​
outflow view; (d) RVOT view.
congenital heart disease, the RV two-​chamber view can also be
acquired. Familiarity with normal variants can help distinguish
normal from abnormal wall motion abnormalities. End-​systolic
bulging of the distal RV free wall adjacent to the moderator band
due to through plane motion, the so-​called butterfly-​motion, can
be mistaken for inferior wall dyskinesis. Similarly, the mid-​RV
free wall can be tethered to the anterior chest wall, which could
be mistaken for focal dyskinesis (E Fig. 35.10). Flattening of
the interventricular septum can be assessed on four-​chamber or
short-​axis  views.
RV function can be quantitated using RVEF or less com-
monly by TAPSE. RVEF is calculated based on the RVEDV and
RVESV using the Simpson’s method. Normal values based on
the recommended reference ranges and cut-​offs for severity in
the 2019 EACVI Consensus paper [9]‌are presented in E Table
35.3. The lower limit of normal for RVEF is 51% in females and
52% in males. In a study of healthy volunteers and patients with
acquired heart disease, the interstudy variability in RVEF was
8% [23].
The measurement of TAPSE differs from the echocardiography.
The distance from the lateral basal tricuspid annulus to the RV
apex is measured in systole and in diastole (E Fig. 35.11) [64].
The difference in the measurements (diastolic length-​ systolic
length) is the TAPSE [65]. Values less than 20 mm are considered
(b)
(d)
 Ri g ht ven tri cu l a r f un c t i on 531

Fig. 35.10  Normal variants of RV wall

motion abnormalities. Left: butterfly
apex; right: tethering of mid-​RV free
wall to anterior chest wall.
Reproduced from te Riele AS, Tandri
H, Bluemke DA. Arrhythmogenic right
ventricular cardiomyopathy (ARVC):
cardiovascular magnetic resonance
update. J Cardiovasc Magn Reson.
2014;16(1):50. Published 2014 Jul 20.
doi:10.1186/​s12968-​014-​0050-​8 with
permission from Springer Nature.

abnormal. MRI-​derived TAPSE is reflective of basal annular mo-
tion rather than global RV function.
RV diastolic function
While there are limited parameters to assess RV diastolic func-
tion, the presence of end-​diastolic forward flow through the pul-
monary valve is a finding that has been suggestive to be consistent
with restrictive RV filling (E Fig. 35.12).
Tissue characterization
T1 imaging (with and without fat suppression) and late gado-
linium enhancement (LGE) can characterize the myocardium of
the right ventricle.
Fibrofatty infiltration of the RV free wall can be seen in
arrhythmogenic ventricular cardiomyopathy however can
be a non-​ pathologic finding in older patients. Assessment
for fibrofatty infiltration is performed using an axial stack of
T1-​weighted images (e.g. double inversion recovery TSE/​FSE).
Fat will be hyperintense on T1 images. Repeating the stack with
fat suppression applied is used to determine if hyperintense re-
gions are in fact fat.
Administration of gadolinium contrast can identify areas of the
RV myocardium that are actively inflamed or fibrosed. RV LGE
can be seen in areas of prior surgical repair (e.g. transannular
patch in patients with repaired tetralogy of Fallot), in areas of
active inflammation (e.g. sarcoidosis or myocarditis), or in areas
of fibrosis (e.g. arrhythmogenic cardiomyopathy or RV myocar-
dial infarction). LGE can also be visualized in the superior and/​
or inferior ventricular insertion points, a non-​specific finding
consistent with septal strain seen in pulmonary hypertension,
congenital heart disease, non-​ ischaemic cardiomyopathy, or
hypertrophic cardiomyopathy [66]. Technical aspects can limit

Fig. 35.11  TAPSE measurement using MRI. A line connecting the lateral tricuspid valve annulus is drawn in end diastole and end systole. The values are
subtracted to obtain the TAPSE. In this case, the TAPSE was 21 mm, which is normal.
532 CHAPTER 35   Im aging of th e righ t  h eart

Flow volume (ml)

0 10 20 30 40 50 60 70 80 90 100
450
400
350
300

Velocity (ml/s)
250
Systolic flow
200
150
End-diastolic
100
forward flow
50
Fig. 35.12  End-​diastolic forward flow 0
noted in phase contrast of pulmonary –50 Regurgitant flow
artery, suggestive of restrictive RV –100
filling in a patient with tetralogy of 0 100 200 300 400 500 600 700 800 900 1000
Fallot. Time (msec)

the assessment of RV myocardial LGE. The RV myocardium is
much thinner than the LV myocardium which can make it chal-
lenging to distinguish LGE from the blood pool. Acquiring im-
ages at end-​systole can improve the detection of RV LGE. It is
challenging to distinguish fat from LGE, given the lack of LGE
sequences with fat suppression. This can be a relevant distinc-
tion, particularly in patients with suspected arrhythmogenic
cardiomyopathy.
Right heart and pulmonary artery
haemodynamics
Estimation of right atrial pressure with
echocardiography
Evaluation of right atrial pressure (RAP) is of great clinical im-
portance yet remains one of the great challenges in non-​invasive
assessment of cardiac haemodynamics. RAP increases as a re-
sult of right ventricular failure. It is reflected by a dilated RA,
dilated non-​ collapsing inferior (or superior) vena cava, di-
lated coronary sinus, or pericardial effusion in certain clinical
scenarios. Assigning an ordinal value to RAP is a key compo-
nent to estimating right ventricular pressure and PA pressure,
yet suboptimal performance by echo in reliably estimating RAP
by echo has resulted in dropping the RAP component from
establishing probability of pulmonary hypertension (PH) in
ESC/​ERS guidelines [14].
The most commonly used method to estimate RAP is based
on the measurement of IVC diameter combined with degree of
collapse with inspiration. The IVC is easily visualized on TTE
in the subcostal window and is in direct communication with
the RA. Numerous investigators have evaluated IVC size with
or without degree of collapse and have found modest correl-
ations with invasively measured RAP [67]. Despite this weak
relationship, guidelines and recommendations have continued
to advocate this method, owing to its simplicity and ease of
measurement. The EACVI/​ASE recommendations for chamber
quantification state that an IVC dimension of >21 mm with
collapse of <50% represents an elevated RAP (>15 mmHg),
while an IVC diameter of <21 mm with collapse of > 50% rep-
resents a normal or low RAP (3 mmHg) [6]‌. The intermediate
range representing 5–​10 mmHg has been simplified to 8 mmHg.
This intermediate category can be adjusted based on additional
parameters such as hepatic vein systolic:diastolic flow ratios as
illustrated in E Table 35.4.
There are a number of caveats and technical considerations
when using the IVC. Guidelines provide a range of 3–​15 mmHg,
which may significantly underestimate RAP in patients with se-
vere disease wherein RAP can exceed 30 mmHg. When imaging
the IVC, the measurement must be made between 1 and 3 cm
from the orifice. Occasionally anatomic variations result in
prominent valves at the ostium which can affect the IVC diam-
eter. In addition, the IVC may transition from one plane to an-
other giving it the appearance of collapse. Care must be taken to
follow the track of the IVC plane with respiration. Additionally,
studies have suggested that IVC size cut-​off should be indexed
to BSA, with a cut-​off of 17 mm demonstrating greater discrim-
inatory ability in a population of Asians, with a smaller average
BSA [68].
Right atrial size and volume have also been studied as a measure
of RAP. With increasing RA pressure, the RA dilates, however
there may be cases of acute rises in RA pressure without signifi-
cant dilatation and conditions of dilated RA without a very ele-
vated RA pressure (e.g. chronic atrial fibrillation). A dilated RA in
Table 35.4  Estimation of right atrial pressures using
echocardiography
Mean RAP (mmHg) IVC % collapse Hepatic vein flows
0–​5 >50 Vs>Vd
5–​10 >50 Vs=Vd
10–​15 <50 Vs<Vd
>20 <50 Vd flow only
Abbreviations: IVC = inferior vena cava; RAP = right atrial pressure; Vs = hepatic vein
systolic velocity; VD = hepatic vein diastolic velocity.
 Ri g ht hea rt a n d pu l mona ry a rtery ha emody na m i c s
the context of PH is associated with a poor prognosis [69] as it is a
reflection of RV failure. Studies have suggested that a RA volume
35 > ml/​m2 suggests elevated RA pressure and combinations of
indexed RA volume and IVC size may better correlate with RA
pressure [70].
Estimation of pulmonary artery systolic
pressure with echocardiography
Estimation of PA pressure is a frequent indication for echocar-
diography in patients with unexplained dyspnoea, as well as
screening in conditions such as familial PH or connective tissue
diseases [71, 72]. The most commonly used method employs
continuous wave Doppler interrogation of the TR signal using
the simplified Bernoulli equation. This velocity is converted into
a pressure drop between the RV and RA. Knowledge of the RA
pressure, and its addition to this gradient yields a right ventricular
systolic pressure (RVSP). As the pulmonary valve is open in sys-
tole, in the absence of obstruction at this level, the sPAP is equal
to the RSVP (E Fig. 35.13). From the numerous components in-
volved in this calculation, it is clear that there are caveats, both
technical and non-​technical.
(a)
(b)
Fig. 35.13  (a) Schematic representing the assumptions of using the
simplified Bernoulli equation to estimate pulmonary pressures. (b) Example
of calculating the RVSP using the simplified Bernoulli equation using the peak
TR velocity and IVC diameter and collapsibility.
Abbreviations: IVC = inferior vena cava; RA = right atrium; RAP = right atrial pressure;
MPA = main pulmonary artery; PV = pulmonic valve; sPAP = systolic pulmonary arterial
pressure; TR = tricuspid regurgitation; TRV = tricuspid regurgitation peak velocity.
533
As Doppler is angle-​dependent, one must ensure optimal align-
ment of the cursor (<15 degrees) with the jet. This requires con-
sideration of all potential windows including subcostal widow
when eccentric medially-​directed jets are present. Gain settings
are critical since overgaining is amplified, while undergaining
may result in underdiagnosis of PH. Equally important is to en-
sure reproducibility among laboratory readers. Estimation of
sPAP by the Bernoulli equation requires an estimation of RAP
using the methods described above with the stated limitations.
sPAP may be higher than normal in high output conditions
with increased stroke volume, such as in anaemia, thyrotoxicosis
or in athletes, or in the setting of increased pulmonary venous
pressure (left atrial pressure), such as in congestive heart failure
or mitral valvulopathies, without alterations in pulmonary vas-
cular structure or tone. Conversely, with a failing RV, sPAP may
decline as stroke volume falls, such as with advanced PH or
acute pulmonary embolism. Finally, in presence of severe TR,
the simplified Bernoulli equation is not mathematically valid as
the flow is not turbulent. In addition, it may underestimate the
RV-​RA gradient because of an early equalization of RV and RA
pressures.
Factoring in all the above limitations, it is not surprising that
contemporary literature has provided mixed messages on this
topic. Rich et al. [73] and Fisher et al. [74] suggested that echo-
cardiography yields very low bias (i.e. good accuracy) but broad
limits of agreement (i.e. insufficient precision) of between 30
and nearly 40 mmHg above and below those found by RHC by
Bland–​Altman analysis [73, 75]. Each of these studies had im-
portant limitations, and the great majority of scatter that drove
the wide confidence intervals was in the severe PH range. D’Alto
et al. [76] similarly demonstrated a small bias of 3 mmHg, sug-
gesting high accuracy, but confidence limits of 15–​20 mmHg,
again suggesting inadequate precision for single number-​
derived diagnosis. Steckelberg et al. [77] using derivation and
validation samples suggested a very high correlation between
catheter-​derived sPAP and mPAP, which translated to a high de-
gree of correlation between echo-​derived mPAP and catheter-​
derived mPAP. In addition, the bias was low (1–​3 mmHg), but
they did not provide limits of agreement. Out of 109 subjects in
the validation cohort, only two patients with mPAP ≥25 mmHg
were ‘missed’ by echocardiography.
The exact upper reference limit for sPAP is challenging to de-
fine, since a diagnosis of PH is made based on an invasively meas-
ured mean pulmonary arterial pressure (PAP). In general, a sPAP
of > 35–​40 mmHg should provoke a more detailed evaluation for
PH, particularly in symptomatic patients or in high risk groups
such as scleroderma. It should be noted that sPAP increases with
age and BSA [78]. Finally, to avoid the limitations of estimation of
RAP, the ERS/​ESC guidelines on PH recommend that a TR gra-
dient to establish a probability of PH [14].
Mean PAP
The diagnosis of PH is currently based on mPAP measured by
RHC, while by echo, sPAP is most commonly estimated. There
534 CHAPTER 35   Im aging of th e righ t  h eart
are several methods of estimating mPAP non-​invasively, with
invasive validation including: the empiric Chemla formula [79]
(mPAP = 0.6 × sPAP + 2), the method of Aduen [80], which
traces the tricuspid regurgitation envelope to yield a mean pres-
sure gradient, the Mahan method [81], by using pulmonary ac-
celeration time (AccT) measured by pulsed-​wave Doppler of the
pulmonary artery in systole, whereby mPAP = 79 –​(0.45*AccT),
and the Abbas method [82], based on pulmonary regurgitation,
where mPAP = 4*(early pulmonary regurgitation velocity)2 +
estimated RAP.
Pulmonary vascular resistance (PVR)
PVR is an important complimentary parameter in patients with
PH and for those undergoing evaluation for cardiac transplant-
ation. A markedly elevated PVR may assist in separating PAH
from secondary PH due to left heart disease. PVR can be meas-
ured using TR velocity (m/​s)—​a measure of resistance—​and
VTIRVOT (cm)—​a measure of flow. It can be estimated using the
equation: PVR (Wood units) =10 × (TRV/​VTIRVOT) + 0.16. Here,
a TRV/​VTIRVOT <0.175 corresponds approximately to a PVR of
<2 Wood units [17]. These authors proposed that in patients
with increased pulmonary artery systolic pressure (PASP) on
Doppler echocardiography and TRV/​TVIRVOT >0.175, an elevated
PVR is suggested, and these patients may require further inva-
sive workup. Conversely, in patients with TRV/​TVIRVOT <0.2, PVR
values are likely to be normal, even in the presence of Doppler evi-
dence of increased PASP, suggesting that the high PA pressure is
related to increased flow. A TRV/​VTI RVOT >0.275 was accurate
in predicting a PVR >6 WU, while squaring the TRV (TRV2/​
TVIRVOT) performed even better at these high PVR levels [83].
Haemodynamic assessment with MRI
At present, MRI has a limited role in estimation of right-​sided
cardiac pressures. There is an emerging interest in MRI-​derived
parameters that correlate with elevated pulmonary pressures.
Compared to controls, patients with PAH have four abnor-
malities in the PA: less distensibility, decreased average flow,
decreased peak velocity, and decreased average time to peak vel-
ocity [84]. As in echocardiography, PVR can be estimated from
MRI-​derived parameters [85, 86] albeit these calculations are not
routinely used clinically.
Fig. 35.14  Visualization of superior
sinus venosus ASD with SSFP sequence
on MRI. The sinus venosus ASD was
not visualized in the standard four-​
chamber view (left), however was
well visualized (arrow) on the superior
horizontal long-​axis view (right).
Conditions associated with right
ventricular pathology
Conditions associated with RV volume
overload
Interatrial shunt
Interatrial shunts include patent foramen ovale, primum atrial
septal defect (ASD), secundum ASD, sinus venosus ASD, and cor-
onary sinus defects.
A comprehensive echocardiography protocol, including an
agitated saline contrast study if required, is recommended
to assess for interatrial shunts. MRI evaluation of possible
interatrial shunt includes short-​axis and axial stacks of SSFP
images, phase contrast of the pulmonary artery, aorta, and
possibly through the atrial septal defect, and magnetic reson-
ance angiography (MRA) to evaluate the pulmonary venous
anatomy [87].
The goals of imaging in these lesions, particularly the ASDs,
include determining the type of defect, determining if the defect
is haemodynamically significant, determining if there are any
associated defects (e.g. anomalous pulmonary venous drainage)
and determining if there are any contraindications to closure,
such as PH (sPAP >50% of systemic systolic blood pressure and/​
or PVR >1/​3 SVR).
Echocardiography and MRI can both visualize atrial septal de-
fects, however there are situations where one modality may be
advantageous. Injection of agitated saline during echocardiog-
raphy is a sensitive test to exclude atrial septal defects. Dynamic
imaging when gadolinium is injected can also be used to detect
the presence of an interatrial shunt on MRI. The relatively poorer
spatial resolution of MRI limits visualization of small defects,
given the standard slice thickness of 6–​8 mm. While thinner slices
(4 mm) can be acquired, the lower signal to noise ratio could limit
the image quality of thinner slices. Accordingly, it is challenging
to identify a patent foramen ovale on MRI. Visualization of sinus
venous defects using echocardiography can be challenging using
standard imaging windows. The ability to acquire images in any
plane with MRI has advantages when a sinus venosus defect is
suspected (E Fig. 35.14).
 C ondi ti on s as s o ciated w i th ri g ht ven tri cu l a r pat h ol o g y
ASDs are typically visualized with axial-​and short-​axis stacks
of SSFP images.
The direction of flow can be determined using colour
Doppler on echocardiography and in-​ plane phase contrast
imaging on MRI.
The haemodynamic significance of the defect can be assessed
by the Qp:Qs or right-​sided chamber enlargement. Qp:Qs values
of >1.5 are consistent with a haemodynamically significant shunt.
Qp:Qs can be calculated using echo or MRI, with the MRI assess-
ment viewed as more reliable. The echo assessment is based com-
paring the RV stroke volume (RVOT area × RVOT VTI) to the LV
stroke volume (LVOT area × LVOT VTI). Although this method
is technically feasible, its clinical utility is limited by error par-
ticularly in the RVOT and LVOT measurements used to calculate
the outflow tract areas. The MRI assessment of Qp:Qs compares
the RV stroke volume to the LV stroke volume. Stroke volumes
are preferably obtained by direct measurement of forward flow
through the main pulmonary artery and aorta using phase con-
trast sequences, however stroke volumes obtained from the volu-
metric assessment from short-​axis or long-​axis stacks can also be
used provided there is no significant valvular regurgitation.
Right-​sided chamber enlargement can be assessed by echocar-
diography or MRI, with MRI being viewed as the relative gold
standard for volumetric quantification of right ventricular size.
Diastolic septal flattening indicative of RV volume overload can
be observed on echocardiography and MRI.
Pulmonary venous anomalies can coexist with ASDs. Most
frequently, the right upper pulmonary vein drains across a su-
perior sinus venosus defect, however there could also be anom-
alous pulmonary venous connection with the right upper and/​or
middle pulmonary veins connecting more cranially to the SVC.
Transthoracic echocardiography has limited utility in delineating
the pulmonary venous anatomy in adults. Transoesophageal
echocardiography can identify the pulmonary venous anatomy, as
(a)
Fig. 35.15  (a) TTE image depicting secundum ASD with left-​to-​right shunting on colour Doppler (b) 3D TEE of the same patient further depicting the large
secundum ASD (measuring 17 × 25 mm) used to guide percutaneous ASD closure.
535
described in Section 3. Using MRI, pulmonary venous anatomy
can be assessed with black blood sequences or MRA.
Assessment of PH can be performed non-​invasively on echo-
cardiography or invasively with heart catheterization. Although
techniques for estimation of pulmonary pressures and PVRs using
MRI are emerging, the utility of MRI to measure pulmonary pres-
sures and pulmonary vascular disease remains limited.
Finally, both methods can delineate the size of the defect and
assess for feasibility for percutaneous closure, though three-​
dimensional echocardiography is more commonly used for this
indication—​particularly for secundum defects (E Fig. 35.15).
Transoesophageal or intracardiac echocardiography are routinely
used to guide closure of these defects.
E Table 35.5 summarizes the utility of each modality in assess-
ment of interatrial shunts.
Tricuspid regurgitation
Right ventricular dilation could be the cause or consequence of
TR. In evaluation for the mechanism of TR, the spatial and tem-
poral resolution of echocardiography provides advantages over
MRI in investigating the mechanism of the TR, which is often
critical in determining surgical approach, when indicated. The
right atrium should be assessed as well, as a dilated right atrium,
particularly in the setting of permanent atrial fibrillation, can
contribute to TR severity. The thin tricuspid leaflets are often not
well visualized on MRI. Measurement of the tricuspid valve an-
nulus at end diastole in the four-​chamber view can be performed
on both echocardiography and MRI, although normal values are
less well defined using MRI.
From a management perspective, surveillance of RV size and
function with echocardiography or MRI can identify progressive
changes in the right ventricle. In patients with mildly symptom-
atic or asymptomatic primary TR, progressive RV dilation or dys-
function is a Class 2a indication for valve intervention [88].
(b)
536 CHAPTER 35   Im aging of th e righ t  h eart

Table 35.5  Comparison of the utility of echocardiography and MRI in the assessment of atrial septal defects

Transthoracic Echocardiography MRI

Visualization of the shunt
Evaluation of haemodynamic significance
Estimation of pulmonary pressures
Evaluation for associated defects (i.e. PAPVR)
Can visualize small shunts
Off-​axis imaging for sinus venosus defects
Visualization of RA and RV dilation
Measurement of Qp:Qs challenging due to
measurement errors
Possible
Limited visualization of pulmonary veins on TTE
Visualization of sinus venosus defects
Limited utility in small or fenestrated shunts
Non-​invasive reference standard for RV volumes
Reliable assessment of Qp:Qs
Limited value
Pulmonary veins can be visualized using axial stacks
of black blood images or MRA

Pulmonary regurgitation can be identified. Once a TR velocity >2.8 m/​sec has been identi-
Significant pulmonary regurgitation is most commonly en- fied, the next step is to look at the pulmonic valve and possibly the
countered as a sequalae of repaired congenital pulmonary sten- pulmonary artery bifurcation to rule-​out any pulmonary stenosis.
osis with pulmonary valvotomy or repaired tetralogy of Fallot. The pulmonary valve can be seen from the parasternal RV out-
Quantification of the degree of pulmonary regurgitation is pos- flow tract view. In a normal pulmonic valve, the cusps appear mo-
sible with both echocardiography and MRI and is fully described bile and open in a parallel position to the pulmonary artery wall.
in Section 3. Pulmonic stenosis
The measurement of RV size, RV function, and RVSP informs
In pulmonary stenosis the leaflets will appear ‘doming’ in systole
whether significant pulmonary regurgitation requires interven-
with restricted mobility. By colour Doppler, there is evidence of
tion in asymptomatic patients. In asymptomatic patients with
pulmonary stenosis (PS) as accelerated flow beyond the stenotic
repaired tetralogy of Fallot, PVR is recommended as a Class 2a
pulmonary valve (PV). Echocardiography has a significant role
recommendation if two of the following five parameters are pre-
in timing and identifying candidates for transcatheter pulmonic
sent: (1) More than mild RV or LV dysfunction; (2) RV dilation
valve intervention. The size of the pulmonary annulus should
by MRI (RVEDVi >160 ml/​m2 or RVESVi >80 ml/​m2); (3) relative
be measured, either on echocardiography or CT to determine
RV dilation defined as RVEDV >2 times the LVEDV; (4) RVSP
if the valve size is suitable for available transcatheter pulmonic
>2/​3rds of the systemic pressure; and (5) objective decline in ex-
valves and to determine the optimize size the balloon if balloon
ercise tolerance as measured by cardiopulmonary exercise testing
valvotomy is considered. Indications for intervention include
[89]. Four of these five criteria are based on imaging parameters,
asymptomatic patients with and peak gradient >60 mmHg and
requiring both echocardiography and MRI. The volume-​related
symptomatic patients and peak gradient >50 mmHg.
criterion is based on multiple studies focused on identifying cut-​
Typically, chronic severe RV pressure overload is characterized
offs of RV dimensions beyond which valve intervention does not
by a hypertrophied RV wall and a systolic D-​shape deformation
result in RV remodelling [62, 90–​94]. Findings from a cohort of
of the ventricular septum as seen from parasternal short-​axis pro-
339 patients with tetralogy of Fallot identified the optimal time
jections at mid-​LV level. As a result, the short-​axis of the LV will
for detection of progression was 3 years [95], forming the basis of
appear circular in diastole but during systole will assume an oval
the recommendations to perform serial exams at 3 year intervals.
shape with systolic flattening of the ventricular septum. Thus, the
In patients with RVEDVI >150 ml/​m2 or a progressive increase
LV short-​axis will cease to be circular and instead present with
in RVEDVi (>25 ml/​m2 from previous) or progressive decline in
two asymmetric diameters perpendicular to each other during
RVEF (RVEF <48% or a decline in RVEF more than 6% from pre-
systole; the major axis and the minor axis. The ratio of major over
vious), a repeat study in 12 months is recommended [96].
minor axis is called the eccentricity index (E Fig. 35.16a, b). The
Progressive worsening of MRI-​derived RV volumes or RVEF
greater the eccentricity index the greater the severity of elevated
are criteria for intervention in patients with pulmonary regurgi-
RV systolic pressure. In addition to those anatomic changes, the
tation following repair of congenital pulmonic stenosis, although
RV may become hypokinetic with reduced systolic function, visu-
cut-​off values are not well defined.
alized from numerous imaging planes, using quantitative meas-
Beyond measurement of RV size and function, cardiac MRI
ures presented above. This overall RV hypokinesis separates a
can provide anatomical details to inform whether transcatheter
pressure loaded RV from a volume loaded RV, where the RV will
pulmonary valve implantation is technically feasible, including
retain its preserved systolic function until very late in the disease
the measurement of the RVOT and pulmonary valve annulus.
process.
Conditions associated with RV pressure overload
Estimation of RV pressure overload is of great clinical importance Pulmonary embolism
and Doppler echocardiography can be used to screen patients in In pulmonary embolism (PE), the echocardiographic signs are
the community as long as the maximal tricuspid regurgitant jet often indirect and reflected primarily by the RV size and function.
 C ondi ti on s as s o ciated w i th ri g ht ven tri cu l a r pat h ol o g y
(a) (b)
(c) (d)
The greater the RV with a poor function may be related to an ad-
verse outcome. A distinctive pattern of mid-​free-​wall hypokinesis
with a normal or hyperdynamic RV apex, the McConnell sign,
has been described in patients with acute pulmonary embolism
(PE), but this wall motion pattern is not specific and has also been
seen in some patients with RV infarction or acute hypoxemia and
acidosis (E Fig. 35.16c).
Acute PE may lead to RV pressure overload and dysfunction.
TTE findings include:
◆ RV dilatation
◆ free-​wall hypokinesis
◆ paradoxical interventricular septal motion
◆ tricuspid regurgitation
◆ raised pulmonary pressure
◆ dilated non-​collapsing IVC
◆ LV diastolic abnormalities
Direct visualization of right heart thrombus using echocardi-
ography is uncommon, with thrombus seen in less than 4%
of suspected PE patients and therefore its main role in these
patients is in identifying the indirect signs of acute pressure
overload. The direct visualization of mobile thrombi within the
right heart is rare but highly diagnostic when detected and is
associated with increased mortality. With transthoracic echo-
cardiography thrombus is seen most commonly in patients
with suspected PE within the proximal IVC or right atrium and
537
Fig. 35.16  (a, b) The LV appears
circular in diastole (left) while in
RV pressure overload (right) the LV
appears ‘deformed’ with a major
and a minor axis that forms the
eccentricity index. (c) The McConnell
sign. This is characterized by a regional
RV dysfunction with mid-​free-​wall
hypokinesia while the apical motion is
preserved (arrow). (d) RV inflow tract
view with a highly mobile thrombus
in the RA.
appear as mobile, often worm-​like masses, which if unattached
appear to swirl around within the associated chamber, usually
in the atria (E Fig. 35.16d).
Chronic pulmonary hypertension
PH is presently defined as an increase in mean pulmonary arterial
pressure to ≥25 mmHg at rest as assessed by right heart cath-
eterization. It is classification includes five categories. The most
common category is the post-​capillary PH, that of secondary PH
due to left heart disease (Group 2), an elevated PA wedge pres-
sure (≥15 mmHg), and a normal PVR of ≤3 WU [14]. Hence a
comprehensive echocardiographic study with measures of eleva-
tion in left-​ventricular systolic and diastolic function, left-​sided
valvular disease, and left atrial volume must be performed in all
cases. Precapillary PH is characterized by a mean PAP ≥25 mmHg,
an elevated PVR of ≥3 WU, and a low PA wedge pressure of ≤15
mmHg [14]. Patients with precapillary PH have generally more
pronounced signs of RV pressure overload with a normal left-​sided
E/​e’ ratio, a very dilated IVC (usually >20 mm), a very dilated
RV cavity with the RV apex dominating the apical four-​chamber
view, an eccentricity index >1.2, and notching of the RVOT pulsed
Doppler envelope, suggesting high PVR and a prominent reflected
wave [97]. Echocardiographic parameters that provide prognostic
information in the past had focused on indirect signs of RV failure
(RA dilatation and pericardial effusion) [69], but more recently,
direct measures of RV systolic function such as TAPSE and RV free
538 CHAPTER 35   Im aging of th e righ t  h eart
wall strain have predicted outcomes [61, 75]. It should be noted
that one cannot simply rely on TAPSE or S’ to assess RV systolic
function in PAH, as the RV may be significantly impaired with
focal preservation of the basal free wall segment only.
Cardiomyopathic conditions associated with
RV pathology
Arrhythmogenic cardiomyopathy
Arrhythmogenic cardiomyopathy (AC, formerly termed
arrhythmogenic ventricular cardiomyopathy) is a rare yet im-
portant diagnosis given its associated risk of sudden cardiac death
and autosomal dominant inheritance pattern. Echocardiographic
and MRI-​derived parameters are components of the Modified
Task Force Criteria for AC [15] (E Table 35.6).
The positive predictive value of the Modified MRI-​derived cri-
teria is 55% [64]. There are five important aspects of the criteria.
Firstly, patients need to have RV wall motion abnormalities plus
abnormalities in either RV size or function to fulfil the criteria.
The presence of RV dilation or global RV dysfunction on its own
does not fulfil the criteria. Secondly, the imaging parameters do
not make the diagnosis; tissue characterization (myocardial bi-
opsy), repolarization abnormalities, depolarization/​conduction
abnormalities, arrhythmias, and family history must also be as-
sessed. A definite diagnosis includes two major or one major
and two minor criteria or four minor criteria from different cat-
egories. Thirdly, the cut-​offs for RV dilation differ from the nor-
mative values used in non-​AC assessments. Fourthly, although
the presence of fibro-​fatty infiltration is often assessed in patients
with suspected AC, it is a non-​specific finding and is not included
in the criteria for AC [98]. Lastly, right ventricular LGE is not a
component of the criteria however can be identified in patients
with AC. RV LGE has been reported in up to 88% of patients with
AVRC [99, 100]. Approximately 50% of cases also involve in the
LV, highlighting the need to comprehensively evaluate the LV,
including tissue characterization with LGE. LGE can be identified
in the basal inferolateral wall of the LV in patients with AC [64].
The multimodality imaging approach to AC is outlined in
the EACVI expert consensus statement on AC [98]. The echo-
cardiographic assessment for AC includes a comprehensive
Table 35.6  Imaging-​related criteria for AC
Major
Echocardiographic Regional RV akinesis, dyskinesis or aneurysm, AND 1 of the
following (end diastole)
◆​  PLAX RVOT  ≥2 mm
(≥19  mm/​m2)
◆​  PSAX RVOT  ≥36 mm
(≥21  mm/​m2)
◆​  Fractional area change
≤33%
MRI Regional RV akinesis, dyskinesis or dyssynchronous contraction,
AND 1 of the following (end diastole)
◆​  RVEDVi ≥110 ml/​m2 (male) or RVEDVi ≥100 ml/​m2 (female)
◆​  RVEF ≤40%
echocardiogram, including the required RVOT measurements,
multiple views of the RV to identify regional wall motion abnor-
malities (E Fig. 35.17a, b) and FAC to assess the Modified Task
Force criteria. There is an emerging role for 3D TTE to identify re-
gional wall motion abnormalities and assess RV size and function
in AC, albeit cut-​offs for abnormal values specific to AC are not
well defined [98].
The MRI assessment for AC includes an axial stack of double
inversion TSE/​FSE with and without fat suppression, axial, and
short-​axis stacks of SSFP cines covering the entire right ventricle,
RV inflow-​outflow SSFP cine and RVOT SSFP cine [8]‌. Close at-
tention should be paid to identify any regional wall motion ab-
normalities on each view. The ‘accordion sign’ to describe focal
‘crinkling’ of the myocardium has been described in patients
with AC (E Figure 35.17c, d) [101, 102]. Recognition of normal
variants is important to avoid overdiagnosis of regional wall mo-
tion abnormalities (E Fig. 35.10). Delayed gadolinium imaging
is performed including axial stack, short-​axis stack, and four-​
chamber and vertical two-​chamber slices [8].
Athlete’s heart
As in many other conditions, the focus of cardiac remodelling
was on the left heart with criteria established to help assist in
the differentiation between normal and pathologic [103]. Only
more recently have investigators looked rightward to study ana-
tomic and physiologic changes in the athlete. This distinction is
particularly important when different remodelling patterns exist
between strength training and endurance-​trained athletes, with
evidence of RV chamber dilatation by RV basal diameter, as well
as indexed RV EDV in the endurance-​trained athletes (ETAs),
particularly with increased duration of training [104]. The evi-
dence for increased wall thickness is less robust, with a trend
found in strength training athletes (STAs). From Ohm’s law, the
relationship between pressure and flow and resistance, greater
flow should yield a higher pressure. Accordingly, the ETAs also
had evidence of increased resting PAP with a 2SD cut-​off of 40
mmHg. Interestingly, both ETAs and particularly STAs demon-
strate lower free wall strain, but have increased Isovolumetric
Ventricular acceleration and no difference in B-​type natriuretic
peptide (BNP) levels, suggesting that this reduced strain may
Minor
Echocardiographic
Regional RV akinesis or dyskinesis, AND 1 of the following
(end diastole)
◆​  PLAX RVOT ≥29 to <32 mm (≥16 to <19 mm/​m2)
◆​  PSAX RVOT ≥32 to <36 mm (≥18 to <21 mm/​m2)
◆​  Fractional area change >33%
Regional RV akinesis, dyskinesis or dyssynchronous
contraction, AND 1 of the following (end diastole)
◆​  RVEDVi ≥100 to <100 ml/​m2 (male) or RVEDVi ≥90 to
<100 ml/​m2 (female)
◆​  RVEF >40 to ≤45%

(a) (b)
(c) (d)
not be maladaptive [105]. Finally, sometimes the differentiation
between athlete’s heart and AC remains challenging, as cer-
tain phenotypic appearances overlap. The RV dilation is seen in
both, and parameters of global dysfunction such as strain may
be reduced in both. Careful evaluation for regional dysfunction
including areas of akinesis or thinning or bulging may be of value,
but even this finding may be seen in athlete’s heart and may be ac-
companied by regions of LGE uptake with MRI, suggesting some
overlap, albeit without typical desmosomal mutations [106]. The
EACVI’s multimodality cardiac imaging approach to the athlete’s
heart recommendations suggest that suspected AC should be
pursued with both echocardiography and CMR, recognizing that
neither modality may conclusively differentiate and that diag-
nosis remains a clinical one [107].
Future directions
◆ Derivation and validation of gender-​ specific and indexed
echocardiographic-​derived parameters for right-​sided size and
function could improve the standardization of echocardio-
graphic measurement of right-​sided chambers.
◆ Further attention to RA function, using either RA strain or
estimations of RA ejection fraction on echocardiography and
MRI, could enhance our understanding of the impact of RA
function in various disease states.
◆ With further standardization of RV free wall strain through
collaborative societal and industry cooperation, the clinical
Sum m a ry a n d rec o m m e n dat i on s 539
Fig. 35.17  (a, b) TTE images
identifying focal dyskinesis of the
mid-​inferior wall. Note the focal
outward motion of the inferior wall
in systole (b) as compared to the
diastolic image (a). (c, d) Accordion
sign in arrhythmogenic ventricular
cardiomyopathy on MRI. Yellow
arrow points to focal crinkling of
myocardium.
utility of RV free wall strain for diagnosis, management, and
prognostication could increase.
◆ Improved 3D imaging through enhanced imaging quality and
improvements in the post-​processing software is anticipated.
◆ Disease-​based values for indices of chamber size and function
to assist in prognostication as well as in guiding therapy, e.g. RV
size and function in the setting of severe TR.
◆ Evolving research to further explore ventricular-​arterial coup-
ling will enhance our understanding of RV dysfunction in the
presence of elevated PVR.
Summary and recommendations
This chapter has outlined how echocardiography and MRI can
assess right ventricular size and function qualitatively and quan-
titatively. The basic right heart evaluation by echo and MRI are
shown in E Table 35.7.
Each modality has its respective strengths and weaknesses
demonstrated in E Table 35.8.
Strengths of echocardiography include portability, ability to
obtain haemodynamic measurements such as estimated right ven-
tricular systolic pressures, and lack of imaging artefacts from car-
diac implantable devices. Weaknesses of echocardiography include
challenges to comprehensively assess the right ventricle due to its
position in the chest and complex geometry, poor acoustic win-
dows limiting image quality, and challenges in measuring right ven-
tricular volumes and RVEF. Although 3D acquisitions on echo can
540 CHAPTER 35   Im aging of th e righ t  h eart

Table 35.7  Summary of parameters to quantify RV size and function provide RV volumes and RVEF, the availability of analysis software
on echocardiography and MRI and the ability to visualize the entire RV in patients with RV dilation
limit the widespread use of 3D echo to routinely assess the RV.
Echocardiographic parameter Abnormal cut-​off
The strengths of MRI include the ability to visualize the entire
Chamber size RV to obtain right ventricular volumes and RVEF, less interstudy
  RA volume Females >33 ml/​m2: Males >39 ml/​m2 variability in volume and RV function measurements as compared
  RA major-​axis diameter >5.3 cm to echocardiography, the ability to image in any plane, the ability
  RV basal diameter >4.2 cm to image associated structures such as the pulmonary veins, and
to some extent, tissue characterization. Weaknesses of MRI in-
  RVOT parasternal long-​axis >3.3 cm
  diameter clude poor image quality due to breathing artefacts or arrhythmias,
limited scans due to patient claustrophobia, artefacts from cardiac
Function
implantable devices and limited assessment of haemodynamics.
  TAPSE <1.7 cm While precise RV volumes and RVEF can be measured, normative
  S’ <9.5 cm/​s values may vary based on institution and acquisition parameters.
  Fractional area change <35% The RV is often first assessed with echocardiography, with fur-
  MPI, pulsed Doppler method >0.42 ther evaluation by MRI when required. In situations where pre-
cise measurements of RV size and function are required, such as
  RVEF, 3-​Dimensional Echo > 45%
in the assessment of the haemodynamic significance of an atrial
Haemodynamics
shunt or the evaluation of suspected AC, volumetric analysis
  IVC diameter >2.1 cm with MRI has advantages. In situations where estimation of RV
  IVC collapse with sniff <50% or pulmonary pressures are required, MRI has limited value. It is
  SPAP >35–​40 mmHg important to recognize that both modalities have strengths and
MRI parameter Abnormal cut-​off
weaknesses; valuable and clinically applicable information can be
identified from each modality. In situations where both echocar-
  RA volume (biplane) >126 ml/​m2
diography and MRI are performed, review of both imaging mo-
  RV end-​diastolic volume Females >112 ml/​m2: Males >121 ml/​m2 dalities to integrate the imaging findings and to use the modalities
  RV end-​systolic volume Females >52 ml/​m2: Males >59 ml/​m2 in a complementary fashion may allow for the optimal compre-
  RVEF Females <51%, Males <52% hensive assessment of RV size and function.

Table 35.8  Comparison of strengths and weaknesses of multimodality assessment of the right ventricle

Echocardiography MRI
Safety +++ +++
Acoustic window dependent Yes No
Patient factors Claustrophobia
Inability to breath hold
Effect of cardiac implanted devices None No longer contraindicated
Diagnostic yield 74% for RV assessment [108]
Effect of arrhythmias Limits image quality of 3D acquisitions Limits image quality of SSFP and phase contrast sequences
Temporal resolution +++ ++
Spatial resolution +++ ++
Evaluation of RV thickness + ++
RV dimensions ++ +++
RV volumes With 3D echo +++
Inter-​rater reliability ++ +++
Accuracy of RV systolic function 2D echo ++ +++
3D echo +++
Tissue characterization Limited assessment RV LGE and fibro-​fatty infiltration can be identified
Major limitations Geometric assumptions limit volumetric assessment Cannot reliably assess PA or RV pressures
Poor visualization of RV endocardial border

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Contents
What is myocardial viability?  545
Myocardial stunning  545
Myocardial hibernation  546
Non-​transmural necrosis  546
Transmural necrosis  546
Assessment of myocardial viability by
echocardiography  546
Methodology  546
Interpretation  547
Other stress modalities  549
Contrast echocardiography  549
Coronary flow reserve  549
3D echocardiography  549
Myocardial deformation  549
Clinical settings  551
Other indications  553
Ischaemic mitral regurgitation  553
Clinical implications  553
Assessment of myocardial viability by
nuclear imaging  554
Nuclear methods for assessing myocardial
viability  554
Accuracy of nuclear imaging in assessment of
myocardial viability  554
Application of nuclear viability assessment in
patient management  554
Assessment of myocardial viability by
cardiac magnetic resonance (CMR)  555
Principles of myocardial viability detection
by CMR  555
Native T1 mapping  557
Clinical results of MR viability imaging  557
CHAPTER 36
Assessment of viability
Luc A. Pierard, Paola Gargiulo,
Pasquale Perrone-​Filardi, Bernhard Gerber,
and Joseph B. Selvanayagam
What is myocardial viability?
Ischaemic left ventricular (LV) dysfunction due to coronary artery disease (CAD) is
steadily increasing as a consequence of the ageing of the population and of improved
survival of patients with acute coronary syndromes and currently represents the first
cause of heart failure (HF).
Myocardial function is dependent on blood supply, as anaerobic reserve is minimum
due to a nearly maximal arteriovenous oxygen extraction. At rest, myocardial blood
flow remains normal even in the presence of severe coronary artery stenosis (up to 85%
diameter stenosis) by coronary autoregulation. In the presence of transstenotic pressure
gradient due to epicardial coronary stenosis, arteriolar dilatation maintains normal myo-
cardial flow at rest but with a progressive reduction in flow reserve. When arteriolar
dilatation is maximal, autoregulation is exhausted and myocardial ischaemia develops.
The limit of autoregulation depends on myocardial oxygen demand and is influenced
by heart rate. Tachycardia increases oxygen demand and supply is reduced because of
a decreased diastolic perfusion time. In the presence of acute ischaemia, there is a close
relation between subendocardial perfusion and transmural function. Indeed, the con-
tribution of subendocardium to myocardial thickening largely exceeds the contribution
of the subepicardium. Akinesia can therefore result from subendocardial ischaemia and
transmural ischaemia is not necessary. Acutely, there is perfusion-​contraction matching.
An intervention that reduces heart rate (recovery after exercise or beta-​blocker therapy)
results in increased diastolic perfusion time, increased subendocardial perfusion, and
improvement of myocardial thickening. However, different altered myocardial states can
result from either prolonged ischaemia or briefer severe ischaemia followed by restor-
ation of normal perfusion (stunning) or the presence of severe chronic coronary stenosis
or coronary occlusion with insufficient collateral circulation (hibernation).
Myocardial stunning
Myocardial stunning is characterized by transient myocardial dysfunction after a pro-
longed and severe ischaemia or a brief coronary artery occlusion followed by a res-
toration of normal myocardial perfusion [1]‌. This state implies perfusion-​contraction
mismatch. Stunned myocardium is viable; functional recovery is classically observed
after several hours or days and is complete and spontaneous if no necrosis had occurred
and if flow reserve is present [2]. In this situation, oxidative metabolism is preserved
without ultrastructural alterations. This state was first demonstrated in experimental
studies [3]. Importantly, stunned myocardium has extensive contractile reserve that can
be elicited by catecholamines: dobutamine infusion coupled with an imaging technique
or epinephrine and norepinephrine during exercise.
546 CHAPTER 36   Asse ssment of viabilit y
Myocardial hibernation
Myocardial hibernation corresponds to persistent dysfunction of
viable myocardium due to chronic reduction of myocardial per-
fusion, or more frequently flow reserve. This chronic contractile
dysfunction at rest acts as a protective mechanism finalized to en-
sure myocyte survival.
Myocardial metabolism is impaired with a flow-​metabolic mis-
match: myocardium utilizes glucose rather than free fatty acids.
Metabolic changes can be imaged by18F fluorodeoxyglucose
(FDG) using nuclear techniques, although the limited spatial
resolution does not permit measurements in the different layers
of the myocardium. There may be however variations in relative
flow and FDG uptake, with more reduction in flow and more
FDG uptake in the subendocardium.
In contrast with myocardial stunning, the concept of hiberna-
tion was introduced from clinical observations: chronic dysfunc-
tion, reversible after revascularization [4]‌. Hibernation was first
considered an adaptation to chronic reduction in resting myocar-
dial flow [5]. Clinical and experimental studies have shown that
chronic dysfunction can also develop after repeated episodes of
transient ischaemia resulting in cumulative chronic myocardial
stunning. This is due to impaired coronary vasodilator reserve,
in other words reduced flow reserve and not necessarily reduced
perfusion at rest [6].
In this condition, ultrastructural changes can develop: reduc-
tion of the number and function of the mitochondria; intracellular
accumulation of glycogen; intercellular fibrosis; and reduction
of contractile material [7]‌. Recruitable contractile reserve with
dobutamine can be observed, but obviously depends on the per-
sistence of some contractile material, on beta-​receptor density,
on the level of flow reserve and on heart rate. Improvement in
regional thickening can be transient with ischaemia and thus re-
duced contraction when myocardial demand is increased and the
flow reserve is too low [8].
Distinction between stunning and hibernation is interesting
from a pathophysiologic point of view [9]‌. Clinically, it should
be known that there is an important heterogeneity in myocardial
Fig. 36.1  Echocardiographic markers
of scar tissue: left: akinetic, thin, and
hyperechogenic myocardium; right:
absence of perfusion at myocardial
contrast echocardiography.
states from patient to patient, from segment to segment in the
same patient and from layer to layer. Function recovery depends
on the restoration of sufficient flow reserve, usually by myocar-
dial revascularization, but also possibly by a reduction in heart
rate at rest and during the daily activities of the patients through
beta-​blocker therapy or the use of pure bradycardic agents such
as ivabradine.
Non-​transmural necrosis
In patients with acute myocardial infarction rapidly treated by
primary percutaneous intervention, myocardial and capillary sal-
vage limit the transmural extent of necrosis. When necrosis oc-
curs in >20% of myocardial thickness, the segment is akinetic. In
this state, the subepicardial layer is normal and an inotropic agent
or exercise recruits the contribution of the outer layer. This con-
dition should not be defined as myocardial viability, but rather as
presence of contractile reserve.
Transmural necrosis
When necrosis is transmural, there is no recovery after revasculari­
zation. Imaging of complete necrosis is also clinically relevant,
indicating absence of myocardial viability. (E Fig. 36.1).
Assessment of myocardial viability by
echocardiography
Echocardiography is a versatile imaging technique, non-​ionizing,
easily reproducible, and can be obtained at the bedside. However,
the assessment of myocardial viability frequently requires a
multimodality approach.
Methodology
Although resting echocardiography can provide valuable in-
formation regarding myocardial viability or necrosis, stress
echocardiography is the most frequently used method. Several
 Asses sm en t of m yo ca rdia l via b i l i t y b y echo ca rdi o g r a ph y
pharmacologic agents have been tested: arbutamine, enoximone,
nitroglycerin, levosimendan, dipyridamole, but the most widely
used test is dobutamine stress echocardiography (DSE).
Logistics
Stress echocardiography requires appropriate material and ex-
perienced physicians or sonographers and constant surveillance
throughout the test. Appropriate training is mandatory: acquisi-
tion and interpretation of at least 100 stress exams under supervi-
sion and >100 exams/​year to maintain competence [10, 11].
The best echo machine in the laboratory should be used to obtain
adequate images. Secondary harmonic imaging is necessary [12].
A nurse is present to adapt the infusion doses, monitor the blood
pressure and inject an antidote if necessary (beta-​blocker with
DSE or aminophylline with dipyridamole test). Pulse oximetry
and a resuscitation equipment including defibrillator, drugs, and
oxygen delivery should be available. The test can be performed in
outpatients but in an hospital with an intensive care unit [13].
A full digital stress echo package is necessary.
Acquisition of images
Most tests are obtained using two-​ dimensional transthoracic
echocardiography. Images are triggered at peak R wave which
requires a good quality electrocardiograph (ECG) and an ap-
propriate amplitude of R waves. Complete cardiac cycles are
obtained. It is preferable to record the previous cycle or to select
the best loop among several recorded cycles. The protocol of ac-
quisition is predefined: number of views, number of steps, tissue
Doppler images, or contrast use. Interpretation should be avail-
able on stations with possible slowing of the images. A complete
quantification package is also needed.
Most patients in whom viability is tested are treated with a
beta-​blocker. Long withdrawal is not recommended. If resting
tachycardia is present or if heart rate increases too rapidly, the
eventual hibernating myocardium can be already ischaemic at the
onset of the test.
Recording
Classically, five different views are recorded (parasternal long-​
and short-​axis views, apical four-​chamber, two-​chamber, and
long-​axis views) at rest, low-​dose, peak dose of dobutamine and
recovery. Usually, the duration of each step is 3 minutes, but can
sometimes be shortened to 2 minutes or lengthened to 5 min-
utes. The first low dose is frequently 10 mcg/​kg/​min but can be
decreased to 5 mcg/​kg/​min or even 2.5 mcg/​kg/​min to avoid a
too rapid increase in heart rate, especially if a beta-​blocker has
been withdrawn. Incremental doses are 20, 30, and 40 mcg/​kg/​
min with the eventual addition of atropine from 0.25 mg to 1 mg
to obtain the target heart rate when both viability and inducible
ischaemia are evaluated [14]. Larger doses of dobutamine (50
mcg/​kg/​min) or atropine (1.5–​2 mg) are rarely used. Atropine can
be added earlier than at peak dobutamine dose to obtain a more
gradual increase in heart rate.
With a dedicated table, a low charge of exercise can be added to
completely eliminate the vagal tone.
547
Table 36.1  Semiology of stress echocardiography
Rest Stress Myocardial state
Normokinesis Hyperkinesis Normal
Normokinesis Hypokinesis Ischaemia
Hypokinesis Normokinesis Viability, C Reserve
Akinesis Biphasic response Viability, at jeopardy
Akinesis Akinesis Scar
No contractile material
Infusion of a beta-​blocker (intravenous metoprolol) is system-
atic in some laboratories or performed only in case of side effect,
too low decrease in heart rate or arrhythmias.
Interpretation
Echocardiography permits the evaluation of endocardial mo-
tion, but more importantly myocardial thickening and its timing,
with eventual delayed thickening or post-​systolic thickening
(E Table 36.1).
Hypokinesis at rest implies the presence of some viability.
Akinesis is present not only in regions with transmural necrosis
but as soon as >20% of myocardial thickness is necrotic [15].
There are several responses during DSE:
◆ Sustained improvement of myocardial thickening, not delayed
at low to peak dobutamine doses. This implies contractile re-
serve with preserved or recovered flow reserve, without in-
duced myocardial ischaemia. In acute coronary syndrome,
this response is seen in stunned myocardium. In chronic con-
ditions, the response corresponds to contractile reserve of the
preserved subepicardial layer (E Fig. 36.2).
◆ Biphasic: akinetic regions showing improvement of thick-
ening at low dose of dobutamine followed by deterioration at
higher doses. This is observed in viable segments perfused by
a coronary artery with reduced flow reserve [16, 17]. The con-
tractile reserve is due to the inotropic effect of dobutamine
without a significant increase in heart rate; the deterior-
ation develops at higher heart rate when myocardial oxygen
demand has increased to a level that cannot be supplied by
the stenotic vessel. The myocardium is at jeopardy. Rapid
revascularization is indicated to obtain functional recovery
[18, 19] (E Fig. 36.3).
◆ Contractile reserve limited to the border zone of a necrotic re-
gion, approximately 1 cm. This type of response should not be
considered as myocardial viability when the improvement is
only seen in tethered regions.
◆ Worsening of thickening in hypokinetic segments, implying
inducible ischaemia.
◆ Asynergy developed in adjacent segments perfused by the
same artery as the akinetic segment, suggesting a residual
stenosis of this artery.
◆ Akinesis without change: this is the sign of necrosis,
but could also be seen if the myocardium is severely
548 CHAPTER 36   Asse ssment of viabilit y

Fig. 36.2  Sustained improvement

with dobutamine stress
echocardiography: end-​systolic
stop-​frame images in the apical
two-​chamber view: top left: severe
hypokinesis of both the anterior and
the inferior wall; top right: moderate
contractile reserve; bottom left:
intense contractile reserve of anterior
and inferior walls

hibernating with loss of contractile material. This can also be
observed if resting heart rate is high or if the increase in
heart rate is too rapid, in particular after beta-​blocker
withdrawal.
◆ Additional ischaemic segments during the recovery period
after beta-​blocker infusion: this may relate to stimulation of
alpha 1 receptors leading to epicardial vasoconstriction.
◆ Asynergy in another coronary territory, indicating multivessel
coronary artery disease.
When the coronary anatomy is known, with a severely sten-
otic coronary artery, it is indicated to use a very low dose of
dobutamine (2.5 mcg/​kg/​min during a longer step of 5 min) to re-
cruit the potential flow and contractile reserve before the induc-
tion of myocardial ischaemia. The test can be performed under

Fig. 36.3  Biphasic response: end-​

systolic stop-​frame images in the
apical long-​axis view; top left: severe
hypokinesis of the anteroseptal
segment; top right: improved
contractility; bottom left: deterioration
of systolic contraction
 Asses sm en t of m yo ca rdia l via b i l i t y b y echo ca rdi o g r a ph y
beta-​blocker therapy with incremental doses to obtain at least a
small increase in heart rate (10 beats/​min).
In most laboratories, the interpretation remains qualitative and
is dependent of the experience of the operator. Even in experi-
enced hands, there is a significant interobserver variability.
Other stress modalities
DSE is the most frequently used modality, but other stress mo-
dalities have been evaluated. Low-​dose dipyridamole (0.28 mg/​
kg) can induce endogenous adenosine accumulation. The stimu-
lation of adenosine receptors can induce coronary vasodilation,
recruiting flow reserve and in turn improving contraction [20].
Low-​ dose dipyridamole can be combined to low-​ dose
dobutamine [21]. High doses of dipyridamole with the addition
of atropine can provoke myocardial ischaemia and detect a bi-
phasic response.
Levosimendan can increase contractility without increasing
myocardial oxygen demand and induces vasodilation. A study
suggests that levosimendan stress echo provides similar specifi-
city, around 80% but shows a better sensitivity (75% for a sensi-
tivity of 59% with DSE) [22].
Exercise induces catecholamine stimulation. A low charge of
exercise can induce contractile reserve and detect viability [23]
but the disappearance of the vagal tone may lead to a rapid in-
crease in heart rate masking the contractile reserve. Of note, a
complete exercise test has been shown to identify a biphasic re-
sponse and detect jeopardized myocardium [24].
Contrast echocardiography
Left ventricular opacification
The quality of images is essential for a correct interpretation and
in turn improves the diagnostic accuracy.
The intravenous infusion of a contrast agent with second har-
monic imaging can enhance through LV opacification a better
endocardial definition and provides a better interobserver repro-
ducibility [25]. Some laboratories use contrast in most cases. LV
opacification is recommended when at least two myocardial seg-
ments are not correctly visualized in basal conditions (most fre-
quently the anterior wall in the two-​chamber view or the lateral
wall in the four-​chamber view).[26]
Myocardial contrast echocardiography
Contrast agents consist in microbubbles remaining in the intra-
vascular space. Microvascular integrity is a prerequisite for myo-
cardial viability. The presence of microbubbles in a myocardial
segment implies the presence of preserved microvasculature.
Several modalities have been used. The usual method consists in
a continuous intravenous infusion of the contrast agent, a flash
with high mechanical index which destroys the microbubbles
and the observation and quantitation of reopacification of the
myocardial segments. The signal intensity corresponds to the
capillary blood volume; the speed of contrast replenishment
denotes myocardial blood velocity. The product of myocardial
549
blood volume and red cell velocity corresponds to myocardial
blood flow [27].
Absence of myocardial opacification denotes the absence of
microvascular integrity and thus absence of contractile reserve
(E Fig. 36.1). When both signs are lacking, there will be no
functional recovery. Viability is present when myocardium is
fully replenished with homogenous, normal contrast intensity
[28]. The observation should be done during 10 to 15 cardiac
cycles [29].
The utility of myocardial contrast echocardiography is more
powerful when combined to the presence or absence of con-
tractile reserve [30, 31].
Coronary flow reserve
Harmonic imaging and high frequency probes enable the
non-​invasive assessment of coronary flow and coronary vel-
ocity reserve by transthoracic Doppler echocardiography.
Coronary flow reserve examines complete function of the
coronary circulation from the epicardial arteries to the
microcirculation [32].
It is relatively easy to record coronary flow in the left anterior
descending artery, but it is more difficult in the right coronary
and circumflex arteries. Normal coronary flow is biphasic with a
predominance of the diastolic component.
After the recording in basal conditions, coronary velocity is
measured during intravenous infusion of adenosine (140 mcg/​
kg/​min over 5 minutes) which induces maximal coronary vaso-
dilation and in turn increase in coronary velocity. Dividing the
peak and basal velocities defines coronary reserve related to the
severity of coronary artery stenosis. This technique is not fre-
quently performed but can be useful in the presence of mod-
erate coronary stenosis in addition to the analysis of regional
contractile reserve.
3D echocardiography
3D echocardiography can provide the three apical views of the
same cardiac cycle which can be useful for the assessment of re-
gional contractility and contractile reserve. Real-​time 3D echo
can reconstitute a series of short-​axis views from basal to apical
left ventricle during the same cardiac cycle. The increase in tem-
poral resolution of the most recent machines will permit a better
analysis at higher heart rates.
3D contrast low-​dose dobutamine permits LV enhancement
and analysis of myocardial perfusion. The technique has been
shown to be useful and effective [33].
Myocardial deformation
The major drawback of echocardiography is the qualitative inter-
pretation and in turn a significant variability in the presence of
subtle changes. Parameters of myocardial deformation—​strain
and strain rate—​have recently be used to provide more quantita-
tive parameters. Strain consists in the percentage of deformation
and strain rate the rate of deformation of a specific segment. The
550 CHAPTER 36   Asse ssment of viabilit y
parameters can be obtained by tissue Doppler imaging and pref-
erably by the speckle tracking method which has the advantages
of being independent of the angle of insonation and of providing
a better signal/​noise ratio [34].
Tissue Doppler imaging
Experimental studies have shown that the method can identify
myocardial viability. Clinical studies are rather scarce (E Fig. 36.4).
Hoffmann et al. have found a good concordance with perfusion
imaging and demonstrated that strain rate measurement allows
improved assessment of myocardial viability in patients with de-
pressed LV function [35]. Hanekom et al. have studied several
parameters to predict functional recovery after revascularization.
The addition of strain rate to the conventional wall motion
score index improved the sensitivity from 73% to 83% without
Fig. 36.4  Example of strain rate curves with dobutamine showing improvement in the anterior and inferior walls at low dose (top right) and deterioration at
peak dose (bottom left).
decreasing the specificity [36]. The best cut-​ off value for
predicting recovery was a dobutamine induced increase of strain
rate of 0.25/​s.
Speckle tracking
The speckle tracking method can evaluate longitudinal, circum-
ferential, and radial deformation and rate of deformation with a
good reproducibility.
Hoffmann et al. have demonstrated that an increase of >
0.23/​s, as compared to 18FDG, identified viable myocardium
with a sensitivity of 83% and a specificity of 84% [37]. Bansai
et al. showed that longitudinal and circumferential strain
during low-​dose dobutamine predicted functional recovery
after revascularization with a sensitivity of 83% and a specifi-
city of 93% [38].
 Asses sm en t of m yo ca rdia l via b i l i t y b y echo ca rdi o g r a ph y
Longitudinal myocardial fibres are predominant in the
subendocardial layer. Therefore, a layer specific analysis of strain
and strain rate can be more predictive than a full thickness as-
sessment. A study has shown similar sensitivity, specifity, and ac-
curacy as single photon emission computed tomography (SPECT)
without the use of a pharmacological test [39].
Global longitudinal strain is probably the most robust param-
eter [40]. Compared with contrast-​enhanced MRI, it was found
that a strain <15% obtained at rest was associated with necrotic
tissue [41]. Higher, thus more negative strain was present in vi-
able myocardium.
Clinical settings
Acute coronary syndrome
Echocardiography
When the patient is admitted to the hospital rapidly, he is sub-
mitted to percutaneous coronary intervention. The coronary
anatomy is known. The culprit artery is recanalized when oc-
cluded, dilated with stent implantation. The detection of myocar-
dial viability is only justified when thrombolysis in myocardial
infarction (TIMI) flow is reduced and in patients with a long time
interval between chest pain and intervention. Stress imaging is
also useful in the presence of intermediate stenosis of another
coronary artery. Searching viability is important when the pa-
tient is admitted late or if he has been treated by thrombolysis.
Before hospital discharge, a low-​dose dobutamine can be used in
the presence of akinetic segments to detect contractile reserve in
the presence of myocardial stunning which predicts full or par-
tial functional recovery. Later, contractile reserve in persistent
akinetic regions indicate non-​transmural myocardial necrosis.
Fig. 36.5  Stunned myocardium. Left: normal perfusion and glucose uptake during the early phase(top) and at follow-​up (bottom); right: end-​diastolic (top)
and end-​systolic (bottom) stop-​frame images akinesis of anteroseptal wall; contractile reserve with low-​dose dobutamine; complete recovery at follow-​up.
551
Recruitment of contractile reserve of the subepicardial layer
is useful in daily life activities. Patients in whom no interven-
tion has been performed should be submitted to the test: viable
myocardium can indeed be present because of collateral circu-
lation or rapid spontaneous reperfusion. The seminal study as-
sessing myocardial viability in acute myocardial infarction has
been published by Pierard et al. [41]. Positron emission tomog-
raphy (PET) was used to compare the effects of dobutamine with
perfusion and glucose utilization obtained by PET. Patients with
ST elevation myocardial infarction treated by thrombolysis were
studied. All patients with stunned myocardium, defined as un-
coupling between akinesis and normal perfusion and metabolism
developed important contractile reserve at low-​dose (10 mcg/​
kg/​min) of dobutamine. Spontaneous full functional recovery
was observed at follow-​up (E Fig. 36.5). Most patients but
not all with hibernating myocardium defined as abnormal flow
but intense fixation of 18F fluorodeoxyglucose (FDG) has some
contractile reserve. Functional recovery was dependent of myo-
cardial revascularization but was not systematic. Follow-​up PET
in patients without recovery showed disappearance of glucose up-
take and absence of perfusion (E Fig. 36.6). The patients with
absence of perfusion and metabolism in the acute phase had no
contractile reserve and no functional recovery. Other studies have
confirmed the utility of low-​dose DSE [42, 43].
However, in the presence of myocardial viability, it is essential,
if the coronary anatomy has not yet been defined, to detect re-
sidual ischaemia in the affected region. This requires a complete
dobutamine test to obtain the target heart rate and identify a bi-
phasic response [16, 17].
Other tests are available: dipyridamole stress echocardiography
[20] or combined low-​doses of dipyridamole and dobutamine
552 CHAPTER 36   Asse ssment of viabilit y
Fig. 36.6  Hibernating myocardium. Left: abnormal perfusion and intense glucose uptake in the early phase (top) and absence of both perfusion and
metabolism at follow-​up; right: end-​diastolic (top) and end-​systolic(bottom) stop-​frame images in the short-​axis view: small contractile reserve of the septum in
the early phase and disappearance of viability at follow-​up.
[21]. An alternative test is exercise stress echocardiography.
Contractile reserve can be identified at low charge which predicts
functional recovery and full exercise can detect a biphasic re-
sponse and the importance of percutaneous intervention [23, 24].
Comparison between echocardiography and
electrocardiography
Interpretation of the ECG during DSE can be useful. Persistence
of ST elevation at rest usually represents transmural necrosis with
dyskinesis or myocardial aneurysm. Normalization of negative T
waves is frequently an indicator of viable tissue [44]. The develop-
ment of ST elevation during DSE or exercise correlates with a bi-
phasic response and has good specificity for predicting functional
recovery [45, 46]. A small QT dispersion (<65 ms) is associated
with viable myocardium. An increase of QT dispersion during
DSE predicts contractile reserve and residual ischaemia [47].
Chronic coronary artery disease and heart failure
Which patients?
LV systolic dysfunction in CAD is usually associated with large
myocardial infarction or extensive hibernating myocardium.
Identification of viability can be useful in the presence of HF
and severely reduced LV ejection fraction. In patients with an-
gina pectoris who can be submitted to revascularization, its role is
limited. Identifying viability can however be performed to justify
coronary artery bypass or recanalization of an occluded artery
corresponding to an akinetic segment.
Myocardial viability is absent in a patient with one-​vessel dis-
ease if resting echo shows extensive necrosis with regional ex-
pansion, thin (<5 mm) hyperechogenic myocardium indicating
transmural necrosis. In patients who cannot be revascularized
because of diffuse atherosclerosis, the search of regional viability
is purely academic. The presence of viability could, however,
justify the optimal dose of beta-​blocker or the prescription of
a bradycardic agent such as ivabradine to improve the ratio be-
tween oxygen demand and supply.
Markers of viability
Markers of viability differ between techniques [48] (E Table 36.2).
Thallium SPECT assesses perfusion and membrane integrity.
SPECT with technetium such as MIBI identify mitochondrial
function. Cardiac mitral regurgitation (CMR) measures the
transmural extent of necrosis [49]. Dobutamine test analyses the
presence and extent of contractile reserve. This contractile reserve
can be identified by echocardiography or CMR.
The level of cellular integrity required to identify viable
myocardium is also different between the methods used.
Recruitment of contractile reserve obviously requires perfu-
sion reserve and the presence of contractile material in the
myocytes. In the presence of ultrastructural changes and loss
of contractile material, contractile reserve will be absent but
Table 36.2  Diagnostic tools for viability 
Myocardial blood flow SPECT (99m MIBI), PET (13NH3)
Myocardial contrast echo, cardiac MR
Membrane function SPECT (201 Thallium)
SPECT (18F-​FDG)
Contractile reserve Dobutamine echo, dobutamine CMR
Scar CMR, CT, 3D echo
Abbreviations: SPECT = single photon emission cardiac tomography; PET = positron
emission tomography; CMR = cardiac magnetic resonance; echo = echocardiography.
 Asses sm en t of m yo ca rdia l via b i l i t y b y echo ca rdi o g r a ph y
membrane integrity can be revealed by thallium SPECT. This
can explain the differences in sensitivity and specificity be-
tween the methods.
Dobutamine stress echocardiography
The classical method is used. The first dose can be lowered to 2.5
mcg/​kg/​min in patients with very severe coronary stenoses sug-
gesting a reduced flow reserve. In this case, a low dose is suffi-
cient. It is necessary to obtain at least a low increase in heart rate,
especially if the beta-​blocker has not been withdrawn. Absence of
initial improvement of contractility can be due to deregulation of
beta-​1 receptors.
In the absence of contra-​indication, a complete test is prefer-
able to detect an eventual biphasic response. Such biphasic re-
sponse has the best predictive value for functional recovery after
revascularization. It has been shown that 72% of segments with
biphasic response recovered after revascularization but only
15% of segments exhibiting sustained improvement or akinesis
without change [50].
An improvement of global LV function requires at least four
segments with contractile reserve.
The identification of improvement of systolic thickening is usu-
ally easy to identify in the presence of myocardial stunning. It can
be more difficult in the presence of hibernation. A biphasic re-
sponse can be very subtle. In this case, quantitation can be useful
or preferably the use of an alternative method, such as CMR.
Prognostic implications
Intuitively, it was considered that revascularizing viable tissue
would be accompanied by improved survival.
A meta-​analysis merged 24 studies in more than 3,000 patients
in whom myocardial viability was assessed by different methods,
but not CMR.
Mean LV ejection fraction was 30%. The mean follow-​up was 25
months. In patients with viable myocardium and revascularization,
a 80% reduction in annual mortality was observed when compared
to patients with viable myocardium who were treated medically. In
contrast, there were no significant difference of mortality in patients
without myocardial viability with or without revascularization [51].
These results would be in favour of searching viability to select pa-
tients who would benefit from revascularization. This study has,
however, several limitations: retrospective studies included, no ran-
domization, no standardized methods, possible suboptimal med-
ical treatment, no correction for comorbidities.
These results contrast with those of the STICH trial. A total
of 1,212 patients with LV ejection fraction <35% who could be
revascularized were randomized between optimal medical treat-
ment (602 patients) and surgical revascularization (610 patients)
The primary endpoint was all-​cause mortality. There was no sig-
nificant difference in survival during a 5-​year follow-​up [52]. A
substudy has evaluated myocardial viability in 601 patients with
thallium SPECT or DSE. Viability was considered to be present
when at least 11 segments were viable with SPECT and at least
five segments showed contractile reserve with dobutamine. There
was no significant interaction between presence or absence of via-
bility and medical vs. surgical treatment [53]. This study has also
553
numerous limitations. Most patients were relatively young, pre-
sented with angina, and had mild HF. Mortality of patients under
medical treatment was low (7%/​year). There was no randomiza-
tion in the use of the viability test. Patients were dichotomized:
presence vs. absence of viability. With DSE, there was no distinc-
tion between sustained improvement and biphasic response.
This study does not exclude the usefulness of viability testing.
More studies, including CMR will be welcomed.
Other indications
Prediction of response to cardiac resynchronization
therapy (CRT)
Despite clear indications of CRT, 30% of patients are non-​
responsive. There are several potential explanations: absence of
significant intraventricular dyssynchrony, choice of an inappro-
priate vein, electrical stimulation of a necrotic region.
DSE can be useful at low dose or exercise stress echocardiog-
raphy at low charge: contractile reserve, especially of segments
corresponding to the lead target or global improved contractility
are good independent predictors of survival without events and
reverse LV remodelling [54–​56].
Ischaemic mitral regurgitation
Combined surgery (coronary artery bypass grafting [CABG] and
mitral valve repair) is indicated in patients with severe secondary
mitral regurgitation (MR). A recent randomized trial has shown
no improvement of combined surgery in patients with moderate
MR [57]. Contractile reserve induced by exercise echocardiog-
raphy, if present in the basal posterior region is associated with
a good prognosis: recruitment induces a temporal reduction of
mitral valve deformation, of the tenting area and a temporal im-
provement of closing forces [58].
In contrast, exercise-​induced severe increase in MR and of pul-
monary pressures is associated with a guarded prognosis. Exercise
echocardiography can thus be helpful in the individual patient.
Clinical implications
There is a high number of patients with CAD in whom the iden-
tification of myocardial viability can be useful. Several tech-
niques are available for the clinician: DSE, CMRCMR, SPECT.
Appropriate indications are essential. The usefulness is currently
limited in acute coronary syndromes and in patients with angina
and moderate LV dysfunction; it is more important in HF pa-
tients. The choice of the method depends on the local experience
and expertise.
Echocardiography is frequently the first technique in daily clin-
ical practice. Resting echo can identify asynergic regions, LV ejec-
tion fraction, asynchrony, and valvular abnormalities. Necrotic
segments can be identified. DSE is highly validated and is a useful
tool in the presence of good echogenicity and obvious changes
in contractility. Quantitative methods are available but require
more validation. If LV dysfunction is very severe, its diagnostic
accuracy is less established. In the absence of contractile reserve
of a segment with normal or mildly reduced thickness, viability
554 CHAPTER 36   Asse ssment of viabilit y
cannot be excluded and an alternative method is indicated. CMR
is preferable, as it does not expose to radiation and provides infor-
mation on perfusion, myocardial thickness, and thickening and
extent of necrosis and can be coupled with dobutamine. SPECT
has the highest sensitivity as it can identify membrane integrity in
segments with absent contractile reserve.
Assessment of myocardial viability by
nuclear imaging
Nuclear methods for assessing myocardial
viability
18
F-​Fluorodeoxyglucose  (FDG)
Since dysfunctional myocardium must retain sufficient coronary
blood flow and metabolism to sustain myocyte metabolism, the
combined assessment of regional myocardial perfusion and me-
tabolism is an attractive method to delineate myocardial viability.
After assessing stress-​induced ischaemia, regional glucose up-
take can be evaluated with administration of FDG, a marker of
exogenous glucose uptake that provides an index of myocardial
metabolism and cell viability. The FDG tracer, intravenously ad-
ministered, is transported across cell membrane, and is converted
to FDG-​6-​phosphate that is a poor substrate for further metab-
olism and remains trapped in the cell.
Using the sequential perfusion-​FDG approach, four perfusion-
​metabolism patterns can be observed in dysfunctional myocardium:
1. Normal perfusion and normal FDG uptake
2. Reduced perfusion with preserved or enhanced FDG uptake studies, preserved oxidative metabolism (estimated by kinetic of
(perfusion-​metabolism mismatch), which reflects myocardial C11 acetate) in dysfunctional myocardium is predictive of func-
viability
3. Reduced perfusion with reduced FDG uptake (perfusion-​
metabolism match), which reflects non-​viable myocardium
4. Normal or near normal perfusion with reduced FDG uptake
(reversed perfusion-​metabolism mismatch), which reflects a
condition of repetitive myocardial stunning
Use of polar maps to quantify regional myocardial perfusion, as-
sessed by perfusion SPECT or PET, and FDG tracer uptake and
their difference can be helpful to objectively assess the magni-
tude of viability. In addition, gated SPECT or PET provide useful
parameters of global and regional LV function, closely correlated
with those obtained with CMR [59]. Gated images are particu-
larly useful when FDG PET patterns are interpreted in relation to
non-​attenuation-​corrected SPECT perfusion images. In addition,
assessment of LV function and volumes can be used to predict
functional recovery after revascularization [60] together with in-
formation regarding viable myocardium.
Carbon-​11 acetate
After IV injection, C11-​acetate is extracted from circulation in
proportion to coronary blood flow (CBF), with an average ex-
traction of 63% under baseline conditions. After extraction,
C11-​acetate is converted in tricarboxylic acid cycle and then into
CO2 and water. The uptake and clearance of C11-​acetate are af-
fected by change in CBF. During ischaemia, there is a reduction
in initial uptake, with rapid clearance phase, that is proportional
to myocardial blood flow reduction.
Accuracy of nuclear imaging in assessment of
myocardial viability
Contractile dysfunction is predicted to be reversible after
revascularization when resting regional CBF is >50% of normal
and irreversible when it is <50% of normal. Using these criteria
as reference, the average predictive accuracy of PET is 63% (45–​
78%), whereas average negative predictive value is 63% (45–​100%)
[61]. While normal or near normal CBF in dysfunctional segments
served by a stenotic coronary indicates viable myocardium and se-
vere reduced myocardial blood indicates non-​viable myocardium,
intermediate CBF deficits are more difficult to interpret because
they could represent an area of extensive subendocardial necrosis
that unlikely could recover after revascularization or an area of ex-
tensive ischaemic but viable myocardium that could recover after
revascularization. In this context, FDG assessment adds significant
independent information to distinguish viable from nonviable
myocardium. PET or PET/​SPECT perfusion/​FDG imaging pre-
dicts contractile myocardial recovery after revascularization
with average positive predictive accuracy of 76% (52–​100%) and
average negative predictive accuracy of 82% (67–​100%).
The experience with C11-​acetate is more limited. Only three
studies, including globally 89 patients, evaluated the role of C11-​
acetete in prediction of myocardial recovery [62–​64]. In these
tional recovery after revascularization. Using this criterion as ref-
erence, the average positive predictive accuracy is 72% (62–​88%),
whereas the average negative predictive accuracy is 76% (65–​89%).
Application of nuclear viability assessment in
patient management
The available evidence suggests that nuclear imaging provides
accurate prediction of LV function and symptom improvement
after revascularization [65].
In patients with ischaemic HF, the extent and severity of indu-
cible ischaemia, independently on the imaging modality used, is
a key prognostic determinant and identifies patients at high risk
in whom revascularization is recommended by the guidelines
[66, 67].
Although based on retrospective studies, the guidelines recom-
mend revascularization in patients with 10% inducible ischaemia
in a nuclear imaging stress study or with >3 echocardiographic or
CMR ischaemic segments during stress examination. In addition,
in patients with ischaemic HF assessment of myocardial viability
has been used to recommend revascularization (in patients with
evidence of viability and suitable coronary anatomy).
Despite the robust and extensive evidence supporting the use of
viability for selecting patients as candidates for revascularization,
 Assessment of myo ca rdia l via b i l i t y b y ca rdiac m ag n eti c res ona n c e   (C M R )
there are several critical aspects. There is a significant reduction in
the accuracy of methods assessing viability, including nuclear tech-
niques, in predicting functional recovery after revascularization in
patients with severe reduction of LV function (LVEF <30%). There
have been only a limited number of studies with small number
of patients assessing diagnostic accuracy of nuclear techniques in
patients with a severe reduction of LV function. Furthermore, the
accuracy of methods assessing viability appears to decrease sig-
nificantly with worsening of LV function [68]. In addition, mul-
tiple factors (i.e. the timing and the success of revascularization,
the vessel culprit, the time of LV function assessment), beyond the
extension of viable myocardium, can affect changes in LV function
after revascularization. As a consequence, the prediction of func-
tional recovery based on viability information alone is inadequate,
in particular in patients with severe depression of EF.
In addition, the STICH study [53] reported no impact of viability
on the primary endpoint of all-​cause mortality in patients with is-
chaemic severe HF randomized to revascularization or optimal
medical therapy. This trial contradicted results of a previous meta-​
analysis of retrospective studies reporting a substantial benefit
of revascularization in ischaemic HF patients with viability [53].
Despite its relevance, the STICH trial presented some limitations
[69, 70] (original study design, patient selection, poor standardiza-
tion of nuclear protocol used to assess viability, type of nuclear test
used—​PET or SPECT, no follow-​up LV function assessment).
Although the benefits of viability assessment on functional,
clinical, and prognostic improvement after revascularization
re­main not fully documented, current guidelines [71, 72] con-
sider that non-invasive stress imaging (CMR, stress echocardiog-
raphy, SPECT, and PET) may be considered for the assessment
of myocardial viability in patients with HF and CAD considered
suitable for coronary revascularization before the decision on
revascularization (ESC recommendation Class IIB level B). Future
studies [73] focusing on understanding the rela­tionship between
viability and ischaemia and molecular changes subtending myo-
cardial tissue damage, and LV remodelling need to clarify the role
of viability assessment in patients’ management.
Assessment of myocardial viability by
cardiac magnetic resonance (CMR)
CMR allows a comprehensive evaluation of patients with is-
chaemic cardiomyopathy. The most established methods used
to reveal viable myocardium are late gadolinium enhancement
and low-​dose dobutamine stress MRI: late gadolinium-​enhanced
CMR reveals myocardial necrosis and fibrotic scar indicating
absence of myocardial viability. By contrast dobutamine CMR,
similar to dobutamine echocardiography evaluates the ability of
dysfunctional segments to improve regional wall motion during
inotropic challenge. CMR allows significant further character-
ization of ischaemic myocardium: cine studies in long and short
axis evaluate global and regional LV function, T2 imaging detects
myocardial oedema in acute myocardial infarcts, corresponding
555
to area at risk. Resting myocardial perfusion and early gadolinium
enhancement can detect the no-​reflow phenomenon, while T2
and T2* imaging may detect intramyocardial haemorrhage in
acute infarcts. Stress myocardial perfusion allows detection of
detect ischaemia thereby demonstrating mechanisms of dysfunc-
tion such as stunning or hibernation. More recently non-​contrast
T1 and T2 mapping have also been proposed for further charac-
terization of dysfunctional myocardium.
Principles of myocardial viability
detection by CMR
Late gadolinium enhancement (LGE)
LGE imaging is currently the most widely used method for via-
bility detection by CMR. LGE is based on unique fact that Gd
based contrast agents have extravascular distribution volume,
and shorten T1 time in direct proportion to their concentration.
When myocardial membranes become disrupted, such as in acute
infarcts, or when myocardial tissue is replaced by focal replace-
ment fibrosis, the distribution volume of Gd-​contrast agent in the
heart increases. This leads to higher Gd concentration and shorter
T1 times in areas of myocardial fibrosis, relative to normal tissue,
when imaging is performed at time when the contrast agent has
equilibrated between with blood (i.e. at equilibrium or several
minutes after bolus injection). LGE maximizes contrast between
abnormal tissue (scar or necrosis) with high Gd concentration
through nulling signal in normal myocardium, appearing as
bright areas of Gd accumulation relative to normal tissue.
LGE can thus reveal both acute myocardial infarction or
chronic infarcted scar, both representing non-​viable myocardium
[74–​76]. Animal studies demonstrated that LGE has excellent
correspondence to histopathology [77], and LGE can thus be
considered an almost perfect measurement of myocardial scar, or
non-​viable myocardium, in all situations except very early after
acute myocardial infarction (MI), where LGE may overestimate
scar because of inclusion of myocardial oedema. Conversely in
dysfunctional myocardium, absence of LGE, is a marker of ab-
sence of scar and indicates preserved myocardial viability, either
due to hibernating, stunned myocardium or other aetiologies.
The main advantage of LGE MRI is its very high spatial resolution
which allows for better delineation of scar transmurality, and
detection of subendocardial scar [78] (E Fig. 36.7). Therefore
LGE-​CMR can precisely reveal the complex distribution of scar
in patients with chronic CAD and demonstrate the wavefront
phenomena of ischaemia as myocardial scar in different degrees
of transmurality [79]. This, however, makes interpretation of via-
bility by LGE-​CMR somewhat more complex. Indeed by LGE-​
CMR, patients with CAD, are rarely free of scar, but often present
scar in different amounts and transmural distribution. Unlike
other methods for myocardial viability, CMR thus discloses myo-
cardial non-​viable not a binary parameter (present or absent), but
a continuous range of transmurality of LGE in a dysfunctional seg-
ment (E Fig. 36.8, z Video 36.1). Absence of segmental scar or
only small amounts of subendocardial scar (<25% transmurality)
in dysfunctional segments indicate large amounts of remaining
556 CHAPTER 36   Asse ssment of viabilit y

LGE for myocardial viability

Rationale

Dysfunctional myocardium

Fig. 36.7  Rationale of CMR evaluation of viability

in dysfunctional myocardium. Absence of LGE
indicates non-​infarcted myocardium which is
potentially viable. Subendocardial scar indicates
admixture of viable and non-​viable myocardium. Non-infarcted Sub-endocardial necrosis Transmural necrosis
Transmural scar is non-​viable. Viable Partially viable Non-viable

Increasing transmurality of scar

Amount of viable myocardium
No scar Sub-endocardial scar Transmural scar
Fully viable Partially viable Non-viable
Fig. 36.8  Examples of corresponding coronary angiography, SSFP, and LGE images in different patients with coronary artery disease and different amounts of
myocardial viability. Patients on the left have no scar and thus completely viable myocardium, Patients on the right have transmural scar (non-​viable). These
examples highlight the inverse relationship between the amount of viable myocardium and the extent of transmural scar shows that myocardial viability is not a
binary phenomenon but a continuum.
 Assessment of myo ca rdia l via b i l i t y b y ca rdiac m ag n eti c res ona n c e   (C M R )
dysfunctional viable myocardium, on the other hand, high de-
grees of transmural scars (>75% transmurality) indicate near
absence of residual viable myocardium [80, 81]. Since recovery
of dysfunction may depend more on the amount of viable than
non-​viable myocardium, rather than reporting the degree of
transmurality of LGE, i.e. the measurement of non-​viability, some
authors have suggested express myocardial viability as absolute or
percent relative thickness of myocardium free of LGE.
Inotropic response during low-​dose dobutamine
injection
Measurement of inotropic response during low-​ dose
dobutamine injection is another approach used to detect myo-
cardial viability, through the well-​known ability of stunned or
hibernating myocardium to respond and improve contractility
to infusion of inotropic drugs. The method of detecting myo-
cardial viability during dobutamine stress MRI mimics that of
dobutamine echocardiography described earlier, and evaluates
the contractile response of dysfunctional segments to low (5–​
10 ug/​kg/​min) doses of dobutamine infusion followed eventu-
ally by high (30–​40 ug/​kg/​min) dose infusion for detection of
ischaemia. Interpretation of dobutamine response is identical to
that in dobutamine echocardiography, i.e. for detection of via-
bility, regional improvement of levels by one grade or improve-
ment of global wall motion scores are considered significant and
dysfunctional myocardium presenting either sustained response
(improvement of wall motion without subsequent deterioration)
or a biphasic response (initial response to low-​dose dobutamine
infusion followed worsening of wall motion at high doses) due
to superposed ischaemia is considered viable, while absence of
improvement during dobutamine infusion is considered to indi-
cated non-​viable myocardium (E Fig. 36.9, z 36.2). Advantages
of dobutamine CMR over stress echo are better delineation of
myocardial wall motion abnormalities, in particular in patients
with poor echocardiographic windows. The detection of wall
motion abnormalities can be improved by use of tagged imaging
with or without strain analysis or DENSE or strain-​encoded car-
diac magnetic resonance (SENC) imaging techniques.
Native T1 mapping
Recent works also demonstrated that T1 mapping techniques
might have value for detection of myocardial viability (E Fig.
36.10). Indeed T1 times increase both in acute infarcts and fi-
brotic scar relative to normal myocardium [82–​84], and therefore
increased T1 times may identify non-​viable myocardium in acute
or chronic similar to LGE [85–​90]. This approach has the advan-
tage of not requiring the injection of contrast. Disadvantages are
however limited low contrast between chronic MI and remote
myocardium, and poor specificity for scar, since increases in T1
times may also result from other disease states, such as acute oe-
dema, or amyloid deposition in the myocardium.
Clinical results of MR viability imaging
Most studies have evaluated the ability to predict recovery of re-
gional myocardial dysfunction after CMR. For LGE, it was shown
557
that the likelihood of recovery of regional contractility in dys-
functional segments decreases progressively as the transmurality
of the hyperenhancement before revascularization increases [91–​
93]. This was first demonstrated by Kim et al. [5]‌and confirmed
by Selvanayagam et al. [94] (E Fig. 36.11). Indeed the probability
of recovery of segmental dysfunction is inversely related to the
transmural extent of myocardial necrosis. In segments without
myocardial necrosis, the probability of recovery of dysfunction
is high (73–​78%), whereas it is minimal (2–​4%) in segments with
>75% of transmural extent of necrosis.
Meta-​analysis of 11 studies evaluating LGE to predict recovery
of regional dysfunction [95] showed that LGE >50% transmurality
has high sensitivity (91%) for predicting non-​recovery of dysfunc-
tion (i.e. non-viable myocardium) but only limited (51%) specificity
for predicting recovery of dysfunction (i.e. viable myocardium).
The main limitation of LGE is that segments with intermediate
transmurality (25–​75%) LGE have intermediate likelihood (50%)
and thus the accuracy of DE-​cMR is to predict recovery of dys-
function is low. Dobutamine MR has lower sensitivity (81%) but
higher (91%) specificity for predicting recovery of regional dys-
function than LGE [96] (E Fig. 36.12) and it was suggested that
dobutamine CMR could be useful to predict better recovery of
dysfunction in segments with intermediate transmurality of LGE
(1–​75% transmurality of LGE) [97]. Integration of LGE with
low-​dose dobutamine test could thus further improve guiding of
revascularization therapy in patients with chronic LV dysfunction
[98]. This finding, i.e. that metabolic viability and recovery has
higher sensitivity than inotropic response is in line with other tests
of detection of viability such as PET and SPECT and illustrates the
complex relationship between metabolic viability as measured by
LGE and functional viability evaluated by recovery of dysfunction
Dobutamine stress MR
viability
BL LD HD
Viable (sustained)
Viable (biphasic)
Non-viable
Fig. 36.9  Short-​axis dobutamine stress CMR images illustrating the
myocardial response in the presence of viable and non-​viable myocardium
(BL: baseline, LD: low-​dose, HD: high-​dose).
558 CHAPTER 36   Asse ssment of viabilit y

Native T1 mapping for viability

LGE T1 Map
Raw Processed Raw Processed
(a) (b) (c)
50 p = 0.46 10 50
Basal

T1 Maps Infarct Size (% LV)

Mean + 2SD

Difference in Infarct Size

40 * * 5 40

Infarct Size (% LV)

(T1 -LGE, %LV)

Mean
30 0 30

STEMI
20 –5 20
Mean – 2SD
10 –10 10
Mid-Ventricular

R2 = 0.93
0 –15 0
LGE T1 Maps 0 10 20 30 40 50 0 10 20 30 40 50
Mean Infarct Size (%LV) LGE Infarct Size (%LV)

(d) (e) (f)

50 10 50

T1 Maps Infarct Size (% LV)

Difference in Infarct Size
p = 0.27 Mean + 2SD
Apical

40 5 40

Infarct Size (% LV)

(T1 -LGE, %LV)

0
NSTEMI
30 30
Mean
20 –5 20
Mean – 2SD
10 –10 10
Infarct Size Transmurality Infarct Size Transmurality R2 = 0.85
0 –15 0
LGE T1 Maps 0 10 20 30 40 50 0 10 20 30 40 50
Mean Infarct Size (%LV) LGE Infarct Size (%LV)

Fig. 36.10  Examples of native T1 mapping images for detection of fibrosis and corresponding LGE images in patients with subacute ST-​elevation myocardial
infarction (STEMI) and NSTEMI. Native T1 size corresponded closely to LGE extent both in STEMI and NSTEMI.
Reproduced from Kali A, Choi EY, Sharif B, et al. Native T1 Mapping by 3-​T CMR Imaging for Characterization of Chronic Myocardial Infarctions. JACC Cardiovasc Imaging.
2015;8(9):1019–​30. doi:10.1016/​j.jcmg.2015.04.018 with permission from Elsevier.

LGE prediction of functional recovery after CABG

All Dysfunctional Severe Hypokinesia, Akinesia or
Segments Akinesia or Dyskinesia Dyskinesia
2
/1
100 12
48
8/1
12 8
9 /2
/ 32 23
80 2 56
6
/8
Improved contractility (%)

1 83 56
9/
60 10

10 /6
8 20
/1 29 9/
46
40

Fig. 36.11  Association between the transmural extent

20 24
of myocardial infarction before revascularization and
/1 03
/1 54
the probability of improvement in contractility after 13 10
8 7 4/
revascularization. Modified with permission from Kim 1/5 0/5 0/
et al NEJM 2000) 0
Source data from Kim RJ, Wu E, Rafael A, et al. The use
0

76 5

0
25
0
25

76 5
00

0
25

00

0
5
00
–5
–7

–5
–7

–5
–7
–1

1–

–1

1–
1–

–1

of contrast-enhanced magnetic resonance imaging to

26
51
26
51

26
51
76

identify reversible myocardial dysfunction. N Engl J Med.

2000;343(20):1445-1453. doi:10.1056/NEJM200011163432003 Transmural extent of hyperenhancement (%)
 Assessment of myo ca rdia l via b i l i t y b y ca rdiac m ag n eti c res ona n c e   (C M R )
Metaanalysis of DE and LGE for viability
LGE
DE Studies DE Studies
Becker 2008 Becker 2008
Bordarenko 2007 Bordarenko 2007
Gutberlet 2005 Gutberlet 2005
Kim 2000 Kim 2000
Kuhl 2006 Kuhl 2006
Pegg 2010 Pegg 2010
Sandstede 2000 Sandstede 2000
Schvartzman 2003 Schvartzman 2003
Selvanayagam 2004 Selvanayagam 2004
Wellnhofer 2004 Wellnhofer 2004
Wu 2007 Wu 2007
Summary Summary
0.8 0.85 0.9 0.95 1 0.2
Sensitivity
Fig. 36.12  Meta-​analysis forest plots of individual and pooled sensitivity and specificity for predicting improved segmental LV contractile function after
revascularization by CMR by LGE and low-​dose dobutamine).
Reproduced from Romero J, Xue X, Gonzalez W, Garcia MJ. CMR imaging assessing viability in patients with chronic ventricular dysfunction due to coronary artery disease: a meta-​
analysis of prospective trials. JACC Cardiovasc Imaging. 2012;5(5):494–​508. doi:10.1016/​j.jcmg.2012.02.009 with permission from Elsevier.
[99]. LGE is overall a histological evaluation of absence of myocar-
dial viability, however the absence of scar may not necessarily lead
to improvement of dysfunction after revascularization. Indeed
dysfunction in hibernating viable myocardium may be some-
times very advanced relating to cardiomyocyte dedifferentiation
with myofilament and contractile protein loss [100] impairment
of myocardial perfusion reserve [100], and reduced β-​receptor
density which may impair contractile reserve in histologically
viable myocardium. Also in subendocardial scars with viable
epicardial layers the amount of residual viable myocytes in the
epicardium may be insufficient to allow recovery of dysfunction
radial thickening and functional recovery. Also tethering from
neighbouring transmurally necrotic segments or extreme LV re-
modelling may prevent the contractile improvement of some seg-
ments. Another explanation the discrepancy between metabolic
viability assessed by LGE and functional improvement is that the
recovery of dysfunctional myocardium is typically assessed binary
using semiquantitative Likert scales. Indeed the relation between
quantitative improvement of regional strains in dysfunctional seg-
ments and transmural extent of necrosis is complex [101], and the
semiquantitative assessment of recovery of dysfunction may ex-
plain the lower accuracy of LGE in segments with intermediate
transmurality of LGE, and relation between functional recovery.
This factor is however also a limitation for the interpretation of
dobutamine response which is generally interpreted visually, re-
sulting in larger interobserver variability than interpretation of
LGE transmurality. The relation between viability and recovery of
global dysfunction (i.e. improvement of ejection fraction) and re-
verse remodelling (i.e. improvement of LV volumes) might be a
more important endpoint for assessment of myocardial viability on
a per patient basis than that of regional dysfunction. Indeed several
studies [102–​104] demonstrated linear relation between number
of viable segments by LGE (less than 50% of transmurality) and
recovery of global dysfunction. It was suggested that presence of
at least 10 viable + normal segments predicted significant recovery
559
Dobutamine echo
LDD Studies LDD Studies
Baer 1998 Baer 1998
Baer 2000 Baer 2000
Gutberlet 2005 Gutberlet 2005
Lauerma 2000 Lauerma 2000
Sandstede 1999 Sandstede 1999
Sayad 1998 Sayad 1998
Schmidt 2004 Schmidt 2004
Van Hoe 2004 Van Hoe 2004
Wellnhofer 2004 Wellnhofer 2004
Summary Summary
0.4 0.6 0.8 1 0.4 0.5 0.6 0.7 0.8 0.9 1 0.6 0.7 0.8 0.9 1
Specificity Sensitivity Specificity
of global function by >3% and positive remodelling with sensitivity
of 95% and specificity of 75% [105]. Interestingly in the sole study
using both LGE and low-​dose dobutamine (LDD) CMR [26] found
that LDD did not provide additional information for predicting
LVEF improvement over LGE alone. While several studies demon-
strated that revascularization of dysfunctional viable segments by
CMR also results in significant improvement of LV volumes after
revascularization; this endpoint has been less evaluated in terms of
diagnostic accuracy. So far there have been only few retrospective
non-​randomized studies evaluating the impact of revascularization
of viable myocardium detected by LGE-​CMR on survival [106,
107]. Indeed survival in patients was significantly worse if viable
(or jeopardized myocardium) remained without revascularization,
but could be improved by revascularization of viable myocardium
(E Fig. 36.13). Interaction between revascularization and via-
bility provided significant additional value to baseline predictors
of survival (NYHA class, wall motion score, and peripheral artery
disease). These findings, although in retrospective trials of a rela-
tively small population of patients support that revascularization
of viable myocardium may have beneficial effects on survival.
Other studies [108, 109] clearly demonstrated that presence and
transmurality of LGE are independent predictors of mortality
[110, 111] with higher predictive value than LV ejection fraction
and volumes [112]. To this end LGE-​cMR might allow to identify
HF patients at higher risk of sudden cardiac death with greater
benefit of implantable cardioverter-​ defibrillator (ICD). Indeed
both the size of scar and presence of grey borderzone in infarct
have been related to higher risk of arrhythmic events [113]. These
markers could identify greater scar heterogeneity with more ex-
tended re-​entry circuits and have been associated with ventricular
irritability and spontaneous ventricular arrhythmia and subse-
quent ICD therapy [110–​115]. Similar to LGE, also T1 and ECV
mapping have recently been shown to predict outcome in patients,
as both increase in T1 times and ECV were shown to indicated
greater risk of death, HF and arrhythmic events in patients [116].
560 CHAPTER 36   Asse ssment of viabilit y

Prognostic value of viability by LGE

Whole population Propensity score matched
100 100
M/IR NV
CR V CR NV
80 80 CR V
M/IR NV

Overall Survival (%)

Overall survival (%)

CR NV
60 60

M/IR V M/IR V
40 40 Medical R/ or Incomplete Revasc. Non-Viable (M/IR NV)
Complete Revascularization Viable (CR V)
Medical R/ or Incomplete Revasc. Non-Viable (M/IR NV) Complete Revascularization Non-Viable (CR NV)
Complete Revascularization Non-Viable (CR NV) Complete Revascularization Viable (CR V)
20 20 Medical R/ or Incomplete Revasc. Viable (M/IR V)
Medical R/ or Incomplete Revasc. Viable (M/IR V)

p (Mantel Cox) = 0.006 p (Mantel Cox) = 0.045

0 0
0 1 2 3 0 1 2 3
Time (years) Time (years)

CR V 68 61 48 35 M/IR NV 16 16 13 11
M/IR NV 25 24 17 15 CR NV 14 12 12 10
CR NV 18 15 14 10 CR V 29 24 18 12
M/IR V 33 24 17 12 M/IR V 37 10 13 10

Hazard Ratio [95% Cl]

Subgroup No.
0.71 [0.18–2.8]
Without viability 43
With viability 101 4.56 [1.93–10.8]

0.1 0.2 0.5 1 2 5 10

medical R/ Revascularization
better better

Fig. 36.13  Kaplan–​Meier survival curves showing overall survival in the whole population and propensity score–​matched patients according to treatment and
presence of myocardial viability in the presence of LV dysfunction in patients with coronary artery disease and LVEF <35%.
Reproduced from Gerber BL, Rousseau MF, Ahn SA, et al. Prognostic value of myocardial viability by delayed-​enhanced magnetic resonance in patients with coronary artery disease
and low ejection fraction: impact of revascularization therapy. J Am Coll Cardiol. 2012;59(9):825–​35. doi:10.1016/​j.jacc.2011.09.073 with permission Elsevier.

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Contents
Summary  565
Introduction  565
Cardiac 123I-​mIBG imaging  565
Cardiac PET imaging of postganglionic
presynaptic sympathetic innervation  568
Imaging cardiac innervation in coronary
artery disease (CAD)  568
Imaging cardiac innervation in
arrhythmogenesis  570
Imaging cardiac innervation in HF  570
Assessment of prognosis  570
Monitoring therapy  571
Device therapy  571
Imaging cardiac innervation in
dysautonomias  573
Neurodegenerative diseases  573
Diabetes mellitus  573
Future perspectives  574
Conclusion  574
CHAPTER 37
Imaging cardiac
innervation
Albert Flotats and Ignasi Carrió
Summary
Cardiac autonomic nervous system contributes to maintain cardiovascular homeostasis
to changing demands by regulating cardiac output, vasoreactivity, and metabolism. There
is increasing evidence supporting the use of cardiac innervation imaging in patients
with different cardiac disorders, especially with heart failure (HF), where it has an inde-
pendent prognostic value.
Cardiac innervation imaging is possible using either single photon emission or posi-
tron emission tracers. This chapter updates the subject with inclusion of new data,
highlighting the use of sympathetic cardiac innervation imaging for improving the man-
agement of patients with HF.
Introduction
Different radiotracers have been developed for the assessment of pre-​and postsynaptic
receptors of the cardiac autonomic nervous system [1–​6]. As parasympathetic innerv-
ation of the heart is relatively scarce, and as radiotracer analogues of acetylcholine (the
neurotransmitter for the parasympathetic system) are difficult to synthesize, their use is
mainly limited to animals. Conversely, cardiac sympathetic innervation is profuse, and
analogues of norepinephrine (NE, the neurotransmitter for the sympathetic system) are
relatively easy to produce. Thus, this chapter is limited to imaging sympathetic cardiac
innervation. The majority of the existing radiotracers target postganglionic presynaptic
sympathetic neurons. They are dominated by radiolabelled neurotransmitters or analo-
gous compounds (‘false’ neurotransmitters) that take advantage of the uptake-​1 neuronal
recycling pathway (see E Fig. 37.1). Radiotracers designed for imaging postsynaptic
α-​and β-​receptors are basically limited to research.
Clinically, cardiac innervation imaging is mainly performed by means of myocardial
123
I-​metaiodobenzylguanidine (123I-​mIBG) planar scintigraphy and SPECT.
Cardiac 123I-​mIBG imaging
123
I-​mIBG is an analogue of NE but with poor affinity for adrenergic receptors and only
weak adrenergic effects. 123I-​mIBG has the same neuronal mechanism of uptake (uptake-​1),
storage, and release than NE, but unlike this one, 123I-​mIBG remains unmetabolized in
the neurosecretory vesicles, resulting in a specific concentration in contrast to cells of
other tissues [7]‌.
566 CHAPTER 37   Im aging cardiac innervat ion
Fig. 37.1  Diagram of the sympathetic neurotransmission. Norepinephrine
(NE) is synthesized in the presynaptic nerve terminal by the conversion
of tyrosine to dihydroxyphenylalanine (DOPA) by tyrosine hydroxylase
(TH). Aromatic L-​amino acid decarboxylase (AAAD) then converts DOPA
to dopamine (DA), which is transported into storage vesicles through
vesicular monoamine transporter (VMAT). Once inside these vesicles,
DA is transformed to NE by dopamine-​β-​hydroxylase (DβH). Following
an action potential and nerve depolarization, NE is released into the
synaptic cleft by exocytosis of vesicles stimulating pre-​and-​postsynaptic
adrenoceptors (α and β). Green dotted arrow and red dashed arrow
indicate, respectively, positive and negative feedback mechanisms that
affect NE exocytosis.
Interaction of stimulated postsynaptic adrenoceptors with GTP-​associated
regulatory proteins (G prot) leads to activation of phospholipase C
(PC) –​α1 receptors–​or adenyl cyclase (AC) –​β1 and β2 receptors–​,
which, respectively, increase inositol triphosphate and cyclic adenosine
monophosphate (cAMP), and intracellular calcium. Through protein kinase
C, this leads to phosphorylation of enzymes and alteration of ion channels,
with electrolyte transfer in and out of cells leading to the cellular response:
– ​for α1 receptors: smooth muscle contraction and peripheral arterial (and
venous) vasoconstriction; increase of LV inotropy and coronary artery
vasoconstriction.
– ​for β1 and β2 receptors: increase of LV inotropy, chronotropy and
automaticity, and decrease of large coronary tone (especially β2 receptors).
β1 receptors also increase conduction velocity and β2 receptors increase
the refractory period.
Post-​synaptic α2 receptors are coupled to inhibitory Gi protein, which
inactivates AC, decreasing cAMP thus preventing protein kinase activation
leading to constriction of vascular smooth muscle. This includes limited
coronary artery vasoconstriction that may be overridden by the coronary
vasodilatory effects of β2 activation.
The most important mechanism for the termination of NE action in the
synaptic cleft is active reuptake into the neuron through the NE uptake-​
1 transporter (NET), which accounts for >75% of NE removal. Once in
the neuron again, the majority of the reabsorbed NE is repacked into
secretory vesicles by VMAT, while a small portion is metabolized to 3,4-​
dihydroxyphenylglycol (DHPG) by monoamine oxidase (MAO). The
remaining NE in the synaptic cleft diffuses into the vascular space and very
little is taken up in postsynaptic cardiomyocytes by the energy-​independent,
uptake-​2 mechanism, with subsequent metabolization to normetanephrine
(NMN) by catechol-​O-​methyltransferase (COMT).
Patient preparation for 123I-​mIBG scintigraphy includes tem-
porarily interruption (4–​5 biological half-​lives) of some medica-
tions known to affect 123I-​mIBG uptake, principally the tricyclic
antidepressants (e.g. desipramine and imipramine) and by ana-
logy, the serotonin-​NE reuptake inhibitors (e.g. milnacipran);
the NE depletors (e.g. reserpine, tetrabenazine); the sympatho-
mimetic amines (phenylpropanolamine, phenylephrine) and
similar monoamines with abuse potential (e.g. cocaine, amphet-
amines); and the non-​selective α-​and β-​receptor blocking agents,
prototypically labetalol [8]‌. For the same reason, it is also advis-
able to stop food containing vanillin and catecholamine-​like com-
pounds (e.g. chocolate and blue-​veined cheeses) [9].
123
I-​mIBG is administered intravenously with the option of
blocking thyroid uptake of free 123I (reducing gland irradiation)
by oral administration of either potassium perchlorate (500 mg)
or, if the patient is not allergic to iodine, potassium iodide solu-
tion or Lugol’s solution (equivalent to 130 mg iodide) at least 30
min before the injection of 123I-​mIBG  [9]‌.
Planar scintigraphic images in the anterior view of the thorax
are acquired 15 minutes (early image) and 4 hours (late image)
after intravenous injection of 111–​370 MBq of 123I-​mIBG, with
the patient lying in the same supine position and using either
low-​energy (LE) or, preferably, medium-​energy (ME) parallel
hole collimators. Images are acquired for 10 minutes and stored in
128×128 or 256×256 matrix [9]‌(see E Fig. 37.2). Additionally,
SPECT can be performed immediately following planar images
using customary myocardial perfusion protocols, with 64 projec-
tions at 30 seconds each, in 64 × 64 matrix [10] (see E Fig. 37.3).
Image interpretation is done by systematic visual review on a
computer screen, assessing the quality of the study, left ventricular
(LV) size and degree of myocardial and lung 123I-​mIBG uptake
[9]‌. Normal myocardial 123I-​mIBG distribution includes a rela-
tively low uptake in the inferior wall, which is more pronounced
in the elderly (see E Figs. 37.2 and 37.3). There may also be sub-
stantial 123I-​mIBG uptake in the liver, which may overlap the in-
ferior LV wall. Scattering from the lung field to the lateral LV wall
may also occur [9]. SPECT slices should be assessed scaled to the
planar appearance using a continuous colour scale. Accordingly,
a five-​point scale ranging from 0 (normal uptake) to 4 (uptake ab-
sent) can be used to score each segment. The total score of the LV
is referred to as the summed score according to the standardized
17-​segment LV model [9].
In addition to visual assessment, 123I-​mIBG uptake can be semi-​
quantified by calculating a heart-​to-​mediastinum ratio (HMR), after
drawing regions of interest (ROI) over the heart (including or not
the cavity) and the upper mediastinum (avoiding the thyroid gland)
(see E Fig. 37.4). Average counts per pixel in the myocardium
are divided by average counts per pixel in the mediastinum. The
myocardial washout rate (WR) from early to late images is also
calculated, and expressed in percentage, as the rate of decrease in
myocardial counts over time between both images (normalized to
mediastinal activity) [9]‌. The early HMR probably reflects the in-
tegrity of presynaptic nerve terminals and uptake function. The late
HMR combines information on neuronal function from uptake to
 I n t roduc t i on 567

Fig. 37.2  Planar scintigraphic images in the anterior view of the thorax at 15 min (early image) and 4 h (late image) of 123I-​mIBG injection, representing cardiac
sympathetic innervation of a 78-​yr old woman. Imaging was performed in this lady without known heart disease because she had symptoms of parkinsonism
to rule out a Lewy body disorder. Myocardial 123I-​mIBG uptake is severely reduced or absent in Lewy body disorders. Thus, 123I-​mIBG imaging is useful for
differentiating these disorders from other forms of parkinsonism, and for differentiating dementia with Lewy bodies from Alzheimer’s disease and other
dementias. Images show a normal variant of myocardial distribution of 123I-​mIBG. A homogeneous distribution of the radiotracer over the left ventricle can be
seen, except for the relatively low uptake in the inferior wall. Heart to mediastinum ratios: early 1.86, late 1.66; washout rate 24%.

release through the storage vesicle at the nerve terminals. The WR
reflects the degree of sympathetic drive. Increased sympathetic ac-
tivity is associated with high WR and low late HMR [1, 2, 5].
The assessment of these parameters bids simplicity and high
intralaboratory reproducibility [11–​13], but low interlaboratory
reproducibility depending on the type of camera-​collimator used,
imaging time delay, and acquisition duration. The widespread
availability of LE collimators determines their common use for
imaging tracers labelled with 123I, but ME collimators have shown
better quantitative accuracy. Nakajima et al. [14] published the
results of a large Japanese multicentre study of cross-​institution
phantom calibrations for the quantification of the HMR by

Fig. 37.3 Cardiac 123I-​mIBG SPECT of the subject shown on E Figure 37.2 obtained at 4 h of 123I-​mIBG injection. Both the representative mid left ventricle SPECT
slices (left, upper row: short-​axis; middle row: vertical long-​axis; inferior raw: horizontal long-​axis) and the polar map (right) show reduced tracer uptake in the
inferior wall and apex, which is more apparent than on planar images and should be considered a normal variant in the elderly.
568 CHAPTER 37   Im aging cardiac innervat ion
Fig. 37.4  Regions of interest (ROI) drawn on the planar scintigraphy over
the heart (H) and the upper mediastinum (M) for the semi-​quantification of
cardiac 123I-​mIBG uptake.
various gamma camera and collimator combinations from
common vendors. Recently, Verschure et al. [15] performed a
similar cross-​calibration cardiac 123I-​mIBG phantom multicentre
study in Europe to calculate conversion coefficients for specific
individual gamma camera-​collimator combinations. Results from
these studies support the concept that cross-​calibration cardiac
123
I-​mIBG phantom studies allow for an easy conversion of dif-
ferent institutional HMRs to standardized HMRs, which, reducing
variation in outcome measures, may facilitate multicentre com-
parison of cardiac 123I-​mIBG imaging, thereby further strength-
ening the clinical role of cardiac 123I-​mIBG scintigraphy [16].
Development of different methods to derive quantitative param-
eters for SPECT imaging has also been proposed, including itera-
tive reconstruction techniques with compensation for scatter and
septal penetration [17, 18] and the use of volumetric analysis tech-
niques [19, 20]. In addition, development of cardiac 123I-​mIBG
databases for healthy subjects has also provided a more reliable
means for quantifying the significance of reduced uptake [20].
Cardiac PET imaging of postganglionic
presynaptic sympathetic innervation
PET imaging offers higher spatiotemporal resolution than planar
or SPECT imaging, allowing for improved regional analysis,
kinetic modelling, and quantification [1, 3, 4, 6]. Several PET
tracers have been developed for cardiac sympathetic imaging.
They include catecholamines (susceptible to metabolism) such
as 11C-​epinephrine, 11C-​phenilephrine and 18F-​fluorodopamine,
and non-​catecholamine sympathomimetic amines such as 11C-​
hydroxyephedrine (11C-​HED). However, they are not used in
daily clinical practice, mainly due to the short half-​life of 11C
(20.4 min) and/​or difficult kinetic modelling. 11C-​HED, the most
routinely used, is a metabolically resistant analogue of NE, with
higher binding affinity and selectivity for myocardial uptake-​1
than 123I-​mIBG. It is partially repacked upon uptake, and released
back into synaptic space by passive diffusion or active release
with endogenous NE. Thus, the retention of 11C-​HED represents
continual recycling of the tracer by the presynaptic neuron. 11C-​
HED distribution in the myocardium is regionally more homo-
genous than 123I-​mIBG, and myocardial uptake is quantified by
the retention index, a ratio of activity in the myocardium in the
final 40–​60 minute image of a dynamic sequence to the integral
of the image-​derived arterial blood pool time-​activity curve. WR
of 11C-​HED has been suggested to reflect sympathetic neuronal
activity [3, 4, 6].
Currently, 18F-​labelled radiotracers have been developed to
take advantage of the longer half-​life of 18F (109.8 min), which
allows for more flexibility both in the study design and delivery
from producing cyclotrons. 18F-​LMI1195 (N-​[3-​bromo-​4-​(3-​
[18F]fluoro-​propoxy)-​benzyl]-​guanidine) is a benzylguanidine
analogue structurally similar to 123I-​mIBG, and readily trans-
ported and stored into synaptic vesicles. It can be easily
obtained by a simple one-​step 18F replacement reaction, and
currently is in phase 1 and 2 trials, which have shown favourable
kinetics allowing early imaging and image quality superior to
123
I-​mIBG. Animal and initial first-​in-​human studies with 18F-​4-​
fluoro-​m-​hydroxyphenethylguanidine (18F-​4F-​MHPG) and its
structural isomer 3 18F-​3-​fluoro-​m-​hydroxyphenethylguanidine
(18F-​ 3F-​PHPG) suggest that they have slow uptake and
longer neuronal retention times, with low liver and lung uptake
interfering with the myocardial signal, potentially allowing to
reflect even modest alterations of cardiac sympathetic nerve
conditions [6, 21].
Imaging cardiac innervation in
coronary artery disease (CAD)
The uptake-​1 mechanism is an energy-​dependent process that re-
quires oxygen for proper function. As such, sympathetic nerve
fibres have been found to be more sensitive to ischaemia than
cardiomyocytes [22] and 123I-​mIBG uptake is significantly reduced
in areas of myocardial infarction (MI) and adjacent non-​infarcted
regions, as well as in areas with acute and chronic ischaemia (see
E Fig. 37.5). 123I-​mIBG uptake reappears late after MI, which in-
dicates re-​innervation, in part potentially responsible for the im-
provement of function. Probably, ischaemic induced damage to
sympathetic fibres takes a long time to regenerate, which may be
 Imaging ca rdiac i n n ervati on i n c orona ry a rtery di se ase   (C A D ) 569

Fig. 37.5  High-​risk cardiac 123I-​mIBG imaging of a 64-​yr old male with ischaemic heart failure (NYHA class III, left ventricular ejection fraction 15%) with a
history of coronary artery disease and inferior myocardial infarction, arterial and pulmonary hypertension, type 2 diabetes mellitus, and mitral and aortic valve
replacement. On the top of the figure early (15 min) and late (4 h) planar scintigraphic images showing impaired cardiac sympathetic innervation with severely
decreased 123I-​mIBG uptake, which is more pronounced in the late image (early and late heart to mediastinum ratios of 1.39 and 1.08, respectively; washout rate
of 45%). The bottom of the figure shows the reconstructed slices at mid left ventricle and polar maps of 99mTc-​tetrofosmin SPECT myocardial perfusion imaging
at rest (in the upper row) and late 123I-​mIBG SPECT innervation imaging (in the lower row). Note that myocardial innervation is more impaired than myocardial
perfusion (perfusion/​innervation mismatch).

important in the pathophysiology of HF and arrhythmias [23],
offering potential for 123I-​mIBG imaging at rest for the detection
of sporadic transient ischaemic attacks and for the evaluation
of the area at risk in the subacute phase of acute coronary syn-
dromes by revealing more extensive defects than myocardial per-
fusion imaging at rest, as well as a marker of reversible ischaemia
in patients with contraindications for stress myocardial perfusion
imaging [2, 24].
Zhou et al. [25] developed a new tool to measure myocardial
scar and peri-​infarct border zone (a mixture of scar and viable
myocardium), and to quantify 123I-​mIBG uptake in border zone
from 123I-​mIBG and resting 99mTc-​tetrofosmin myocardial per-
fusion SPECT imaging. 123I-​mIBG uptake in the border zone
predicted ventricular arrhythmia (VA) inducibility on cardiac
electrophysiological testing (EPS) with higher accuracy than
the border zone extent alone. Therefore, 123I-​mIBG uptake
in the border zone could be a physiologically relevant par-
ameter for predicting the occurrence of VA in patients with
previous MI.
Recently, Klein et al. [26] studied 15 patients with ischaemic
heart disease referred for radiofrequency ablation for pharmaco-
logically refractory ventricular tachycardia (VT). Preprocedural
cardiac 123I-​mIBG imaging was used to create three-​dimensional
innervation models and registered to high-​density voltage maps.
123
I-​mIBG innervation defects were more than twice the size of
voltage-​defined scar and could not be detected with standard
voltage criteria. Interestingly, 36% of successful VT ablation sites
demonstrated normal voltages, but all ablation sites were within
570 CHAPTER 37   Im aging cardiac innervat ion
the areas of abnormal innervation. Thus, 123I-​mIBG innervation
maps may provide crucial information about VT substrate not
available from the current anatomical VT substrate model, of-
fering supplemental guidance for VT ablations in ischaemic VT
patients.
Imaging cardiac innervation in
arrhythmogenesis
Sudden cardiac death (SCD) occurs mainly among subjects
with no previous cardiovascular history, which highlights the
need of better identification of patients at risk. Heterogeneity
of sympathetic innervation in response to injury is highly
arrhythmogenic. Sequential changes consisting of nerve degen-
eration followed by neurilemma cell proliferation and axonal
regeneration have been described in different altered states
of the myocardium [27]. The coexistence of denervated and
hyperinnervated areas in the diseased myocardium could result
in increased electrophysiological heterogeneity during sym-
pathetic activation, leading to VA and SCD [27]. On the other
hand, sympathetic denervation of viable myocardium (see E
Fig. 37.5) may also result in denervation supersensitivity, with
exaggerated response of myocardium to sympathetic stimula-
tion and increased vulnerability to VA [23].
Impaired cardiac sympathetic imaging has been described in
idiopathic ventricular fibrillation (VF), long-​QT and Brugada
syndromes, and arrhythmogenic right ventricular cardiomyop-
athy, as well as in most of the disorders that result in LV dysfunc-
tion and potentially lethal VA [2]‌. Furthermore, in patients with
idiopathic paroxysmal atrial fibrillation (AF)—​and no structural
heart disease, LV systolic dysfunction (LV ejection fraction, LVEF
≥50%) or symptoms of HF—​a low late HMR was reported to be
an independently powerful factor for predicting not only the
transit to permanent AF but also the occurrence of HF with per-
manent AF [28]. These findings may have important implications
for the management of patients with paroxysmal AF before the
occurrence of remarkable structural remodelling of atria and sub-
sequent cardiac dysfunction of the LV caused by AF.
Imaging cardiac innervation in HF
HF pathophysiology involves a vicious cycle where myocardial
injury leads to reduced cardiac output, which activates a com-
plex network of compensatory mechanisms, including sequential
neurohormonal pathways with implication of the sympathetic
nervous system, to maintain heart function, but leading to fur-
ther cardiac damage and progressive impairment of function if
such mechanisms persist [29].
Plasma NE is associated to disease progression, prognosis, and
risk of SCD [30]. Several studies have shown impaired cardiac
sympathetic imaging in different cardiomyopathies (see E Fig.
37.5), which could reflect the contribution of the altered cardiac
sympathetic nervous function to the development of the myocar-
dial disorder [1–​6].
Assessment of prognosis
HF has a general poor long-​term prognosis but it is difficult to de-
termine prognosis in an individual patient. To improve survival,
adequate risk stratification is needed. Impaired cardiac sympa-
thetic imaging is strongly related to mortality in HF patients in-
dependently of its cause [1–​6].
The prospective, multicentre, international trial ‘AdreView
Myocardial Imaging for Risk Evaluation in Heart Failure
(ADMIRE-​HF)’ [31], which included 961 patients with New
York Heart Association functional class (NYHA) II–​III and LVEF
≤35%, showed that a late HMR <1.6 more than doubled (from 15%
to 37%) the incidence of worsening NYHA class, life-​threatening
arrhythmias, and cardiac death for a 17-​month median follow-​up.
Late HMR ≥1.6 had a composite hazard ratio of 0.40 (P <0.001)
and was a predictor of cardiac and all-​cause deaths independent
of variables such as age, NYHA class, LVEF, and brain natriuretic
peptide (BNP) at multivariate analysis. These results confirmed
the high negative predictive value (>99%) of a preserved late
123
I-​mIBG HMR with respect to cardiac death or cumulative ar-
rhythmic events from previous studies in less consistent popula-
tions, and that 123I-​mIBG cardiac imaging in otherwise high-​risk
HF patients can identify a significantly large subgroup being in
fact at low risk. Based on the results of this trial, in March 2013
the Food and Drug Administration approved 123I-​mIBG for use in
patients with NYHA class II or III HF and a LVEF ≤35%, to help
identify patients with 1-​to 2-​year mortality risk as indicated by
HMR ≥1.6.
The ADMIRE-​HF extension (ADMIRE-​HFX) study, with com-
plete 2-​year follow-​up survival analysis showed that late HMR
treated as a continuous variable for risk assessment rather than
dichotomized at 1.60 as in the primary analyses, added mean-
ingful prognostic information when combined with the modified
Seattle Heart Failure Model (SHFM-​D), an algorithm of routinely
collected demographic, imaging, laboratory, and therapeutic
parameters that determine the likely 1–​5 year mortality. Net re-
classification improvement for such a combination was 22.7%,
with 14.9% of patients who died reclassified into a higher risk cat-
egory and 7.9% of patients who survived reclassified into a lower-​
risk category [32].
Another subanalysis of the ADMIRE-​HF trial reported that
123
I-​mIBG imaging had the same predictive prognostic value
across the LVEF spectrum (recalculated at core lab). At all levels
of LVEF (range 20–​58%), a late HMR of <1.6 was associated with
a higher risk of death or potentially lethal arrhythmic event and
of the composite of cardiovascular death, arrhythmic event, and
HF progression. Comparing subjects with LVEF ≤35% and >35%,
there was no evidence of effect modification of LVEF on the risk
associated with low HMR for death or arrhythmic event and for
the composite. For the outcome of death or arrhythmic event, late
HMR improved the risk discrimination beyond clinical and bio-
marker data among both LVEF groups [33].

An additional subanalysis of the ADMIRE-​HF trial showed
that late HMR may also risk stratify HF patients for cardiac-​
related hospitalization, especially when used in conjunction with
BNP [34].
A further and more recent subanalysis of the ADMIRE-​HFX
study showed a very low all-​cause mortality in patients with
HMR ≥1.6 (~5%), and no deaths in 47 patients with HMR
≥1.8. Particularly, this study demonstrated that when added to
a proportional hazards model containing BNP and LVEF, HMR
provided a net reclassification improvement for prediction of
mortality and mortality equivalent events (resuscitated arrest, de-
fibrillation for VT/​VF) [35].
SPECT imaging may provide additional insights, as shown
by Clements et al. [36] in 938 patients from the ADMIRE-​HFX
study. Despite the 2-​year all-​cause and cardiac mortality not
being significantly different between patients with ischaemic
and non-​ischaemic HF, mortality was higher in patients with
dysinnervation involving >50% of the LV. Highest cardiac mor-
tality risk for ischaemic HF patients was seen with perfusion de-
fects involving 20–​40% of the LV. By comparison, non-​ischaemic
HF patients with smaller perfusion abnormalities (<20% of the
LV), but with a large 123I-​mIBG/​99mTc-​tetrofosmin mismatch,
were at highest risk of cardiac death. These results suggest that
accurately defining the amount of dysinnervated myocardium is
more important than obtaining precise estimates of the severity
of dysinnervation, which could potentially simplify the clinical
use of 123I-​ mIBG imaging [36]. Additionally, combination of
late HMR and scar quantification by resting myocardial perfu-
sion SPECT showed to further improve risk stratification for VA
beyond late HMR in patients from the ADMIRE-​HF trial [37].
Patients with non-​ischaemic cardiomyopathy with a summed rest
score (SRS) >8 and a HMR <1.6 were found to be at a higher risk
for VA. Conversely, those patients (ischaemic or not) with a rela-
tively preserved late HMR (≥1.6) and a SRS ≤8 were found to have
a trend towards a lower risk of VA [37].
Two meta-​analyses on the prognostic role of 123I-​mIBG in
HF based on published aggregate imaging and outcome results,
respectively including a total of 1,755 and 1,357 HF patients,
showed that patients with a decreased late 123I-​mIBG HMR and
an increased WR had a significantly worse prognosis compared
with those with relatively preserved cardiac 123I-​mIBG param-
eters [38, 39]. More recently, two additional meta-​analyses re-
spectively involving a collection of the individual data records
of 1,322 and 636 patients, with detailed analyses of the full
combined population and the merged data from the partici-
pating sites, provided consistent evidence, somewhat equivalent
to that typically obtained from a multicentre prospective trial,
of the long-​term prognostic value of late HMR in HF patients
[40, 41]. Interestingly, the study of Nakata et al. [40] could also
effectively risk stratify HF patients on different LVEF ranges,
which is of importance taken into account that most SCD oc-
curs among subjects with minimal to no evidence of arrhythmic
risk. From its part, the study of Verschure et al. [41] also re-
vealed that while the HMR helps predict the likelihood of pump
I m ag i n g ca rdiac i n n ervat i on   i n   H F 571
failure-​related outcomes, it may be less effective for identifying
risk for lethal VA.
Because of the large number of cardiac mortality risk factors
in HF patients makes it difficult to quantify the contribution of
each individual factor to final outcomes and prevents their use in
clinical models, Nakajima et al. [42] produced simple dedicated
mortality risk charts combining late 123I-​mIBG HMR and three
clinical parameters (NYHA class, age and LVEF) with 2-​and 5-​
year mortality risk estimations aimed to provide a flexible plat-
form for short-​and long-​term treatment decision-​making.
Monitoring therapy
As clinical status and/​or LV function improve in response to con-
ventional medical treatment for HF, there is a parallel improve-
ment in cardiac sympathetic function as assessed by radionuclide
imaging [1–​5], supporting the concept that a restoration of car-
diac neuronal uptake of NE is one of the beneficial effects of such
treatment.
Kasama et al. [43] reported that the variation in the WR be-
tween the sequential 123I-​mIBG scans was the only independent
predictor of cardiac death in 208 stable HF patients, which raises
the possibility that patients showing worsening on serial 123I-​
mIBG studies would need additional or alternate therapies (e.g.
device therapy and cardiac transplantation) to improve outcome.
Likewise, 123I-​mIBG imaging could provide a method to deter-
mine, in patients who do not tolerate full proven therapeutic
doses, which drug and dose are indicated.
Device therapy
Prevention of SCD is an important target in HF since about 50%
of mortality occurs suddenly and unexpectedly, especially in
patients with milder symptoms and related to VA. Implantable
cardioverter-​defibrillators (ICD) reduce mortality in survivors
of cardiac arrest and in patients with sustained symptomatic VA,
being recommended in the secondary prevention of such patients
provided a life expectancy of >1 year and good functional status
[44]. An ICD is also recommended in the primary prevention
of patients with symptomatic HF (NYHA class II–​III), a life ex-
pectancy of >1 year with good functional status, and LVEF ≤35%
despite ≥3 months of optimal pharmacological treatment [44].
In these last patients, recommendations derive largely from four
large randomized trials [45–​48] from which LVEF ≤30–​35% be-
came a principal variable for deciding who should receive an ICD.
However, >50% of HF patients who die suddenly have a LVEF
>30% [49]. Other independent univariate predictors of SCD have
been identified including low NYHA class, unsustained VT, and
inducibility of VT in EPS. However, they have a low positive
predictive value, and better individual risk assessment to select
HF patients who would benefit from an ICD placement is still
needed, most of all considering the potential complications (in-
appropriate shocks and ICD infection) and the elevated cost of
such devices. In addition, although techniques such as analysis
of heart rate variability (HRV) and measurement of baroreflex
sensitivity have shown an association between cardiac autonomic
572 CHAPTER 37   Im aging cardiac innervat ion
innervation abnormalities and SCD [50], they are of difficult use
in clinical practice.
In a phase 2, open-​label, multicentre study among 50 patients
with LV dysfunction and previous MI, Bax et al. [51] found that
late 123I-​mIBG SPECT defect score was the only variable that
showed a significant difference between patients with and without
positive EPS. A defect score of ≥37 yielded a sensitivity of 77%
and specificity of 75% for predicting EPS results. Tamaki et al.
[52] prospectively compared the predictive value of 123I-​mIBG
imaging for SCD with that of the signal-​averaged ECG, HRV,
and QT dispersion in 106 patients with chronic stable HF (LVEF
<40%). After a follow-​up of 65 ± 31 months, only WR and LVEF
were significantly and independently associated with SCD. In
addition, the ADMIRE-​HF trial showed that arrhythmia was sig-
nificantly more common in patients with late HMR <1.60 than in
patients with higher values (10.4% vs. 3.5%) [31].
Other studies have shown the usefulness of 123I-​mIBG car-
diac imaging to predict VA in HF patients receiving an ICD for
primary prevention. Nishisato et al. [53] reported that patients
with a late HMR ≤1.9 and a summed score ≥12 had a signifi-
cantly greater ICD discharge rate than did those patients who
had a late HMR >1.90 and a summed score <12 (94% vs. 18%).
The former combination was associated with a hazard ratio of 3.8
and independently predicted ICD shocks or cardiac death, in a
better way than age, sex, signal-​averaged ECG, BNP, medications,
EPS, and LVEF. In addition, in a study among 116 HF patients,
Boogers et al. [54] reported that late 123I-​mIBG SPECT summed
defect score was an independent predictor for both arrhythmias
causing appropriate ICD therapy as well as the composite of ap-
propriate ICD therapy or cardiac deaths in patients referred for
ICD therapy. Patients with a large defect score (>26) showed sig-
nificantly more appropriate ICD therapy (52% vs. 5%) and appro-
priate ICD therapy or cardiac death (57% vs. 10%) than patients
with a small defect score (≤26) at 3-​year follow-​up. Remarkably,
only two (3%) patients with a small defect score received appro-
priate ICD therapy vs. 22 (40%) patients with a large defect score.
Furthermore, the risk for appropriate ICD therapy was 13 times
higher in patients with a large defect score as compared with pa-
tients with a small defect score; besides, in patients with a large
defect score the risk for appropriate ICD therapy or cardiac death
was eight times higher than in patients with a small defect score.
Marshall et al. [55] followed up 27 patients with HF referred
for ICD implantation for a median of 16 months. Patients who
experienced a significant arrhythmic event (37%) had lower early
and late 123I-​mIBG HMR and higher SPECT defect score and mis-
match perfusion-​innervation score than patients with no events.
Optimal thresholds for predicting arrhythmia were <1.94 for
early HMR (sensitivity 70%, specificity 88%); <1.54 for late HMR
(sensitivity 60%, specificity 88%); and SPECT defect score ≥31
(sensitivity 78%, specificity 77%).
The ADMIRE-​HF subanalysis of Al Badarin et al. [56] re-
vealed late HMR <1.6 (HR 3.48, 95%CI 1.52 to 8), LVEF <25%
(HR 1.97, 95%CI 1.28 to 3.05) and systolic blood pressure (SBP)
<120 mmHg (HR 1.19, 95%CI 1.03 to 1.39) as independent
predictors of potentially life-​threatening arrhythmic events. The
risk score using these three simple variables effectively stratified
the study population with primary prevention indications for
ICD implantation.
Verschure et al. [57] in a prospective multicentre study that
enrolled 135 stable HF patients who were referred for prophy-
lactic ICD implantation and followed up a median of 30 months
reported that late HMR and defect size of 123I-​mIBG SPECT were
not associated with appropriate ICD therapy. However, late HMR
ratio was significantly and independently associated with the
combined endpoint of appropriate ICD therapy, progression of
HF and cardiac death (hazard ratio –​HR 0.135 [0.035–​0.517]).
Post-​hoc analysis showed that the combination of late HMR (HR
0.461 [0.281–​0.757]) and LVEF (HR 1.052 [1.021–​1.084]) was
significantly associated with freedom of appropriate ICD therapy,
thus proposing that cardiac 123I-​mIBG scintigraphy might be
helpful in identifying HF patients who might not benefit from
ICD implantation. The less robust performance of the late HMR
for prediction of arrhythmic events than for cardiac or all-​cause
death may be related with a non-​linear relationship between oc-
currence of arrhythmic events and late HMR as a measure of
global cardiac innervation. Patients with intermediate late HMR
are more likely to have appropriate ICD therapy compared to pa-
tients with low and high late HMR [35, 57, 58]. These findings
are in line with those derived from a reanalysis of ADMIRE-​HF
SPECT images, which were reprocessed with iterative reconstruc-
tion, showing that ischaemic HF patients with intermediate de-
fects on SPECT summed score appeared to be at the highest risk
for cardiac events [59]. Despite the fact that patients with lower
HMR are more likely to succumb to pump failure, intermediate
degrees of cardiac denervation may well lead to more electrical
heterogeneity and higher arrhythmic risk. In agreement with
the latter hypothesis, an additional ADMIRE-​HF substudy ana-
lysis following 777 patients without an ICD at study enrolment,
showed that while the HMR did not help identify patients with
enhanced survival from subsequent ICD implant, the number of
additional lives saved per 100 patients treated with an ICD was
related to HMR that peaked in patients with an intermediately
decreased value of ~1.5, in whom ICD placement would appear
most cost-​effective [60].
A decision-​analytic model was developed to compare screening
with 123I-​mIBG imaging and no screening over 2-​year and 10-​year
time [61]. According to the model, screening of guideline eligible
HF patients selected for ICD with cardiac 123I-​mIBG scintigraphy
may be cost-​effective and may help reduce costs associated with
implantation of ICDs, with a minimal impact on survival (losses
of 0.001 and 0.040 life-​years, respectively, over 2 and 10 years).
Incorporating cardiac 123I-​mIBG scintigraphy into the assess-
ment of HF patients eligible for an ICD was associated with a
21% reduction in device implantation. Consequently, the number
needed to screen to prevent one ICD implantation is five [61].
In 204 patients with ischaemic cardiomyopathy (LVEF
≤35%) eligible for primary prevention ICDs, the prospective
‘Prediction of ARrhythmic Events with Positron Emission
 I m ag i n g ca rdiac i n n ervati on i n dys au ton o m ias
Tomography (PAREPET)’ trial proved that the volume of de-
nervated myocardium as assessed by 11C-​HED PET was a strong
predictor of sudden cardiac arrest (arrhythmic death or ICD
discharge for VF or VT >240 beats/​min), independently of
other parameters such as LVEF, infarct volume, or hibernating
myocardium. Quantitatively, each 1% increase in the denerv-
ated myocardial volume was associated with a 5.7% increase in
sudden cardiac arrest [62].
More recently, in a study including 52 patients with similar
demographics as the PAREPET trial, Rijnierse et al. [63] showed
that patients with newly placed ICDs and inducible VA during
an EPS had larger denervation areas as assessed with 11C-​HED
compared to non-​inducible patients. Additionally, there were no
differences in the innervation/​perfusion mismatch ratio in pa-
tients with and without inducible VA. Contrary to the PAREPET
study, denervation volume did not remain an independent pre-
dictor of inducible VA in multivariate analysis. Nevertheless,
both studies indicate that global denervation size may be more
important in predicting VA and SCD than regional denerv-
ation. Moreover, these studies indicate that cardiac sympathetic
innervation imaging by PET may also help to risk stratify pa-
tients who most likely benefit from ICD therapy. However, no
single measurement provides sufficient reassurance to obviate
device implantation if otherwise indicated by current guide-
lines. Future larger scale trials are needed to reinforce the role of
cardiac innervation imaging in this setting. Meanwhile, a joint
document of the ASNC/​SNMMI has been published as a gen-
eral guide for clinicians and payers, outlining the clinical ap-
plications in which cardiac 123I-​mIBG imaging could provide
incremental risk stratification and could guide patient manage-
ment on the basis of current evidence or supported by expert
consensus opinion [64]. The document indicates that 123I-​mIBG
imaging can be appropriate when there is uncertainty on the
part of a physician in patients who meet criteria for ICD implant
in whom 123I-​mIBG imaging would promote more informed
clinical decision-​making when the result of 123I-​mIBG study is
likely to influence the decision regarding ICD implant. In add-
ition, the policy includes a potential/​emerging indication after
an ICD device has been removed due to infection and there is
uncertainty on the part of treating physician to proceed with
ICD replacement, when the result of 123I-​mIBG study is likely to
influence the decision regarding device replacement [64].
Even though current guidelines include specific recommenda-
tions for the use of cardiac resynchronization therapy (CRT) in
patients with HF [44], ∼30% of candidates continue to fail to re-
spond to this therapy (due to lack of consensus regarding the def-
inition of non-​response, technological limitations to the delivery
of therapy, and many other factors) [65]. CRT has been shown
to have a favourable effect on cardiac sympathetic innervation as
reflected by improved 123I-​mIBG uptake, which supports the po-
tential value of cardiac innervation imaging in the assessment of
the efficacy of CRT in patients with HF [66–​68]. Furthermore,
decreased late HMR has been associated with poor response
to CRT [69, 70], probably reflecting the severity of ventricular
573
damage to respond to pacer stimuli or to reverse remodelling.
Tanaka et al. [71] found that HF patients with dyssynchrony had
significantly less cardiac sympathetic activity than those without
dyssynchrony despite having similar LVEF. Dyssynchrony and
late 123I-​mIBG HMR ≥1.6 were associated with a high frequency
of response to CRT and favourable long-​term outcome over
3 years, thus highlighting the potential value of 123I-​mIBG cardiac
imaging for predicting the response to CRT.
In selected patients presenting with end-​stage HF, ventricular
assist devices for mechanical circulatory support may be used as a
‘bridge to decision’ or longer term [44]. Drakos et al. [72] reported
that LV assist device therapy produces clinical, functional, and
haemodynamic improvements accompanied by improvements
in 123I-​mIBG imaging, which might be relevant, particularly for
recipients of ventricular assist devices whose native cardiac func-
tion is difficult to evaluate. Moreover, improvement in 123I-​mIBG
imaging together with sustained myocardial functional recovery
could potentially identify responders to mechanical circulatory
support who might become candidates for explantation of the de-
vice [73]. Further studies are needed to determine if patients with
severe HF and a poor vs. favourable cardiac sympathetic imaging
to maximal medical therapy have a more favourable outcome
with ventricular assist devices compared to continued medical
therapy alone.
Sobajima et al. [74] have recently shown significant improve-
ment of 123I-​mIBG WR two weeks after transcatheter aortic valve
implantation (TAVI) in patients with severe aortic valve stenosis.
Significant correlation was found either negatively, between WR
and aortic valve area and cardiac output, or positively, between
WR and NE and log NT-​proBNP levels, thus implying that car-
diac 123I-​mIBG scintigraphy might serve as a risk stratification
tool or monitoring means for the therapeutic efficacy of TAVI.
Imaging cardiac innervation in
dysautonomias
Cardiac 123I-​mIBG uptake may be impaired in some patients with
disorders of the central and peripheral nervous system associated
with autonomic dysfunction.
Neurodegenerative diseases
Lewy body disorders (Parkinson’s disease, dementia with Lewy
bodies and pure autonomic failure) present with dysautonomia
and usually show severely reduced cardiac 123I-​mIBG uptake,
which helps differentiation from other neurodegenerative dis-
eases with similar symptoms [75].
Diabetes mellitus
Cardiac 123I-​mIBG imaging appears to be more sensitive than
autonomic nervous function tests for the detection of auto-
nomic diabetic neuropathy. 123I-​mIBG defects initially predom-
inate in the LV inferior wall, but can be complete in advanced
574 CHAPTER 37   Im aging cardiac innervat ion
dysautonomic states. Atherosclerosis of the large coronary ar-
teries is not a prerequisite cause for these findings since 123I-​mIBG
defects are present even in the absence of CAD, but the role of
microvascular disease has not been well defined [76].
Association of reduced 123I-​mIBG uptake and autonomic dys-
function has been reported to correlate with increased mortality
in diabetics. A substudy of the ADMIRE-​HF trial showed that
the presence of diabetes was associated with increased rate of HF
progression only in those diabetics with evidence of cardiac sym-
pathetic impairment as revealed by a late HMR <1.6 [77].
Future perspectives
The challenge before cardiac innervation imaging can be broadly
adopted in clinical practice is the success of research demon-
strating that this simple and safe non-​invasive imaging technique
can guide management in a way that enhances patient outcome.
The currently recruiting, event-​ driven phase 3b multicentre,
randomized, corporate sponsored prospective clinical trial
‘International study to determine if AdreView heart function scan
can be used to identify patients with mild or moderate HF that
benefit from implanted medical device (ADMIRE-​ICD)’ seeks
to finally demonstrate the clinical value of cardiac 123I-​mIBG
imaging in HF patients with NYHA class II–​III HF, and LVEF
25–​35%. The trial plans to randomize 2001 patients to 123I-​mIBG
Further reading
This chapter is mainly focused on cardiac presynaptic sympathetic
imaging with planar scintigraphy and SPECT. The reader will find
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with ischemic heart failure: intermediate severity innervation defects
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Contents
Introduction  577
Guideline criteria for CRT patient
selection  577
Definition of CRT response  577
Imaging dyssynchrony  578
Atrioventricular dyssynchrony  578
Interventricular dyssynchrony  578
Intraventricular dyssynchrony  579
Intraventricular dyssynchrony amendable
by CRT  579
Echocardiographic parameters for CRT
candidate selection  579
Other imaging modalities to detect LV
mechanical dyssynchrony  582
Imaging viability in the context of CRT  582
Scar effect on myocardial motion patterns
and CRT response  582
Scar assessment  582
Imaging venous anatomy  584
CHAPTER 38
Cardiac resynchronization
therapy: Selection of
candidates
Victoria Delgado and Jens-​Uwe Voigt
Introduction
Guideline criteria for CRT patient selection
Cardiac resynchronization therapy (CRT) is an established therapy for patients with
heart failure who remain symptomatic despite optimal medical treatment. Guideline
recommendations for patient selection have been published by all major scientific so-
cieties including the European Society of Cardiology (ESC) and are regularly updated
[1]‌. Unfortunately, the rate of patients who do not respond to CRT remains stable in the
range of 30–​40% even in indication class I [2].
It is important to understand that the recommended selection criteria for CRT candi-
dates derive from the inclusion criteria of large, randomized trials and were—​at the time
of the trial design—​arbitrarily chosen by the investigators. The treatment success shown in
these trials confirms the benefit of the therapy for the included patients, but it is no proof,
that the used inclusion criteria were optimal. On the contrary, the high non-​response
rate suggests that there is substantial need for improvement. Current selection criteria
refer mainly to the symptoms of the patient, QRS width, and morphology, as well as left
ventricular (LV) ejection fraction. Non-​invasive imaging can provide potentially helpful
additional structural and functional information which is, however, not uniformly used
and occasionally questioned. While the advantage of determining the location and extent
of myocardial scar is usually seen, other, potentially highly selective criteria, such as LV
mechanical dyssynchrony are commonly ignored [1]‌. This chapter will therefore discuss
and propose, to a large extent, applications of cardiac imaging to select patients with heart
failure who may benefit from CRT which are beyond current guideline criteria.
Definition of CRT response
The individual definition of response to CRT remains subject to debate. Echocardiographic
response (frequently defined as LV reverse remodelling with a left ventricular end-​systolic
volume (LVESV) reduction of >15%) occurs less often than clinical response (e.g. improve-
ment in New York Heart Association (NYHA) class or 6-​minute walk distance) but has
been shown to be associated with better long-​term outcome than clinical response [3]‌. It is
statistically difficult to establish a meaningful cut-​off value for LV volume reduction [4] as it
is only a surrogate parameter for a treatment success: no change in LVESV can be a therapy
failure in one patient, while it can mean a success in another patient which would otherwise
have further increased in LV size. The 15% LVESV reduction is therefore an accepted cut-​
off value but establishes by no means an ideal response criterion.
On a group level, the treatment effect can be more easily demonstrated by means of hard
end points such as hospitalization rates or survival, which, however, requires a meaningful
578 CHAPTER 38   C ardiac resynch roniz at ion ther a p y: Sel ecti on of ca n di dates

number of subjects and follow-​up time of several years. Therefore,
smaller studies use frequently echocardiographic or clinical surro-
gate parameters as endpoints despite all their limitations, as they
have the advantage to be available within 6 to 12 months after ini-
tiation of CRT.
Imaging dyssynchrony
Atrioventricular dyssynchrony
Prolonged atrioventricular conduction leads to impaired LV
diastolic filling and reduces LV preload and stroke volume. This
type of dyssynchrony can be assessed with pulsed-​wave Doppler
echocardiographic recordings of the mitral valve inflow: fusion
of the early (E) and late (A) diastolic waves can be observed
leading to a reduced LV filling time relative to the cardiac cycle
length (E Fig. 38.1 (lower left panel)). An LV filling time <40%
of the total cardiac length denotes significant atrioventricular
dyssynchrony [5]‌. The atrioventricular coordination should al-
ways be optimized after device implantation. It is of lesser rele-
vance for the prediction of CRT response.
Interventricular dyssynchrony
The time difference between right ventricular and LV ejection de-
fines interventricular mechanical dyssynchrony and can be de-
termined from pulsed-​wave Doppler traces as the time elapsed
between the onset of flow in the right ventricle (RV) and LV out-
flow tract (E Fig. 38.1 (lower mid panel)). A time delay >40 ms

Fig. 38.1  Electrical and mechanical dyssynchrony. Electrical atrioventricular and ventricular conduction delays are visible as prolonged PQ interval or abnormal
QRS morphology and width on ECG (top panel) and result in different mechanical phenomena: (lower left) prolonged atrioventricular conduction may result in
a fusion of E and A waves and a reduced left ventricular filling time on transmitral PW-​Doppler measurements. (lower middle) Left bundle branch block causes
interventricular dyssynchrony that can be assessed as time delay between the onset of right and left ventricular ejection on pulsed-​wave Doppler recordings of
right and left ventricular outflow tracts. (Lower right) Prolonged intraventricular conduction can be also reflected by mechanical events in the LV which can be
assessed by non-​invasive imaging (here septal and lateral strain curves).

is considered a significant interventricular mechanical delay, but
does not predict CRT response with sufficient accuracy [6]‌.
Intraventricular dyssynchrony
Intraventricular dyssynchrony refers to the dyssynchronous mo-
tion or deformation of the different regions of the left ventricle.
Alternatively, the term ‘LV mechanical dyssynchrony’ is used to
contrast it to the electrical phenomena seen on electrocardio-
gram (ECG). Intraventricular dyssynchrony is not well defined
and many, mainly echocardiographic parameters have been pro-
posed for its measurement. These parameters could sensitively
detect mechanical dyscoordination among the different regions
of the LV and were therefore sensitive selection criteria [7–​10].
However, they failed to selectively identify patients who would
benefit from CRT and did not provide added value beyond estab-
lished guideline criteria [6, 11]. In order to improve patient se-
lection by means of non-​invasive cardiac imaging, it is therefore
important to find selection criteria which are not only sensitive,
but also specific and identify motion or deformation patterns
which are amendable by CRT (E Fig. 38.1 (lower right panel)).
Intraventricular dyssynchrony
amendable by CRT
A typical left bundle branch block causes an early activation of
the septum and a delayed activation of the lateral wall (E Fig.
Isovolumic
End diastole End systole
contraction
Fig. 38.2  Mechanical dyssynchrony in LBBB. Typical sequence of
mechanical (top panels) and electrical (bottom panel) events in LBBB.
An early electrical activation of the septum results in a short initial septal
contraction and causes the apex to move septally while the septum
moves leftward (SF, yellow arrow in the middle panel). The delayed
activation of the lateral wall pulls then the apex laterally during the
ejection phase while stretching the septum. This typical sequence of the
septal-​to-​lateral apex motion is described as ‘Apical Rocking’. The septal
inward motion is described as ‘Septal Flash’.
Reproduced from Stankovic I, Prinz C, Ciarka A, et al. Relationship of visually
assessed apical rocking and septal flash to response and long-​term survival
following cardiac resynchronization therapy (PREDICT-​CRT). Eur Heart J Cardiovasc
Imaging. 2016;17(3):262–​9. doi:10.1093/​ehjci/​jev288 with permission from Oxford
University Press.
I m ag i n g dyssy n c h ron y 579
38.2). The septal activation ends diastole when the cavity pres-
sure and the load on the septal myocardium is low. The delayed
contraction of the lateral wall then bears the main load of systolic
ejection while the septum is stretched (E Fig. 38.3). The septal
stretching can be observed as a short ‘notching’ in the strain curve
of a functional septum, but may become holosystolic when the
septum is thin and weak in an more advanced state of LV remod-
elling [12, 13]. This imbalance in loading leads to progressive
atrophy of the septum, hypertrophy of the lateral wall and dila-
tation of the LV [14, 15]. Furthermore, the uncoordinated con-
traction of the LV myocardium causes a slower pressure rise (long
isovolumic contraction time), an un-​coordinated relaxation with
long isovolumic relaxation time, and, consequently, a very short
LV filling time which reduces preload and impairs LV function
further (E Fig. 38.1 (lower left panel)).
Regional LV deformation patterns in left bundle branch block
(LBBB) have to be distinguished from those caused by ischaemic
scar. Here, a reduced shortening in systole and a delayed short-
ening peak after aortic valve closure (post-​systolic shortening)
are common findings [16]. If only the temporal occurrence of
myocardial deformation peaks is considered, a ventricle with
scar shows a ‘dispersion’ of shortening peaks of its segments
(E Fig. 38.4). LV dispersion has been shown to be related to the
risk of life threatening arrhythmia [17], but should not be used in
the context of dyssynchrony assessment.
In ischaemic cardiomyopathy with conduction delay, the typ-
ical LBBB pattern of intraventricular dyssynchrony may be com-
plicated by regional dysfunction due to scar. Such hearts show a
mechanical dyssynchrony, but not all patterns of dyssynchrony
amendable by CRT. It is therefore of outmost importance, that
imaging parameters used to identify potential CRT responders
are specific enough to identify dyssynchrony patterns which are
amendable by CRT [18]. Several of such parameters have been
successfully tested in retrospective studies, but all are lacking
supportive evidence from prospective, randomized trials.
Echocardiographic parameters for CRT
candidate selection
Visual analysis. The early activation of the septum causes a short
and rapid inward motion of the septum which is commonly
referred to as ‘septal flash’ (E Fig. 38.2) [19]. Septal flash is a
very sensitive parameter, but may lack some specificity as it may
appear even if relevant parts of the septum are ischaemic scar.
Nevertheless, it has been shown to identify CRT responders with
good accuracy [19, 20]. A low-​dose dobutamine challenge in-
creases mechanical dyssynchrony and can help to unmask septal
flash in a minority of difficult cases [21, 22].
‘Apical rocking’ describes the typical LV motion pattern
caused by a LBBB conduction delay (E Fig. 38.2). The early
septal contraction at end-​diastole pulls the LV apex shortly to-
wards the septum, while the lateral wall contraction causes a
long pronounced lateral motion of the apex during the ejection
phase [23]. Detecting such a pattern has been demonstrated in
580 CHAPTER 38   C ardiac resynch roniz at ion ther a p y: Sel ecti on of ca n di dates

(a) (b) (c)

Fig. 38.3  Deformation of the septal wall in LBBB. Typical septal longitudinal strain curves in left bundle branch block. (a) With preserved septal function, the
strain curves show only a short systolic ‘notching’, when contraction of the lateral wall starts (yellow part of the curve). (b) With advanced septal dysfunction,
a holosystolic septal lengthening may be observed (yellow part of the curve) followed by a shortening in diastole. (c) Lateral infarct scar can lead to a
pseudonormal septal strain curve with holosystolic septal shortening (yellow part of the curve).
Reproduced from Leenders GE, Lumens J, Cramer MJ, et al. Septal deformation patterns delineate mechanical dyssynchrony and regional differences in contractility: analysis of patient
data using a computer model. Circ Heart Fail. 2012;5(1):87–​96. doi:10.1161/​CIRCHEARTFAILURE.111.962704 with permission from Wolters Kluwer.

(a) (b)

(c)

Fig. 38.4  Regional myocardial deformation patterns in ischaemic myocardium. (a) ECG of a patient with posterior infarction. (b) MRI delayed enhancement showing
transmural scar in the posterior wall of the LV. (c) Echocardiographic assessment of the same patient by speckle-​tracking-​based strain. Myocardial scar causes systolic
lengthening and a pronounced post-​systolic shortening (PSS, arrow) in the affected segments. Furthermore, peak myocardial deformation occurs at different points in
time (‘dispersion’). Dispersion can be quantified by calculating the standard deviation of the segmental time-​to-​peak values (bull’s eye at the lower right).
 I m ag i n g dyssy n c h ron y 581

several studies to be sensitive and specific for CRT response and
strongly associated with successful outcome after CRT [20, 24].
Apical rocking is also related to favourable outcome in patients
undergoing an upgrade from regular pacing to CRT and in CRT
recipients with QRS below 150 ms [20, 25]. Apical rocking is
diminished in the presence of scar, which is advantageous
in the assessment of CRT patient candidates with ischaemic
cardiomyopathy [26].
Quantitative analysis: Echocardiographic strain imaging
visualizes LV segmental deformation and is therefore a useful
aid for the analysis of LV mechanical dyssynchrony. While a
speckle-​tracking-​based strain assessment is easy and comfort-
able, it may sometimes fail to accurately reflect very local and
short lived events due to smoothing, or to accurately track the
apical myocardium which is frequently covered by near field
artefacts. Tissue-​Doppler-​based strain is more noisy, but has
advantages in showing short lived events and apical motion
patterns.
Several studies have analysed septal strain patterns as pre-
dictors for CRT response [12, 27]. In early disease, the delayed
lateral wall contraction causes a short ‘notching’ in the septal
strain curve, while in advanced disease, the septum shows sys-
tolic stretching (E Fig. 38.3). Lateral scar or ischaemia leads to
a pseudo-​normalization of the septal deformation pattern [12,
13], indicating that the chance of a successful CRT implantation
is limited. It is therefore recommendable, to analyse septal strain
curves always in the context of the deformation pattern of the
lateral wall.
Several other parameters that integrate the information of
the functional and temporal interplay of septum and lateral
wall have been proposed [28, 29]. More recently, the calcu-
lation of segmental myocardial work has been suggested.
For this, segmental pressure-​ strain (or stress-​strain) loops
are constructed utilizing echocardiographic speckle tracking
strain and an estimate of the LV pressure [30] (E Fig. 38.5).
Regional work distribution is associated with LV remodelling
in LBBB [15] and reverse remodelling after CRT implantation

(a) (b)

Fig. 38.5  Work analysis. Combining segmental strain measurements with estimated LV pressure allow to construct pressure-​strain-​loops. The area of these
loops reflects the performed segmental work per volume unit. Green—​segmental loops of the highlighted segment, Red—​global loop. (a) In the basal segment
of the anteroseptal wall of this patient with LBBB, a ‘figure of eight’ formation of the pressure-​strain loop is found. This formation reflects negative work, which
can be interpreted as ‘wasting’ work that had been performed by other parts of the ventricle. (b) The pressure-​strain-​loops of the basal segment of the posterior
wall is bigger than the average as it has to compensate for the early activated walls.
582 CHAPTER 38   C ardiac resynch roniz at ion ther a p y: Sel ecti on of ca n di dates

[31]. Its use for predicting CRT response, potentially com-
bined with scar assessment by magnetic resonance imaging
(MRI), has been shown in clinical trials [32–​34]. An added
value of echocardiographic work analysis over systolic strain
analysis remains to be established.
Other imaging modalities to detect LV
mechanical dyssynchrony
Any imaging modality that is able to provide sufficient temporal
and spatial resolution may be used to identify the typical deform-
ation patterns described earlier which indicate a likely success
of CRT. Modern 3D-​echocardiography can reach sufficient tem-
poral resolution, and can provide time-​aligned information on the
deformation of all segments of the LV within one acquisition
(E Fig. 38.6). Speckle tracking echocardiographic three-​
dimensional data sets with good regional quality, however, is
challenging, has low feasibility and reproducibility and, in its
current form, limited added value over 2D approaches [35]. MRI
sequences with sufficient frame rate are available and tracking
methods can be applied similar to echocardiographic images
(E Fig. 38.7). Especially regional tracking has a low reproducibility
in MRI and must be used with caution [36, 37]. Radial tracking,
tagging approaches, and velocity encoded imaging sequences may
provide better results but require cumbersome post-​processing.
Computed tomography (CT) data, when acquired with ECG-​
tagging and throughout the entire cardiac cycle, has sufficient tem-
poral and excellent spatial resolution to assess LV dyssynchrony,
but the disadvantage of ionizing radiation. Though having limited
temporal and spatial resolution, also scintigraphic methods can
provide dyssynchrony information through amplitude (reflecting
wall thickening) and phase (reflecting timing of regional wall mo-
tion) of tracer uptake. Studies have suggested to use the standard
deviation of phase–​related parameters as criterion [38], but due to
the loss of regional information, this approach is likely to be too
unspecific in a real world scenario. Furthermore, scintigraphy has
the disadvantage of ionizing radiation.
Imaging viability in the context
of CRT
Scar effect on myocardial motion patterns
and CRT response
Approximately half of the patients referred for CRT have an is-
chaemic aetiology of heart failure. The presence, location, and ex-
tent of scar tissue may determine less favourable response to CRT.
Lateral scar is a hinder for efficient LV free wall pacing. It reduces
CRT response and increases the risk of heart failure, hospitalization,
and death [39, 40]. Lateral scar reduces apical rocking and leads to
pseudonormal strain curves in the septum which therefore need to
be interpreted in the context of the lateral curves [13] (E Fig. 38.3).
Septal scar reduces the chance for a recovery of septal func-
tion and is therefore equally detrimental to successful CRT. Septal
flash is diminished [26]. Septal strain curves may show systolic
stretch and septal stress-​strain loops a figure of eight in both
LBBB dyssynchrony and septal scar so that additional informa-
tion on myocardial viability is needed.
Scar assessment
Different imaging modalities can detect myocardial scar and
viability in CRT candidates. On echocardiography scarred
myocardium appears thin, echodense, and is dysfunctional
[41] and dobutamine stress echo may be used to proof viability
based on contractile reserve [42]. However, visual assessment
of myocardial texture and motion by echocardiography with
the aim to identify scarred myocardium is challenging and
may be particularly unreliable in the presence of dyssynchrony.

Fig. 38.6  Quantitative 3D echo analysis. Modern echocardiography allows to obtain regional motion information from 3D data sets. (a) Normal heart.
All segmental partial volumes behave the same. (b) Patient with dyssynchrony. Note the abnormal sequence of segmental partial volume changes.
 I m ag i n g via b i l i t y i n the c on t e xt of   C RT 583

15
Septum
Lateral
10

Velocity (cm/s)
0
0 0.2 0.4 0.6
–5

–10

–15
Time (s)

Velocity-encoded MRI

20

Radial wall thicness (mm)

3

15
2
4

5 10
1

6
0
0 300 600 800

Cine steady-state free precession (SSFP)

10

0
Strain

–5

–10

–15

Septal Posterior Lateral Anterior

–20
MRI-tagging
Fig. 38.7  Magnetic resonance imaging techniques to assess LV dyssynchrony. (a) Velocity encoding: phase
contrast MRI allows to measure through-plane velocities. Data can be used to extract regional velocities, and
deformation information. (b) Tracking myocardial contours. In similarity to echocardiography, MRI images can be
tracked. The strong contrast between cavity and myocardium allows good contouring and, thus, global assessments
of volumes and strains. Due to the limited myocardial texture, regional tracking is rather noisy and less reliable. (c)
MRI tagging: special sequences cause a magnetic saturation patterns in the myocardium. These black lines or grids
are a temporary myocardial property and move with the tissue. Specific analysis tools can follow the patterns and
use the information to calculate regional motion, deformation data.

Perfusion defects at rest on single photon emission computed volume effects due to the thin septum and the lower work per-
tomography (SPECT) or positron emission tomography (PET) in- formed in this LV region and does not necessarily indicate scar (E
dicate the presence of scar tissue. In the presence of dyssynchrony, Fig. 38.8) [43]. The accuracy to identify scar tissue based on nuclear
however, a reduced septal tracer uptake is also caused by both, partial methods is therefore reduced in the presence of LV dyssynchrony.
584 CHAPTER 38   C ardiac resynch roniz at ion ther a p y: Sel ecti on of ca n di dates

(a) (b)
Fig. 38.8  Scintigraphy with reduced septal tracer uptake in LBBB. Left bundle
branch block causes an underuse of the early activated septum with thinning
of the wall and low regional work performed and a thickened lateral wall with
high workload. In PET images this leads to a reduced tracer uptake in the
septum and high uptake values in the lateral wall.
(a) FDG-PET in a 50-year-old female with LBBB; (b) same patients after
resynchronization therapy.
Reproduced from Nowak B, Sinha AM, Schaefer WM, et al. Cardiac resynchronization
therapy homogenizes myocardial glucose metabolism and perfusion in dilated
cardiomyopathy and left bundle branch block. J Am Coll Cardiol. 2003;41(9):1523–8.
doi:10.1016/s0735-1097(03)00257-2 with permission from Elsevier.
MRI delayed enhancement is the method of choice for
determining scar transmurality and extent (E Fig. 38.9])
(see Chapter 36). Segments with >75% scar are considered
non-​viable  [44].
Imaging venous anatomy
Stable LV lead placement in one of the tributaries of the cor-
onary sinus with good capture thresholds and without phrenic
nerve stimulation, can be challenging. Anatomical variants
of the coronary sinus ostium, i.e. pronounced Thebesian or
Vieussens valves, may be important hurdles to cannulate the
coronary sinus or to advance the wires through the distal
vessels. Moreover, in patients with ischaemic cardiomyop-
athy, areas with previous infarction may contain less veins.
Therefore, accurate knowledge of the cardiac venous anatomy is
important. Non-​invasive assessment of venous anatomy by car-
diac computed tomography (CCT) or MRI allows to collect this
information prior to the device implantation (E Fig. 38.10).
In addition, fusion of 3D maps of venous anatomy and sites
of latest mechanical activation may provide a roadmap to de-
cide on the feasibility of transvenous LV lead positioning and
may improve therapy success [45, 46]. However, in routine clin-
ical practice, invasive venography is the most frequently used
method to identify the potential tributaries of the coronary
sinus. Frontal or right anterior oblique projections visualize the
distribution of veins in the basal, mid-​ventricular, and apical
regions, whereas the left anterior oblique projection visualizes
anterior, postero-​lateral, or inferior veins (E Fig. 38.11).

(a) (b)

Fig. 38.9  Delayed contrast-enhanced

MRI to assess myocardial scar. Panels
(a) and (b) show the example of a (c) (d)
patient with dilated cardiomyopathy.
On the four-chamber view (a) the arrow
indicates mid-wall septal late gadolinium
enhancement. On the short-axis view (b)
the arrow indicates the presence of mid-
wall fibrosis. Panels (c) and (d) provide
an example of a patient with ischaemic
cardiomyopathy and extensive apical
transmural scar on the two-chamber
view (c) that spreads towards the anterior
wall. On the short-axis view, the arrows
indicate a large area of transmural scar.
Only the lateral, posterior, and inferior
segments contain viable myocardium.

Fig. 38.10  MDCT for assessment of the cardiac
venous anatomy. (a) Obtained from a patient
with non-ischaemic cardiomyopathy. The first
tributary is the posterior inter-ventricular vein
(PIV) that runs through the inter-ventricular sulcus.
Subsequently, a small posterior vein of the left
ventricle (PVLV) can be visualized followed by a
well-developed left marginal vein (LMV) suitable
for LV lead implantation. Afterwards, the coronary
sinus is followed by the great cardiac vein (GCV).
(b) Example of a patient with prior posterolateral
myocardial infarction. Note the absence of a suitable
LMV and the presence of a small PVLV.
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the diagnosis and treatment of acute and chronic heart failure: the
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the special contribution of the Heart Failure Association (HFA) of the
ESC. Eur Heart J 2016; 37: 2129–​200.
2. Beela AS, Ünlü S, Duchenne J, et al. Assessment of mech-
anical dyssynchrony can improve the prognostic value of
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on the long-axis view of the left ventricle
(arrows) and the position of the LV lead
can be divided into basal, mid-ventricular
and apical regions. In the left anterior
oblique projection the short-axis view
of the left ventricle is displayed and the
position of the LV lead can be classified
into anterior, anterolateral, lateral,
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Contents
Introduction  587
CRT optimization  587
Rationale for optimizing the programming of
the device  587
How to optimize the programming of CRT
devices with imaging  588
Optimization of the AV delay  588
Optimization of the VV delay  589
Impact of optimization of CRT
programming  589
Acute effect of optimization of the
programming of CRT devices  589
Effect of optimization of CRT device
programming on clinical outcomes  589
Current perspective: limitations and
unresolved issues  591
Follow-​up of patients treated with CRT  591
Importance of checking the reverse
remodelling of the left ventricle  591
Evidence for reverse remodelling
in randomized controlled trials
testing CRT  592
‘Super-​responders’  592
Effects of CRT on mitral regurgitation  593
Effects of CRT on left ventricular diastolic
function and right ventricular
function  593
Predictors of LV reverse remodelling
with CRT  593
Clinical response and reverse
remodelling  593
Conclusion  594
CHAPTER 39
Cardiac resynchronization
therapy: Optimization and
follow-​up
Marta Sitges and Erwan Donal
Introduction
While the role of cardiac imaging in the selection of candidates for cardiac resynchroni­
zation therapy (CRT) remains controversial, it is well established that imaging is essential
to evaluate response to the therapy. Also, echocardiography is often used to optimize
device programming. In the present chapter, the role of cardiac imaging in optimizing
the programming of CRT devices, as well as the usefulness in the follow-​up of patients
treated with CRT will be discussed.
CRT optimization
Rationale for optimizing the programming of the device
In patients with heart failure, the presence of a prolonged atrio-​ventricular (AV) interval
is not unusual. Also, left bundle branch block (LBBB) is present in up to one-​third of
these patients. Both prolonged AV interval and LBBB result in delayed ejection and con-
sequently, in shortened diastolic time (E Fig. 39.1). This leads to shortened filling time,
decreased preload, and the consequent decrease in stroke volume. Restoring adequate
AV interval and intraventricular conduction delays results in a longer filling time and
an increased preload. However, excessively short AV delays may result in early closure
of the mitral valve impeding the whole contribution of the atrial contraction to left ven-
tricular filling (A-​wave truncation). Consequently, finding the optimum AV delay that
yields the longest diastolic filling time without truncating the atrial contribution to ven-
tricular filling is of most interest.
On the other hand, optimization of the interventricular (VV) delay may be justified
according to several issues. First, a good ventricular synchronization may explain why
patients in atrial fibrillation also benefit from CRT and not only because of the benefit
on diastolic filling due to optimized AV intervals. Additionally, the epicardial position
of the lead implies that transmural activation, usually lasting for 30 ms, should be taken
into account when considering time delays between both ventricles. Finally, delayed ven-
tricular segments may be located at different sites of the left ventricle due to underlying
myocardial scars or different conduction abnormalities. Consequently, dyssynchrony
may be corrected by a different device programming.
588 CHAPTER 39   C ardiac resynch roniz at ion ther a p y: Op ti m i z ati on a n d fol l ow - u p

methods based on invasive approaches (assessment of dP/​dt and

LBBB cardiac output with catheters at the time of the implantation)
and non-​invasive approaches such as impedance cardiography,
NORMAL intracardiac electrograms, endocardial acceleration detected by a
microaccelerometer, or algorithms based on electric intervals de-
tected by the device. The big advantage of these latter ones is that
they are incorporated in the device, can be performed automatic-
E E Left ventricular inflow ally and continuously, allowing for adaptative optimization of the
A A AV interval according to physical activity or heart rate. The limi-
tation is that these methodologies are not well validated and are
limited to each vendor’s device. Based on the experience demon-
strating the benefits of AV interval optimization in dual chamber
pacing, most of the large clinical trials proving the clinical benefit
Left ventricular of CRT such as the Multicenter InSync Randomized Clinical
outflow Evaluation (MIRACLE) [1]‌or the Cardiac Resynchronization—​
Heart Failure (CARE-​HF) [2] trials have performed AV optimiza-
tion with echocardiography. Accordingly, AV optimization using
Aortic Aortic
ejection ejection
echocardiography has been recommended [3].
The most often used echocardiographic method to optimize
Fig. 39.1  Patients with LBBB have delayed aortic ejection as a consequence the AV delay is the iterative method. By the use of pulsed-​wave
of their delayed conduction and mechanical contraction. Delayed aortic
(PW) Doppler of the left ventricular inflow, diastolic filling time
ejection results in shortened diastolic time which in turn causes fusion of the
E and A wave of the left ventricular filling flow. is measured from the onset of the E wave to the end of the A wave.
The AV delay is reduced by 10–​20 ms until the longest diastolic
filling time is obtained without interrupting the A wave (E Fig.
39.2). Another approach, derived from dual chamber pacing in
How to optimize the programming of patients with AV block and not validated in CRT, is the Ritter’s
CRT devices with imaging method. This calculates the optimum AV interval by calculations
derived from a setting with a very long AV delay and another one
Optimization of the AV delay with a very short AV delay. For each AV delay, the time from QRS
Echocardiography has typically been used for optimizing the onset to the end of the A wave is determined and the optimum
AV interval to obtain the greatest diastolic filling time and the AV delay is calculated by a formula (AVopt = AVlong –​(QAshort-​
optimum haemodynamic effect. However, there are also other QAlong)). This optimum AV corresponds in fact to the longest

Fig. 39.2  Optimization of the AV

interval according to the iterative
method: the AV interval is progressively
reduced at 20 ms intervals trying to
obtain the largest diastolic filling time
and consequently, the largest left
ventricular filling. As the AV interval
decreases, the diastolic filling time
increases until the A wave is early
interrupted (green arrows). Accordingly,
the optimum AV interval selected in
this patient was 120 ms, which yielded
the largest diastolic filling time without
interrupting the A wave.
 I m pact of op ti m i z ati on of CRT pro g r a m m i n g
diastolic filling time without interrupting the A wave resulting in
similar AV delays to those obtained by the iterative method but in
a shorter procedure.
Another approach to optimize the AV delay with echocardiog-
raphy has been proposed by determining the maximum mitral in-
flow or the aortic velocity time integral, both as surrogates of the
left ventricular cardiac output. In one study including 30 patients
[4]‌, the optimization of the AV delay with these four echocardio-
graphic methods was compared to invasive dP/​dt. The optimum
AV delay invasively determined was largely concordant with the
one determined by the maximum mitral velocity time integral
(97%) while there was no agreement with the AV delay deter-
mined by Ritter’s method. Agreement of dP/​dt with the iterative
method and the aortic velocity time integral was modest (67%
and 43%, respectively).
The AV delay has been also optimized by echocardiography
with similar iterative methods that aim to obtain the highest car-
diac output as determined by the left ventricular outflow tract
velocity time integral (as a surrogate of cardiac output) or the
Doppler-​derived left ventricular dP/​dt as well as the myocardial
performance index (Tei index). Again, the widespread use and
especially the validation and utility of the methodologies among
CRT patients remain uncertain.
Optimization of the VV delay
The VV delay can be optimized by determining invasive left ven-
tricular dP/​dt or cardiac output, by the surface electrocardiograph
(ECG) or by a variety of device-​based algorithms or intracardiac
electrograms. Echocardiography has also been used to optimize
the VV delay either by empirically assessing the VV delay that
yields the highest cardiac output or the best left ventricular syn-
chrony. The most commonly used echocardiographic method for
VV delay optimization is the evaluation of cardiac output deter-
mined by the left ventricular outflow tract velocity time integral.
Several VV delays are programmed at 20 ms interval and the ef-
fect on cardiac output is tested (E Fig. 39.3). Few authors have
also used tissue Doppler imaging to evaluate left ventricular syn-
chrony and optimize the VV delay, by testing the effect of sev-
eral VV intervals on left ventricular dyssynchrony assessed with
Fig. 39.3  Optimization of the VV interval according to the iterative method using left ventricular outflow tract velocity time integral: the VV interval is tested
to obtain the largest velocity time integral. In this patient, despite variation was not large, optimum VV was set at –​30 ms (left ventricular pre-​activation at 30
ms) as this yielded the largest velocity time integral.
589
tissue displacement or strain rate traces of opposite myocardial
walls (E Fig. 39.4, z Video 39.1). A small study has reported
good agreement between optimization of the VV interval ac-
cording to either left ventricular outflow tract velocity time in-
tegral or intraventricular dyssynchrony, indicating that the best
intraventricular synchrony results in the best haemodynamics [5]‌.
Impact of optimization of CRT
programming
Acute effect of optimization of the
programming of CRT devices
Several groups have reported the beneficial acute effect of op-
timization of the CRT programming on haemodynamics and
left ventricular dyssynchrony either by invasive or non-​invasive
methods [6, 7]. When the VV delay has been optimized with
echocardiography, mainly by using an iterative method to reach
the largest aortic or left ventricular outflow tract velocity time in-
tegral, an additional 5-​point increase in left ventricular ejection
fraction and a 20% increase in cardiac output have been reported
[8–​11]. On the other hand, selecting a non-​optimal VV delay may
have a deleterious impact, reducing cardiac output by even more
than 25% [8, 11].
Effect of optimization of CRT device
programming on clinical outcomes
Despite compelling evidence that AV and VV delay optimization
may have an acute haemodynamic beneficial effect, scarce evi-
dence supports the clinical impact of such an optimization.
Among CRT patients, few studies have used optimization only
of the AV interval and evaluated the clinical evolution. One study
reported the optimization of AV delay by maximizing the left ven-
tricular outflow tract velocity time integral in 33 patients, which
resulted in improvements in functional capacity and plasma levels
of BNP [12]. Sawhney et al. [13] compared AV delay optimization
by echocardiography (iterative method using aortic velocity time
integral) to an empirical AV delay set at 120 ms in a randomized
590 CHAPTER 39   C ardiac resynch roniz at ion ther a p y: Op ti m i z ati on a n d fol l ow - u p

VV–30 ms VV 0 ms VV +30 ms

Fig. 39.4  Optimization of the VV interval according to the iterative method using left ventricular dyssynchrony: the superposition of the displacement of two
opposing walls is evaluated both in the four and two chamber apical views with tissue Doppler imaging. The superposition and the amount of displacement
were maximal with the setting of a VV interval of –​30 ms, especially present and evident in the traces from the four-​chamber view.
In the two chamber images, there are no significant changes among the different VV intervals. These images come from the same patient shown in E Figure
39.3. The selected optimum VV interval was the same either by the velocity time integral or dyssynchrony assessment. Quantitative and semiqualitative analysis
of intraventricular dyssynchrony or quantification of aortic velocity time integral provided useful information to select the optimum VV interval. Importantly, no
clear decision for optimal timing of VV interval could be determined when it was taken based only on visual assessment of left ventricular motion (see z Video
39.1); there was a slight improvement with a little more synchronic motion in the VV 0 ms and VV –​30 ms loops as compared to that without CRT (OFF) and in
VV +30 ms; no significant difference in visually estimated ventricular motion and synchrony could be observed between VV 0 ms and –​30 ms.

study of 40 patients with CRT, finding an improvement in quality
of life and NYHA functional class at 3 months with the echo-​
guided approach. Morales et al. [14] evaluated 41 CRT patients
who were randomized to receive an empirical AV delay of 120 ms
or to optimize their AV delay with echo Doppler-​derived dP/​dt.
At 6-​months follow-​up, left ventricular ejection fraction was sig-
nificantly higher and NYHA functional class significantly lower
in the AV-​optimized group.
Regarding the clinical impact of VV interval optimization, re-
ports have also been scarce. Mortensen et al. [11] reported the
acute beneficial effects on haemodynamics of VV delay opti-
mization with echocardiography (left ventricular outflow tract
velocity time integral), but they were unable to show any add-
itional clinical improvement in the optimized group as com-
pared to conventional simultaneous biventricular pacing at 3
months follow-​up.
In another study [15], the 6-​month clinical outcome of 359 pa-
tients included in the InSync III Study who received VV delay op-
timization with echocardiography (iterative method using the left
ventricular outflow tract velocity time integral) were compared
against the outcome of the patients included in the MIRACLE
study (without VV optimization). All patients received AV delay
optimization with echocardiography. There was an incremental
benefit on the 6 minute walking distance (median increase in the
InSync 38% versus 15% in the MIRACLE, P <0.0001) while no
differences in quality of life or NYHA functional class could be
demonstrated.
The first randomized study trying to demonstrate the bene-
ficial clinical effect of VV delay optimization has been the
Resynchronization for the HemodYnamic Treatment for Heart
Failure Management II implantable cardioverter defibrillator
(RHYTHM II ICD) [16] which included 121 patients with CRT.
AV delay was optimized in all patients. VV delay was optimized
only in randomly assigned patients using echocardiography (with
the maximum aortic velocity time integral). Similarly to pre-
vious findings, VV optimization conferred no benefit in 6 mi-
nute walking distance, quality of life, NYHA functional class,
or hospital admissions. More recently, another randomized
double blinded study [17] including 238 CRT patients showed
only modest benefit on a composite clinical endpoint with op-
timized sequential VV stimulation as compared to simultaneous
biventricular pacing. VV delay optimization was performed ac-
cording to dyssynchrony indices derived from M-​mode echo-
cardiography. The results of these echocardiography-​ based
optimization studies are in keeping with the observations found
in another trial which used a device-​based algorithm to optimize
the VV delay [18]. In this study, sequential pacing was equiva-
lent but not superior, to simultaneous biventricular pacing for

the composite endpoint of peak oxygen consumption and left
ventricular end-​systolic dimension. A larger impact of VV opti-
mization has been described in ischaemic heart failure patients as
compared to non-​ischaemic patients [19].
Finally, the effect of optimizing both the AV and the VV delay
was evaluated in a single centre study comparing two historical
cohorts of CRT patients [5]‌: the first 50 patients with an empirical
AV delay set at 120 ms and simultaneous biventricular pacing and
the next 51 patients undergoing a standardized systematic echo-
cardiographic optimization of the AV and VV intervals. Once
the optimum AV delay was chosen (iterative method), the VV
interval was optimized and selected as the one that resulted in
larger superposition of the systolic displacement of two opposing
ventricular walls with the use of tissue Doppler imaging (i.e. less
dyssynchrony) (E Fig. 39.4). Patients undergoing optimization
had increased 6 minute walking distance and left ventricular car-
diac output at 6-​months follow-​up. However, there were no dif-
ferences in NYHA functional class, quality of life, left ventricular
ejection fraction and dimensions and, more importantly, in the
rates of cardiac death or heart transplantation.
More recently, several studies have compared the outcomes
of optimizing the programming of CRT by echocardiography or
other methods (intracardiac devices or device algorithms) with
controversial results. Kamdar et al. [20] already showed a poor
agreement between optimal AV and VV delays determined by
echocardiography or a device algorithm (QuickOptTM), with echo-
cardiographic optimization yielding a superior haemodynamic
acute outcome. On the other hand, in a small study, optimiza-
tion of CRT by an intracardiac electrogram-​based algorithm or by
echocardiography resulted in a similar exercise capacity [21]. The
largest compelling evidence on CRT optimization was provided
by the SmartDelay Determined AV Optimization: A Comparison
to Other AV Delay Methods Used in Cardiac Resynchronization
Therapy (SMART-​AV) Trial [22]. In this study, 980 CRT patients
were randomized to a fixed empirical AV delay (120 ms), an
echocardiographically optimized AV delay or to AV delay opti-
mized with an electrogram-​based algorithm (SmartDelay). Left
ventricular reverse remodelling was evaluated at 6 months follow-​
up showing that neither SmartDelay nor echocardiography was
superior to a fixed AV delay of 120 ms. Additionally, the Frequent
Optimization Study Using the QuickOpt Method (FREEDOM)
trial [17] evaluated the impact of frequent optimization of the
AV and VV delays using an algorithm based on the intracardiac
electrogram (as compared to empiric device programming or
echocardiographic optimization on clinical heart failure) among
1,500 CRT patients. There was no significant difference in a clin-
ical composite endpoint regardless of optimization.
Current perspective: limitations and
unresolved issues
Many questions remain unanswered regarding optimization of
the programming of CRT devices. Methodology is not completely
Fol l ow - u p of pati en ts treate d w i t h   C RT 591
standardized, although most groups use the iterative method for
optimization of the AV and the VV delay, trying to obtain the lar-
gest diastolic filling time without truncating the A wave and the
largest aortic velocity time integral.
However, little is known about the interaction (and sequence)
between programming of the AV and VV delays. Most authors
have reported a stepwise optimization usually starting with the
AV and finishing with the VV; the impact of optimizing the VV
first and then the AV delay is unknown.
Also, the equivalence between different methods is far from
being established, especially regarding the programming of the
AV delay. Another matter of controversy is the stability of the
programming of the delay through follow-​up when reverse ven-
tricular remodelling develops and potentially impacts on AV and
VV delays. Should therefore the AV and VV delays be periodic-
ally optimized and, if so, how frequently?
Current recommendations state that AV or VV delay opti-
mization may be considered only in selected patients although
their role in improving response has not been proven. Indeed, in
clinical practice, AV and VV optimization is not performed in
a high proportion of patients. A recent study showed that indi-
vidual optimization of the delays yielded additional acute haemo-
dynamic effect in only 23–​45% of CRT patients [18]. Therefore,
the most common opinion is that complex, echocardiography-​
based optimization of the programming should only be applied
to non-​responders while easy, widely available programmes that
are incorporated in the device systems should be used for the vast
majority of CRT patients to allow adequate AV and VV program-
ming at rest and during exercise. However, their potential to im-
prove response in all CRT patients remains to be proved.
Follow-​up of patients treated
with CRT
Importance of checking the reverse
remodelling of the left ventricle
By acting on resynchronizing the heart cavities, CRT has dem-
onstrated a significant and consistent impact on left ventricle
(LV) size and function [19]. It can be summarized by a significant
decrease in LV end-​systolic volume (decrease in LV size and in-
crease in LV function). The impact on LV size and function has
been considered as a surrogate marker for harder events like car-
diac death and indeed, the change in LV size over time has been
linked to the clinical impact of CRT [20, 21].
Dyssynchrony has marked adverse consequence on ventricular
pump function leading to prolonged contraction time, reduced
ejection time, delayed and prolonged relaxation, reduced dia-
stolic filling time, and secondary mitral regurgitation. The overall
result is for many patients, left ventricular dilatation, distortion
of cavity shape towards sphericity, disruption of the mitral valve
geometry with tenting and development of mitral regurgitation,
and deterioration in contractile function that culminates in heart
592 CHAPTER 39   C ardiac resynch roniz at ion ther a p y: Op ti m i z ati on a n d fol l ow - u p
failure [22]. This has been illustrated in the concept of conductive
cardiomyopathies [23].
The left ventricular remodelling process is the final common
pathway for all of the causes of heart failure and portends a poor
prognosis. Treatments used in heart failure have all an impact of
LV remodelling but this has been also extensively demonstrated
for CRT.
Cardiac imaging techniques and especially echocardiography
(easily applied in the follow-​up of these patients) play a key role
in the diagnosis of reverse remodelling. Currently used MRI sys-
tems still have limitations on their application among patients
with pacemakers.
A properly performed two-​dimensional biplane Simpson ap-
proach is the minimum to consider when evaluating response
to CRT in terms of LV size and function. Three-​dimensional
transthoracic echocardiography is better because it provides
better robustness of the measurements. Real-​time 3D echocar-
diography has been used to describe reverse remodelling after
CRT. Marsan et al. [24] reported a good inter-​and intraobserver
agreement for the assessment of left ventricular end-​ systolic
volume and left ventricular ejection fraction evaluation post CRT
implantation.
Evidence for reverse remodelling in
randomized controlled trials testing CRT
The effects of CRT on reverse LV remodelling are additive and
larger than those observed with medical therapy. Reverse remod-
elling has been considered as a criterion for defining the positive
response to treatment (i.e. decrease in LV end systolic volume
≥15% after 6 months of CRT).
The MIRACLE study [1]‌demonstrated significant reductions
in LV end-​diastolic and end-​systolic volumes at 3 and 6 months
in the CRT group as compared with the control group (inactive
pacing), in which no change was observed from baseline values.
In addition, LV mass also significantly decreased whereas LV
contractile function increased in the CRT group but not in the
control group. These beneficial effects on LV remodelling were
sustained after 2 year follow-​up.
The MUltisite STimulation In Cardiomyopathy (MUSTIC)
trial [25] showed sustained reduction in LV size measured by
echocardiography at 1 year in a small cohort of patients. The
Cardiac Resynchronization—​ Heart Failure (CARE-​ HF trial)
[2]‌, was the first to demonstrate conclusively that CRT alone can
reduce mortality, presumably by favourable effects on LV func-
tion. In addition, reverse LV remodelling was assessed at 3 and
18 months, showing a significant and sustained increase in left
ventricular ejection fraction (+3.7% and +6.9%, respectively) as-
sociated with a decrease in left ventricular end-​systolic volume
index (–​18.2 ml/​m2 and –​26 ml/​m2, respectively) and in mitral
regurgitation area.
The REsynchronization reVErses Remodeling in Systolic left
vEntricular dysfunction (REVERSE) study [21] enrolled 684 pa-
tients with NYHA functional class I or II, in sinus rhythm, with
QRS duration ≥120 ms, and LV ejection fraction ≤40%. The LV
end-​systolic volume index decreased (–​18.4 ± 29.5 ml/​m2) in the
CRT-​ON group (n = 324) as compared with the CRT-​OFF group
(–​1.3 ± 23.4 ml/​m2; n = 163; P <0.0001 versus CRT-​ON), espe-
cially (three times greater) in the patients with non-​ischaemic
cardiomyopathy. LV ejection fraction also improved significantly
with active CRT but not in the CRT-​OFF group. Both groups were
under optimal medical therapy. This result suggests that CRT pro-
duces significant additive effects on ventricular remodelling that
occur in addition to heart failure drug therapy and it has led to a
clinical benefit.
Similarly, the Multicenter Automatic Defibrillator Implantation
Trial With Cardiac Resynchronization Therapy (MADIT-​CRT)
[26] and the Resynchronization/​Defibrillation for Ambulatory
Heart Failure (RAFT) [27] trials also demonstrated reductions
in LV volumes and increase in ejection fraction among patients
with NYHA functional class I-​II with CRT. Subsequent analysis
of MADIT-​CRT showed that CRT-​ICD therapy also resulted in
a significant improvement in both LV dyssynchrony and con-
tractile function measured by global longitudinal strain at 1 year
and improvement in dyssynchrony and contractile function were
associated with better clinical outcomes [28]. The occurrence of
LV reverse remodelling with CRT has been also described in pa-
tients with atrial fibrillation undergoing CRT [29], with similar
reductions in LV end-​ systolic volume and increase in ejec-
tion fraction between patients with atrial fibrillation and sinus
rhythm.
Figure 39.5 summarizes the main results regarding LV reverse
remodelling after CRT, showing the changes in LV end-​systolic
volume, end-​diastolic volume, and ejection fraction reported in
some of the largest randomized controlled trials.
‘Super-​responders’
These patients are improving dramatically after CRT with al-
most complete symptomatic recovery and marked reverse
remodelling (E Fig. 39.6a, b, z Video 39.2a, b). In an obser-
vational longitudinal study recruiting 520 patients, Gasparini et
al. [30] observed 16 remissions per 100 person-​years, usually
reached within the first 2 years of CRT. The most powerful pre-
dictors of heart failure remission included a baseline LV ejection
fraction of 30–​35%, a baseline LV end-​diastolic volume of 180
ml, and non-​ischaemic heart failure. The concomitance of all
three factors was strongly predictive of heart failure remission.
In a multicentric French study [31], 186 patients were investi-
gated before and 6 months after CRT by two-​dimensional strain.
Super-​responders were defined as a reduction of LV end-​systolic
volume of at least 15% and an ejection fraction >50% at follow-​
up and were compared to normal responder patients (reduction
of end-​systolic volume of at least 15% but an ejection fraction
<50%). CRT super-​ responders were observed in 9% of the
population and were associated with less reduced LV function
at baseline as determined by strain analysis (global longitudinal
strain: –​12.8 ± 3% versus –​9 ± 2.6%, P <0.001). LV global longi-
tudinal strain was identified as the best parameter for predicting
super-​response with a cut-​off value of –​11% (sensitivity 80%,

Δ LVEDV (ml) Δ LVESV (ml)
0 0
–5 –5
–10 –10
–15 –15
–20 –20
–25 –25
–30 –30
–35 –35
–40 –40
–45 –45
MIRACLE-CRT REVERSE-CRT MADIT-CRT
MIRACLE-NO CRT REVERSE-NO CRT MADIT-NO CRT
specificity 87%, area under curve 0.89, P <0.002) and was con-
firmed as an independent predictor by logistic regression (RR:
21.3, P <0.0001).
Conversely, a subgroup of patients do not present reverse re-
modelling after CRT in a proportion around 50%. Cardiac imaging
in any of its modalities allows for identification of these non-​
responder patients in serial follow-​up. Factors related to the ab-
sence of reverse remodelling have been lack of resynchronization,
extensive scar, and advance stage of myocardial dysfunction [32,
33] (E Fig. 39.7a, b; z Videos 39.3a, b).
Effects of CRT on mitral regurgitation
Reduction of mitral regurgitation is one of the immediate and
often substantial effects of CRT, and reduction in mitral regurgi-
tation by CRT is associated with an improved outcome. CRT can
reduce mitral regurgitation by improved temporal coordination
of mechanical activation of the papillary muscles acutely and by
later improvements in LV size and geometry from reverse remod-
elling [34]. Indeed, there is some evidence that the decrease in
the severity of mitral regurgitation precedes the reduction in LV
volumes and the associated changes in LV and mitral valve archi-
tecture. The reduction in MR after CRT has been associated with
an improvement in the timing of longitudinal deformation of the
papillary muscle sites.
In addition, the progressive reduction in LV volumes and
architecture with CRT are associated with restoration of mitral
valvular geometry towards normal. In the MIRACLE study, the
severity of mitral regurgitation had decreased significantly with
CRT at 3 months, and this improvement was maintained at 6 and
12 months, particularly in non-​ischaemic patients. In contrast, no
change was observed in the control group [22].
Effects of CRT on left ventricular diastolic
function and right ventricular function
The effect of CRT on LV diastolic function remains debated.
Some studies with long-​term follow-​up report increases in dia-
stolic filling time and decreases in E wave velocity and E/​e´ ratio
indicating improvements in filling pressures mainly in responder
patients [35]. Studies looking at left atrial size and function favour
Fol l ow - u p of pati en ts treate d w i t h   C RT 593
Δ LVEF (%)
12
10
8
6
4
Fig. 39.5  Graphs showing overall
2 decrease in left ventricular end-​
diastolic volume (LVEDV), end-​
0 systolic volume (LVESV) and election
fraction (LVEF) in three landmark CRT
randomized studies in the CRT and in
the non-​CRT groups: MIRACLE [22],
REVERSE [26], and MADIT-​CRT [29].
the concept that in patients without severely altered diastolic
function, CRT induces a significant improvement.
The effects of CRT on right ventricular function are strongly
related to LV reverse remodelling. D’Andrea et al. [36] demon-
strated a significant improvement in right ventricular peak sys-
tolic strain and global longitudinal strain in responders to CRT.
Conversely, in non-​responders to CRT, improvement in right
ventricular function was not observed. Right ventricular dysfunc-
tion is a powerful determinant of prognosis among candidates for
CRT [37].
Predictors of LV reverse remodelling with CRT
LV reverse remodelling does not occur in all patients. SEPTAL-​
CRT is one of the most recent randomized study and still, the per-
centage of ‘echo-​responders’ defined by LV end-​systolic volume
reduction ≥15% between baseline and 6 months was 50% [38].
There is no current consensus on baseline clinical data that may
predict optimal LV reverse remodelling after CRT. Among the
number of possible mechanisms that have been proposed, the ab-
sence of mechanical LV dyssynchrony, the advanced and irrevers-
ible left ventricular dysfunction and the suboptimal placement of
the leads are the most likely causes. Small, non-​randomized studies
have generated interest in markers of mechanical intraventricular
dyssynchrony to predict reverse remodelling as extensively dis-
cussed in the previous chapter. Conversely, the identification of
non-​responders is also crucial since non-​responders represent
approximately 30% of CRT patients and CRT is an invasive treat-
ment with potential complications.
Clinical response and reverse remodelling
In general terms, the clinical response to CRT is greater (up to
70% of patients in most studies) than the remodelling response
(up to 50% as described by most groups). Consequently, there is
a correlation between remodelling and clinical response in some
patients, while other may show paradoxical responses [39, 40].
In the MIRACLE trial, changes in left ventricular end-​
diastolic volume and NYHA class correlated weakly and reverse
LV remodelling was greater in patients with non-​ischaemic car-
diomyopathy whereas clinical outcomes improved irrespective
594 CHAPTER 39   C ardiac resynch roniz at ion ther a p y: Op ti m i z ati on a n d fol l ow - u p

(a)

Baseline 6-month later after CRT

LVEF 33%
LVEF 50%
LVESV 159 ml
LVESV 105 ml
LV Global longitudinal strain-10%
LV Global longitudinal strain-14,8%
NYHA II with optimal medical
NYHA II
treatment
LBBB with QRS 155 ms

(b)

Fig. 39.6  (a) Left ventricular reverse

remodelling in a patient effectively
treated with CRT: 4, 2, and 3 chamber
apical view of the left ventricle at
baseline and 6 months after CRT. The
decrease in left ventricular end-​systolic
volume is >15% and the improvement
in left ventricular ejection fraction is
remarkable. Strain curves before and at
6-​month show the pre-​implantation
mechanical dyssynchrony and the
quite normalization of the strain
curves according to their timing at
6-​month post resynchronization
(E Fig. 39.6b). There is no more the Baseline 6-month laterafter CRT:
too early deformation of the septum There was a too early deformation of The longitudinal strain traces are
(septal flash) and the lateral wall the septum and a delayed deformation resynchronized
deformation come before the aortic of the lateral wall
valve closure (efficient then for the
LV Global longitudinal strain-14,8%
LV Global longitudinal strain-10%
output)

of heart failure aetiology [6]‌. The paradox between the effects
of CRT on LV function and outcome in patients with ischaemic
heart disease suggests that only some of the benefit of CRT is
mediated by improving ventricular function. CRT reduces the
risk of sudden cardiac death and it is possible that CRT sup-
presses arrhythmias directly or by even small improvements in
cardiac function.
In a study on 302 patients it was shown that a more ex-
tensive LV reverse remodelling relates to a greater clinical
improvement. More LV reverse remodelling resulted in less
heart failure hospitalizations and lower mortality during long-​
term follow-​up [41].
Conclusion
The use of echocardiography has been proposed for the opti-
mization of AV and VV intervals acutely after CRT. Quick and

(a)
(b)
Baseline one year later after CRT
LVEF 33% LVEF 35%
LVESV 153 ml LVESV 160 ml
LV Global longitudinal strain-11,1%
LV Global longitudinal strain-11,1%
NYHA II with optimal medical treatment
NYHA II
LBBB with QRS width 163 ms
personalized methods to continuously optimize CRT program-
ming are available, but further studies are needed to clarify the
precise value of (echocardiographic) CRT programming at
longer-​term follow-​up.
Cardiac imaging is fundamental in the follow-​up of patients
treated with CRT, since it provides objective evidence on the
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Fig. 39.7  (a) An example of a patient
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patient had no significant mechanical
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despite the left bundle branch block
morphology
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9 For additional multimedia materials please visit the online version of the book at M oxfordmedicine.com/esccvimaging3
RE F E RE N C E S 597
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40. Vidal B, Sitges M, Marigliano A, et al. Relation of response to cardiac
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Contents
Introduction  599
Indications for extracorporeal support  599
Diagnosis  599
Exclusion/​diagnosis of relevant underlying
pathology  600
Diagnosing requirement for support and
ability of the heart to support the
circuit  600
Echocardiographic contraindications to
extracorporeal support  600
Extracorporeal respiratory support  602
VV-​ECMO  603
Extracorporeal cardiac support  604
Impella  604
Impella RP  604
TandemLife ProtekDuo  605
VA-​ECMO  605
Ventricular assist devices  607
Echocardiographic detected complications
of extracorporeal support  608
Cannula displacement  608
Worsening valvular regurgitation  609
Tamponade  609
Thrombus  609
Excessive/​inadequate offloading of one or
both ventricles  610
Conclusion  610
CHAPTER 40
Echocardiography
evaluation in extracorporeal
support
Susanna Price and Alessia Gambaro
Introduction
Extracorporeal support became a reality with the discovery of heparin a century ago,
however it was not until the mid-​twentieth century before its clinical application became
routine [1]‌. Since this time, the use of extracorporeal therapies has gradually emerged
as a plausible option for advanced cardiac and/​or respiratory support in the critically ill.
Echocardiography has a vital role in its successful implementation, extending beyond
diagnosis to excluding contraindications, confirming/​guiding correct cannula place-
ment, ensuring the goals of support are met, detecting complications, assessing tolerance
to assistance, and in weaning from mechanical circulatory support.
Indications for extracorporeal support
Extracorporeal support may be indicated in cardiac and/​or respiratory failure. Most fre-
quently this is temporary, used as a bridge to recovery, transplantation, or decision re-
garding further intervention(s) [2]‌. In a very small number of patients, extracorporeal
cardiac support may be used as destination therapy. Common indications for require-
ment of circulatory support include cardiogenic shock and refractory low cardiac output
(CI <2.2L/min/m2) and hypotension (SBP <90 mmHg) despite adequate intravascular
volume and high-​dose inotropic agents, inability to wean from cardiopulmonary bypass
post-​cardiotomy, primary graft failure after heart/​heart–​lung transplantation, severe
myocardial depression due to sepsis, drug toxicity, myocarditis, and post-​cardiac arrest
[3–​6]. The use of different systems providing extracorporeal support for severe acute
respiratory failure (SARF) has similarly increased over recent years [7, 8]. The types of
advanced mechanical circulatory and respiratory support commonly used are shown in
E Table 40.1. Clinical indications relating to the timing of ventricular assist and ECMO
are found in the respective national and international registries, in addition to published
guidelines [2, 3, 5, 9].
Diagnosis
Echocardiographic imaging in the critically ill, in particular where advanced extracor-
poreal support is potentially indicated can be challenging. Diagnostic 2D transthoracic
echocardiography (TTE) images are unobtainable in up to 30% of the general intensive care
unit (ICU) patient population, rising to 85% in patients with SARF (E Fig. 40.1). Where
600 CHAPTER 40   E c ho cardio graph y evaluat i on i n extr ac orp orea l su pp ort

Table 40.1  Types of advanced mechanical circulatory and respiratory support

Respiratory support required

Cardiac support required Oxygenation required CO2 removal required Nil respiratory support required
Right heart VA-​ECMO/​ProtekDuo + oxygenator VA-​ECMO RVAD/​VA-​ECMO/​Impella RP/​Protek Duo
Left heart VA-​ECMO –​ LVAD/​VA-​ECMO/​Tandem heart/​Impella
Biventricular VA-​ECMO –​ BiVAD/​VA-​ECMO/​TAH
Nil VV-​ECMO (AV) ECCO(2)R –​
Abbreviations: CO2 = carbon dioxide; VA-​ECMO = venoarterial extracorporeal membrane oxygenation; VV-​ECMO = venovenous extracorporeal membrane oxygenation; (AV)
ECCO(2) R = arteriovenous extracorporeal carbon dioxide removal; RVAD = right ventricular assist device; LVAD = left ventricular assist device; BiVAD = biventricular assist device;
TAH = total artificial heart.

transoesophageal echocardiography (TOE) is performed, the co-
agulation status of the patient should be known, and if required
and acceptable any coagulopathy corrected prior to the study.
Oropharyngeal bleeding can be life-​threatening in patients fully
anticoagulated on ECMO, and generally oesophageal intubation
using direct laryngoscopy is recommended. Echocardiographic
diagnosis in patients being considered for advanced extracor-
poreal support has three main components:
◆ Excluding important underlying potentially treatable pathology
◆ Determining the requirement for right and/​or left ventricular
support, and the level of support required, and assessing the
ability of the right and left ventricles to support the extracor-
poreal circuit
◆ Exclusion of cardiovascular contraindications to initiation of
support
Exclusion/​diagnosis of relevant underlying
pathology
Extracorporeal support is not a treatment per se, but rather a
supportive therapy, while awaiting resolution of the under-
lying pathological process. Where this remains undiagnosed
and untreated, patient prognosis is poor. Thus, a comprehen-
sive echocardiographic examination must be undertaken in pa-
tients referred for cardiac and/​or respiratory support, and where
a potentially treatable cause is found, appropriate intervention
undertaken in a timely manner. This applies equally for patients
referred for respiratory support, as interstitial oedema due to dif-
fuse acute lung injury may be radiographically indistinguishable
from that due to elevated left atrial pressure, and here, a cardiac
cause of pulmonary oedema must be excluded/​diagnosed [10].
An example is shown in E Figs. 40.2a, b, and c.
Diagnosing requirement for support and
ability of the heart to support the circuit
The types of systems used are predominantly determined by
the failing organ(s), and the level of support required, i.e. re-
spiratory and/​ or cardiac failure (ETables 40.1 and 40.2).
Determining the requirement for support is clinical, however,
once this decision is made, echocardiography becomes pivotal
to guide the type and configuration used. In every case each
side of the heart must be assessed while considering the existing
level of inotropic and respiratory support, and anticipating
the additional circulatory load of any extracorporeal circuit.
A further challenge in extracorporeal cardiac support is to an-
ticipate the effect of the additional forward stroke volume de-
livered to the apparently non-​affected ventricle, as a significant
increase may reveal covert ventricular failure. Some commonly
used types of support, together with their related flows are
shown in E Table 40.2.
Different configurations are thus determined by the type and
level of assistance required, and defined additionally by the pos-
ition of the inflow (ventricular/​ atrial/​
peripheral) and return
(atrial/​aorta/​pulmonary artery/​peripheral) cannulae. The site and
mechanism of cannulation in turn depends not only on the pa-
tient pathology but also local expertise.

Fig. 40.1  Transthoracic echo, parasternal long axis view in a patient with
severe acute respiratory failure with poor windows due to lung interstitial
oedema.
LA = left atrium; LV = left ventricle.
Echocardiographic contraindications to
extracorporeal support
There are a number of absolute and relative contraindications
to extracorporeal support, some of which can be detected using
echocardiography (E Table 40.3). Additional contraindications
may exist that relate to the specific device, for example aortic sten-
osis (AS) and the Impella [11].
 Diag n o si s 601

(a)

(b) (c)

Fig. 40.2  (a) Chest radiograph and CT thorax of a patient referred to a national centre with severe acute respiratory failure for venovenous extracorporeal
membrane oxygenation, demonstrating bilateral diffuse pulmonary infiltrates. (b) Continuous-​wave (CW) Doppler transthoracic echocardiography of transmitral
filling in a patient with severe acute respiratory failure referred for venovenous extracorporeal membrane oxygenation, demonstrating high forward velocities
(arrowed). (c) Two dimensional transoesophageal echocardiogram in a patient with severe acute respiratory failure referred for venovenous extracorporeal
membrane oxygenation, demonstrating flail posterior mitral valve leaflet (arrowed) and severe mitral regurgitation (broken arrow) on colour Doppler.
LA = left atrium; LV = left ventricle.

Table 40.2  Flow rates associated with some types of extracorporeal support

Device Flow (L/​min) Comments

Impella (2.5, CP, 5.0, LD) ≤2.5, 4.3 or 5.0 Percutaneous (2.5, CP) and surgical (5.0, LD) positioning across AV (left heart)
Impella RP ≤4 Percutaneous positioning across TV & PV (right heart)
ProtekDuo ≤4.5 Percutaneous positioning across TV & PV (right heart)
Tandem heart ≤4.0 Catheter insertion with transeptal puncture
Centrifugal VA-​ECMO ≤9.0 Surgical or percutaneous
Centrifugal VV-​ECMO ≤5 Surgical or percutaneous
(AV) ECCO(2)R ≤1.0–​1.8 Percutaneous femoral
Abbreviations: AV = aortic valve; RA = right atrium; PA = pulmonary artery; PV = pulmonary valve; TV = tricuspid valve; VA-​ECMO = venoarterial
extracorporeal membrane oxygenation; VV-​ECMO = venovenous extracorporeal membrane oxygenation; (AV) ECCO(2)R = arteriovenous extracorporeal
carbon dioxide removal. For all devices, a significant limit to the amount of flow deliverable is cannula dimension.
602 CHAPTER 40   E c ho cardio graph y evaluat i on i n extr ac orp orea l su pp ort

Table 40.3  Echocardiographic contraindications to extracorporeal support

Absolute contraindications to VA-​ECMO/​LVAD Absolute contraindications to VV-​ECMO

Unrepaired aortic dissection Severe ventricular dysfunction
Severe AR Severe pulmonary hypertension
Unrepaired coarctation of the aorta
Relative contraindications to VA-​ECMO/​LVAD Relative contraindications to VV-​ECMO
Severe aortic atheroma Large PFO/​ASD
Abdominal/​thoracic aneurysm with intraluminal thrombus TV pathology (TS/​TVR)
Contraindications to Impella Contraindications to Impella RP/​ProtekDuo
Mural thrombus in the left ventricle Thrombus in the right-​sided venous system
Mechanical aortic valve Abnormal anatomy precluding device positioning
Pericardial constriction Mechanical tricuspid/​pulmonary valves
AS (equivalent orifice area ≤ 0.6) Severe tricuspid/​pulmonary valve pathology
Moderate to severe AR (≥ +2)
ASD/​VSD
Abbreviations: VA-​ECMO = venoarterial extracorporeal membrane oxygenation; LVAD = left ventricular assist device; VV-​ECMO =
venovenous extracorporeal membrane oxygenation; PFO = patent foramen ovale; TV = tricuspid valve; TS = tricuspid stenosis; TVR =
tricuspid valve replacement; AR = aortic regurgitation; ASD = atrial septal defect; VSD = ventricular septal defect; AS = aortic stenosis.

in the context of any pulmonary hypertension. In addition to the

Extracorporeal respiratory support standard assessment of RV function and pulmonary circulation,
evidence of RV restriction should be sought and any intracardiac
In its most extreme form, patients with SARF are impossible to
shunt assessed with respect to its size and direction, if necessary
oxygenate, mandating extracorporeal support with venovenous
using contrast [12]. When the right heart is judged on echo-
(VV-​)ECMO (E Fig. 40.3). In other circumstances, only CO2 re-
cardiography to be significantly impaired, either use of isolated
moval is required. Both situations require adequate right ventricle
right-​sided heart plus lung support with a ProtekDuo plus oxy-
(RV) function to tolerate the circuit, however the clinical status
genator (E Fig. 40.4) [13], or full cardiorespiratory support with
of such patients makes a universal definition of what constitutes
‘adequate’ for all patients impossible. RV function must be inter-
preted in the context of the level of inotropic support, degree of
hypoxaemia and/​or hypercarbia (increased pulmonary vascular
resistance), ventilatory pressures used, and degree of hypotension

Fig. 40.3  Transversal CT thorax in a patient with severe H1N1 influenza
referred for venous-​venous extracorporeal membrane oxygenation (VV-​
ECMO). There is no airspace shadowing in the lungs (L) and the patient is
unventilatable. Treatment has been started with VV-​ECMO, and the cannula
can be seen clearly in the right atrium (arrowed).
H = heart.
Fig. 40.4  Chest radiograph in a patient with profound right ventricular failure
following aortic valve replacement. The device is inserted through the right
internal jugular and seen passing through the right atrium, right ventricle, and
into the right ventricular outflow tract distal to the pulmonary valve.
TOE = transoesophageal echocardiography probe; AVR = aortic valve replacement;
Protek = ProtekDuo.

Fig. 40.5  Dual lumen cannula for internal jugular vein catheterization in order
to deliver venovenous extracorporeal membrane oxygenation (VV-​ECMO).
The inlets to the cannula (removing deoxygenated blood, shown as blue
arrows) are in the superior and inferior cavae, and the returning oxygenated
blood (arrowed in red) is directed towards the tricuspid valve orifice.
Source: http://​www.avalonlabs.com.
VA-​ECMO may be indicated, however achieving normoxia may
result in rapid resolution of RV dysfunction, therefore RV func-
tion must always be evaluated in the context of arterial blood
gases, and the potential for RV improvement (or not) anticipated.
VV-​ECMO
Current commonly used adult VV-​ECMO systems generally use
either bifemoral cannulation or a dual lumen cannula, with blood
drawn from the superior vena cava (SVC) and inferior vena cava
(IVC), returning blood into the mid-​right atrium (RA) directed
towards the tricuspid valve (TV) (E Fig. 40.5). Echocardiography
Fig. 40.6  Transoesophageal echocardiogram demonstrating cannula position for a dual lumen ECMO cannula. In the figure on the left, the cannula (solid
arrow) is seen passing into the inferior vena cava (IVC), close to the suprahepatic vein (dashed arrow), with the inlet (dashed circle) away in the centre of the IVC.
In the figure on the right, the cannula is seen crossing the right atrium (RA) (solid arrow) with the inlet (circled) at the superior vena cava/right atrium junction,
and the return jet (broken arrow) directed towards the tricuspid valve and away from the interatrial septum.
Extr ac orp orea l respi r atory supp ort 603
is used to confirm and/​or guide correct cannula placement
(E Figs. 40.6 and 40.7) [14].
In case of dual lumen cannulation [15], the distal part of the
IVC cannula should ideally have its cannula inlet distal to the
suprahepatic vein, and a suprahepatic diameter of >10 mm, thus
avoiding venous obstruction. The SVC inlet should be just prox-
imal to SVC/​RA junction, with no SVC obstruction. There should
be no kinking of the cannula in the RA, and the return jet should
be directed away from the cavae and interatrial septum, towards
the TV inlet. When using a bifemoral approach, two single lumen
cannulae are used (access and return cannulae) [14]. The correct
position of the tip of the access cannula is proximal to the IVC-​RA
junction. The tip of the return cannula is ideally mid-​RA, remote
from the interatrial septum and tricuspid valve. The distance be-
tween cannulae tips should be monitored in order to prevent recir-
culation and a clear understanding of the shape and characteristics
of the different cannulae and their echocardiographic appearances
is required. A daily targeted TTE confirms there has been no su-
perior/​inferior migration or rotation of the cannulae, no deterior-
ation of RV function and no significant change in the presence/​
direction of any intracardiac shunt (which may be dynamic).
Additional studies are indicated where a complication of ECMO
is suspected (see ‘Echocardiographic detected complications of
extracorporeal support’). When interpreting ventricular function
in any patient on VV-​ECMO the flow rates should be routinely re-
corded as although when a greater proportion of the venous return
is aspirated and better oxygenation achieved, this may be at the ex-
pense of progressive RV failure, or conversely where arterial gases
improve, pulmonary vascular resistance and RV function may im-
prove significantly, and can reveal the extent of any left ventricle
(LV) dysfunction. Finally, where the circulation is hyperdynamic
and ventricular function hyperdynamic, beta blockade may be
used to reduce the cardiac output and oxygen demand. Thus, bal-
ancing biventricular function, inotropy, and oxygenation requires
a level of expertise, and collaboration between echocardiographer
604 CHAPTER 40   E c ho cardio graph y evaluat i on i n extr ac orp orea l su pp ort
Fig. 40.7  Transthoracic echocardiogram (parasternal long axis view)
demonstrating correct placement of the Impella in a patient with
hypertrophic cardiomyopathy. The inlet portion of the cannula can be seen
in the left ventricle (solid arrow), approximately 3 cm below the aortic valve
(broken arrow).
LA = left atrium.
and intensivist. Where cardiorespiratory stability is not achievable,
VA-​ECMO may be required.
Extracorporeal cardiac support
A range of devices for mechanical circulatory support are avail-
able (E Table 40.2). These are defined by the type (left/​right/​
biventricular), duration (short/​intermediate/​long term), mech-
anics (continuous flow/​volume displacement) and implantation
approach (percutaneous/​ surgical/​combination). Where severe
respiratory failure co-​exists, extracorporeal oxygenation will
additionally be required (E Table 40.1). Support may be insti-
tuted as a bridge to recovery, transplantation, or decision [2]‌.
Knowledge of different devices is mandatory prior to attempting
to use echocardiography to guide their use, as for each, specific
Fig. 40.8  Transoesophageal echocardiogram (mid-​oesophageal left ventricular outflow tract view) in a patient with severe pulmonary oedema despite
venoarterial extracorporeal membrane oxygenation for cardiac support. On the left is a diastolic frame, with the aortic valve closed and mitral valve open
(arrowed). On the right is a systolic frame. The aortic valve remains closed, and there is persistent (systolic) opening of the mitral valve (arrowed). This
demonstrates inappropriate left ventricular offloading.
LA = left atrium; Ao = ascending aorta.
considerations exist. All echocardiographic studies performed on
support should have pump speed, ventilator settings (if relevant),
level of vasoactive support, and haemodynamics recorded.
Impella
This axial pump may be used to provide short-​term partial as-
sistance to either left or right heart. For LV support, the device
is usually inserted percutaneously, positioned across the aortic
valve into the cavity of the LV [16, 17] under fluoroscopic and
echocardiographic guidance to monitor catheter progression
across the aortic valve, ensure there is no disruption/​distortion of
the mitral subvalvular apparatus and no increase in mitral regur-
gitation. Correct positioning is confirmed by demonstration of
inlet flow in the LV (no more than 40 mm below the aortic valve),
and return flow approximately 10 mm above the aortic valve
(E Figs. 40.7 and 40.8). As the LV is decompressed, its dimen-
sions should decrease in parallel, with a reduction in any previ-
ously documented mitral regurgitation.
Impella RP
The Impella RP is a temporary percutaneous RV support device
[11–​18] used to allow the RV to recover, or as a bridge to another
intervention/​support device. The device is a preformed three-​
dimensional catheter-​based percutaneous microaxial pump. It
is advanced under fluoroscopic and echocardiographic guid-
ance via the femoral vein, into the RV, pulmonic valve, and into
the main pulmonary artery. Echocardiography can be used to
confirm correct inflow/​outflow positioning, detect any disrup-
tion to tricuspid/​pulmonary valve or right ventricular morph-
ology and guide repositioning if required. Decompression of
the right heart and reduction in the degree of functional tri-
cuspid regurgitation are echocardiographic features of efficacy.
Echocardiographic evaluation of RV function (diameters, area,
TAPSE, S’ TDI) are associated with central venous, pulmonary
artery pressures and cardiac index, and are important param-
eters to guide weaning [18].
 Extr ac orp orea l ca rdiac supp ort 605

TandemLife ProtekDuo
TandemLife ProtekDuo is a temporary right ventricular assist de-
vice (RVAD) which may be used with or without an oxygenator
[13, 19] (E Table 40.4). Insertion is percutaneous via the right
internal jugular vein using TOE and fluoroscopic guidance, with
the inflow in the RA and the outflow in the main PA [13, 19].
Echocardiographic monitoring is as for the Impella RP.

VA-​ECMO
VA-​ECMO is indicated for the short-​term assistance of either or
both ventricles, with/​without associated respiratory failure. It can
be used as a bridge to cardiac recovery, or to improve organ func-
tion prior to longer-​term ventricular assist device (VAD) insertion
or heart transplant. Cannulation may be peripheral or central,
draining blood from the RA and pumping it through an oxygen-
ator to be returned to either the ascending (central) or descending Fig. 40.9  Transoesophageal echocardiogram in a patient on venoarterial
(peripheral) aorta. In addition to diagnosis of the underlying con- extracorporeal membrane oxygenation for cardiac support post-​aortic valve
dition and exclusion of contraindications (E Table 40.3) echo- replacement. Colour M-​mode across the aortic valve shows continuous aortic
regurgitation, with no aortic valve opening.
cardiographic findings may also influence the choice of central
vs. peripheral cannulation. Here, in the presence of very severe
LV failure the return delivery of blood to the descending aorta VA-​ECMO is called ECMELLA) [21], atrial septostomy [22], a
can increase LV afterload, resulting in worsening pulmonary con- pigtail across the AV [23], cannulae across the interatrial septum
gestion. If aortic regurgitation (AR) co-​exists, in the absence of and connected to venous cannula of VA-​ECMO circuit [24, 25]
aortic valve (AV) opening (E Fig. 40.9), AR becomes continuous or directly as a surgical procedure [26]. Regardless the type of
(E Fig. 40.10), and may become progressively more severe, venting used, echocardiography must detect the degree of LV
worsening LV dilatation, transmural pressure, left ventricular offloading and assess whether the AV is opening and the presence
end-diastolic pressure and potentially therefore preclude LV re- of thrombus inside the LV or at the level of proximal aorta.
covery (E Fig. 40.11). One potential option is to introduce a During VA-​ ECMO insertion, TOE is used to confirm the
minimal level of inotropic support in order to achieve some de- ECMO inlet and outlet cannulae positions, specifically confirming
gree of LV ejection and AV systolic opening (monitored by echo-
cardiography). Where this is not possible and/​or measurement
of the pressure difference between the ascending aorta and LV
indicates a potentially very high LV diastolic pressure (E Fig.
40.12), offloading/​decompression of the LV is required. The echo-
cardiographic features of insufficient LV unloading include severe
MR, pulmonary oedema, and intracardiac thrombosis, including
at the level of the ascending aorta, LV, and pulmonary veins (E
Fig. 40.13). LV offloading may be undertaken using a number of
techniques including IABP [20], Impella (the combination with

Table 40.4  Characteristics of temporary RVAD

Impella RP ProtekDuo
Insertion Femoral vein Right internal jugular vein
Outflow Main PA Main PA
Inflow Inferior vena cava Right Atrium
Venous Lower part of the Upper and lower parts body Fig. 40.10  Transthoracic echocardiogram (parasternal long axis view) in
drainage body systole of a patient requiring extracorporeal mechanical circulatory support
for cardiogenic shock following implantation of a transcatheter aortic valve
Function Temporary RVAD Temporary RVAD (TAVI). Due to continuous delivery of flow to the ascending aorta, the TAVI
VV-​ECMO (if associated to has displaced inferiorly into the left ventricle (LV) resulting in severe AR. As
an oxygenator)
equal pressures were present in the ascending aorta and LV, no colour flow
Abbreviations: RVAD = right ventricular assist device; VV-​ECMO = venovenous was seen on colour Doppler. Consequently there was severe LV dilatation with
extracorporeal membrane oxygenation; PA = pulmonary artery. progressive mitral annular dilatation and free MR during systole and diastole.
606 CHAPTER 40   E c ho cardio graph y evaluat i on i n extr ac orp orea l su pp ort

The frequency of echocardiographic assessment in VA-​ECMO

Fig. 40.11  Transoesophageal echocardiogram in a patient on venoarterial
extracorporeal membrane oxygenation for cardiac support post-​aortic valve
replacement. CW Doppler reveals continuous aortic regurgitation (broken
arrow), with a low pressure difference between the ascending aorta and left
ventricle (16 mmHg). In this patient the pressure in the ascending aorta was
65 mmHg indicating a high LV pressure in systole and diastole.
avoidance of the cannulae impacting on any cardiac/​extra-​cardiac
structure, no kinking/​distortion of the cannulae, and avoidance
of suprahepatic vein cannulation/​obstruction. The inlet cannula
should be located in the mid-​RA providing unobstructed flow
of blood into the circuit. In peripheral VA-​ECMO although the
tip of the return cannula is not visible using TOE, during inser-
tion arterial cannulation can be confirmed by demonstration of
the guidewire in the aorta (E Fig. 40.14). Echocardiography is
then used to ensure there is no inappropriate unloading of the LV
(progressive dilatation/​failure to decompress). This may addition-
ally be suggested by retrograde diastolic transmitral flow and/​or
retrograde systolic waves in pulmonary venous flow [27].
is debated, however echocardiography should probably be per-
formed daily (E Fig. 40.15), and is definitely indicated when a
complication is suspected (see ‘Echocardiographic detected com-
plications of extracorporeal support’). Although this would usually
be indicated by haemodynamic instability, on occasion a change
in oxygenation should prompt echocardiographic evaluation.
First, a paradoxical improvement in oxygenation may be due to
impedance to mechanical flow (i.e. tamponade) rather than de-
terioration in respiratory function or the oxygenator. In this situ-
ation a comprehensive examination of the heart and circuit should
be undertaken. Second, in a patient requiring cardiorespiratory
support, where there is persistent severe respiratory failure, as
the heart begins to recover and eject this can result in the upper
body being supplied by profoundly deoxygenated blood, while
the lower body is hyperoxygenated (supplied by the ECMO cir-
cuit)—​the Harlequin syndrome. If cardiac recovery is seen in this
situation the echocardiographer should warn the attending team
that their monitoring should be changed accordingly, and possibly
consider changing to VV-​ECMO if cardiac function is adequate.
Daily assessment should be undertaken if the patient has potential
to be weaned [28–​29]. Potential weaning success is suggested by
haemodynamic stability, persistent LV ejection with only minimal
inotropic support and adequate gas exchange. Echocardiographic
parameters suggesting the patient is potentially weanable include
an EF>20–​25%, left ventricular outflow tract (LVOT) velocity-​
time integral (VTI)>10 cm, absence of LV dilatation and no tam-
ponade [30]. When weaning from VA-​ECMO, the role of the RV
must be respected, as patients with RV EF≤24.6% have a worse
prognosis [31], however definitive echocardiographic param-
eters are not yet defined for this scenario. Currently there are no
universally applied protocols for predicting successful weaning
from VA-​ECMO. In general it requires staged reduction in flows,

Fig. 40.12  Transoesophageal echocardiography (mid-​oesophageal view) in a patient requiring insertion of an apical left ventricular vent due to persistent
and worsening AR when on venoarterial extracorporeal membrane oxygenation (VA-​ECMO) post-​aortic valve replacement. In the image on the left, flow into
the vent can be seen (arrowed). Monitoring the position of all cannulae during extracorporeal support is vital. In the image on the right taken 24 hours later,
the vent (V, broken arrow) has migrated beneath the anterior mitral valve leaflet to the subaortic area. If not repositioned, this can result in worsening aortic
regurgitation.

Fig. 40.13  Transoesophageal echocardiogram in a patient requiring
venoarterial extracorporeal membrane oxygenation three days after failure to
wean from cardiopulmonary bypass for aortic valve replacement. Due to very
severe left ventricular failure, no aortic valve opening was possible. Despite
full anticoagulation there is extensive thrombus seen from the left ventricular
outflow tract (LVOT) across the aortic valve prosthesis and extending to
the ascending aorta (arrowed). The thrombus additionally occluded both
coronary artery ostia.
LA = left atrium.
monitored by clinical, haemodynamic, and echocardiographic
variables. Various regimens exist including gradual reduction to
0.6 L/​min/​m2 over a few minutes, or sequential reduction (66%
15 mins, 33% 15 mins) [32]. VA-​ECMO weaning failure should
be determined in the context of each patient, with the cause for
weaning failure being clearly defined, and any potentially remedi-
able cause addressed. Where a weaning trial is deemed successful,
echocardiographic guidance of removal is indicated. If weaning is
not feasible, and isolated cardiac support required, ventricular as-
sist device should be considered.
Fig. 40.14  Transoesophageal echocardiogram in a patient receiving venoarterial extracorporeal membrane oxygenation. On the left (bicaval view) the
inlet cannula is seen, with the inlet jet (arrowed) in mid-​right atrium (RA). Note the interatrial septum is not impeding flow into the cannula. On the right
(descending aorta, Ao) the return jet is seen (broken arrow) directed to the centre of the aortic lumen.
LA = left atrium.
Extr ac orp orea l ca rdiac supp ort 607
Ventricular assist devices
Ventricular assist devices (left/​right/​biventricular) are used ac-
cording to existing guidelines and registries as longer-​term sup-
port for cardiac failure. Echocardiography plays a key role in the
management of such patients [25, 26, 33]. Some of the echo-
cardiographic contraindications to VAD insertion are shown in
E Table 40.3. With left ventricular assistance device (LVAD) in-
sertion a major echocardiographic challenge is predicting the tol-
erance of the RV to the increased preload [34]. This is important
as RV dysfunction post-​LVAD insertion is associated with in-
creased mortality and morbidity [35]. Further, where significant
RV dysfunction occurs, it limits function of the LVAD. A number
of parameters have been proposed to predict adequate RV func-
tion including RV transverse diameter <3.8 cm, FAC >40%,
TAPSE >1.5 cm and systolic strain/​strain rate <–16%/​1.1 m/​s,
however none taken alone is ideal. The strongest preimplantation
predictors of RV failure are pulmonary hypertension (PASP >50
mmHg) and severe RV systolic dysfunction [36]. Studies which
compared patients who did and did not require RVAD support
after LVAD implantation have shown that low peak RA longi-
tudinal strain and low peak RV free wall longitudinal strain as-
sociated with an higher degree of intra-​RV and interventricular
dyssynchrony were associated with the necessity of RVAD im-
plantation [37, 38]. Another important aspect to be considered is
AR. In types of LVAD, AR may become continuous, and increase
pulmonary capillary wedge pressure (PCWP) and PASP, further
impairing RV function. When judged to be severe, AR may re-
quire surgical intervention at the time of VAD implantation.
Intraoperative TOE is used to assist in optimal placement of
both inflow and outflow cannulae, ensuring they do not impact
on any intracardiac structure and are orientated appropriately
[29]. Immediately after implantation echocardiography is used to
assist de-​airing, assess AV opening, detect RV dysfunction, and
608 CHAPTER 40   E c ho cardio graph y evaluat i on i n extr ac orp orea l su pp ort

Fig. 40.15 Transoesophageal
echocardiogram in a patient with a
left ventricular assist device showing
pulsed-​wave (PW) Doppler of inflow
into the cannula (thin arrow), and
simultaneously showing transmitral
flow (thick arrow). In the miniaturized
2D image at the top of the figure, the
inflow cannula at the apex of the left
ventricle can be seen.
Image courtesy of Spectrum Health, Grand
Rapids, USA.

optimize LV filling while increasing pump speed to the required
level of support. Here, using the mid-​oesophageal four chamber
view, the interventricular septum should be in the midline. A
rightward shift suggests a too high pump speed, and leftward too
low. Finally, the aortic valve should be seen to open every few
beats, although this may not be achievable in all patients. Various
protocols have been suggested in order to achieve the goals of
(a) adequate LV offloading while (b) maintaining intermittent
aortic valve opening and (c) avoiding RV dysfunction. One such
protocol is an echocardiographic ramped speed study. Here the
revolutions per minute (RPM) are decreased until one or more of
the following are seen; the aortic valve opens with each beat, the
LV becomes more dilated, and/​or MR worsens (minimal speed).
In order to determine the maximal speed the RPM are increased
from the set speed until there is septal shift and/​or development
of ventricular dysrhythmias. The ideal state is that which allows
tolerance of normal alterations in volume status, and is generally
approximately 400 ml/​min below the maximal speed. Of note, op-
timal pump speed can vary over few hours after LVAD implant-
ation due to fluctuation of LV preload and afterload.
Longer-​term assessment of LVAD using echocardiography has
five main components:
◆ LV unloading: for continuous flow devices measure ven-
tricle end-​systolic dimension (LVESD) and left ventricle end-​
diastolic dimension (LVEDD); for pulsatile devices (becoming
obsolete) the largest LVEDD (at the end of diastole, just after
MV closure) and smallest LVESD [29].
◆ RV function and pulmonary hypertension: requires a compre-
hensive right heart examination [25, 32].
Cardiac output: right-​sided CO should be estimated in parallel
◆ to circuit flow by obstruction to the inlet/​outlet, or compression/​
with degree of AV opening assessed by M-​mode (normal/​inter-
mittent/​complete closure) [39–​40].
◆ Valvular function: demonstration of minimal tricuspid regurgi-
tation (TR), no worsening of AR, no aortic thrombus (E Fig.
40.11) and ideally intermittent AV opening [29].
◆ Ventricular recovery: There are no uniformly accepted cri-
teria or protocols for predicting successful weaning from
LVAD, although a number exist. The decision for explant-
ation is based on clinical stability, echocardiography (with
or without dobutamine stress) and measurement of invasive
haemodynamics [41, 42]. Here, application of strain/​ strain
rate imaging is a potentially exciting avenue for future research
[43, 44].
Echocardiographic detected
complications of extracorporeal
support
Echocardiography is key in detecting complications resulting
from extracorporeal support. The most frequent include:
◆ Cannula displacement
◆ Worsening regurgitation
◆ Tamponade
◆ Thrombus (from clotted aortic valve), or clotted pulmonary
valve
◆ Inadvertent overload/​excessive offloading of one/​both ventricles
Cannula displacement
This may be major or minor, and result in significant disruption
obstruction of other structures (for example the suprahepatic
vein, E Figs. 40.12 and 40.16). The echocardiographer should
 Ech o cardio graph ic detected c o m pl i cati on s of extr ac orp ore a l supp ort
know the anticipated position of the cannulae, and compare se-
quential studies.
Worsening valvular regurgitation
In VV-​ECMO worsening TR is common, but difficult to assess
due to hugely increased non-​pulsatile forward flow. In patients
undergoing VA-​ECMO AR is important, in particular where
there is no AV opening (E Figs. 40.8–​40.10). Where inappro-
priate offloading is suspected (worsening LV dilatation, high LV
diastolic pressure and/​or LA pressure) venting should be con-
sidered (E Figs. 40.11 and 40.12).
Tamponade
Tamponade (compromise of cardiac output and/​or the circuit
filling/​emptying) due to a pericardial collection is common, par-
ticularly early after institution of therapy. Echocardiographic diag-
nosis is challenging, in particular in the presence of non-​pulsatile
flow and small/​no tidal volume ventilation plus severe ventricular
impairment (possibly with no ejection). Further, a large collec-
tion, even causing significant compression of a cardiac chamber,
may have no clinical relevance until weaning from extracorporeal
support is attempted (E Fig. 40.17). If tamponade is clinic-
ally suspected however, and a collection is demonstrated that is
impeding filling/​emptying, evacuation should be considered.
Thrombus
Despite full anticoagulation thrombus may be detected using
echocardiography which may be related to the cannulae, car-
diac chambers or across the ventriculo-​arterial valves (E Figs.
609
Fig. 40.16 Transthoracic
echocardiogram, modified subcostal
view. Cannula displacement in a
patient on venovenous extracorporeal
membrane oxygenation where the
cannula (C) has become displaced
from the superior vena cava (SVC)
and migrated into the suprahepatic
vein (SHV). Due to the small diameter
of this vessel (<10 mm) it has become
collapsed around the cannula with
high velocity aliasing flows (arrowed).
40.13, 40.18, and 40.19). Where VAD or VA-​ECMO are used
post-​aortic valve replacement, thrombosis of the valve (par-
ticularly where there has been no ejection) has been reported.
Pulmonary artery thrombosis has also been described in VA-​
ECMO in the absence of right heart ejection. Thrombus related
to the cannulae is not uncommon, but when small, are usually
not clinically important. Large thrombi and/​or the presence of
Fig. 40.17  Transoesophageal echocardiogram, modified mid-​oesophageal
four chamber view. An incidental finding of a pericardial collection (C)
in a patient receiving peripheral extracorporeal cardiac support following
repeat cardiotomy for coronary artery disease. The collection is localized
and compressing the right ventricle (RV) but there was no compromise to
haemodynamics or the extracorporeal support.
LA = left atrium; RA = right atrium; LV = left ventricle; RV = right ventricle.
610 CHAPTER 40   E c ho cardio graph y evaluat i on i n extr ac orp orea l su pp ort

Fig. 40.18 Transoesophageal
echocardiogram bicaval view in a
patient with haemodynamic and
circuit instability on extracorporeal
membrane oxygenation (ECMO).
The inlet cannula (C) is seen in the
right atrium (RA) (broken arrow).
Associated with the tip of the cannula
is a thrombus (T, solid arrow). This is
obstructing inlet flow, as shown on
colour Doppler on the right (double-​
headed arrow).

an interatrial communication, or thrombi in the systemic cir- be found where thrombus is seen related to the cannula inlet.
culation may require intervention. The situation with long-​ Indirect evidence may be provided by insensitivity of echo
term LVAD differs in that the consequences of thrombosis of parameters to change with altering pump speed, and/​or when
an indwelling device may be catastrophic. Direct evidence may new AV opening is seen.

Excessive/​inadequate offloading of one or

both ventricles
Where excessive offloading is attempted, cardiac tissue may be
seen prolapsing towards the cannula, resulting in partial obstruc-
tion and high Doppler velocities (E Fig. 40.20). This is usually
associated with juddering of the cannulae and swings in flows.
Inadequate offloading of one or both ventricles may be due to
inadequate circulatory assistance or inappropriate discharge. In
these circumstances, comprehensive echocardiographic examin-
ation, performed in the context of the degree of mechanical and
inotropic circulatory support is mandated.

Fig. 40.19  Transthoracic echocardiogram, modified short axis aortic valve
view, focusing on the right ventricular outflow tract (RVOT), pulmonary valve,
main pulmonary artery, and pulmonary artery bifurcation(double-​headed
arrow). This image is from a patient 5 days after initiation of venoarterial
extracorporeal membrane oxygenation for severe biventricular failure
following transcatheter aortic valve implantation (TAVI). There had been no
right heart ejection, and despite full anticoagulation, the patient thrombosed
(T) his main pulmonary artery extending beyond the pulmonary artery
bifurcation.
Conclusion
Echocardiography is of unique importance for this patient popu-
lation, where cardiac magnetic resonance (CMR) is contraindi-
cated, and cardiac CT has limited applications. As the role of
extracorporeal support expands, this will require echocardiog-
raphers to become familiar with the normal and abnormal fea-
tures of the hearts and circuits of these highly complex patients, as
well as the pathophysiology of critical illness. The main challenges
remain predicting the response of the heart to the load imposed
by extracorporeal support, and determining the optimal time for
weaning.

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Contents
General considerations  613
Aims of imaging in cardio-​oncology  613
Organization of imaging structures in
cardio-​oncology services  613
Myocardial diseases and ventricular
function  614
Introduction  614
Echocardiography  614
Cardiac magnetic resonance  615
Radionuclide imaging  616
Primary amyloidosis  616
Myocarditis  617
Coronary artery disease  618
Introduction  618
Stress-​echo  618
Myocardial scintigraphy  619
Coronary computed tomography
angiography (CCTA)  619
Cardiac magnetic resonance (CMR)  619
Valvular heart disease (VHD)  619
Introduction  619
Echocardiography  619
CT SCAN  619
Cardiac magnetic resonance (CMR)  620
Pericardial disease  620
Introduction  620
Echocardiography  620
CMR and cardiac CT  620
Vascular diseases  621
Introduction  621
Vascular echo Doppler  621
Vascular CTS and MR  621
Pulmonary hypertension (PH)  622
Conclusions  622
CHAPTER 41
Cardiac imaging in
cardio-​oncology
Riccardo Asteggiano, Patrizio Lancellotti,
Maurizio Galderisi†, Stephane Ederhy, and
Marie Moonen
General considerations
Aims of imaging in cardio-​oncology
Cardio-​oncology is a cardiology subspecialty for the prevention, diagnosis, therapy, and
follow-​up of cardiovascular side effects of cancer therapy [1]‌. Cardiac imaging in the
management of these patients plays an essential role. Chemotherapy (CT) and radiation
therapy (RT) may indeed cause damages to all major cardiac and vascular structures
(myocardial dysfunction and heart failure [HF], coronary artery disease [CAD], valvular
heart disease [VHD], arrhythmias, arterial hypertension, thromboembolic disease, per-
ipheral vascular disease, and stroke, pulmonary hypertension [PH], pericarditis. Many
conditions may develop singularly or together complicating each other. Consequently,
every single pathology should be accurately treated. CT and RT may lead to irreversible
cyto-​toxicity with permanent dysfunction or to interaction with functional aspects of
cardiac cells not primarily cytotoxic, potentially reversible. Acute toxicity may appear at
the first administration of CT, rarely with the modern RT devices. Concomitant CT and
RT treatments may reciprocally potentiate toxicity. Clinical signs and symptoms, electro-
cardiographic modifications, troponin, and natriuretic peptides elevations together with
imaging tools may identify early CT toxicity.
Cancer-​cardiac patients may undergo different treatment if managed separately by
oncologists or cardiologists: the best treatment may be achieved by their interaction,
avoiding continuation of an excessively toxic cancer therapy, or permitting a toxic cancer
therapy using concomitant preventive measures for cardiovascular dysfunctions and
modifying cardiovascular therapy potentially dangerous. Chronic toxicity incidence may
develop over many years. Cardiovascular mortality however in cancer survivors is su-
perior to that of a cancer relapse.
Cardiac imaging is the main method to screen and diagnose long-​term complications
of cancer therapy, often evolving without overt symptoms. Imaging tools should be used
periodically according to current indications in this setting [1]‌.
Organization of imaging structures in
cardio-​oncology services
Cardio-​oncology services include dedicated professionals for the multidisciplinary
specialized evaluation and continuous, coordinated, cost-​effective care pre, during, after
†
  In beloved memory of our great friend Professor Maurizio Galderisi.
614 CHAPTER 41   C ardiac imaging in cardio- on c ol o g y
cancer therapy [2–​4]. These services may differ according to the
size of the hospital where are located. Technical resources of basic
services (<10 patients/​week) should be at least standard echo-
cardiography with strain and possibly three-​dimensional (3D)
echocardiography. Large services inside a university or oncologic
hospital should have availability of cardiac magnetic resonance
(CMR), cardiac computed tomography scan (CTS), positron
emission tomography (PET) and angiography room.
Myocardial diseases and ventricular
function
Introduction
Cancer and cardiovascular diseases are the leading causes of death
in the western world. Newer cancer therapies have improved the
survival of cancer patients but, in some cases, turned cancer into
a chronic cardiovascular disease [5]‌. Millions of patients in the
world are now surviving long enough to develop adverse car-
diovascular effects of cancer therapies to become the main de-
terminant of quality of life, and in some cases cause premature
mortality [6]. Imaging plays a major role for the screening, risk
stratification, and serial follow-​up of patients receiving anticancer
treatment. Echocardiography continues to be the mainstay in the
evaluation of cardiac toxicity, although the complementary role of
CMR is growing steadily [7].
Echocardiography
2D Echocardiography
Transthoracic echocardiography (TTE) can be used at different step
of cancer management to evaluate the risk of cancer therapeutics-​
related cardiac dysfunction (CTRCD) due to a regimen poten-
tially associated with a type 1 (anthracycline) or type 2 toxicity
(trastuzumab, tyrosine kinase inhibitors (TKI), monoclonal anti-
body inhibitors and proteasome inhibitors) [1, 8]. Its availability,
cost-​effectiveness, and lack of radiation make TTE the method
of choice to evaluate cancer patients before, during, and after CT.
However, TTE has some limitations including geometrical assump-
tion made to measure left ventricular ejection fraction (LVEF) and
load dependency, need to have a good image quality and relative
low sensitivity to detect subtle change in LVEF [8]‌.
◆ Systolic dysfunction
LVEF measurement
● dependent predictor of anthracycline-​
The ASE/​ EACVI recommend applying the modified
Simpson biplane method to measure LVEF and per-
form longitudinal evaluation in cancer patients [8]‌. The
methodology used to measure LVEF should be robust in
order to minimize individual variability. Load depend-
ency should be considered during LVEF measurement; its
variation in cancer patients is submitted to fluid variation
(vomiting, anaemia, fever, diarrhoea) interfering with
this evaluation.
● Cancer therapeutics-​related cardiac dysfunction (CTRCD)
definition
According to the NORRE study and several echocardio-
graphic databases, normal LVEF varies from 53% to 73%.
In cancer patients, the minimal level of LVEF variation that
TTE is able to detect is around 10% [9]‌. The ASE/​EACVI
Expert Consensus for multimodality imaging during and
after CT has defined CTRCD as a decrease of >10% of LVEF
unit with an LVEF <53%. This initial measurement should
be confirmed after3 weeks [8].
  A change of LVEF of 4% between baseline and low-​dose
anthracycline was the best predictor of CTRCD [10], closed
to the variability of 2D echocardiography, limiting the
interest of this parameter in daily practice. A larger study
identified LVEF value at completion of anthracyclines as a
marker of CTRCD [11].
◆ Diastolic dysfunction
Grading diastolic function and left ventricular (LV) filling pres-
sure should be evaluated in cancer patients both at baseline and
during CT administration.
CTRCD prediction with Doppler-​derived diastolic indexes
Several diastolic parameters (E/​A ratio, myocardial performance
index, isovolumic relaxation time) were tested and evaluated in
order to predict CTRCD. Even though each of these parameters
varies in patients receiving anthracyclines, none was able to iden-
tify patients at high-​risk of developing CTRCD [12].
CTRCD prediction with speckle-​tracking
echocardiography
Modification of strain parameters were evaluated in patients
treated with anthracyclines and trastuzumab but there are few
data in patients treated with molecular targeted agents and no
data in patients treated with immunotherapy.
Tissue Doppler imaging (TDI) is able to detect early alteration
of myocardial parameters in anthracycline treated patient [13].
Studies using speckle-​tracking echocardiography (STE) dem-
onstrate that an early reduction of 10–​15% of global longitudinal
strain (GLS) appears as the best parameter to predict CTRCD.
Even though radial and circumferential strain are altered in
cancer patients treated with anthracycline, none of them were
able to predict cardiotoxicity [14]. A GLS greater than –​17.45%,
obtained after 150 mg/​m2 of anthracycline therapy, was an in-
induced cardiotoxicity
[15]. In non-​ Hodgkin’s lymphoma treated with epirubicin
a >15.9% decrease in GLS was an independent predictor of
cardiotoxicity [16]. In patients treated with vascular endothelial
growth factor (VEGF) inhibitors GLS was significantly lower in
patients developing CTRCD [17]. The prognostic value of GLS
was evaluated retrospectively showing that GLS measured before
anthracycline administration was an independent predictor of
HF and cardiac death [18]. According to ASE/​EACVI consensus,
a GLS variation >15% compared to baseline values is the optimal
 M yo ca rdia l di seases a n d ven tri cu l a r f un c t i on
parameter to predict CTRCD [8]‌. However, when used in clin-
ical practice, same vendor and same software should be used to
monitor GLS during longitudinal evaluation of cancer patients
receiving cardiotoxic CT [8]. Of note, the ‘strain-​oriented ap-
proach’ proposed by ASE/​EACVI consensus has been recently
demonstrated to be useful in reducing the rate of overt CRRCD
and of CT interruption by a timely cardioprotective treatment ini-
tiation in a population of 116 consecutive female patients with
HER2-​positive breast cancer [19].
Contrast echocardiography
There are limited data on the use of contrast echocardiography
(CE) in the context of cardio-​oncology. As in other populations,
CE should be used when endocardial border of more than two
adjacent LV segments are not adequately visualized. Adjunction
of contrast to 3D echocardiography to measure LVEF shows
no additional benefit over non-​3D CE. According to the ASE/​
EACVI Expert Consensus, it is not recommended for longitu-
dinal follow-​up  [8]‌.
3D echocardiography
In the context of cancer patients and as already shown in others
population, 3D echocardiography appears as the best method to
measure LVEF, to detect low LVEF modification compared to 2D
echocardiography, with the technical advantage of lower tem-
poral variability. However, its cost, feasibility, need for expertise,
and limited availability particularly in non-​academic centres con-
stitute limitation to the use of 3D in cancer patients. In breast
cancer patients treated with anthracycline, the feasibility of 3D-​
derived LVEF was 66% compared to 90% for 2D echocardiog-
raphy [20]. According to the ASE/​EACVI Expert Consensus, 3D
echocardiography is the method of choice to monitor LV function
and detect CTRCD.
Dobutamine stress echocardiography (DSE) and exercise
stress test
In post-​anthracycline cancer patients, dobutamine stress-​echo
(DSE) and exercise stress-​echo were evaluated in children and
cancer survivors to detect subclinical cardiac dysfunction. Few
works analysed the role of DSE to predict CTRCD. In breast
cancer treated with high-​dose anthracycline an alteration of con-
tractile reserve at cycle 3 can predict cardiotoxicity defined by an
LVEF <50% [21].
Due to limited data, the ASE/​EACVI consensus does not rec-
ommend its routine use to detect CTRCD.
Cardiac magnetic resonance
CMR measures ventricular volumes, mass, and function accur-
ately and may be considered as gold standard for these evalu-
ations [22], and shows morphology of the tissues of heart and
para-​cardiac structures (myocardial oedema, early stage fibrosis,
tissue infiltration) helping to identify cardiotoxicity in early stages.
CMR therefore substitutes a prior echocardiogram when non-​
conclusive, mainly in early stages, to initiate a treatment, and/​or
615
during follow-​up. A limitation of CMR might be a pacemaker,
although compatible devices have been implanted from years.
Claustrophobic attacks are decreasing with the new wide bore (70
cm) scanners. Gadolinium-​based contrast agents (GBCAs) can
be associated with: (1) allergic reactions (incidence of 1:10,000 to
1:40,000); (2) rare nephrogenic systemic fibrosis in renal insuffi-
ciency; (3) accumulation of gadolinium in the brain stem after re-
petitive administration with unknown clinical significance [23].
These risks should be considered in patients with cancer who may
receive repetitive GBCAs.
Ventricular function/​volumes and mass
CMR measures of LVEF are quantified from a contiguous
short-​axis series of 2D cine slices. A real 3D data set is acquired
without limitations of geometric assumptions regarding the
shape of the LV. Summing the volumes of all slices, can be de-
rived end-​diastolic and end-​systolic volumes using the modified
biplane Simpson method [24]. Usually two-​and four-​chambers
views are used for calculations similarly to echocardiography. In
contrast to 2D-​T TE, the ‘real’ apex can be displayed and, gen-
erally, volumes quantified vs. 2D-​echo are overestimated. This
should be considered comparing the 3D acquisition of volumes
and LVEF is recommended when cardiac function is reduced
and LV has an abnormal shape and/​or regional wall abnormal-
ities. The cine sequences provide without contrast medium an
excellent contrast between cavity blood pool and myocardium,
identifying endocardial and epicardial borders inclusive of the
trabeculations. Some issues in the measurements should be
pointed out: (1) a breath-​hold time of 10 sec is required to cover
the whole RR cycle and calculate systole and diastole; (2) in case
of arrhythmias, only real-​time CMR acceleration techniques
acquiring many images/​second provide a good signal-​to-​noise
ratio and may be used; (3) acceleration techniques may be used
to decrease the breath-​hold time (from 12 to 2 secs), helpful for
very sick patients.
Distinguishing small changes in LVEF related to cardiotoxicity
from variance in the technique can be problematic. CMR shows
the best interstudy coefficient of variability [25]. Reproducibility
for CMR versus 2D echocardiography was:
◆ LV end-​systolic volume 4.4% to 9.2% (versus 12.7 to 20.3% for
2D echocardiography);
◆ LVEF 2.4% to 7.3% (versus 8.6% to 9.4%);
◆ LV mass 2.8% to 4.8% (versus 11.6% to 15.7%) [25, 26].
Concerns appeared for using only LVEF to define ‘cardiotoxicity’
from CT. In cancer patients LVEF may be unreliable, like for fluid
over or underload (infusions, de-​hydration, etc.). Moreover, many
consequences like VHD, myocardial injury, diastolic dysfunction,
do not lead to early change in LVEF [27, 28] and regional diastolic
relaxation may be affected well before.
Strain imaging (GLS)
Cine CMR with a temporal resolution less than 10 sec provides
information about diastole and depicts changes useful for strain
616 CHAPTER 41   C ardiac imaging in cardio- on c ol o g y
imaging. Early dysfunction of LV may consequently be identified
by GLS assessed by feature-​tracking CMR. GLS changes were as-
sessed in 72 patients for 3 months undergoing CT [26]. GLS wors-
ened (–​17.6 vs. –​18.8, P <0.001) and was strongly correlated with
early reduction of LVEF (r = 0.49, P <0.0001).
T1-​weighted mapping
Myocardial fibrosis due to cancer therapy generally is diffuse
[28]. Myocyte death and interstitial oedema leads to expansion of
extracellular space and to the volume of distribution of contrast
medium, associated with early pathological remodelling [29],
which may be shown by T1 mapping [30, 31] better than late en-
hancement imaging.
T1 relaxation time can be measured pre and post contrast al-
lowing calculation of the extracellular volume (ECV), which cor-
relates with anthracycline dose, dysfunction, and remodelling
of LV in paediatric [32] and adult patients after completion of
anthracycline-​based CT [33].
T2-​weighted  images
Acute myocardial inflammation, as in myocarditis, leads to
an increased signal in the myocardium on T2-​ weighted im-
ages [34]. Myocardial oedema after anthracycline therapy has
been documented in small studies. It is unclear if indicates
early cardiotoxicity and adverse prognosis. T2 mapping is less
depending on heart rate and arrhythmias.
Late gadolinium enhancement (LGE)
LGE imaging detects focal myocardial fibrosis after admin-
istration of GBCAs. Detection of myocardial fibrosis by LGE
is important because its pattern (intramural or subepicardial
distribution) enables differentiation of ischaemic from non-​
ischaemic causes (myocarditis, amyloidosis, autoimmune
diseases) [35].
LGE pattern in anthracycline toxicity include subepicardial,
intramural and LGE at right ventricular insertion points with a
range between 8% and 100% [36–​38].
Radionuclide imaging
Radionuclide imaging can assess cardiac functional param-
eters and structural parameters and might be used to evaluate
cardiotoxicity. Radiation exposition is the main concern for the
use of radionuclide imaging, and in paediatric populations these
imaging techniques are not generally used.
Multiple gated cardiac blood pool imaging (MUGA)
MUGA, or radionuclide ventriculography, evaluates LVEF with
high reproducibility vs. 2D echocardiography. MUGA being a 3D
technique does not depend on geometric assumptions. Due to
the radiation exposure risk it should be used only if echocardiog-
raphy is not diagnostic and CMR not available [39]. MUGA scan
acquires about 1,000 cardiac cycles in 20 minutes with a radiation
exposure of 5 to 10 mSv for 20 to 30 mCi of 99mTc pertechne-
tate. MUGA provides information about regional and global wall
motion abnormalities, LV volume, and LVEF. These values for
echo, nuclear imaging, and CMR differ. Consequently the same
technique has to be used for baseline and follow-​up of cancer
treatment assessment. Whether the addition of exercise increases
the prognostic value remains unclear [40, 41]. Evaluation of dia-
stolic function requires a better temporal resolution (32 images
instead of 16 images) per RR interval [42]. MUGA is less feasible
in patients with arrhythmias also with new modified acquisition
and post-​processing methods.
Gated single-​photon emission tomography (SPECT)
SPECT detects myocardial contours and less accurately LV meas-
ures. A decreased uptake of a radioactive tracer (technetium-​99m
or thallium-​201) indicates a myocardial scar or ischaemia. SPECT
requires a regular rhythm for ECG-​gating. Automatic border de-
tection reconstructs endocardial and epicardial surfaces. LVEF
can be calculated by quantitative gated SPECT algorithms with
high accuracy, comparable to CMR with close correlation (R2 =
0.75 to 0.85) [43].
E Figure 41.1 shows the case of a man with gastric cancer
who present a clear evidence of an enlarged LV with low ejection
fraction (EF) without signs of inducible ischaemia, after CT with
anthracyclines: this picture strongly supports a CTRCD.
Positron emission tomography (PET)
PET is mainly used in the assessment of metastatic lesions and
their response to CT. High costs and low availability limit clinical
use of PET whose use is limited to monitor cardiotoxicity.
123I-​labelled MIBG scintigraphy
123I-​metaiodobenzylguanidine (123I-​MIBG) SPECT is prom-
ising in early identification of cardiotoxicity and high-​risk pa-
tients. CT-​induced cardiomyopathy activates sympathetic and
renin-​angiotensin systems with consequent norepinephrine re-
lease and depletion of norepinephrine deposit.
MIBG is not metabolized by catechol-​O-​methyl transferase
and monoamine oxidase and has longer stay in adrenergic recep-
tors, generating scintigraphy images of cardiac efferent sympa-
thetic innervation with a good reproducibility and sensitivity to
detect abnormalities of myocardial adrenergic innervation before
reduction of LV function [44, 45]. This technique is promising but
not widely used.
Primary amyloidosis
Primary amyloidosis is a relatively rare disease, with a rapid clin-
ical progression. The amyloid tissue is composed of monoclonal
light chains and is associated with plasma cell abnormalities
(multiple myeloma and other B-​cell dyscrasias). Myocardial in-
filtration is common in amyloidosis with detrimental impact on
prognosis.
Echocardiography is recommended in all patients with sus-
pected cardiac amyloidosis (CAL). Typical findings include LV

hypertrophy with granular sparkling aspect of myocardium
(E Fig. 41.2), bi-​atrial enlargement, disappearance of atrial
septal drop-​ out, valve thickening, LV abnormal relaxation
filling pattern (E/​A<1 and E velocity deceleration time >240
msec) and increased E/​e’ ratio. However, none of these findings
is specific.
STE allows to identify a specific phenotype defined as ‘ap-
ical sparing’ (E Fig. 41.2), characterized by the impairment of
longitudinal strain (LS) in LV basal segments whereas the ap-
ical cup is preserved, at least in the initial disease stages [46]. A
relative apical LS strain ratio (average apical LS/​(average basal
LS + average mid-​LS)>1 has 93% sensitivity and 82% specifi-
city in differentiating CAL from other kinds of LV hypertrophy
(AUC 0.94). Relative apical LS ratio exerts an adverse prognostic
value [47].
LGE cardiac MRI is diagnostic for CAL (sensitivity = 80%,
specificity = 94%) [47]. LGE (E Fig. 41.2) indicates amyloid
infiltration in the interstitium. Global transmural or diffuse
subendocardial LGE are important criteria for detecting CAL in
early stages, i.e. before the wall thickness increase, and are asso-
ciated with the disease severity [48]. By using T1 mapping CMR,
a short T1 time and a large extracellular volume correspond to
amyloid infiltration [49]. T1 hyperenhancement has important
diagnostic and prognostic power in suspected CAL [50, 51].
Myocarditis
Immune checkpoint inhibitors (ICIs), upregulating T-​cell ac-
tivity, provoke an immune response against tumour cells, with
Myo c a rdi t i s 617
Fig. 41.1  Gated SPECT in a man affected by gastric
cancer, after anthracycline therapy. The absence of
signs of inducible ischaemia (stress/​resting) in an
enlarged LV and low EF indicates CRTCD.
Courtesy of Prof. Wanda Acampa, Federico II University
Hospital, Naples, Italy.
survival improvement in advanced melanoma and other cancers
[52]. The increased T-​cell activity can induce also autoimmune
reactions [53]. Although clinical trials reported limited numbers
of ICIs-​related cardiac events, the description of life-​threatening
myocarditis is increasing. In a recent collection of 30 cases with
ICI-​related cardiotoxicity, dyspnoea, palpitation, and signs of
right ventricular congestion were the most frequent manifest-
ations. 2D echocardiography showed a reduction of LVEF in
79% and Tako-​Tsubo-​like cardiomyopathy in 14% of patients;
troponin elevation was found in 26 and LGE-​CMR in 13 of
these patients [54]. In a more recent report of 35 patients, the
prevalence of myocarditis was 1.14% with a median onset time
of 34 days after the beginning of ICIs therapy [55]. The extent
of serum troponin elevation was an important discriminator of
cardiotoxicity whereas EF remained normal in half of the pa-
tients. Data on LV diastolic function were not available in both
the studies. Diagnostic complexity and heterogeneous clinical
presentation of ICIs toxicity have made detection of myocar-
ditis with high specificity challenging, limiting the possibility
to clearly understand incidence, prognosis, and predictors of
these complication. Accordingly, an uniform definition of ICIs
derived myocarditis is needed for improving the knowledge of
these events [56].
These findings also underline the need of a comprehensive
echo (including diastolic function and pulmonary arterial pres-
sure) of patients undergoing ICIs at baseline, at onset of car-
diac manifestations and after the second/​third month, a timing
corresponding to the greatest incidence of cardiac complica-
tions. ICIs should be interrupted based on symptoms/​signs and
troponin levels more than the severity of LVEF reduction, whose
618 CHAPTER 41   C ardiac imaging in cardio- on c ol o g y

Fig. 41.2  Typical echocardiographic and LGE

cardiac MRI features of cardiac AL. In the upper
panel, typical myocardial sparkling aspect of an
hypertrophied heart and disappearance of atrial
septal drop-​out (left) associated with apical
sparing at the bull’s eye of speckle-​tracking
echocardiography (right). In the lower panel,
corresponding LGE cardiac MRI showing myocardial
amyloid infiltration, involving in particular LV basal
segments.

power seems questionable. Echo should be repeated to follow
the benefit of cardioprotective therapy and corticosteroids, of
substantial benefit for recovering cardiac function. Because the
number of patients treated by ICIs will substantially increase,
standardized strategies are needed to detect early and manage
timely these complications.
Coronary artery disease
Introduction
While acute coronary syndromes may be observed with some CT,
a chronic CAD essentially may complicate RT. Its pathophysiology
seems similar to that of accelerated coronary atherosclerosis. Left
anterior descending, right coronary, and left main stem are the
most commonly involved arteries [57, 58]. Generally the lesions
occur in the proximal tract and ostia [59, 60]. The screening of
a pre-​existing CAD [61] for the choice of CT drugs requires a
careful evaluation with diagnostic imaging tests for ischaemia. RT
related CAD has clinic specific characteristics [62]. Sudden death
instead of progressive symptoms’ appearance may be the first and
unique event. These patients should undergo imaging tests of in-
ducible ischaemia.
Stress-​echo
According to guidelines, stress-​echo is a recognized imaging
tool for detection and prognostic stratification of stable CAD.
Procedures, interpretation, and diagnostic criteria are stand-
ardized in the Expert consensus on stress-​echo of the European
Society of Cardiology [63]. Although few reports are available
on its use in cancer setting, stress-​echo should be considered the
first-​line imaging to be utilized for diagnosing CAD in patients
with intermediate to high probability for CAD who are under-
going cancer therapy/​radiotherapy [1, 8]. Stress-​echo has higher
specificity than exercise ECG, is not expensive, easy to perform,
and without radiation exposure. It is also promoted as a screening
test in survivors of Hodgkin lymphoma (HL) who underwent RT
[64]. Stress-​echo (both physical or dipyridamole) allowed to iden-
tify a 2.7% prevalence of left main stenosis or three vessels disease
and a 7.5% prevalence of intermediate (= 50%) CAD, with a pre-
dictive value of 80% in presence of severe CAD (stenosis >75%) in
294 asymptomatic patients with HL treated with mediastinal RT
(≥35 Gy) [65]. 23 of these patients (7.8%) developed symptom-
atic CAD after a median follow-​up of 6.5 years. Stress-​echo is also
more sensitive and specific than myocardial perfusion imaging
in the identification of radiation-​induced CAD [62]. Therefore,
patients undergoing irradiation should be followed by repeating
stress-​echo at least every 5 years if the first exam shows no indu-
cible ischaemia.
Physical or pharmacological (dobutamine or dipyridamole)
stressors can be chosen in relation with the individual exercise
capacity, to achieve the diagnosis of CAD [62]. Inducible is-
chaemia can be identified by the development of new-​onset wall
motion abnormalities or by the worsening of abnormalities al-
ready evident at rest. Location and magnitude of abnormal wall
motion as well as ischaemic thresholds shall be carefully ana-
lysed. The test interpretation is strongly dependent on the quality
of the ultrasonic window. Myocardial contrast agents can be used
in patients with inadequate window, to improve border detec-
tion and identification of LV dyssynergy segments. An incom-
plete visualization of endocardial borders can occur particularly

in breast cancer patients after mastectomy and in patients with
HL after RT.
Myocardial scintigraphy
SPECT and PET have been used to assess myocardial ischaemia
in cancer patients. After RT, studies have been limited by small
number of patients and broad ranges of radiation dose, but showed
that 12% of asymptomatic patients have stress induced perfusion
defects 15 ± 7 years after treatment [66]. However, in many of
these patients, the distribution pattern did not match with a typ-
ical coronary territory and the perfusion defect increases over
time after exposure, suggesting a disease of the microvasculature
rather than of epicardial vessels [66]. During CT, data are limited,
but stress nuclear imaging may be useful in the evaluation of
patients with intermediate or high probability of CAD, who are
undergoing regimens that may be associated with ischaemia (e.g.
5-​fluoracil, bevacizumab, sorafenib, and sunitinib) [1]‌. However,
concerns about additional radiation exposure require careful
consideration.
Coronary computed tomography
angiography (CCTA)
Coronary computed tomography angiography (CCTA) is a non-​
invasive imaging technique allowing coronary arteries analysis
and quantification of coronary artery calcification. Its use is po-
tentially limited by iodine contrast media injection and ionizing
radiation. Limited data are available on its role as a screening
tool to document post-​radiation CAD. In a cross-​sectional single
centre study, evaluating asymptomatic HL patients with CCTA,
12% were found to have proximal left anterior descending sten-
osis and 1.6% to have a critical right ostial stenosis [67]. In one
hundred and seventy-​nine (179) asymptomatic HL patients, pro-
spectively evaluated, severe stenosis was observed in 12 (6.7%) of
the patients, leading to stent placement or bypass graft in 80% of
them [68]. The weak number of publications, the limited number
of patients included, generally in retrospective study, with cross-​
sectional design, generates a low level of evidence. The use of
CCTA or calcium scoring could not be recommended in daily
clinical practice to document post-​radiation CAD in asymptom-
atic patients [1]‌.
Cardiac magnetic resonance (CMR)
The role of CMR is very limited in evaluating CAD in patients
exposed to RT. LGE was found in 26% of 31 patients treated with
RT for HL [69]. As for CCTA there is not enough robust data to
recommend the use of CMR for post-​radiation CAD [1]‌.
Valvular heart disease (VHD)
Introduction
VHD induced by cancer therapy are almost due to RT (10% of
treated patients) [70, 71]. RT leads to fibrosis and calcification of
Va lvu l a r hea rt di se ase   (V H D ) 619
aortic root, aortic valve leaflets, mitral valve annulus, and base
and mid-​portions of mitral valve leaflets. Mitral valve tips and
commissures are spared [72, 73]. RT toxicity is commonly seen
after 10 years from the treatment and it is associated to other
structures damage. Echocardiography is the assessment method
of choice [8, 74] but all imaging methods may be used for specific
searches. Routine echocardiograms should periodically be done
during the long-​term follow-​up for searching valve diseases in all
patients with previous RT on the chest.
Echocardiography
TTE is highly sensitive in detecting any degree of VHD [60].
Recommended frequency of echocardiographic screening varies,
but is typically performed every 2 years in asymptomatic individ-
uals and more often once symptomatic. Mitral and aortic valve
regurgitations are the most common defects, and when stenosis
occurs, it most commonly affects the aortic valve [72–​74]. A char-
acteristic finding in radiation-​induced VHD involves the pro-
gressive thickening and calcification of the aorto-​mitral curtain,
providing incremental prognostic value in these patients [75].
3D echocardiography is particularly useful for the assessment of
presence or absence of commissural fusion and should be used
in situations where there is incomplete visualization of the mitral
commissures by 2D echo [62].
Grading stenosis or regurgitation severity as mild, moderate, or
severe, requires the use of different echocardiographic modalities,
should integrate multiple parameters, and should be combined
with clinical data. Though 2D is often sufficient for diagnosis,
2D/​3D transoesophageal echocardiography is often performed
for further diagnostic refinement. The severity of mitral stenosis
is evaluated according to mitral valve area, mitral valve diastolic
Doppler gradients, and PH. Aortic stenosis severity is evaluated
according to aortic valve area, aortic mean Doppler gradient, and
aortic valve peak systolic velocity [76, 77]. In these patients, po-
tential confounding factors relate to the presence of a significant
low flow state due to myocardial disease with or without reduced
LVEF. When LVEF is reduced, DSE can help in differentiating
pseudo-​severe from severe stenosis [78]. Regurgitation severity
is evaluated by a combination of quantitative and qualitative
parameters. Calculation of the regurgitation volume and effective
regurgitation orifice area should be attempted in all patients.
Difficulties in assessing regurgitation severity are related to calci-
fication of the aortic valve or mitral annulus. Stress-​echo enables
evaluation for myocardial ischaemia and dynamic assessment of
VHD [78].
CT SCAN
Cardiac CTS provides high-​resolution, cross-​sectional and 3D
information of the cardiac valves [79, 80]. Multislice CTS play
a major role in planning cardiac surgery and for preprocedural
preparation of transcatheter valve replacement [79]. Thin calci-
fication may indicate medial calcium, which will allow for safe
aortic clamping, whereas more dense and circumferential calcifi-
cation should merit planning for more cautious aortic approach.
620 CHAPTER 41   C ardiac imaging in cardio- on c ol o g y
Multislice CTS is relevant in assessing the degree and extent of
valvular and/​or annular calcification and the shape and size of
the annuli (aortic, mitral, and tricuspid). Stenosis or regurgi-
tation severity evaluation has a good accuracy, comparable to
transoesophageal echocardiography [79, 80]. Significant calcifi-
cation may however preclude the quality of the planimetry of the
regurgitant or stenotic orifice. Dynamic imaging is more challen-
ging with multislice CTS, and CTS is not able to assess the func-
tional significance of VHD.
Cardiac magnetic resonance (CMR)
In patients with poor acoustic window or non-​conclusive echo-
cardiography results, CMR emerges as an alternative for the as-
sessment of VHD. CMR provides both anatomical and functional
valvular evaluation, but also LV function and size quantification.
Pericardial disease
Introduction
Pericardial damage of cancer patients may be due to malignant
metastasis or, more frequently, CT (anthracyclines, cytarabine
and bleomycin, imatinib and dasatinib, busulfan) and, in par-
ticular, to thoracic RT [81]. Acute pericarditis from CT is rare.
Acute tamponade may occur in 2–​5% RT treated patients until 145
months. Chronic pericardial effusion may arise from 6 months
to 15 years after RT [62, 82, 83], with evolution in constrictive
pericarditis (CP) in 20% of cases. Delayed chronic pericarditis
(extensive fibrosis and constriction) may appear 6–​15 years after
RT. Radiation-​induced CP is dose-​dependent and is reported in
4–​20% of patients after high-​dose thoracic RT [82, 83].
Echocardiography
Echocardiography is the first-​line imaging in detecting pericar-
dial damage in cancer patients [8, 62] and should be performed
according to the recommendations of EACVI and the ESC
Working Group on Myocardial/​Pericardial diseases [84, 85].
Pericardial thickening, i.e. increased pericardial echogenicity
(>2 mm) on 2D imaging and corresponding multiple reflections
posterior to the LV on M-​mode, is a sign of pericardial inflam-
mation. However, the differentiation between normal and thick-
ened pericardium is difficult by echocardiography. Pericardial
effusion (PE), i.e. echo-​free space external to LV wall, can be
diagnosed (≥20 ml) with good accuracy by 2D and M-​mode
echocardiography but needs sometimes to be distinguished from
pleural effusion (PLE) or pericardial fat (PF). In parasternal
long-​axis view, PE is localized anterior and PLE posterior to the
descending aorta (E Fig. 41.3). Although PF has a brighter echo
density than PE, the differential diagnosis requires often more
advanced imaging tools. PE should be quantified and graded ac-
cording to standardized procedures [84, 85]. Cardiac tamponade
may be detected by large PE, compression of cardiac chambers,
and right-​sided venous congestion (E Fig. 41.4). A composite
echo diagnosis of CP includes increased pericardial thickness,
Fig. 41.3  Concomitant pericardial and pleural effusion in a woman with
breast cancer.
Ple = pleural effusion; Pe = pericardial effusion, Ao = descending aorta/​see arrows)
hampering the diastolic expansion of LV free wall.
prominent respiratory phasic rebound of septal wall, E/​A ratio
≥2 and E velocity deceleration time <140 msec (= restrictive
filling pattern), E velocity inspiratory variation >25%, diastolic
flattening of LV posterior wall, plethoric inferior vena cava, and
expiratory diastolic flow reversal in the hepatic veins. The dif-
ferentiation from restrictive cardiomyopathy can be done meas-
uring a normal/​increased e’ velocity of septal mitral annulus and
a pulmonary systolic pressure <50 mmHg. The diagnosis is often
challenging because the two conditions can coexist in oncologic
patients. Serial echo exams are indicated to follow PE and CP
but are less useful for identifying pericardial thickening and
calcifications.
CMR and cardiac CT
CMR and cardiac CT are more accurate than echo in diagnosing
anatomical pericardial alterations. Accordingly, they are indi-
cated for identifying primary cardiac tumours, with or without
pericardial involvement, and CP, when the echo results remain
challenging. E Figure 41.5 shows areas of pericardial thick-
ening during anthracycline therapy by CMR. Real-​time cine
loop CMR may be useful to evaluate the dynamic physiological
effects of pericardial damage, in particular the respiration im-
pact on the septal shape and motion. This allows an easy de-
tection of the increased ventricular interdependence occurring
in CP [62]. CMR-​derived LGE suggests residual pericardial in-
flammation, own of transient constriction, a condition that may
be managed by anti-​inflammatory therapy, without the need of
pericardiectomy. Localization and severity of pericardial al-
terations can be detected also using T1-​weighted CMR, but
pericardial calcifications are underdiagnosed also using CMR.
Cardiac CTS permits a fruitful assessment of intrapericardial
space and pericardial leaflets as well as the identification of epi-
cardial fat and PF, even without contrast injection. Pericardial

Fig. 41.5  CMR imaging showing areas of pericardial thickening (see arrows)
during anthracycline therapy.
Courtesy of Dr. Santo Dellegrottaglie, Acerra –​Naples, Italy.
calcifications and large PE can be detected with an optimal ac-
curacy by non-​enhanced cardiac CTS images. By intravenous
injection of a contrast agent, the enhancement of pericardial
thickness can be helpful to identify pericarditis or tumour
infiltration.
Vascular diseases
Introduction
Venous thromboembolism (VTE) is reported in up to 20% of
hospitalized cancer, being due to cancer itself or CT; the risk of
VTE is sixfold increased and twofold in patients treated by CT and
VEGF inhibitors, respectively [86]. Pulmonary embolism compli-
cation should always be excluded. The risk of arterial thrombotic
complications is elevated in patients undergoing CT with VEGF
inhibitors and aromatase inhibitors [1]‌. Severe peripheral artery
Vas cu l a r di se ase s 621
Fig. 41.4  Detection of cardiac tamponade by 2D
echocardiography. In the right panel schema and in
the left panel 2D image of an apical four-​chamber
view showing a severe collapse of the right atrium.
LA = left atrium; LV = left ventricle; RA = right atrium;
RV = right ventricle.
disease (PAD) of legs can occur early or after several years in 30%
of patients treated with nilotinib or ponatinib, and TKI [1], mainly
in patients with common cardiovascular risk factors. Ischaemic
stroke may occur with cisplatin, methotrexate, 5-​FU, and paclitaxel
[1]. Stroke risk of is doubled after mediastinal, cervical, or cranial
RT [87, 88]. Endothelial damage and thrombus formation may
occur after irradiation of cerebral small vessels [89]. RT may also
lead to intracranial aneurisms. Also aorta and other peripheral ar-
teries, including the subclavian and ilio-​femoral, may be involved
with ischaemic limb symptoms [90].
Vascular echo Doppler
Cancer patients undergoing TKI should undergo vascular echo
of lower extremities at baseline, during and after therapy as they
can develop occlusive PAD [1]‌. Significant asymptomatic PAD
could be diagnosed also by ankle-​brachial index (ABI): this index
indicates a significant peripheral atherosclerosis when <0.9 [91].
Patients with high cardiovascular risk profile should be followed
with repeated ultrasound exam (including ABI) during and after
TKI treatment. Similarly, patients undergoing high-​dose neck RT
or those combining CT and RT should perform a carotid ultra-
sound at baseline and every five years after RT completion, for
detection of increased intima-​media thickness (IMT) (>0.9 mm),
carotid plaque (focal wall thickness >1.5 mm), and stenosis [62].
E Figure 41.6 and E Figure 41.7 show increased IMT and ca-
rotid plaques respectively in two patients with HL, several years
after neck RT. This screening should become more frequent 5
years after RT. Shorter follow-​up should be planned in older pa-
tients, in symptomatic and in those presenting carotid abnormal-
ities at baseline. Notably, an increase of IMT has been reported
5 years after RT in 24% of patients with HL [62]. Radiotherapy-​
related carotid stenosis are in general more extensive than in pa-
tients not undergoing neck RT.
Vascular CTS and MR
RT can induce accelerated atherosclerosis and calcification of
thoracic aorta [62]. The identification of aortic calcification rep-
resents a marker of subclinical atherosclerosis and address to
622 CHAPTER 41   C ardiac imaging in cardio- on c ol o g y
Fig. 41.6  Pathologically increased IMT (= 1.1 mm) in a common carotid
artery of a patients with Hodgkin’s disease 4 years after neck irradiation.
IMT is normal until 0.9 mm and is considered increased when ranging
between 0.9 and 1.2 mm. After 1.2 mm a definite plaque is established.
The simple increase of IMT represents a recognized marker of early
atheromasic vascular disease.
Fig. 41.7  Hyperechoic plaques at the level of right carotid bulb and
prolongation of the same plaque at the origin of internal carotid artery
in a patient with Hodgkin’s lymphoma, six years after high-​dose neck
radiotherapy.
look for underlying CAD. CT angiography is routinely used to
evaluate carotid, subclavian, and aortic abnormalities due to RT,
and can easily show the distribution of calcification in the aorta.
The ‘porcelain aorta’ (severe calcification of the ascending aorta
and aortic arch) can be observed even 10–​20 years after medias-
tinal RT. Contrast-​enhanced MR angiography is an optimal tool
for evaluating great vessels. Besides 3D and ‘4D’ angiographic
techniques using the contrast first-​pass into the vessels, black-​
and bright blood MR can be used to visualize the morphology
of the arterial abnormalities, whereas phase-​contrast MR makes
possible the evaluation of flow over the arterial stenosis.
Pulmonary hypertension (PH)
PH is defined as an increase in mean pulmonary arterial pressure
≥25 mmHg at rest as assessed by right heart catheterization (RHC)
[92]. PH is a rare but serious cardio-​oncology complication, po-
tentially attributable to some CT. To date, the most common
forms are PH (group 1) with dasatinib [90], a second generation
multitargeted TKI used for chronic myeloid leukaemia treat-
ment, and pulmonary veno-​occlusive disease (group 1’), mainly
described with cyclophosphamide and mitomycin C [93, 94].
Baseline cardiac assessment is recommended before treatment
with those agents [1]‌. The evaluation should include the search of
risks factors and associated conditions for PH, the NYHA/​WHO
functional class and baseline TTE, including the search for signs
of right ventricular overload in addition to tricuspid regurgita-
tion velocity measurement and a 6-​minute walk test and base-
line NT-​proBNP. During the treatment, the assessment of NYHA/​
WHO functional class and the monitoring of TTE should be re-
peated every three months in asymptomatic patients or without
delay in case of exertion dyspnoea. In case of intermediate or high
echocardiographic probability of PH, further assessment of PH
including RHC should be considered, following the current ESC/​
ERS PH guidelines [92].
Conclusions
Every cancer related toxicity condition requires imaging for its
management.
Echocardiogram is generally the basic and easier tool. In some
specific setting another technique could be better performing.
Sometimes however echocardiogram may present technical
difficulties with poor definition, obliging to alternative choices.
Echocardiogram inter (and intra)operator dependency should
be avoided as possible; when necessary CMR and other methods
without this limitation should be employed.
During the long-​term follow-​up of cancer treated patients
the same imaging method should be used, possible in the
same centres and with the same machine and operator to avoid
variability.
Scintigraphy methods reduced their impact due to the danger
related to radiation damage and to CMR and CTS progresses, and
generally has been replaced by these techniques.
Every imaging tool should be used according to the character-
istics of the Cardio-​Oncology Service where the patient is evalu-
ated. Small centres may obtain complex imaging exams referring
patients to large university or oncology centres with a ‘hub and
spoke’ model.
In E Table 41.1, the main indications for imaging tools in every
pathology condition related to cancer treatment are summarized.
 RE F E RE N C E S 623

Table 41.1  Cardiac imaging approach in cardio-​oncology

PATHOLOGY 2D Echo STE MCE 3D Echo Stress-​Echo CMR CT scan MUGA/​ SPECT
MYOCARDIAL ++++ ++++ NR NR NR ++++ NR ++
DISEASES
Pros Availability, costs, lack Reproducibility No geometric Gold standard, Reproducibility
of radiation assumption radiation free,
Reproducibility reproducibility
Contras Geometrical Same machine/​ Availability, costs, Gadolinium Radiation
assumption, same software feasibility, only contrast,
reproducibility GLS Reduction research studies pacemaker,
Poor echo-​window 10–​15% costs
Parameters/​ Reduction EF>10%
timing and EF<53% at 3 W
CA ++++ ++++
Specific aspects Specific aspects
MYOCARDITIS ++++ ++++ LGE
CAD ++++ NR NR ++ (SPECT)
timing every 5 years
after RT
VHD ++++ NR NR
Timing 5 years after exposure
in high-​risk patients
or 10 years in others
PERICARDIAL +++ +++ +++
DISEASES
VASCULAR Vascular echo +++ +++
DISEASES Doppler
++++
Timing According to clinical
findings
PH ++++
CAD = coronary artery disease; CA = cardiac amyloidosis; CMR = cardiac magnetic resonance; CT = computed tomography; MCE = myocardial contrast echo; NR = not
recommended; PH = pulmonary hypertension; VHD = valve heart disease; STE = speckle-​tracking echocardiography.

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 SECTION 7

Cardiomyopathies

42 Hypertrophic cardiomyopathy  629

Nuno Cardim, Alexandra Toste, and Robin Nijveldt
43 Infiltrative cardiomyopathy  645
Massimo Lombardi, Silvia Pica, Antonella Camporeale, Alessia Gimelli, and Dudley J. Pennell
44 Dilated cardiomyopathy  661
Upasana Tayal, Sanjay Prasad, Tjeerd Germans, and Albert C. van Rossum
45 Other genetic and acquired cardiomyopathies  681
Kristina Haugaa and Perry Elliott

Contents
Introduction  629
Role of imaging in HCM  629
Assessment of anatomy  630
Hypertrophy  630
The mitral valve and the mitral valve
apparatus  630
Intraventricular obstruction  632
Tissue characterization  633
Assessment of myocardial function  634
LV systolic function  634
LV diastolic function  635
Assessment of myocardial ischaemia  636
Anatomical imaging of the coronary
arteries  636
Differential diagnosis  636
Cardiac amyloidosis (CA)  636
Hypertensive heart disease  638
Athlete’s heart  638
Other causes of LVH  638
Family screening/​preclinical diagnosis  638
Imaging in HCM clinical profiles  638
SCD profile  638
HF profile and the natural history
of HCM  639
AF/​stroke profile  639
Imaging in therapeutic procedures  639
Medical treatment  639
Surgical myectomy  640
Alcohol septal ablation  640
Dual-​chamber pacing  641
Future perspectives and conclusions  641
CHAPTER 42
Hypertrophic
cardiomyopathy
Nuno Cardim, Alexandra Toste, and
Robin Nijveldt
Introduction
In cardiac imaging, the expression ‘left ventricular hypertrophy’ (LVH) describes a
phenotype of increased wall thickness (WT) and/​or LV mass. However, this phenotype
is a common feature of multiple situations as it may reflect sarcomeric, intracellular or
interstitial abnormalities [1]‌.
Sarcomeric HCM is the major cause of unexplained LVH. It is a primary myocardial
disease, defined by inappropriate LVH, disproportionate to the degree of loading con-
ditions, in the absence of another cardiac or systemic disease, metabolic, or multiorgan
syndrome associated with LVH. The mitral valve apparatus and the small coronary ar-
teries are also primarily affected [2]‌.
HCM is the most common genetic heart disease and usually results from mutations in
genes encoding sarcomeric proteins, transmitted in an autosomal dominant pattern, with
incomplete penetrance and variable expression [3]‌.
HCM classical phenotypic prevalence in adults is 1:500 (0.2%), but recent studies point
to higher figures (1:200, 0.5%) [4, 5].
The clinical diagnosis of HCM is based on unexplained LVH by imaging, though the
role of genetic diagnosis has increased [2, 3, 6].
HCM is often a benign condition, asymptomatic, with normal life expectancy [7]‌.
Though it is estimated that the prevalence of ‘clinical HCM’ (patients who come to
medical attention) is 1:3200 [8], only a small percentage have adverse clinical profiles.
Symptoms onset classically occur between the ages of 20–​40, but later presentation is
nowadays thought to be common and with better prognosis [9].
Sudden cardiac death (SCD) is the most devastating presentation, and HCM repre-
sents the most frequent cause of SCD in the young and in athletes under 35 years old in
countries without systematic electrocardiograph (ECG) in sport screening programmes.
Heart failure (HF) and atrial fibrillation (AF) represent other important causes of dis-
ability in middle and older age groups. Intraventricular obstruction is a common finding
that often alters the natural history of HCM [2, 7].
The overall mortality of untreated HCM patients is about 1.3% per year (vs. 0.8% in the
general population), but the absolute individual risk is highly variable [2, 7].
Role of imaging in HCM
On account of the limitations of clinical assessment, imaging techniques are useful to
study HCM patients, supplying the clinician with answers to clinical questions.
630 CHAPTER 42   Hy pe rt roph ic cardiomyopathy
Box 42.1  Imaging in HCM: solutions for clinical needs
1 Diagnosis
2 Anatomy: confirmation and characterization of LVH, mi-
tral valve apparatus, intraventricular obstruction, and tissue
characterization
3 Myocardial function: systolic and diastolic function
4 Ischaemia (macro and microvascular)—​functional and ana-
tomical imaging
5 Metabolism, myocardial receptors, and innervation
6 Monitoring of different treatment modalities: medical treat-
ment, surgery, ASA, and pacing
7 Staging and natural history: G +, P–​, non-​hypertrophic
stage, and early phenotype, classical phenotype, adverse re-
modelling, and overdysfunction
8 Clinical profiles: SCD profile, HF profile, AF—​stroke profile
9 Follow-​up
1 0 Prognosis/​risk stratification
1 1 Family screening and preclinical diagnosis
1 2 Differential diagnoses with phenocopies
G+ = genotype positive; P–​= phenotype negative; ASA = alcohol septal
ablation.
Reproduced from Cardim N, Galderisi M, Edvardsen T, et al. Role of
multimodality cardiac imaging in the management of patients with hyper-
trophic cardiomyopathy: an expert consensus of the European Association
of Cardiovascular Imaging Endorsed by the Saudi Heart Association. Eur
Heart J Cardiovasc Imaging. 2015;16(3):280. doi:10.1093/​ehjci/​jeu291 with
permission from Oxford University Press.
Remarkably, a MMI approach is recommended. The different
techniques—​echocardiography (echo), cardiac magnetic reson-
ance (CMR), cardiac computed tomography (CCT), and cardiac
nuclear imaging (CNI)—​must be seen as complementary and
selected to provide answers to specific clinical questions, avoiding
redundant information, taking into account availability, benefits,
risks, and costs (E Box 42.1) [10].
Assessment of anatomy
Hypertrophy
Transthoracic echocardiography (TTE) is the initial technique.
The established HCM diagnostic criteria [10, 11] is the pres-
ence of maximal WT ≥15 mm (or >2 standard deviations for age,
gender, and height) in any myocardial segment, but in first-​degree
relatives of HCM patients a maximal WT ≥13 mm is accepted as
diagnostic [12]. In addition, the longitudinal (medial/​apical) ex-
tension of hypertrophy should be reported.
As in normals there is progressive thinning of WT from base to
apex, lower thresholds have been proposed for apical HCM (WT
>13 mm in the apex; apex/​base WT ratio > 1; apical /​posterior
WT ≥1.5) [13].
In HCM, LVH is often asymmetric, non-​contiguous, and may
affect from one to all LV segments, often the basal interventricular
septum (IVS). Asymmetric septal hypertrophy (septal/​posterior
WT >1.3 in normotensive or >1.5 in hypertensive (HT) patients
is common, but not exclusive of HCM (e.g. inferolateral in-
farcts in HT, sigmoid septum in HT, aortic stenosis, infiltrative
cardiomyopathies).
A standardized approach to report WT is recommended, with
2D-​echo measurements at end-​diastole in the short axis view. All
LV/​right ventricle (RV) segments should be examined. Correct
orientation and beam alignment are essential to avoid foreshort-
ened/​oblique views. As the inclusion of RV structures (trabeculae,
moderator band, tricuspid valve apparatus) may overestimate
septal thickness, special care must be taken to exclude them.
RV WT should also be measured, as the presence of RV hyper-
trophy (usually defined as a RV WT >5 mm) has been associated
with worse prognosis [14].
Septal morphology has been correlated with positive genetic
study for sarcomeric mutations: a ‘reverse IVS’ is strongly associ-
ated with a positive genetic study, apical HCM or neutral morph-
ology have a moderate probability, while a ‘sigmoid IVS’ has low
probability of a positive genetic test [3]‌.
To evaluate other localizations of hypertrophy, LV cavity
opacification with contrast agents is helpful, especially in patients
with suboptimal images.
There is limited data on the value of three-​dimensional (3D)
echo in HCM. It may be helpful in the reproducible assessment
of LV geometry/​mass, and provides insight in LV outflow tract
(LVOT) morphology/​dynamics [10].
CMR is the gold standard for WT and morphology assessment
(E Fig. 42.1) and may detect LVH missed by echo (often an-
terolateral/​apical) [15]. Although WT measured by echo is often
similar to CMR, discordance may be present [15], impacting
diagnosis and SCD management. For the evaluation of LV mass
and WT, cine CMR is performed (balanced steady-​state free-​
precession pulse sequence). Although LV mass is often not in-
creased, it provides a baseline value for follow-​up. In the presence
of flow or metal artefacts, a spoiled gradient-​echo pulse sequence
should be used. Diagnostic criteria and measurement planes are
similar to echo.
In the presence of suboptimal echo quality or when CMR is
contraindicated, CCT should be considered. Due to radiation and
iodinated contrast, CCT is not used routinely. Because of low spa-
tial resolution and radiation the use of CNI is not indicated.
The mitral valve and the mitral valve
apparatus
The majority of HCM patients have primary abnormalities of
the mitral leaflets, with excessive tissue/​elongation (absolute or
relative to LV size) [16], that contribute to LVOT obstruction
(LVOTO) and mitral regurgitation (MR). The chordae are often
elongated, with laxity and hypermobility. Papillary muscle abnor-
malities include anterior/​medial or apical displacement, hyper-
trophy, bifidity, and direct insertion into the anterior mitral leaflet.
Though not specific for HCM (may be seen in HT, hypovol-
emia, inotropic drugs, after mitral surgery) [11], systolic anterior
 As ses sm en t of a nato m y 631

(a) (b) (c)

(d) (e) (f)

(g) (h) (i)

Fig. 42.1  CMR features in HCM. HCM with MV SAM and elongated anterior leaflet shown on the systolic cine image (a), and increased T1 relaxation times
(black arrow) compared to healthy myocardium on the native T1 map (b), but without focal fibrosis and absence of LGE (c). HCM in diastole (d) and systole (e)
without MV SAM and absence of obstruction, but with extensive fibrosis on LGE (f). Apical HCM with spade-​shaped LV cavity in diastole (g) and typical thin-​
walled apical aneurysm in systole (asterisk, h) with LGE (i).
LGE = late gadolinium enhancement; SAM = systolic anterior motion; MV = mitral valve.

motion (SAM) of the mitral valve is an important determinant of
LVOTO [17].
Due to its high temporal resolution, the presence and severity
of mitral SAM is best depicted with M-​mode: incomplete SAM
(does not touch the IVS), mild SAM (mitral-​septal contact in late
systole, <10% of systole) and severe (starts at mid-​systole, >30%
of systole) [18]. Mitral SAM leads to a mismatch in leaflet co-
aptation that classically results in eccentric posterior and lateral
‘SAM-​related’ MR, though this jet direction may also be found in
organic valve disease [19].
The quantification of MR severity is performed according to
the recommendations [20] and its dynamic component with exer-
cise echocardiography [21]. In case of suboptimal image quality,
transoesophageal echo may be considered.
CMR is less accurate in the assessment of mitral valve leaflet
and chordae morphology. However, it is the technique of choice
to assess the papillary muscles, defining their contribution to
LVOTO, essential in the selection of the type of invasive therapy
[16]. The CMR quantification of MR severity is more reprodu-
cible and accurate than echo [22].
632 CHAPTER 42   Hy pe rt roph ic cardiomyopathy

CCT provides excellent definition of the mitral valve (MV) LVOTO at rest is present in one-​third of HCM patients and is
morphology [23] but it is seldom used with this sole purpose in an independent determinant of adverse prognosis [17]. In another
HCM. CNI has no role in this setting. one-​third of patients, LVOTO is only seen after provocative man-
oeuvres [24]. The assessment of obstruction should be performed
Intraventricular obstruction in resting condition and after provocative manoeuvres (e.g.
Obstruction in HCM can occur at the LVOT or at the mid-​ Valsalva, standing, exercise). The use of nitrates or dobutamine is
ventricular level, and its presence and location are suspected by not indicated, since it causes non-​physiological conditions and is
the presence of turbulent colour Doppler flow (E Fig. 42.2). not related to the disease itself [25]. Treadmill exercise echocardi-
In LVOTO, mid-​systolic closure of the aortic valve and mitral ography (E Fig. 42.3, top) is the recommended technique to de-
SAM are best defined with M-​mode. The maximal flow velocity tect labile obstruction, mimicking real-​life conditions. Recordings
is acquired using colour-​wave (CW) Doppler in apical views, and should be performed during exercise and at the beginning of re-
typically shows a late systolic peak, giving the spectral curve a covery, when preload decreases and obstruction may increase.
‘dagger shape’. HCM is defined as obstructive when peak flow vel- Exercise echocardiography should be considered in symptomatic
ocity is >2.7 m/​s (peak gradient ≥30 mmHg) [7]‌. A gradient ≥50 patients if bedside manoeuvres fail to induce a LVOT peak gra-
mmHg is considered haemodynamically relevant. dient of ≥50 mmHg. Care should be taken to avoid contamination

Fig. 42.2  Doppler assessment of left ventricular

outflow tract obstruction. 2D-​echo apical long-​
axis view with PW Doppler recording (top)
demonstrating the mid-​systolic drop in ejection
velocity (from dashed to solid line), until the peak
outflow tract velocity, as seen on CW Doppler
(solid line, bottom), creating a lobster claw shape
of the PWD profile; the inflection point of the
CW recording (bottom) shows a dagger-​shaped
waveform (arrow) reflecting the mitral-​septal
contact, and coincides with the drop in velocity
seen on the PW recording, in the presence of a
gradient >60 mmHg.
LVOT = left ventricular outflow tract; LV = left ventricular;
PW Doppler = pulsed-​wave Doppler; CW Doppler =
continuous-​wave Doppler.
 As ses sm en t of a nato m y 633

(a) (b)

(c) (d) (e)

Fig. 42.3  Dynamic intraventricular obstruction and mitral valve motion. Transthoracic Doppler flow assessment in HCM during rest (a) and during exercise (b),
where pressure gradient rises from 29 mmHg to 177 mmHg. Transoesophageal assessment before (c and d) and after myectomy and MV replacement (e) where
obstruction is relieved and MV regurgitation is absent.
TTE = transthoracic echocardiography; TEE = transoesophageal echocardiography; MV = mitral valve.

with the MR jet, overestimating obstruction severity. The MR
signal starts earlier (after the end of the transmitral A wave) and
ends later (at the onset of the transmitral E wave).
Contributing factors for LVOTO include narrowing of the LVOT
due to IVS hypertrophy and elongated mitral leaflets with SAM
and leaflet-​septal contact in mid-​systole. Due to variable mitral
valve anatomy, location of hypertrophy, loading conditions, and
myocardial contractility, the degree of obstruction is unpredict-
able [26] and can even be paradoxical in response to exercise [21].
Mid-​ventricular obstruction, less common, is caused by mid-​
ventricular hypertrophy and/​or anomalous papillary muscle in-
sertion that results in an ‘hourglass shaped’ LV chamber with a
mid-​cavity gradient, frequently associated with apical aneurysms.
Colour Doppler often shows aliasing in the sequestered apical
area and a paradoxical apex to base diastolic gradient. LV ap-
ical aneurysms increase the risk for arrhythmias and thrombo-
embolism. Apical HCM, with the typical ‘ace of spades’ sign, is
less often associated with obstruction.
CMR is useful in difficult cases of LVOTO, mid-​ventricular or
apical hypertrophy, and in RV outflow tract obstruction [27]. The
quantification of obstruction may be performed by CMR (in-​plane
acquisition to identify the highest velocity where aliasing occurs and
a through-​plane acquisition to assess peak flow velocity), but it is still
challenging [28]. CCT provides excellent visualization of the LVOT,
the mitral apparatus, and localization of hypertrophy, especially
due to the multiplanar reconstructions post acquisition but haemo-
dynamic information cannot be obtained [29]. It is used for this
purpose only when echo is suboptimal and CMR is contraindicated.
Tissue characterization
CMR detects focal (late gadolinium enhancement, LGE) and diffuse
(parametric mapping) myocardial fibrosis (E Fig. 42.1b, c, f, i).
The LGE technique depends on local differences in contrast
concentration. In areas of fibrosis, myocyte loss/​disruption or in-
filtration, gadolinium diffuses into the interstitial space and pre-
sents late wash-​out [30]. At image acquisition (10–​15 minutes
after injection), areas of higher contrast concentration show an
enhanced bright signal (shortened T1-​relaxation times).
Approximately half of HCM patients show LGE, typically intra-
mural, with heterogeneous extent and distribution. In hypertrophic
segments it represents replacement fibrosis, while in non-​
hypertrophic areas, such as the RV insertion points, it corresponds
634 CHAPTER 42   Hy pe rt roph ic cardiomyopathy
to interstitial fibrosis and/​or myocyte disarray [31]. Thick filament
sarcomeric HCM often show typical intramural LGE in hyper-
trophic areas, while a more diffuse distribution in atypical seg-
ments has been described in thin filament mutations [27, 32].
The extent of LGE in HCM (>10% of LV mass) is associated with
outcomes (disease progression [33], LV dysfunction, hospitaliza-
tion for HF, SCD, cardiovascular and all-​cause mortality) [7, 34, 35].
However, its independent value is debated, partially due to the
lack of a standardized quantification method (a cut-​off value of 4
SD and 5 SD above the mean signal of remote myocardium yields
the closest approximation to histopathology) [36].
Since LGE depends on focal differences between segments, dif-
fuse fibrosis may not be recognized. A per pixel analysis of T1
relaxation times—​T1 mapping—​is promising. By comparing pre-​
and post-​contrast images it allows the estimation of the extracel-
lular volume, reflecting interstitial fibrosis [37].
Post-​contrast T1 relaxation times in HCM are associated with
non-​ sustained ventricular tachycardia [38] and may improve
phenocopies identification (new automated algorithms such as
radiomic analysis) [39]. Its overall diagnostic and independent
prognostic value needs validation.
Fig. 42.4  Systolic function in HCM. Top: Normal LVEF and low indexed stroke volume; Bottom: Low systolic myocardial velocities (TDI) and abnormal
GLS (2D-​STE).
GLS = global longitudinal strain; LVEF = left ventricular ejection fraction; STE = speckle-​tracking echocardiography; TDI = tissue Doppler imaging.
CCT also allows the visualization of fibrosis using a similar
technique to LGE-​CMR. The iodinated agent accumulates in
areas without regular myocyte structure, leading to higher density
levels in fibrotic areas [40], depicted in images acquired at 7 min-
utes in retrospective ECG-​synchronized helical mode. Iodinated
contrast, radiation, and inferior tissue characterization capabil-
ities limit its clinical usefulness.
Echocardiography and CNI only provide indirect information
on tissue characterization [41].
Assessment of myocardial function
LV systolic function
Echocardiography is the first-​line technique. HCM patients often
have normal LV ejection fraction (EF) but reduced indexed stroke
volume due to small LV volumes (E Fig. 42.4).
Despite the preserved left ventricular ejection fraction (LVEF),
tissue Doppler imaging (TDI) and 2D-​speckle-​tracking echo-
cardiography (2D-​STE) show that systolic function is often ab-
normal in HCM.

TDI annular and regional LV systolic velocities (s’) are low and
an s′ <4 cm/​s at the lateral annulus predicts adverse prognosis [42].
2D-​STE allows the assessment of longitudinal, circumferential,
and radial function, as well as of rotational and twist mechanics.
HCM patients often have abnormal global longitudinal strain
(GLS), reflecting subendocardial longitudinal fibres involvement,
and several studies have shown that its magnitude has prognostic
impact (HF, SCD, and all-​cause mortality). The cut-​off values for
ominous prognosis are variable, as GLS values below 15%, 13%,
10%, and 7% have been proposed [43–​45].
Other studies have correlated the magnitude of GLS with the
presence and extent of CMR-​LGE [41, 46].
Mechanical dispersion, a temporal index of intra LV
dyssynchrony, has also been described as a marker of ventricular
arrhythmias in HCM [47].
Circumferential strain, dependent on mid-​wall fibres, may be
increased (contributing to the preserved LVEF), normal, or de-
creased in HCM patients, and is an important research topic in
HCM patients with preserved LVEF [10].
Rotational mechanics is also disturbed. Though the extent and
amplitude of rotation and twisting is usually normal, its direction
Fig. 42.5  Diastolic function and LV filling pressures in HCM. E/​e’18; LAVI 48 ml/​m2; peak velocity of tricuspid regurgitation 3.82 m/​s reflecting high LV filling
pressures. Additionally, please note the triphasic transmitral inflow pattern.
LAVI = left atrial indexed volume.
As ses sm en t of m yo ca rdia l f un c t i on 635
may be abnormal and LV twist time prolonged. However, because
of their suboptimal feasibility, this assessment is still a research
tool [48].
3D-​echo and 3D-​STE are also promising in the assessment of
systolic function in HCM [10].
CMR provides a reliable and reproducible quantification of
LVEF and may be useful when image quality is suboptimal with
echo [15]. As described (see tissue characterization section), the
extent of LGE has been related to progressive LV dilatation and
LV systolic dysfunction in HCM [36].
CCT and radionuclide angiography [49] may be useful, but
their use is limited by potential side effects.
LV diastolic function
Diastolic dysfunction (DD) is an important determinant of symp-
toms and outcomes in HCM (E Fig. 42.5). Though DD is al-
most universally present, not all HCM patients have increased LV
filling pressures (LVFP). TTE is the technique of choice [50–​52],
but isolated echo-​Doppler parameters show only weak correl-
ations with LVFP in HCM. Remarkably, the transmitral inflow
profile should not be used alone to quantify LVFP in HCM [50,
636 CHAPTER 42   Hy pe rt roph ic cardiomyopathy
51], except in the presence of a restrictive pattern, still useful to
predict high LVFP.
LA dilation and pulmonary hypertension can reflect increased
LVFP. 2D-​echo LA volume indexed to body surface area (LAVI,
ml/​m2, in the four-​chamber view) is mandatory. It predicts ex-
ercise capacity and if ≥34 ml/​m2 it is associated with increased
LVFP, HF, AF, and increased mortality [53].
Additionally, a ≥30 ms difference between the duration of atrial
reverse wave of the pulmonary venous flow (Ar) and the duration
of transmitral A wave (Ar-​A) is associated with elevated LVFP in
HCM, but its use is limited by low feasibility in TTE. With the use
of LAVI, flow and volumetric methods of assessment of LA func-
tion [54] have lost impact. However, LA deformation emerges
as an early and sensitive marker of DD. 2D-​STE shows that LA
longitudinal strain is reduced in the three atrial phases [54]. The
most important parameter seems to be the LA peak strain during
LV systole (reservoir phase) [54] as it correlates with functional
impairment and HF and predicts the development of AF inde-
pendently of LA dimensions [54–​58].
HCM patients have low early diastolic myocardial velocities (e’)
by TDI [58]. The role of E/​e’ in the assessment of LVFP in HCM
is controversial, as the correlations between this ratio and LVFP
were not consistently confirmed [51, 52].
In accordance with the recommendations [59] a four criteria
approach to assess high LVFP in HCM is suggested: E/​e′ (average
septal-​lateral)> 14, LAVI ≥34 ml/​m2, CW peak velocity of tri-
cuspid regurgitation >2.8 m/​sec and Ar-​A ≥30 ms. In the pres-
ence of severe MR, only the last two are valid. When the total
available variables are three or four, LA pressure is elevated (grade
II DD) if more than half meet the cut-​offs. When less than 50%
of the variables meet the cut-​off values, LA pressure is normal
(grade I DD). In case of 50% discordance with two or four avail-
able parameters, LVFP estimation is inconclusive. Finally, the es-
timation of LVFP is not recommended if only one parameter is
available. In the presence of a restrictive pattern and reduced e’
(septal <7 cm/​sec, lateral <10 cm/​sec) grade III DD is present.
The role of 2D-​STE in the assessment of diastole is technically
challenging, with complex measurements, variable feasibility, and
difficult interpretation, not ready for clinical use. Some studies
have shown that HCM patients have abnormal longitudinal early
diastolic strain rate at rest [60–​63] and exercise, with limited
strain adaptability, as well as delayed and prolonged LV untwist,
extending beyond the initial 25% of diastole [48] and low apical
reverse rotation [62].
The role of other imaging techniques (CMR, CCT, and CNI
[49]) is nowadays limited in this setting.
Assessment of myocardial ischaemia
Microvascular ischaemia is common in HCM and explains symp-
toms and prognosis [2, 64] but its assessment is difficult and
seldom performed.
Microvascular dysfunction-​related decreased coronary flow re-
serve (CFR) is an important mechanism. CFR, assessed by TTE with
pulsed-​wave (PW) Doppler sampling of the left anterior descending
artery during vasodilator stress, is often decreased [64], and when
abnormal (<2) it is a strong independent predictor of outcomes [64].
Stress echo with dual imaging (wall motion and CFR) distin-
guishes microvascular dysfunction (low CFR, no wall motion ab-
normalities) from epicardial coronary artery disease (CAD) (low
CFR and wall motion abnormalities).
Vasodilator stress CMR is also useful (different ischaemic
patterns) in the differential diagnosis between micro and
macrovascular ischaemia.
Though not a first-​line test, SPECT often shows reversible and
fixed defects (ischaemia and scar) in the absence of epicardial
CAD [65]. However, careful interpretation is needed, as LVH seg-
ments appear much brighter (higher uptake and counts), leading
to false-​positive results [2, 7, 49].
Positron emission tomography (PET) imaging quantifies abso-
lute myocardial blood flow in HCM and is the most reliable non-
invasive quantitative method for assessing myocardial ischaemia
in this disease. PET generalization is limited by the cost of cam-
eras and radiotracers [66].
Anatomical imaging of the coronary arteries
Invasive coronary angiography is the most often used method but
the role of CCT is increasing. In the presence of chest pain, CCT
may detect obstructive CAD [67] and/​or myocardial bridging, very
common in HCM (41%). Though myocardial bridging is often
asymptomatic, ischaemic, and arrhythmic events have been de-
scribed in patients with long and deep intramyocardial courses [68].
Studies on the assessment of the origin and proximal segments
of epicardial coronary arteries in HCM with CMR are lacking.
Differential diagnosis
Several diseases show the ‘LVH phenotype’. Their correct diag-
nosis is important, since specific treatment may impact outcomes.
Cardiac amyloidosis (CA)
Amyloid heart disease can result from transthyretin (TTR) (wild
type and familial) or from amyloid light-​chain (AL) amyloidosis,
often associated to plasma cell dyscrasias (E Fig. 42.6) [7]‌.
The discrepancy between ECG (low voltage) and echo (LVH)
is a key diagnostic aspect. Other features include moderate con-
centric LVH, RV free wall hypertrophy, ‘sparkling’ myocardial
texture, valvular and interatrial septum thickening, and mild
pericardial effusion (asymmetric septal hypertrophy [ASH] with
LVOTO may also be present) [69]. DD, often with increased
LVFP, is a classical feature, whereas depressed LVEF is seen in
advanced disease. TDI shows low systolic and diastolic velocities.
2D-​STE is useful, and both relative apical sparing [70] and the
relation LVEF/​GLS are accurate [71].
CMR shows a highly specific pattern of global or segmental
subendocardial LGE, with similar myocardial and blood
pool gadolinium kinetic (similar T1) and with increased T1
mapping [72].
 Di fferen tia l diag n o si s 637

(a) (d)

(e)
(b)

(c) (f)

Fig. 42.6  Example of cardiac amyloidosis, with increased left and right ventricular wall thickness, ‘sparkling’ myocardial texture, mild pericardial effusion (a, b, c)
and evidence of diastolic dysfunction, with pseudonormalization pattern of the PWD mitral inflow and high LV filling pressures (d). Mitral annulus TDI (e) shows
very low velocities. Apical sparing in 2D-​STE (f) is also typical of this disease.
PWD = pulsed-​wave Doppler; STE = speckle-​tracking echocardiography; TDI = tissue Doppler imaging.
638 CHAPTER 42   Hy pe rt roph ic cardiomyopathy
In TTR amyloidosis, 99mTc-​DPD scintigraphy is inexpensive
and useful (TTR is avid for DPD, in opposition to sarcomeric
HCM) [10, 11].
Hypertensive heart disease
HT usually shows concentric or mildly asymmetric hypertrophy,
sometimes with a sigmoid IVS, and maximal WT rarely exceeds
15 mm (except in Black people, in renal failure, and exceptionally
in elderly HT patients). An IVS/​PW thickness ratio >1.5, or an
unusual distribution of LVH suggest HCM [73].
Though LVOTO is suggestive of HCM, it may also be seen in
elderly HT with sigmoid IVS. Associated structural abnormalities
of the mitral valve favour HCM.
TDI and 2D-​ STE may help, as HT patients have higher
homogeneity of velocities and strain and less asynchrony [11].
Moreover, HCM patients have more severe 2D-​STE longitudinal
systolic dysfunction (an LS of <10% suggests HCM) [73].
LGE-​CMR is less frequently found in HT patients and when
present, though also intramural, its distribution does not follow
the typical HCM patterns (hypertrophic areas and RVIP) [74].
Athlete’s heart
About 2–​4% of White and 12–​18% of Black male athletes [75,
76] have left ventricular wall thickness (LVWT) between 13 and
15 mm grey zone LVH. Several criteria are used to differentiate
HCM from an athlete’s heart [77]. Female gender, bizarre ECG
patterns, family history of HCM, a percentage of predicted max-
imal oxygen uptake (VO2 max) <110%, a non-​dilated LV (end-​
diastolic diameter <54 mm) [78], atypical LVH distribution, and
abnormal diastolic function favour HCM.
Other parameters include TDI data (low mitral annulus veloci-
ties, averaged from four sites: s´<9 cm/​s, e´<7 cm/​s; e´/​a´<1 in
any site; e’ septal <10; e’ lateral <12 cm/​s) suggest HCM [79–​81].
With 2D-​STE, a very abnormal GLS, a peak regional LS ≤15%,
and LV untwist extending beyond 25% of diastole also point to
HCM [82].
CMR allows the correct assessment of WT and fibrosis evalu-
ation. As a general rule, in opposition to HCM patients, athletes
neither have LGE [83] nor diffuse fibrosis (normal native T1 and
extracellular volume) [84]. Ultimately, deconditioning leading to
regression of hypertrophy in athletes may clarify the diagnosis.
Other causes of LVH
TTE is essential to exclude other causes of LVH, such as aortic
stenosis and RV hypertrophy due to pulmonary stenosis or pul-
monary hypertension.
Many inherited metabolic diseases (e.g. Anderson–​ Fabry,
Danon disease, and mutations in the PRKAG2 gene) are associ-
ated with LVH. In these conditions, and in others (Friedreich´s
ataxia, mitochondrial diseases, malformative syndromes such as
Noonan or LEOPARD), attention should be given to clinical and
ECG signs.
A reduced LVEF in a patient with the LVH phenotype is an
important imaging red-​flag suggestive of non-​sarcomeric HCM
[85], but other specific signs also point to specific conditions
(biventricular hypertrophy in glycogen storage diseases, con-
comitant right ventricular outflow tract (RVOT) and LVOTO
with biventricular hypertrophy in Noonan syndrome, LGE-​CMR
in the inferolateral wall in Fabry disease).
Family screening/​preclinical diagnosis
TTE is the first-​line technique for clinical screening in first-​
degree relatives. It should be performed at any age in the pres-
ence of symptoms. In asymptomatic relatives, yearly screening is
recommended between 10 and 21 years old; in adults, screening
should be performed every 5 years, as late-​onset hypertrophy can
occur [11]. Screening in preadolescents should be considered be-
fore engagement in intense physical activity.
A lower LVH cut-​off—​13 mm—​is diagnostic of HCM in first-​
degree relatives [12].
In the absence of LVH, small studies have observed functional
and morphological abnormalities in genotype positive (G+) indi-
viduals; however, none is consistently present and none has reliably
been linked with the development of LVH or with outcome [10, 11].
Some relatives show minor mitral valve abnormalities (higher
leaflet length, dysplasia, prolapse, incomplete SAM, chordal elong-
ation, laxity, hypermobility, anterior displacement of papillary
muscle [PM]). Several TDI studies also have shown the presence
of reduced myocardial velocities before the onset of LVH. This
impaired regional longitudinal myocardial function, as well as ab-
normal apical rotation, were later described with 2D-​STE [10, 11].
These abnormalities do not establish the diagnosis of HCM but
identify gene carriers, allowing a closer follow-​up. Limitations in-
clude the absence of large studies confirming cut-​off values and
the low specificity in older individuals, who may present low myo-
cardial velocities due to ageing or coexisting diseases. Moreover,
their predictive value is unknown: given the incomplete disease
penetrance, subjects G+ with these abnormal findings may never
develop the disease and their absence does not exclude the later
development of LVH phenotype.
CMR should be considered in the presence of borderline,
doubtful or suboptimal echo data, in high-​risk families in whom
the diagnosis of HCM would have direct implications on manage-
ment (e.g. implantable cardioverter-​defibrillator [ICD] implant-
ation, exclusion from competitive sports) [11] or when the ECG
is abnormal and the echocardiogram is normal.
CMR may also detect a number of morphologic abnormalities
in G+ individuals without LVH, such as myocardial crypts or
false tendons parallel to the IVS. Again, none of them is specific
of HCM [10, 11].
Imaging in HCM clinical profiles
SCD profile
In the US stratification model [2]‌, massive LVH (>30 mm) by
echo is a major SCD risk factor. Echo is also useful in detection
of non-​conventional risk factors, such as LV aneurysms, LVOTO,

(a)
Fig. 42.7  HCM risk-​SCD calculator. Maximum LV wall thickness (b), left atrial anterior-​posterior diameter (c), and maximal LV outflow tract gradient (d), all
derived from echo, are included in the ESC-​SCD risk prediction model (a).
ESC =European Society of Cardiology; SCD = sudden cardiac death.
LA dilation, LV systolic dysfunction, and low TDI velocities, that
may help decision-​making (E Fig. 42.7).
In the European SCD risk prediction model [7]‌, three out of
seven risk factors are derived from echocardiography (maximal
WT, LA diameter, maximal LVOT gradient) and these data are
mandatory in echo reports.
When echo is doubtful, CMR should be used. It allows the cor-
rect assessment of WT, the detection of apical aneurysms and
provides unique information on the extension of LGE. LGE-​CMR
may be useful in intermediate risk patients, in whom both scores
perform less well. In these patients, a LGE >15% powers the indi-
cation for ICD [86].
HF profile and the natural history of HCM
A broad phenotypic evaluation of HCM patients provides a
simple framework for clinical staging [87]:
1. Non-​hypertrophic HCM (mild morphological and functional
abnormalities in the absence of hypertrophy—​see preclinical
diagnosis section);
2. Classical phenotype: typical LVH phenotype, LVEF normal/​
supernormal, LGE absent or mild;
3. Adverse remodelling: preserved LVEF but near the lower limit
of normal, moderate LGE;
4. Overt dysfunction (‘burn out’ or ‘endstage’): reduced LVEF,
extensive fibrosis. In this stage, two phenotypes exist: the
I m ag i n g i n ther a peu ti c pro c e dure s 639
(b)
(c)
(d)
restrictive type (more common, residual LVH, small LV, severe
DD, mildly or moderated depressed LVEF); and the dilated
type (more rare, dilated LV, no LVH, severely depressed LVEF).
AF/​stroke profile
AF affects about 20% of HCM patients. The assessment of LA
remodelling (dilation and dysfunction) is essential and echo re-
mains the first-​line method. While the clinical importance of
LAVI is well established, the clinical impact LA strain remains
to be elucidated (see diastolic function section). Patients with di-
lated atria should be closely evaluated (dynamic 24 h ECG every
6 months) to detect AF and initiate treatment, including oral
anticoagulation [2, 7, 10, 11].
Imaging in therapeutic procedures
Medical treatment
Echocardiography is the first choice technique in the assessment
of efficacy of medical treatment in HCM patients [88, 89] and in
the evaluation of the effects of experimental agents on morph-
ology and function (animal and clinical studies) (E Fig. 42.3
bottom, Fig. 42.8) [90].
In case of suboptimal echo images or to evaluate treatment
effects on myocardial structure or tissue characteristics, CMR
is indicated. CMR is superior to 2D-​echo in the reproducible
640 CHAPTER 42   Hy pe rt roph ic cardiomyopathy

(a) (b) (c)

(d) (e) (f)

Fig. 42.8  Alcohol septal ablation and surgical myectomy. (a) A systolic cine three-​chamber view with hypertrophic septum and SAM with secondary MV
regurgitation (yellow arrow); (b) late gadolinium enhanced image 1 month after alcohol septal ablation of same patient, with hyperenhanced transmural
infarction and microvascular injury in infarct core (dark), with corresponding systolic cine image in (c) demonstrating reduction in septal mass (asterisk) and
absence of MV regurgitation. (d) Systolic cine three-​chamber view with hypertrophic septum and SAM with secondary MV regurgitation (yellow arrow); (e)
late gadolinium enhanced image 1 month after surgical myectomy showing no new infarction or fibrosis, with corresponding systolic cine image in panel F
demonstrating reduction in septal mass (asterisk) and absence of MV regurgitation.
SAM = systolic anterior motion; MV = mitral valve.
Images courtesy of Prof A.C. van Rossum, Amsterdam University Medical Centers (NL).

quantification of LV volumes/​mass [91]. Several ongoing trials
(for example on the effect of medical treatment on LV mass, focal
and diffuse fibrosis) use CMR as the imaging technique [92]. CCT
and CNI have currently limited applicability in this setting.
Imaging also plays an important role in the selection of the type
of invasive septal reduction therapy (surgical myectomy versus al-
cohol septal ablation, ASA). Echo and CMR are mandatory in this
setting as they provide unique detailed anatomical and functional
information on the site and determinants of intraventricular
obstruction, as well of the mechanism of MR. Accordingly, sur-
gery should be the selected technique in the presence of mid-​
ventricular obstruction, when papillary muscles and/​or chordae
play a major role in the pathophysiology of obstruction and when
severe MR is caused by organic valve disease.
Surgical myectomy
Intraoperative transoesophageal echocardiography (TEE) during
myectomy demonstrates the mechanism of LVOTO, its rela-
tion to the mitral valve apparatus, and the role of the papillary
muscles in obstruction. TEE is useful in the assessment of the
amount—​extension, width, and depth—​of myocardium to be re-
moved (more proximal than with ASA, and, in case of mid-​cavity
obstruction, extended distally). TEE is useful during and shortly
after weaning from cardiopulmonary bypass, before chest closure,
showing immediate results/​complications [93, 94]. Additionally,
mitral valve surgery such as repair or papillary muscle realign-
ment can be visualized [93, 94].
Preoperative assessment is best performed with CMR [92]. It
provides detailed anatomical information, especially of all elem-
ents of the mitral valve apparatus, WT, and their relation to the
LVOTO. CCT is useful in case of contraindications for CMR.
Alcohol septal ablation
In percutaneous transluminal septal myocardial ablation,
intraprocedural echocardiography (TTE or transoesophageal
echocardiography [TOE]) is indispensable. Intracoronary myo-
cardial contrast echocardiography (MCE) allows the visualiza-
tion of the area of perfusion of the selected septal perforator
branch, determining if it supplies the ‘target site’ of hypertrophy,
without opacifying ‘non-​target’ undesired remote territories.
MCE increases the likelihood of success, reduces fluoroscopy
time, the amount of ethanol used, the infarct size, and the inci-
dence of atrioventricular block and remote myocardial infarc-
tion [95, 96].

After ASA, CMR-​LGE is the gold standard to visualize the
area and transmurality of the infarction. Cine CMR shows
the long-​term effects of ASA (LV remodelling and gradient
reduction) [97].
Preprocedural CCT may evaluate the anatomical distribution
of the septal arteries. After an unsuccessful ASA, CT can evaluate
the patency of the septal arteries and the chances of success of a
second procedure.
Dual-​chamber  pacing
The role of dual-​chamber pacing in gradient reduction in HCM
is controversial. It is thought to decrease LVOT gradient by two
mechanisms: (i) RV apex pacing results in paradoxical movement
of the IVS during systole, increasing LVOT dimensions; (ii) AV-​
delay is optimized to allow maximal diastolic filling, according to
the PW transmitral and/​or aortic flow [98]. With the increasing
use of MRI safe pacemaker systems, CMR may have the potential
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septal ablation for symptomatic HOCM: 7 years of experience. Eur J
Echocardiogr 2004; 5: 347–​55.
96. Flores-​Ramirez R, Lakkis NM, Middleton KJ,. Echocardiographic
insights into the mechanisms of relief of left ventricular outflow tract
obstruction after nonsurgical septal reduction therapy in patients
with HOCM. J Am Coll Cardiol 2001; 37: 208–​14.
97. van Dockum WG, Cate ten FJ, Berg ten JM, et al. Myocardial in-
farction after percutaneous transluminal septal myocardial ablation
in HOCM: evaluation by contrast-​enhanced MRI. J Am Coll Cardiol
2004; 43: 27–​34.
98. Posma JL, Blanksma PK, Van Der Wall EE, et al. Effects of permanent
dual chamber pacing on myocardial perfusion in symptomatic
HCM. Heart 1996; 76: 358–​62.

Contents
Introduction  645
Amyloidosis 645
Electrocardiography  646
Echocardiography  646
Cardiovascular magnetic resonance  648
Cardiac nuclear imaging  649
Anderson-Fabry disease 651
Electrocardiography  652
Echocardiography  652
Cardiovascular magnetic resonance  653
Nuclear cardiac imaging  654
Other infiltrative cardiomyopathies  655
Sarcoidosis  655
Myocardial iron loading  656
Acquisition technique 656
Conclusions and future perspectives  657
CHAPTER 43
Infiltrative cardiomyopathy
Massimo Lombardi, Silvia Pica,
Antonella Camporeale, Alessia Gimelli,
and Dudley J. Pennell
Introduction
Infiltrative cardiomyopathies can result from familial/​genetic and non-​familial/​non-​
genetic (acquired) causes, exhibiting substantial differences in pathogenesis, clinical
manifestations, and outcomes. Myocytes and extracellular matrix show alterations in
structure (hypertrophy, atrophy, apoptosis) and composition (infiltrate, oedema, fibrosis),
adapting to infiltration with complex metabolic switches and leading to morphological
and functional cardiac consequences. These changes can now be imaged non-​invasively
by cardiovascular magnetic resonance (CMR) and molecular imaging, which can be used
for differential diagnosis, identification of the type of infiltration and to investigate path-
ways leading from early infiltration to irreversible tissue damage. Compared to histology,
these techniques allow a non-​invasive whole-​heart study, are quantitative and can be re-
peated over time to follow changes, assess disease response to therapy and guiding drug
development.
The prevalent forms of infiltrative cardiomyopathies are amyloid, Anderson–​Fabry;
the other, less common forms are the glycogen storage diseases and cardiomyopathies
due to sarcoidosis and iron overload.
Amyloidosis
Amyloidosis is a systemic disease caused by aggregation of misfolded autologous pro-
teins and deposition in the extracellular space. Its typical ultrastructural appearance is
a fibrillar deposition of β-​pleated sheet structure with the principal precursor giving the
name to amyloid type; to date, more than 30 amyloid proteins have been identified [1,
2]. The deposition can involve several organs and tissues, causing structural disruption
and dysfunction. In the heart, it causes a wide spectrum of morphological presentations
as well as diastolic and systolic dysfunction, culminating in end-​stage heart failure (HF)
[3, 4]. Histopathologic characteristic of cardiac amyloid (CA) is diffuse infiltration of the
subendocardium, sometimes patchy or transmural pattern with left ventricular (LV) and
right ventricular (RV) involvement [5]‌. Amyloid fibrils bind Congo red stain, yielding
the pathognomonic apple-​green birefringence under cross-​polarized light microscopy,
gold standard for amyloid deposits. Furthermore, immunohistochemistry can identify
the specific fibril type (see E Fig. 43.1).
Diagnosis of systemic amyloidosis is frequently delayed due to the wide range of
clinical presentations. Manifestations include nephrotic syndrome, autonomic neur-
opathy, soft-​tissue/​organ infiltrations, bleeding, malnutrition. Initial presentation
may be cardiac, with fatigue and progressive HF. Pleural, pericardial effusions, and
646 CHAPTER 43   In filt rative cardiomyopat hy

(a) (b)

(c) (d) (e)

Fig. 43.1  (a) Histology macroscopic cross-​section at mid-​ventricular level of a heart explanted from cardiac amyloidosis. Mallory trichrome staining showing
in grey/​pale blue amyloid deposits replacing much of the myocardium. (b) Congo red stain and cross-​polarized microscopy showing apple-​green birefringence.
(c–​e) Specific immunohistochemistry for amyloid subtype, from left to right showing transthyretin, kappa, and lambda AL amyloidosis.
Reproduced with permission from Leone O, Rapezzi C, et al. Policlinico S. Orsola-​Malpighi, Bologna, Italy.

atrial arrhythmias are often seen. Syncope and cerebral strokes
may be an early feature. Cardiac involvement is the leading
cause of morbidity and mortality, regardless of the underlying
pathogenesis.
Amyloid light-​chain (AL) is the most frequent type of amyloid-
osis and is caused by a small plasma cell clone that produces tissue
deposition of fibrils composed of monoclonal immunoglobulin
light lambda or kappa chains. The incidence is approximately 9
per million person-​years. Cardiac involvement occurs in half of
cases and sometimes is the only presenting feature; patients may
be rapidly progressive with a survival of 6–​12 months, with death
usually due to electromechanical dissociation or end-​stage HF.
Cardiac dysfunction results from extracellular infiltration, with
additional evidence for cardiotoxic effect by prefibrillar light-​
chain aggregates [6]‌.
Mutations in several genes, such as transthyretin (ATTR), fi-
brinogen, apolipoprotein A can also be responsible for hereditary
amyloidosis, but the most common is variant ATTR. The TTR
gene is synthesized in the liver, and the prevalent mutation is
Val-​122-​Ile, particularly diffuse in African Americans. Because
of the late onset of manifestation, the prevalence of disease is
underdiagnosed. Cardiac involvement is rare in variant Val-​30-​
Met, the commonest cause of familial amyloid polyneuropathy,
while it is early (fourth decade) in Thr-​60-​Ala. Prognosis of
cardiac ATTR is better than AL, with survival of ~6 years from
diagnosis.
Wild-​type ATTR is a predominantly cardiac disease, associ-
ated with carpal tunnel syndrome. It has a male predominance
and is commonly referred to as senile systemic amyloidosis (SSA)
for its late onset (seventh decade); survival is about 7 years from
presentation.
Systemic AA amyloidosis, with amyloid fibrils derived from
acute-​phase reactant serum amyloid A protein, involves the heart
in 2% of cases. Due to better treatment of rheumatological dis-
orders, its incidence is in decline [7]‌.
Electrocardiography
Ventricular wall thickening in CA is due to myocardial infil-
tration rather than hypertrophy, therefore electrocardio­ graph
(ECG) voltages decrease as disease progresses. Low QRS voltage
(limb leads <5 mm) is often associated with poor R wave progres-
sion in chest leads, repolarization abnormalities, AV conduction
delays, atrial fibrillation. The combination of low voltages with LV
thickening is highly suggestive for CA (see E Fig. 43.2).
Echocardiography
Echocardiography is commonly used for assessment of CA, pro-
viding high level of suspicion, especially in advanced disease. CA
 A m y l oi d o si s 647

Fig. 43.2  Twelve-​lead

electrocardiogram of a patient with
cardiac amyloidosis, showing sinus
rhythm and small QRS voltages, poor
R wave progression in the chest leads,
diffuse repolarization abnormalities.

is characterized by increased LV wall thickness, small chamber
volume, valve thickening, and atrial enlargement; diastolic dys-
function is an early abnormality often occurring before symp-
toms develop (see E Fig. 43.3, a–​b).
Although overall LV ejection fraction is preserved until the
end-​stage disease, abnormal systolic function is demonstrable
earlier with reduced longitudinal function, followed by radial
dysfunction with no cavity dilatation, causing stroke volume im-
pairment. Two-​dimensional speckle tracking technique shows re-
duced longitudinal strain with relative apical preservation, which
can be an early clue to CA, distinguishing it from other hyper-
trophic substrates prior to evident morphological changes, with
prognostic role (see E Fig. 43.3e–​g). Other echocardiographic
features result from diffuse infiltration: right ventricle thickening
with diastolic/​systolic dysfunction, interatrial septum thickening,
atrial dysfunction by speckle tracking strain. Pericardial effu-
sion is likely present especially in advanced disease. Myocardial
granular sparkling appearance, a traditional common finding, has
shown low diagnostic accuracy with new image processing tech-
niques and its utility is considered limited [8, 9].

(d)
(b) (f)

(a) (c) (e) (g)

Fig. 43.3  2-​D Echocardiogram in a patient with cardiac amyloidosis. (a) Parasternal long axis view showing LV hypertrophy with small cavity size, RV
hypertrophy, left atrial dilatation, and mild pericardial effusion. (b) Pulsed-​wave Doppler of mitral inflow showing restrictive pattern and very limited atrial
contribution to LV diastolic filling. (c) Pulmonary vein flow showing a very prominent diastolic (D) wave. (d) Tissue Doppler imaging (TDI) pattern with low
systolic (s’) and diastolic (e’, a’) myocardial velocities. E/​e’ ratio is abnormally increased. (e–​g) Significantly reduced LV basal and mid-​longitudinal strain, with
relatively preserved apex.
Reproduced with permission from Mussinelli R, Perlini S. Amyloidosis Research and Treatment Center, Foundation IRCCS Policlinico San Matteo and Department of Molecular
Medicine University of Pavia, Pavia, Italy.
648 CHAPTER 43   In filt rative cardiomyopat hy
Cardiac involvement is particularly prominent in ATTR, while
AL amyloidosis can present with subtler morphological changes,
despite worst clinical course. ATTR shows severe thickening,
prevalent asymmetric septal hypertrophy (80% of cases), larger
atria, smaller cavity volumes, and more severe systolic dysfunc-
tion. AL frequently shows moderate concentric hypertrophy (68%
of cases), and a non-​negligible incidence of non-​hypertrophied
LV, with less severe systolic dysfunction [3, 4].
Despite the several parameters available, echocardiography
alone is often unable to distinguish the different pathologies
that result in increased wall thickness and diastolic dysfunc-
tion. Therefore, a comprehensive clinical and multimodality
imaging assessment is recommended to increase the diagnostic
accuracy.
Cardiovascular magnetic resonance
CMR is becoming a standard of care to diagnose and track
changes in CA. Beyond accurate morpho-​functional evaluation,
its whole-​heart, non-​invasive tissue characterization gives unique
information on tissue composition.
Two main sequences are used: late gadolinium enhancement
(LGE) and myocardial relaxation mapping. Chelated gado-
linium is an extracellular contrast medium that accumulates
in tissues with increased extracellular space. Focal pathologies
can be easily identified, applying the inversion recovery prin-
ciple to T1-​weighted imaging, with an adequate inversion time
to null normal myocardium. The most relevant and pathogno-
monic feature of CA is the LGE appearance, where blood pool
is dark. This is a consequence of infiltration, with extracellular
myocardial and plasma volume that tend to equalize, nulling
approximately at the same time. LGE image acquisition and in-
terpretation with routine magnitude reconstruction technique
can therefore be difficult, especially when the whole heart is af-
fected, with almost no normal myocardium to null. Phase sensi-
tive inversion recovery (PSIR) technique is very useful: it is less
sensitive to operator choice of null point and renders signal in-
tensity truly T1-​weighted. Tissue with the longest T1 (least gado-
linium) is nulled and normal subjects have nulled myocardium,
advanced amyloid have bright transmural myocardium with
nulled blood, intermediate cases have blood and myocardium
nulling concurrently, with bright subendocardium, especially in
basal segments.
Typical LGE patterns, irrespective to amyloid type, are: absent,
subendocardial, and transmural, representing a continuum in the
natural history of cardiac infiltration [10].
Myocardial tissue characterization by T1 mapping sequences
before contrast administration is able to measure intrinsic signal
from the myocardium due to its composition (native myocardial
T1); post-​contrast T1 mapping images can be used to calculate
myocardial extracellular volume (ECV).
Both native T1 and ECV are diffusely elevated in CA, reflecting
the extent of myocardial infiltration; native T1 values can be as
high as 6 SD above normal and ECV is often higher than 50%; this
elevation is higher than any other disease, being almost definitely
diagnostic versus hypertrophic cardiomyopathy (HCM), Fabry
disease, hypertensive heart disease or other hypertrophic pheno-
types such as aortic stenosis (see E Fig. 43.4).
Native T1 and ECV have been extensively validated in CA as
surrogate markers of infiltration. They showed good diagnostic
accuracy and correlation with disease burden [11, 12]. In both
amyloid types, T1 tracks markers of systolic, diastolic function,
and mass, being elevated before the onset of hypertrophy, pres-
ence of LGE, or elevation in blood biomarkers.
Increasing LGE extension from none, subendocardial to trans-
mural is associated with worsening native T1 and ECV, reflecting
increasing amyloid deposition [10] (see E Fig. 43.5a–​i).
Transmural LGE carries the most adverse prognosis; it is an in-
dependent marker of all-​cause mortality, regardless of treatment.
Increasing LGE extension is associated with worsening clinical,
biohumoural, structural, and functional parameters. Both native
T1 and ECV are also prognostic, predicting adverse outcome in
both AL and TTR [13, 14].
Besides morphology, AL and ATTR also differ for tissue charac-
terization. With similar LGE extension, native T1 may be slightly
higher in AL, ECV instead can be higher in TTR. It is plausible
that higher ECV in TTR reflects increased amyloid burden and
cell volume suggesting a compensatory myocyte hypertrophy ab-
sent in AL or balanced by myocyte loss through a toxic effect.
Intriguingly, the greater elevation of native T1 with a smaller
amyloid burden in AL points to an additional pathologic process,
likely myocardial oedema due to rapid deposition or inflamma-
tion by light-​chain toxicity [6]‌.
Recently, T2 mapping sequences, able to quantify myocar-
dial oedema in different diseases, identified oedema in CA, with
histological validation. Patients with untreated AL amyloid had
the greatest increase in T2 (see E Fig. 43.5l–​n).
Myocardial oedema showed prognostic value in AL even when
adjusted for ECV and NT-​proBNP, but not in ATTR, providing an
additional marker for risk stratification [15].
CMR with tissue characterization adds value to the diagnostic
process of CA.
In patients with low/​intermediate pretest probability, LGE and
T1 mapping can help differential diagnosis and management,
increasing the identification of underdiagnosed ATTR amyloid,
particularly wild type [16].
Early diagnosis is particularly crucial in AL because of the
rapid clinical deterioration when the heart is involved, with spe-
cific therapies being very different. Significant changes in CMR
tissue characterization may be observed even when conventional
Mayo classification (biohumoural and echo-​based) does not sug-
gest cardiac involvement.
When initial tests are suggestive of CA, besides a diagnostic
confirmation, CMR can give information about disease burden,
track changes during follow-​up and potentially monitor the effect
of therapies [17].
Over the last decade, chemotherapy regimens for AL amyloid-
osis have markedly improved and the use of autologous stem cell
transplantation refined, so that many patients can now achieve
 A m y l oi d o si s 649

(a) (b) (c)

(d) (e) (f)

Fig. 43.4  CMR native myocardial T1 by ShMOLLI T1 maps in different cardiac disease. (a) ATTR amyloid with patchy native T1 elevation and severe LV
hypertrophy as compared with (b). AL amyloid showing extensive increased T1 and mild hypertrophy. (c) Sarcomeric hypertrophic cardiomyopathy (HCM)
with global mild T1 elevation except for high T1 in the anteroseptum. (d) Fabry disease shows diffuse low T1 and pseudonormal T1 in the inferolateral wall.
(e) Hypertensive heart disease with high-​normal T1 and mild LV hypertrophy. (f) Healthy subject with normal T1.

good haematological response. Several promising therapies are in
development also for ATTR, to inhibit amyloidogenic misfolding
or TTR production. Furthermore, immunotherapies are under
investigation to target and reduce amyloid deposits directly. CA,
however, is still the most important driver of outcome that re-
mains poor, reflecting late diagnosis and need for less toxic and
more rapidly acting therapies.
CMR with T1 mapping and ECV, able to measure global car-
diac involvement as a continuum, is a promising surrogate end-​
point for drug development, as already demonstrated for other
organs and under investigation in cardiac studies [17].
Cardiac nuclear imaging
Single-​photon emission computed tomography (SPECT) had a
tremendous impact on diagnosing CA. It is the only non-​invasive
modality to definitively differentiate AL from ATTR, with intense
uptake in both wild type and hereditary TTR, compared to none/​
minimal in AL [18]. A recent consensus established the diagnostic
utility of Tc-​99 m pyrophosphate (PYP), used in North America,
with positive predictive value and specificity of 100% for ATTR,
obviating the need for endomyocardial biopsy (see E Fig. 43.6)
[19]. FDA has accepted this recommendation as inclusion criteria
in clinical trials of novel therapies for ATTR. A similar tracer, Tc-​
99 m-​3,3-​diphosphono-​1,2-​propanodicarboxylic acid (DPD) is
widely used in Europe [20]. Asymptomatic carriers of TTR mu-
tations also exhibit avidity to Tc-​99 m PYP, suggesting its use for
early diagnosis [21]. It may also be possible to risk stratify patients
with quantitative estimates from Tc-​99 m PYP or DPD scanning.
A multicentre retrospective study reported a significantly worse
survival in ATTR patients with a heart-​to-​contralateral ratio
of 1.6 or greater on Tc-​99 m PYP scan [22]. All bone-​seeking
radiotracers are not amyloid-​specific and a calcium-​mediated
mechanism has been suggested, although not completely dem-
onstrated [23]. Apart from the obvious negative structural and
functional consequences of CA, it has been recently suggested
that amyloid deposition may lead to progressive cardiac auto-
nomic dysfunction, supposedly as a result of the direct toxic ef-
fect on cardiac nervous terminals. Nuclear cardiac imaging with
123I-​metaiodobenzylguanidine (MIBG) allows the evaluation of
cardiac sympathetic tone and, in the case of SPECT, regional in-
tegrity assessment of sympathetic nervous terminals. In Val-​30-​
Met patients, MIBG uptake may be decreased; this finding can
occur before echocardiographic signs of CA [24] and could be an
independent predictor of mortality [25].
650 CHAPTER 43   In filt rative cardiomyopat hy

(a) (b) (c)

(d) (e) (f)

(g) (h) (i)

(l) (m) (n)

Fig. 43.5  CMR Images of three patients with cardiac AL amyloidosis, from left to right: early, intermediate, and advanced disease. (a–​c) Early disease with
no LGE, intermediate disease with subendocardial LGE, advanced disease with transmural LGE. (d–​f ) native T1 maps. (g–​i) Post-​contrast T1 maps (for ECV
measurement), and (l–​n) T2 maps, in the same patients. The patient with no LGE has mildly increased native T1 and ECV, with normal T2; the patient with
subendocardial LGE has increased native T1 and high ECV values with high-​normal T2; the patient with transmural LGE shows very high native T1 values, ECV
and T2 values.
 A n der s on - Fa b ry di se ase 651

Fig. 43.6  Regional (right side) and global (left side) evaluation of TTR Amyloidosis by 99mTc-​HDP scintigraphy.

Positron emission tomography (PET) radiotracers specifically

image CA in AL, with a high target-​to-​background ratio, and the Anderson-Fabry disease
potential to quantify amyloid burden and response to therapy.
11
Anderson–​Fabry disease (AFD) is a rare X-​linked lysosomal dis-
C-​
Pittsburgh compound-​ (PiB) and 18F-​Flutemetamol are
order, caused by deficiency or lack of the enzyme α-​galactosidase
benzothiazoles while F-​florbetaben and 18F-​florbetapir are stil-
18
A (GLA gene) [28]. Reduced enzyme activity results in progres-
bene derivatives with very similar structure. These radiotracers,
sive accumulation of the natural substrate globotriaosylceramide
binding to b-​amyloid plaques, have been developed for PET
(Gb3) in tissues, leading to a systemic disease mainly affecting
imaging of neurodegenerative disorders, but they have enabled
cardiovascular, renal, and nervous systems. Due to the X-​linked
the targeted imaging of CA with accuracy [26]. The evaluation
transmission, men are usually significantly affected, while women
of myocardial perfusion can help to understand the pathophysi-
have a more variable presentation. Heart involvement is due to
ology of amyloidosis. Using 13NH3 and PET in symptomatic
intracellular deposition of Gb3 in all cardiac cells (myocytes, fibro-
amyloid patients with no epicardial coronary disease compared
blasts, conduction tissue, endothelial cells) and it is characterized
with hypertensive heart disease, amyloid group showed signifi-
by left ventricular hypertrophy (LVH), myocardial inflammation
cantly reduced myocardial blood flow (MBF) both at rest and
and scarring, brady or tachy-​arrhythmias, or HF. The heart may
during hyperaemia with lower coronary flow reserve (CFR),
be the only organ involved in the so-​called ‘cardiac variant’ of the
paralleled by an increase of minimal coronary resistance irre-
disease. In men, LVH usually develops after the third or fourth
spective of LV mass or amyloid type [27]. It is conceivable that
decade, while in women the onset of cardiomyopathy is delayed
the reduction of resting MBF can be the result of highly hetero-
by 10 years and is generally less severe. Cardiovascular problems
geneous tissue composition, with mixture of normal and infil-
represent the main cause of death, with the majority being sudden
trated/​fibrotic tissue.
cardiac death (SCD) events [29]. Early diagnosis of AFD is crucial
652 CHAPTER 43   In filt rative cardiomyopat hy
because specific therapies (enzyme replacement therapy (ERT)
since 2001 and the pharmacological chaperone migalastat more
recently) are available to reverse, stabilize, or slow down the dis-
ease course [30–​32].
Cardiac imaging plays at least three important roles:
i) Discriminating Fabry cardiomyopathy from other forms of LVH
(see E Fig. 43.4). AFD may account for about 1% of patients
with unexplained LVH. Integration of imaging findings with
clinical data (pedigree, typical signs and symptoms such as
hypohidrosis, angiokeratoma, proteinuria, corneal deposits)
can give rise to clinical suspicion;
ii) Early recognition of cardiac involvement in patients with a gen-
etic diagnosis of AFD but with no LVH, in order to define the
optimal therapeutic strategy and timing of follow-​up;
iii) Monitoring the effect of specific therapies. LV wall thickness and
LV mass measured by echocardiography and CMR have been
considered as clinical endpoints in most of the studies evaluating
the therapeutic efficacy on cardiac involvement. Furthermore,
the presence of LGE identifies patients in advanced stages and it
is a predictor of unsatisfactory response to ERT.
Electrocardiography
Commonly reported electrocardiographic findings in AFD in-
clude bradycardia, PQ-​ interval shortening, prolonged QRS
interval, high QRS voltages, marked repolarization abnor-
malities, and atrioventricular block [33] (see E Fig. 43.7).
Intracellular Gb3 deposition triggers a reactive hypertrophy
of cardiac myocytes, causing myocardial wall thickening and
markedly increased QRS voltages. Indeed, the amount of Gb3
Fig. 43.7  Twelve-​lead
electrocardiogram of a patient
with Anderson–​Fabry disease and
advanced cardiac involvement,
showing sinus rhythm with short
PQ interval, high QRS voltages, and
marked repolarization abnormalities.
deposited in the heart corresponds only to a fraction of the total
myocardial mass (around 1–​3%).
Echocardiography
Concentric LVH with granular/​sparkling myocardial appearance
and preserved ejection fraction is the typical manifestation of
Fabry cardiomyopathy in adult patients even though apical, asym-
metric, and obstructive patterns of LVH have also been described.
Cardiac valves are mildly involved and can show thickening of the
aortic and mitral leaflets with no significant dysfunction. Other
morphological findings include papillary muscles hypertrophy
and a binary appearance of the LV endocardial border, the so-​
called binary sign [34]; it has been related to a characteristic pat-
tern of glycosphingolipid compartmentalization on histological
examination and often observed in Fabry patients even if it is not
specific (see E Fig. 43.8).
Systolic function as measured by ejection fraction is preserved
until late stages of the disease. Nevertheless, impairment of global
longitudinal strain (GLS) has been described as compared to
controls even when LV ejection fraction is normal. Diastolic dys-
function is common but, unlike CA, a restrictive pattern is rare.
The study of myocardial velocities and deformation using Tissue
Doppler and speckle tracking imaging have proven useful espe-
cially for early detection of cardiac involvement. Both systolic and
diastolic tissue velocities are significantly decreased in Fabry pa-
tients without LVH compared to healthy controls. Circumferential
speckle tracking strain (CS) and base-​to-​apex CS gradient are
lower in Fabry patients without LVH compared to normal con-
trols [35]. The presence of at least one myocardial segment with
impaired longitudinal strain has been reported in 50% of Fabry

(a)
(c)
Fig. 43.8  2D echocardiogram in a patient with Anderson–​Fabry disease and advanced cardiac involvement. (a) Apical four-​chamber view showing LV
hypertrophy with binary appearance of the LV endocardial border. (b) Pulsed-​wave Doppler of mitral inflow showing pseudonormal filling pattern. (c, d) Tissue
Doppler imaging (TDI) pattern with low systolic (s’) and diastolic (e’, a’) myocardial velocities.
patients without LVH by speckle tracking, demonstrating a sub-
clinical myocardial dysfunction in patients with preclinical AFD.
Impairment of GLS goes together with progression of LVH and
myocardial fibrosis. Patients with LGE have lower GLS than those
without and GLS correlates with the amount of LGE [36]. Loss
of global deformation is predominantly caused by basal posterior
and lateral segments, typical location of myocardial fibrosis. Right
ventricle can also be involved in AFD. Echocardiographic studies
described a prevalence of right ventricular hypertrophy (RVH)
ranging from 31 to 71%. RVH is correlated with LVH and disease
severity but, unlike CA, it is not commonly associated with RV
dysfunction evaluated by TAPSE, RV fractional area change and
tissue Doppler imaging (TDI) systolic velocity [37].
Cardiovascular magnetic resonance
In the last years, the growing diffusion of CMR in the field of AFD
added new insight into the study of the cardiac phenotype.
Because of its accuracy in LV volumes and mass quantification,
CMR represents the best technique to discriminate borderline
forms of LVH in the early stage of cardiac involvement and to
monitor changes over time. Also, CMR allows quantification of
the contribution of LV trabeculae and papillary muscles to LV
mass. It has been recently described that papillary muscles and
trabeculae contribute to a greater percentage of LV mass in Fabry
A n der s on - Fa b ry di se ase 653
(b)
(d)
patients compared to healthy controls; failure to account for this
results in significant underestimation of LV mass [38].
Intramyocardial LGE in basal inferolateral wall, corresponding
to myocardial scarring in a histological study, has been reported
as a typical sign of AFD. About 50% of Fabry patients with LVH
show inferolateral scar, but other locations of LGE (apical and
mid-​ventricular) have also been described, mainly in patients with
atypical patterns of LVH. While males usually show a direct cor-
relation between severity of LVH and LGE, females can develop
some replacement fibrosis without hypertrophy (see E Fig. 43.9c,
d). It means that a percentage of female patients with signs of rele-
vant cardiomyopathy could not been detected by standard echo-
cardiographic assessment. While the explanation for the typical
inferolateral location of LGE is not clear, it is well known that LGE
itself identifies patients with irreversible organ damage, who will
probably not benefit from ERT [39]. Regression of myocardial fi-
brosis has not been demonstrated to date, even in patients treated
with ERT. As in sarcomeric hypertrophic cardiomyopathy, LGE is
a risk factor for malignant ventricular arrhythmias.
Fabry cardiomyopathy represents one of the best models for the
application of T1 and T2 mapping. Sado and colleagues demon-
strated that native myocardial T1 values are significantly lower
in Fabry patients compared to other forms of LVH (CA, hyper-
tension, hypertrophic cardiomyopathy, and aortic stenosis), with
654 CHAPTER 43   In filt rative cardiomyopat hy

(a) (b) (c) (d)

(e) (f) (g) (h)

(i) (j) (k) (l)

Fig. 43.9  CMR Images of four patients with Anderson–Fabry disease in different stages of cardiac involvement. (a, e, i) No detectable sign of cardiac
involvement: normal T1 and T2 values, no LGE. (b, f, j) Prehypertrophic phase with diffuse low T1 values, normal T2 values, no LGE. (c, g, k) Female patient
without LVH, showing diffuse low T1 and LGE in inferolateral wall corresponding to pseudonormal T1. (d, h, l) Advanced stage of cardiac involvement with
LVH and LGE in inferolateral; T1 is low in the septum and pseudonormal in infero- lateral wall, where increased signal in T2 map can be observed.

little overlap [40]. The known lowering of T1 by fat and the spec-
troscopic results suggest that native T1 tracks myocardial Gb3
storage. Lowering of native T1 has been reported not only in
hypertrophic Fabry patients, but also in 50% of patients without
LVH, thus representing an early marker of cardiac involvement
(see E Fig. 43.9e–​h). Low T1 in LVH-​negative patients has been
associated with higher LV mass, EF, larger papillary muscles,
and higher frequency of LGE and ECG abnormalities compared
to patients with normal T1 [41]. T1 lowering can be patchy due
to inhomogeneous distribution of Gb3 storage. Noteworthy, in
myocardial segments with LGE, T1 can be ‘pseudonormalized’
or elevated due to increased extracellular space. In LVH-​negative
AFD, T1 shows a negative correlation with LV mass in both sexes,
while this trend is inverted in hypertrophic males and lost in
hypertrophic females [42]. To date, this different behaviour has
not been fully understood due to lack of histological correlations
of CMR data. Moreover, the potential prognostic value of T1 in
predicting disease evolution and its role in monitoring the re-
sponse to therapy is still unclear.
Another new concept in the evolution of cardiac involvement is
the potential role of myocardial inflammation. Elevated T2 values
by T2 mapping sequences have been reported in the same loca-
tion of LGE and correlated with troponin levels and LV mass (see
E Fig. 43.9n). This has been confirmed by histology, describing
myocardial inflammation in up to 56% of patients with Fabry car-
diomyopathy [43]. It remains to be elucidated if myocardial in-
flammation could represent a future therapeutic target.
Nuclear cardiac imaging
In AFD, the compound of myocyte hypertrophy, replacement
fibrosis, hypertrophy, and proliferation of smooth muscle and
endothelial cells narrowing intramural arteries, all contribute
to raised coronary vascular resistance and increase myocardial
oxygen demand. PET studies [44] have shown a significant re-
duction of hyperaemic MBF and CFR and an increase in minimal
coronary resistance in Fabry patients compared with healthy con-
trols. Tomberli et al. [45] investigated the role of gender and LVH
with 13 NH3 and found a marked impairment of microvascular
function, i.e. a 60% reduction in hyperaemic MBF, irrespective
of LVH. Albeit the phenotype is prevalent in males, also females
without LVH had a significant degree of microvascular dysfunc-
tion, which could be the only sign of the disease.

Other infiltrative cardiomyopathies
Glycogen storage diseases (GSD) are a group of inherited meta-
bolic disorders that result from a defect in enzymes required for
either glycogen synthesis or degradation. While some forms of
GSD affect a specific organ, others are multisystemic and the
heart may also be involved. Cardiomyopathy can be the prevalent
manifestation, mainly in LAMP-​2 and PRKAG2 mutations. The
severity of the GSD ranges from those fatal in infancy, to mild
disorders with a normal lifespan. DNA mutation analysis is the
primary method for diagnosing GSD.
Danon disease (GSD Type 2b) is a rare X-​linked metabolic dis-
order caused by LAMP-​2 mutation and characterized by the develop-
ment of cardiomyopathy (hypertrophic or dilated cardiomyopathy),
Wolff–​Parkinson–​White syndrome, ventricular arrhythmias, skel-
etal myopathy, and cognitive disorders. Cardiac manifestations
occur earlier in males with a more aggressive phenotype. Female
patients have milder and later onset cardiac involvement. CMR can
identify LGE with patchy mid-​myocardial accumulation involving
different left ventricular regions [46]. In PRKAG2 syndrome, car-
diac phenotype is usually hypertrophic with low native T1 values in
early stages and diffuse fibrosis in advanced disease.
Sarcoidosis
Sarcoidosis is a rare inflammatory disorder of unknown aetiology
involving multiple organs, most commonly the lymphatic system,
lungs, eyes, skin, and nervous system, and only rarely the heart. It
is characterized by the formation of non-​caseating granulomas in
the affected organs [47].
The most common site of infiltration in the myocardium is the
LV free wall, followed by the septum, right ventricle, and atria. The
granulomatous inflammation damages the myocytes and patchy
replacement fibrosis appears as soon as the myocyte integrity is
affected, while coronary arteries rarely show structural changes
[48]. Only 5% of patients with systemic sarcoidosis complain of
cardiac symptoms; however, post-​mortem studies reported that
the prevalence of subclinical cardiac sarcoidosis (CS) is 25%.
S a rc oi d o si s 655
CS is associated with a poor prognosis, with an increased risk
of ventricular arrhythmias, HF, and SCD. The early recognition is
therefore crucial for early intervention using immunosuppressive
therapies.
The detection of CS can be challenging due to the poor sensi-
tivity and specificity of diagnostic modalities. Thus, the two most
common guidelines used to diagnose CS [49, 50] encourage a
multimodality approach, integrating ECG, echocardiography, nu-
clear medicine and CMR. ECG abnormalities have low prevalence
and low specificity for CS, with the most common being com-
plete heart block and right bundle branch block. Deterioration of
LV and/​or RV systolic function, wall motion abnormalities with
non-​coronary distributions, anterior basal septal thinning with
increased echogenicity, ventricular dilatation, and aneurysms can
be detected by echocardiography in advanced stages. Instead, im-
pairment of GLS has been described in early cardiac involvement.
CMR tissue characterization by T2 weighted images allows the
identification of active, inflamed granulomatous lesions. LGE can
be detected in ~25% of patients with CS. There is neither a specific
LGE pattern nor a typical location of LGE; a multifocal distribu-
tion and a variety of patterns (subendocardial, intramyocardial,
transmural or subepicardial) can be observed. In CS, LGE cor-
relates to areas of fibrosis and granulomatous inflammation by
histology and carries a poor prognosis for all-​cause mortality and
future arrhythmic events [51]. Despite an excellent negative pre-
dictive value, LGE has only modest positive predictive value, per-
forming best in detecting focal rather than diffuse processes. T1
and T2 mapping overcome this limitation: higher native T1 and
T2 values have been described in patients with sarcoidosis com-
pared with healthy controls [52, 53] with a significant reduction
after treatment. While promising, the clinical significance of these
techniques still needs further validation.
PET in combination with computed tomography (CT) scan
can detect active metabolic processes. Cardiac PET involves the
use of 18F fluorodeoxyglucose (FDG) to evaluate myocardial in-
flammation. 18F-​FDG-​PET/​CT captures a wide spectrum of dis-
ease stages (pathologic glucose uptake and active inflammation)
in CS (see E Fig. 43.10) [54]. The classical patterns of myocardial
FDG uptake in patients with active CS are either diffuse, focal,
Fig. 43.10  Regional (right side) and global
(left side) evaluation of TTR Amyloidosis by
99mTc-​HDP scintigraphy.
656 CHAPTER 43   In filt rative cardiomyopat hy
and focal-​on-​diffuse [55]. In early CS, focal areas of increased
FDG uptake are observed, with or without rest perfusion de-
fects. Rest perfusion defects can signify the presence of scar but
can also be seen with intense inflammation compressing the
microvasculature. The hallmark of CS with active inflammation
on cardiac PET is a mismatch between metabolism and perfu-
sion in the same area. In more advanced disease, resting defects
may be seen without inflammation, suggesting the presence of
scar. One advantage of PET imaging is whole-​body FDG imaging
obtained concurrently with the heart, allowing for extracardiac
assessment. Finally, cardiac PET is currently the preferred mo-
dality for monitoring response to therapy, as myocardial FDG up-
take can be quantified and serially followed.
Myocardial iron loading
Myocardial iron loading may occur in patients affected by her-
editary haemochromatosis or more often in patients affected
by thalassemia major (TM), Diamond–​Blackfan anaemia, etc.,
undergoing systematic blood transfusions therapy. While severe
chronic anaemia causes high-​cardiac-​output HF and is fatal at a
young age, regular transfusion therapy results in progressive iron
accumulation [56, 57] which leads to HF and arrhythmias in the
long term. The time from diagnosis of HF to death is usually quite
short (<12 months) while with appropriate chelation therapy life
expectancy may dramatically improve [58, 59] (E Fig. 43.11).
There is evidence that chelation therapy can completely restore
cardiac function in most patients with preclinical dysfunction and
some with clear HF [60, 61]. However, this therapy has to be indi-
vidually tailored, which nowadays is done by CMR and namely by
the T2* technique. Beside iron overload assessment, patients may
(a)
(d)
Fig. 43.11  Myocardial iron loading
and T2* analysis. (a) Electronic
microscope image showing the
iron deposits. (b) Histology of the
myocardium with iron overload
(Ematossiline Eosine). (c) CMR image
of a patient with thalassemia major
and myocardial iron overload. (d) T2*
images obtained by 1.5 T scanner.
The measurements of signal intensity
inside a region of interest is plotted
against the Echo Time to obtain the
exponential curve of the decay hence
the value of T2*.
also benefit from measurement of LV and RV volumes and mass,
where CMR is considered the gold standard and in some by the
assessment of intramyocardial fibrosis by LGE [62].
Acquisition technique
Myocardial iron deposition can be quantified reproducibly
with myocardial T2* which is a relaxation parameter that arises
principally from local magnetic field inhomogeneities that
are increased with particulate iron deposition. T2* is related
to T2 by summation of tissue relaxation (T2) and magnetic in-
homogeneity. T2* is the time taken for decay of the myocar-
dial signal by 63% and is measured in milliseconds. In clinical
medicine, it is usual to use these decay times to assess magnetic
relaxation, but basic science–​based investigations typically use
the rate of relaxation (R), and this relation can be rewritten
as R2*=R2+R2′, with the units of measurement being inverse
seconds (s−1).
The gradient-​echo black-​blood T2* CMR using a single mid-​
ventricular single slice is the most widespread technique, how-
ever different technical approaches have been proposed such as
acquiring multiple short axis slices. Whichever is the selected
procedure, the single operator needs an adequate training and the
single centre must apply a reliable quality control programme.
T2* Normal values
The lower limit of normal is 20 ms. However, this is recognized
as a conservative threshold, because T2* calibration data sug-
gest 20 ms equates to 1.1 mg/​g iron dry weight, which is ap-
proximately twice the historically reported normal mean level
of human myocardial iron [63]. The probability of reduced
ejection fraction increases as cardiac iron increases (cardiac
T2* falls) [64–​65].
(b) (c)
Signal intensity is
related to TE by an
exponential relation
with a rate defined
TE
– by T2*

Iron overload in the liver
Liver iron measurements may be misleading because they cor-
relate poorly with cardiac iron levels [66]. A liver T2* <9.2 ms is
considered indicative of a significant load [67]. This cut-​off cor-
responds to a value higher than 3 mg/​g dry weight [68].
Scanner characteristics
Currently, all T2* MR measurements have been validated at
a field strength of 1.5 T. Although 3 T scanners are now com-
monly installed, there is very little clinical experience of their
use in TM. T2* values at 3 T are shorter than at 1.5 T, and the
potential for artefacts is greater. In view of the importance of the
measurement of myocardial T2* and the very limited clinical
experience at 3 T, it is recommended that all clinical T2* MR be
performed at 1.5 T [69–​70].
When should myocardial iron overload be measured
by T2*?
Although there is evidence that iron overload may occur very early
in the life of transfused patients a pathologic T2* is expected to
be measured only after 10 years of age. At this age, there is the
advantage of spontaneous cooperation by the patient with CMR,
which improves the quality of images. The first CMR for car-
diac T2* should be performed as soon as the child can cooperate
without sedation or anaesthetic. After this, annual assessment of
T2* CMR is typical, but individual patient factors will determine
the frequency of repetition. For example, patients at high risk (T2*
<10 ms, reduced left ventricular ejection fraction (LVEF), poor
compliance, treatment interruption) may require scanning every 6
months. In the patient with stable chelation and stable cardiac T2*
>20 ms, scans can be repeated less frequently (every 2–​3 years).
Other parameters to be measured in iron overload
patients
In TM patients without cardiac iron overload, LV end-​diastolic
volume is increased and LV end-​systolic volume is decreased, which
leads to increased LV stroke volume, LVEF, and cardiac output com-
pared with healthy control subjects after normalization for body
surface area [71–​ 72]. The hyperdynamic circulation also leads
to an increased LV mass. The same is true for the RV: RV stroke
volume and cardiac output are higher, and RV ejection fraction is
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74. Pepe A, Positano V, Capra M, et al. Myocardial scarring by delayed
enhancement cardiovascular magnetic resonance in thalassaemia
major. Heart 2009; 95: 1688–​93.
75. Omura T, Yoshiyama M, Hayashi T, et al. Core protein of hepatitis C
virus induces cardiomyopathy. Circ Res 2005; 96: 148–​50.

Contents
Introduction  661
Definition of dilated cardiomyopathy  661
Making an accurate diagnosis of DCM  661
Differentiating DCM from CAD in LV
dysfunction  662
Differentiating DCM from primary valvular
disease in LV dysfunction  663
Aetiology of DCM  663
Idiopathic DCM  663
Echocardiography in DCM  663
Cardiac magnetic resonance imaging
in DCM  665
Nuclear imaging in DCM  667
Myocardial perfusion imaging  667
Myocardial metabolic imaging  668
Sympathetic nerve imaging  668
Hybrid imaging  668
Using imaging to detect identifiable causes
of DCM  668
DCM and myocarditis  668
DCM and Chagas’ disease  672
Echocardiography in Chagas’ disease  672
Nuclear imaging in Chagas’ disease  672
Cardiovascular magnetic resonance imaging
in Chagas’ disease  672
DCM in neuromuscular disorders  674
DCM and cardiotoxic agents  674
DCM associated with pregnancy and
parturition  676
Isolated left ventricular non-​compaction  676
CHAPTER 44
Dilated cardiomyopathy
Upasana Tayal, Sanjay Prasad, Tjeerd Germans,
and Albert C. van Rossum
Introduction
Dilated cardiomyopathy (DCM) is characterized by enlargement of the heart with as-
sociated reduced left ventricular function. From an imaging perspective, important re-
quirements are to exclude other pathologies, assess disease severity, guide therapeutic
management, and identify complications. Establishing the imaging diagnosis of DCM is
key to guiding the management of DCM. In this chapter we discuss how to use imaging
to make an accurate diagnosis of DCM, and review how to exclude coronary artery dis-
ease (CAD) and valvular disease as these are two important differentials with differing
management strategies. We then review the diagnostic and prognostic capabilities of
echocardiography, cardiovascular magnetic resonance imaging (CMR) and nuclear tech-
niques including single-​photon emission computed tomography (SPECT) and positron
emission tomography (PET) in DCM, with a focus on where imaging can identify par-
ticular causes of DCM.
Definition of dilated cardiomyopathy
Dilated cardiomyopathy is a disease of the myocardium characterized by left ventricular
(LV) dilatation and systolic impairment in the absence of CAD or abnormal loading con-
ditions, such as hypertension or valvular heart disease, sufficient to explain the observed
myocardial abnormality [1–​3]. Right ventricular dilation and dysfunction may also be
present but are not necessary for the diagnosis (E Table 44.1).
Historic estimates of the prevalence of DCM prior to the widespread availability of
echocardiography were in the region of 1 in 2,700 individuals [4]‌. In the absence of large
contemporary population studies, estimated DCM prevalence has recently been revised
to around 1 in 250 individuals [5]. DCM is a leading cause of heart failure and is the pri-
mary global indication for heart transplantation [1, 6, 7].
Making an accurate diagnosis of DCM
DCM is an imaging and clinical diagnosis. The most commonly used imaging modality
is echocardiography, in which the criteria for left ventricular dilation and impairment
are left ventricular end-​diastolic diameter (LVEDd) >117% of that predicted for age and
body surface area (BSA) and left ventricular ejection fraction (LVEF) <45% and/​or frac-
tional shortening (FS) <25%, respectively [8]‌.
More recently, this categorization is being broadened through the advent of more
accurate imaging techniques such as CMR. Patients who do not meet the echocardio-
graphic criteria may still have DCM, as shown by clinically significant myocardial dis-
ease on CMR or endomyocardial biopsy [9]‌. Therefore in 2016, a revision to the 2008
662 CHAPTER 44   Dil ated cardiomyopat h y

Table 44.1  Examples of identifiable causes of dilated cardiomyopathy

Cause Examples
Genetic and syndromic Over 60 genes reported to be associated with DCM including TTN (up to 25%),
LMNA, MYH7, and TTNT2 (all <5%)
Duchenne muscular dystrophy, Barth syndrome
Infectious Viral: Coxsackie, HIV, influenza, adenovirus, cytomegalovirus, varicella, hepatitis,
Ebstein–​Barr, echovirus, parvovirus
Bacterial: Streptococci, mycobacteria
Spirochetal: Lyme disease, syphilis
Fungal: Histoplasmosis, cryptococcocis
Parasitic: Toxoplasmosis, trypanosomiasis, schistosomiasis
Drugs Chemotherapeutic agents including anthracyclines and cyclophosphamide
Antiretroviral drugs including zidovudine
Other, e.g. phenothiazines, chloroquine, clozapine
Toxins Alcohol, cocaine, amphetamines, cobalt, lead, mercury
Nutritional deficiencies and Thiamine, selenium, carnitine, niacin
electrolyte disturbances Hypocalcaemia, hypophosphatemia, uraemia
Endocrine Hypo-​or hyperthyroidism, diabetes mellitus, Cushing’s syndrome,
phaeochromocytoma, growth hormone excess, or deficiency
Inflammatory and Systemic lupus erythematosis, scleroderma, rheumatoid arthritis, autoimmune
autoimmune myocarditis, dermatomyositis, sarcoidosis
Other Tachycardia-​induced cardiomyopathy, pregnancy

European Society of Cardiology (ESC) classification was pro-
posed to include a category of hypokinetic non-​dilated cardiomy-
opathy, to recognize the presence of left ventricular impairment
(LVEF <45%) in the absence of dilation as being on the same dis-
ease spectrum as dilated cardiomyopathy [2]. In this revision, the
authors also proposed a broader definition for DCM: ‘Left ven-
tricular or biventricular systolic dysfunction and dilatation that are
not explained by abnormal loading conditions or coronary artery
disease’ [2]. Crucially, the revised definition accepts abnormal
LVEF measured using any modality and defines LV dilation as
LV end-​diastolic volumes or diameters greater than two standard
deviations from age, gender, and BSA-​adjusted nomograms [2].
Other characteristic imaging features of DCM include the pres-
ence of mid-​wall fibrosis, detected through late gadolinium en-
hancement CMR in approximately one-​third of patients [10]. This
fibrosis is most commonly found in the septum, but can occur
anywhere in the left ventricle. Right ventricular dilation and dys-
function may also be present in a third of patients [11] but are
not necessary to make the diagnosis. Left atrial enlargement is
also recognized as an important prognostic imaging biomarker
and left atrial enlargement is also found in conjunction with LV
enlargement [12].
Differentiating DCM from CAD in LV
dysfunction
Determining whether newly recognized LV dysfunction is due to
CAD or to DCM, is a first critical early step in the risk stratification
and management of patients with a dilated left ventricle with sys-
tolic dysfunction. CAD should be investigated if the patient has any
symptoms suggestive of ischaemia. In the asymptomatic patient, we
would recommend investigating for CAD in patients over the age
of 40 years old. Whether this is done by using invasive coronary
angiography or non-​invasive computed tomography (CT) cor-
onary angiography will depend on the pretest probability of CAD.
Typically, patients with CAD often have a dilated LV with re-
gional wall motion abnormalities, sometimes with thin and
echogenic myocardium due to old myocardial infarction. DCM
patients present with a more diffuse dilatation, often with rela-
tively uniform myocardial wall thickness. The right ventricle is not
often involved in CAD, unless there is proximal right coronary ar-
tery occlusion, while it is involved in approximately a third of pa-
tients with DCM [11]. Nonetheless, multivessel coronary artery
disease with extensive scarring from previous myocardial infarcts
in multiple territories may mimic DCM, and additional testing to
exclude significant CAD will be required.
CMR is of great value as an imaging tool to differentiate DCM
from CAD since it is capable of demonstrating or excluding with
high accuracy the presence of CAD-​related infarct scarring using
late gadolinium enhancement (LGE) imaging, and providing
information on pathologic myocardial tissue composition. A
number of different diagnostic subtypes may be identified [13].
Typical DCM patients will either have no LGE or the typical mid-​
wall distribution of LGE. They will not have any subendocardial
LGE. Patients with CAD sufficient to cause the LV dilation and
impairment will often have extensive subendocardial LGE and
coronary angiography is mandated.
Key distinguishing features are that in CAD, there is either sig-
nificant coronary stenosis (patients with history of myocardial in-
farction (MI) or revascularization (CABG or PCI); patients with
≥75% stenosis of left main or proximal left anterior descending ar-
tery (LAD); patients with ≥75% stenosis of two or more epicardial
vessels) [14], or evidence of significant infarction (usually two or
more segments) sufficient to account for the level of dysfunction.

This is in contrast to DCM where there is either no fibrosis or mid-​
wall fibrosis. Occasionally, a small focal incidental infarct may be
seen reflecting an embolic phenomenon or vessel recanalization.
Differentiating DCM from primary valvular
disease in LV dysfunction
LV dilatation will lead to mitral annular enlargement, which will
cause the mitral leaflets not to oppose properly and consequently
lead to functional mitral regurgitation. This can be visualized
with colour Doppler and quantified when necessary. The causal
link between mitral regurgitation and a dilated left ventricle may
be difficult to establish in some cases, but the association of a glo-
bally hypokinetic LV with mitral regurgitation in the presence of
otherwise structurally normal mitral leaflets, suggests primary
myocardial disease.
Aetiology of DCM
The major identifiable causes of DCM include genetic or syndromic
forms, infectious diseases, drugs and toxins, endocrine disorders,
inflammatory conditions, and nutritional deficiencies (examples
in E Table 44.1). DCM is classified as idiopathic in about 50%
of cases when non-​genetic identifiable causes have been excluded.
The DCM phenotype can be caused by: (i) primary genetic
myocardial defects resulting in reduced force generation and/​
or transmission; (ii) myocardial inflammation and cell damage
(mainly due to infective, immunologic, or toxic mechanisms); or
(iii) a complex interplay of unclear genetic, immune-​mediated,
toxic, or infectious mechanisms that ultimately result in non-​
specific abnormalities of myocardial function, perfusion, and
metabolism and subsequent DCM. This form of DCM is referred
to as idiopathic DCM.
The proportion of DCM cases with a familial basis is between
20 and 30%, though up to 60% has been suggested [15]. Familial
DCM is diagnosed when two or more related affected individ-
uals are present in a single family and should also be suspected
when there is a family history of premature cardiac death, con-
duction system disease, and/​ or skeletal myopathy [16]. The
genetic architecture of DCM has emerged to be particularly
complex, with almost 70 genetic loci and mutations affecting a
range of diverse cellular structures and functions, most notably
I di opat h i c   D C M 663
with the sarcomere. Autosomal dominant patterns of inherit-
ance are predominantly found with mutations in genes encoding
for cytoskeletal, sarcomeric protein/​Z-​band, nuclear membrane,
and intercalated disc proteins. X-​linked diseases associated with
DCM often involve skeletal muscular dystrophies (e.g. Becker and
Duchenne). A matrilinear inheritance pattern and involvement
of different organs suggest mitochondrial disease. Also, inherited
metabolic disorders such as haemochromatosis or familial auto-
immune disease may cause a DCM phenotype.
The electrocardiogram is often abnormal and may show con-
duction abnormalities (e.g. in Lamin A/​C mutations, Lyme dis-
ease, Chagas’ disease) or bundle branch block.
Many genetic variants in DCM exhibit variable penetrance and
expressivity. Variable penetrance means that not all individuals
who carry the variant will develop a phenotype. Variable expres-
sivity refers to variation in the severity of the resulting phenotype.
Therefore even if family history is negative, first-​degree relatives
of newly diagnosed DCM patients should always be encouraged
to undergo clinical screening with electrocardiography (ECG)
and echocardiography/​CMR. In screened family members who
are phenotype negative, interval screening is recommended since
early diagnosis of DCM is crucial to institute early management.
Current American Heart Association (AHA) recommendations
suggest periodic echocardiographic screening of first-​degree rela-
tives [17] whereas ESC recommendations are more prescriptive,
recommending clinical screening including imaging of first-​degree
relatives at 2–​5 yearly intervals until the age of 60–​65 years [18].
If an asymptomatic relative is found to carry a pathogenic genetic
variant then repeated cardiac evaluation is recommended every 1–​
3 years (ESC guidelines) or every 3–​5 years (AHA guidelines).
Idiopathic DCM
Echocardiography in DCM
Two-​dimensional (2D) echocardiography and
quantification of volumes
Two-​dimensional (2D) echocardiography is the cornerstone for
the diagnosis of LV dysfunction, with or without ventricular dila-
tion (E Figs. 44.1 and 44.2; z Video 44.1).
Fig. 44.1  M-​mode echocardiogram
(left) and 2D parasternal long-​axis
(right) from a patient with DCM
and heart failure. The left ventricle is
severely dilated with global hypokinesia
and an EF estimated at 30%.
664 CHAPTER 44   Dil ated cardiomyopat h y

Quantification of LV geometry is important for patient follow-​

up and echocardiography is ideally suited for serial assessment.
LV dimensions are usually sufficient, but assessing LV volumes
may offer a better way to assess DCM severity and progression.
Importantly, therapeutic options in idiopathic DCM, such as in-
stitution of ACE-​inhibitors or selecting candidates for cardiac
resynchronization therapy (CRT), need precise measures of ejec-
tion fraction (EF). Of note, all existing guidelines for the use of
device therapy are based on echocardiography defined LVEF
measurements. To this end, 2D-​echocardiography provides the
first-​line assessment of LV volumes and dyssynchrony. The re-
commended method to measure EF is the modified Simpson’s
method from two apical planes, including the four-​chamber and
two-​chamber views. If the endocardial border cannot be delin-
eated sufficiently with standard 2D-​echocardiography, the use of
ultrasound contrast agents or real-​time three-​dimensional echo-
cardiography is recommended (E Figs. 44.3 and 44.4) in order to
accurately calculate LV volumes and EF. See z Video 44.2.

Speckle tracking derived strain imaging

Myocardial speckles result from interference of subwave sound
lengths that augment or nullify the echo signal from a particular
myocardial element. The change in orientation of the speckle pat-
tern can be tracked throughout the cardiac cycle allowing to quan-
tify deformation (strain) or torsion of the myocardium. Compared
to tissue Doppler imaging, strain imaging has shown to be more
robust since it is relatively independent of the angle of insonation
and tethering artefacts (global longitudinal strain [GLS]) is most
extensively studied and has shown to be a more sensitive marker
for myocardial dysfunction in familial DCM and better predictor
of arrhythmic events than LVEF in DCM patients [19, 20].

Real-​time three-​dimensional imaging

Fig. 44.2  Parasternal long-​axis (top) and short-​axis (bottom) from a patient Real-​time three-​dimensional imaging of the left ventricle has now
with DCM. Note the marked dilatation of the left ventricle. been made available by the vast majority of ultrasound vendors.

(a) (b)

Fig. 44.3  (a) Apical projections

from a patient with poor apical
imaging with no endocardial border
delineation. (b) The same patient after
0.3 ml of Sonovue injection. The entire
endocardial border is now clearly
visualized.
 I di opat h i c   D C M 665

Fig. 44.4  Real-​time three-​

dimensional echocardiography from a
person with a normal heart.

This allows a more accurate and reproducible measurement of

LV volumes in a semi-​automated fashion, thus shortening the
time to quantify LV function and dimensions. It has been dem-
onstrated that LV volumes are more accurately measured with
three-​dimensional echocardiography and match those obtained
by CMR with less test–​retest variability and better interobserver
reproducibility than 2D-​echocardiography [21, 22].

Complications of DCM detected on echocardiography

Intraventricular thrombus formation is a considerable risk
in ventricular dilatation due to diffuse hypokinesia and low
intraventricular velocities. These thrombi are believed to consti-
tute a major risk of systemic embolization. Contrast echocardi-
ography can readily identify the presence of an intraventricular
thrombus and lead to prompt anticoagulant treatment. Thrombi
are usually attached at the apex (E Fig. 44.5) and may be laminar
or protruding with a narrow point of attachment on the endocar-
dial surface.

Cardiac magnetic resonance imaging in DCM

CMR is an excellent imaging modality in DCM, particularly in
patients with suboptimal echocardiographic images. As the gold
standard for assessment of cardiac volumes, combined with being
non-​invasive and not exposing subjects to ionizing radiation, it
is the ideal imaging modality for accurate serial evaluation of pa-
tients with DCM. Fig. 44.5  Apical 4-​chamber view from a patient with DCM. Note
The value of CMR in the diagnosis of DCM relies on de- the presence of an apical thrombus. The patient was not receiving
tailed determination of LV function using fast cine techniques anticoagulation.
666 CHAPTER 44   Dil ated cardiomyopat h y
(steady-​state free precession; SSFP), and myocardial tissue char-
acterization based on the application of techniques that accen-
tuate differences in relaxation properties of the myocardium. This
may help to differentiate normal myocardium from pathologic
processes associated with oedema, fibrosis, haemorrhage, iron,
and protein fibril deposition using T1-​and T2-​weighted imaging,
LGE imaging, and T2-​star imaging. Detailed myocardial tissue
characterization is unique to CMR and may provide a key to the
aetiology of a DCM phenotype.
Quantification of morphology and function
CMR is the gold standard non-​invasive technique for accurate
and reproducible assessment of LV volumes, mass, and EF,
without the need for geometrical assumptions that are required in
2D echocardiography for example [23, 24]. Cardiac chamber cine
images are acquired using SSFP imaging cine. Measurements of
biventricular volumes and function are obtained through manual
planimetry or the use of semi-​automated software. Current gen-
eration artificial intelligence (AI) algorithms are streamlining and
automating this process. The superior quality of images obtained
by this technique facilitate the detection of regional wall mo-
tion abnormalities allowing an easier differentiation between
ischaemic and non-​ischaemic LV impairment. In contrast to
echocardiography, CMR can image in any plane with an unre-
stricted field of view, allowing evaluation of cardiac structures,
regardless of acoustic windows or body habitus.
CMR also provides the gold standard non-​invasive assessment
of right ventricular (RV) dimensions and function due to its
3D capabilities [25, 26]. Accurate assessment of RV dimensions
and function can be challenging with echocardiography, due to
its complex and variable shape. In addition, the low inter-​and
intraobserver variability are great strengths of the use of CMR in
DCM, permitting the early detection of even subtle abnormalities
in ventricular function [27–​30].
Situations in which standard SSFP cine imaging may not pro-
vide such accurate assessment of cardiac volumes and function
include the presence of motion or breathing artefacts, particu-
larly in patients too symptomatic to complete breath holding
or in patients with irregular rhythms, where high quality cine
imaging may not be acquired. In these situations, advanced par-
allel imaging techniques or real-​time cine imaging may be used
as alternatives.
CMR also allows accurate quantification of left atrial (LA)
volume using the biplane area-​length method [31]. As outlined,
functional mitral regurgitation is also a common consequence
of DCM secondary to mitral annular dilatation and leaflet teth-
ering secondary to LV dilatation and functional impairment. A
long-​axis cine stack and a short-​axis cine image across the mitral
valve allows accurate assessment of all parts of the valve appar-
atus including individual leaflet scallops, chordae, and papillary
muscles [32]. Mitral regurgitant volume can be calculated by esti-
mating the aortic forward flow volume, using phase-​contrast flow
imaging, and subtracting this from the total LV stroke volume [32,
33]. This method has been validated against volumes calculated
from echocardiographic indices and catheterization data with
good intertechnique agreement [33, 34].
Non-​contrast tissue characterization
Myocardial tissue can be characterized through modified pulse
sequences. For example, the T2-​weighted short-​tau inversion re-
covery (STIR) sequence can image oedema, suppressing signal
from fat and flowing blood. Long T2 relaxation times of pro-
tons in water generate high signal in areas of myocardial oedema
[35]. The interpretation of STIR images however is subjective and
novel direct quantification of T2 by mapping techniques may
help address this limitation. Another technique, myocardial T2*
mapping, enables the direct identification and quantification of
myocardial iron in vivo, and has been validated against in vivo
histology, making it particularly useful for the detection of myo-
cardial iron overload as a cause of DCM [36].
Interstitial fibrosis
Reactive, or interstitial, fibrosis is characterized by the expansion
of the cardiac interstitial space without significant myocyte loss
and occurs in response to pressure overload, volume overload, as
well as cardiomyopathies. DCM is associated with major changes
in the extracellular matrix and myocardial collagen deposition in
DCM can be diffuse [37]. The gold standard for the detection and
quantification of diffuse myocardial fibrosis is through myocar-
dial biopsy [38]. However, this is limited by sampling error and is
associated with small but significant procedural complication risk
[39]. Diffuse myocardial fibrosis can now be detected with CMR
using T1 mapping.
Either a Modified Look-​Locker Inversion Recovery (MOLLI)
[40] sequence or shortened-​ MOLLI (ShMOLLI) [41] with
balanced steady-​state free precession (bSSFP) readout are used.
As collagen deposition increases the extracellular space, ex-
ogenous contrast (gadolinium) accumulates, and myocardial
tissue longitudinal relaxation time (T1) decreases. The T1 time
is inversely proportional to the concentration of gadolinium in
the tissue.
Extracellular volume (ECV) fraction provides a quantitative
measure of myocardial interstitial volume and is more reprodu-
cible between different field strengths, vendors, and acquisition
techniques than both native and post-​contrast T1 [42]. While
promising, there is a current lack of standardization of techniques.
Replacement myocardial fibrosis
Replacement myocardial fibrosis occurs in response to cardiac
injury (e.g. following myocardial infarction), following which
apoptosis and myocyte loss occurs, with dead cells being re-
placed by collagen-​based scar formation. The conventional and
gold standard method to detect myocardial scar is through histo-
logical examination [38]. However, replacement myocardial fi-
brosis can be detected non-​invasively using CMR by exploiting
the alterations in tissue magnetic resonance properties following
the administration of an exogeneous inert contrast agent such as
gadolinium.
Using an inversion recovery MRI sequence in which normal
myocardial signal is ‘nulled’ to appear black, the area of fibrosis

where gadolinium accumulates appears extremely bright. This is
known as late gadolinium enhancement (LGE-​CMR).
CMR detected replacement myocardial fibrosis occurs in ap-
proximately one-​third of patients with DCM, most frequently in
a linear mid-​wall distribution [43]. Mid-​wall replacement myo-
cardial fibrosis confers an adverse prognosis in DCM, predicting
mortality including sudden cardiac death irrespective of LVEF
[10, 44–​46].
Myocardial perfusion
First pass gadolinium imaging (imaging at rest or stress imme-
diately after administration) is used for myocardial perfusion
imaging. Acquisition protocols are usually based on gradient
echo or SSFP sequences combined with parallel imaging to en-
able ultra-​fast acquisition. First pass stress perfusion CMR can
visualize inducible perfusion defects in DCM, often seen as cir-
cumferential areas of subendocardial hypoperfusion. Patients
with DCM have been shown to have reduced myocardial perfu-
sion reserve during stress, but not altered oxygenation [47]. This
suggests that the perfusion deficit is not sufficient to cause a re-
duction in oxygenation during stress. In addition, as abnormal
resting cardiac energetics are not affected by oxygen adminis-
tration, the resting impairment in energy metabolism is not sec-
ondary to a myocardial oxygen deficit, meaning that the impaired
perfusion in DCM is likely a reflection of disease severity and not
a pathophysiological driver [47]. The degree of myocardial blood
flow impairment in DCM has also been strongly correlated with
prognosis [48, 49].
Myocardial strain
CMR assessment of strain has historically been challenging but
there are novel techniques, each with their own merits and limita-
tions, such as CMR tissue tagging, feature tracking, phase-​contrast
CMR, velocity encoded CMR, DENSE (displacement encoding
with simulated echoes) and SENC (strain encoding) [50]. Tagged
CMR is the method that has been most widely studied. In this, se-
lective presaturation pulses are used to superimpose a grid across
Dilated cardiomyopathy
Reduced MRF after dipyridamole predicts MCE
(Sudden death, progressive LV dysfunction, heart failure)
100
80
Event-tree-survival
60
40
MBF < 1.36
20
0 Source data from Neglia D, Michelassi C, Trivieri MG, et
0 12 24 36 48 60
Months
Nu cl ea r i m ag i n g   i n   D C M 667
the field of view across the heart. The grid lines are deformed by
myocardial contraction, strain, and torsion, allowing direct quan-
tification of myocardial deformation and strain [51]. However it
is limited by tag fade in diastole, thereby reducing the amount of
information available in diastole.
Nuclear imaging in DCM
Myocardial perfusion imaging
Myocardial perfusion imaging has a high accuracy for excluding
CAD in patients with LV dysfunction; thus in the absence of rest
or stress-​induced perfusion defects on SPECT or PET images,
the likelihood of significant CAD as a cause of LV dysfunction
is extremely low [52]. Conversely, the specificity is suboptimal
mainly due to the frequent occurrence of regional perfusion
abnormalities in a significant number of patients with LV dys-
function without detectable CAD (z Video 44.3). PET has the
specific advantage of precisely measuring the absolute myocar-
dial blood flow (MBF, ml.min-​1.g-​1) at rest and during pharma-
cologic stress (i.v. dipyridamole or adenosine), and hence to
measure regional and global MBF reserve. Using 15O-​H2O or
13
N-​NH3 as flow tracers in rest-​stress protocols, quantitative
evaluation of MBF in patients with DCM often demonstrates a
diffuse impairment of myocardial perfusion and MBF reserve.
This is interpreted as a result of coronary microvascular dys-
function, abnormal myocardial contractility, and wall stress,
but is independent of myocardial fibrosis. A global and severe
reduction in MBF reserve may occur even in the earlier stages
of DCM. It is a distinctive marker of the severity of the disease
and of an increased risk of progressive myocardial dysfunction,
heart failure, and sudden death (E Fig. 44.6) [11]. It must be
kept in mind that a similar pattern of globally depressed myo-
cardial perfusion may also occur in multivessel CAD, which still
needs to be ruled out.
MBF > 1.36
Increased relative
risk of 3.5 times
in 5 yrs
P = 0.0012
Dip MBF Fig. 44.6  In patients with DCM and without overt
< 1.36 ml/min/g heart failure, the extent of myocardial blood flow
impairment at rest and during stress, measured by
PET, predicts cardiac death and/​or worsening of heart
failure at follow-​up.
al. Prognostic role of myocardial blood flow impairment
in idiopathic left ventricular dysfunction. Circulation 2002;
105(2): 186–​93.
668 CHAPTER 44   Dil ated cardiomyopat h y
Myocardial metabolic imaging
Myocardial metabolic imaging for the assessment of myocardial
metabolism using 18F-​fluorodeoxyglucose (FDG) in patients with
LV dysfunction is the most frequent clinical application of cardiac
PET. It can be combined either with a 13N-​NH3 PET or a SPECT
perfusion study. It allows identification of different characteristics
of the dysfunctional myocardium based on the relationship be-
tween glucose metabolism and perfusion at rest. Residual meta-
bolic activity is an indicator of myocardial viability and thus of
potential reversibility of myocardial dysfunction. Increased re-
gional FDG uptake relative to myocardial perfusion (perfusion/​
metabolism mismatch) indicates viability, while regional reduc-
tion of FDG uptake in proportion to perfusion (perfusion/​me-
tabolism match) indicates irreversibly damaged myocardium.
It was generally believed that the demonstration of a regional
‘match’ or ‘mismatch’ pattern in patients with newly discovered
LV dysfunction could help to identify a CAD aetiology. Actually,
regionally matched perfusion and metabolic defects, indicating
myocardial scar as well as regional flow metabolic ‘mismatch’
indicating ischaemia, can be frequently found in patients with
idiopathic DCM (E Fig. 44.7) [12]. However, data on the po-
tential prognostic meaning of these findings in idiopathic DCM
are still sparse.
The additional purpose of metabolic imaging in DCM is to
assess abnormalities of intermediate myocardial metabolism
that may further impair and/​or be a consequence of reduced
contractile performance of the myocardium. Myocardial free
fatty acid (FFA) metabolism is decreased and glucose me-
tabolism increased in patients with idiopathic DCM propor-
tionally to the severity of LV dysfunction. This compensatory
metabolic shift towards the more efficient fuel glucose, as well
as the effects of metabolic treatment, can be documented by
PET imaging using 11C-​glucose, 11C-​palmitate, and 11C-​acetate
[13, 14]. In idiopathic DCM, myocardial metabolism, as well
as myocardial perfusion, may not only globally, but also re-
gionally improve after chronic treatment with beta blockers.
Myocardial metabolic efficiency can be assessed by combining
the PET measurement of oxidative metabolic rate (washout
constant (k) from 11C-​acetate myocardial time–​activity curve)
and independent measurements of stroke work. Using this ap-
proach in patients with idiopathic DCM, oxidative metabolism
and metabolic efficiency were shown to be reduced in propor-
tion to the reduction of LV function and of the integrity of pre-
synaptic innervations as assessed using 11C-​hydroxyephedrine
PET imaging [15].
Sympathetic nerve imaging
Sympathetic nerve imaging can be performed with 123-​iodine
metaiodobenzylguanidine (123I MIBG) SPECT. 123I MIBG is an
imaging tracer that shares similar myocardial uptake, storage,
and release characteristics as endogenous norepinephrine in
sympathetic nerve endings. Cardiac sympathetic denervation
documented by this approach in patients with LV dysfunction is
associated with arrhythmias.
Hybrid imaging
Hybrid imaging with SPECT/​CT or PET/​CT scanners may ex-
pand the role of nuclear imaging in the evaluation of patients
with DCM in the near future. Thus, in addition to the func-
tional assessments obtained with SPECT and/​or PET (i.e. myo-
cardial perfusion, metabolism, and innervation), the new hybrid
SPECT-​PET/​CT technology allows non-​invasive anatomic exclu-
sion of underlying coronary atherosclerosis in the same session
(E Fig. 44.8) [3]‌. Moreover, the analysis of the ventriculographic
phase of CT could add a detailed evaluation of regional and
global ventricular function. Independently from the availability
of hybrid scanners, however, SPECT or PET may be combined
with multidetector CT in a new conceptual framework to pro-
vide a unique non-​invasive work-​up to exclude CAD, predicting
risk, addressing treatment, and testing its efficacy. Contemporary
rapid SPECT cameras and hybrid PET-​CT techniques, coupled
with the availability of new F-​18 fluorine-​labelled PET perfusion
tracer and new quantitative methods and software for image pro-
cessing, will most probably expand the use of nuclear cardiology
in the clinical characterization of early stages of the development
of DCM [22]. In addition, this approach might help to study the
relationships between non-​obstructive atherothrombosis, micro-
vascular disease and progressive myocardial dysfunction and to
evaluate new medical treatments targeted to alter or reverse the
progression of heart failure. Prospective outcome studies are war-
ranted to assess the value of this new approach in the evaluation
of patients with DCM also taking into account cost-​benefit and
radiation exposure issues.
Using imaging to detect identifiable
causes of DCM
DCM has a heterogeneous aetiology but the final phenotype of
ventricular dilatation and systolic impairment is often common
to multiple aetiologies. However, multimodality cardiac imaging
offers the potential to detect some particular causes of DCM,
which may change how a patient is clinically managed.
DCM and myocarditis
Myocarditis is strongly suspected when a previously healthy pa-
tient suddenly develops congestive cardiac failure, often after a
period of flu-​like illness. Following standardization of the histo-
pathological diagnosis of myocarditis by the Dallas criteria [53],
evidence of myocarditis in dilated cardiomyopathy varies between
18 and 55%. The therapeutic implications, however, are limited, as
the mere presence of inflammatory infiltrates does not necessarily
signify active myocarditis.
Myocarditis due to viral infection, is a more frequent finding in
DCM than is clinically obvious and can be identified as a cause of
disease in almost 10% of cases using endomyocardial biopsy [54].
Inflammatory DCM is defined by the presence of chronic inflam-
matory cells in association with LV dilatation and reduced EF;
histology and/​or immunocytochemistry are therefore necessary
 U si n g i m ag i n g to detect i den ti fia b l e cau se s   of   D C M 669

(a) NH3 Rest NH3 Dip FDG Post-Dip FDG Rest

(b)

B.L. (male, 56yrl) LVEDD 65mm, LV EF 35% LAD Stenosis 90%

IFC CNR

(c)

D.M. (male, 61yrs) LVEDD 59mm, LV EF 30% Normal Coronary Arteries

IFC CNR

Perfusion Metabolism Viability

Fig. 44.7  (a) Four PET images obtained in a patient with DCM by 13N-​NH3 and 18F-​FDG PET at rest and during dipyridamole stress showing a regional
‘mismatch’ pattern suggesting myocardial ischaemia. (b) Bull’s-​eye plots derived from 13N-​NH3 and 18F-​FDG PET studies of a patient with DCM, showing regional
flow-​metabolism ‘match’ and ‘mismatch’. (c) Bull’s-​eye plots of comparable PET studies obtained in a patient with CAD with poor LV function, demonstrating a
typical flow-​metabolism ‘match’ (green for normal and red for scar segments) and ‘mismatch’ (blue for viable segments).

for the diagnosis. Myocarditis increases the risk of sudden cardiac
death in young adults during sports, and accounts for approxi-
mately 10% of sudden cardiac death cases in macroscopically
normal hearts. The diagnosis may be difficult to establish and
is generally based on a diversity of clinical signs supported by
imaging and laboratory abnormalities. Endomyocardial biopsy
still is considered the gold standard for diagnosis, but this method
has limited sensitivity inherent to the focal nature of myocarditis.
Echocardiography in myocarditis
After the acute phase of myocarditis, the clinical course may be
highly variable, ranging from complete recovery of LV function to
670 CHAPTER 44   Dil ated cardiomyopat h y

(a) (b)

Fig. 44.8  (a) A perfusion 13N-​NH3 PET study at rest (row of upper images) and during dipyridamole stress (row of lower images), performed in a patient
with recent onset left bundle branch block (LBBB) and LV EF 38% to exclude CAD as a cause of LV dysfunction. A non-​reversible perfusion defect involving
the middle-​apical portions of the lateral wall is evident both at rest and during stress. (b) CT angiography performed soon after the PET study shows
angiographically normal coronary arteries allowing the diagnosis of DCM.

the development of overt DCM. There are no echocardiography
specific features of myocarditis that permit the discrimination of
a DCM phenotype due to myocarditis from a DCM phenotype
due to other aetiologies.
Cardiovascular magnetic resonance imaging in
myocarditis
Several CMR techniques are used in the non-​invasive detec-
tion of myocarditis, including T2-​ weighted oedema imaging,
T1-​weighted spin-​echo early gadolinium enhancement imaging
and LGE imaging [55, 56]. When these techniques were com-
pared in patients with clinically suspected acute myocarditis,
T2-​weighted imaging demonstrated the highest sensitivity and
LGE imaging the highest specificity (E Fig. 44.9). The best diag-
nostic accuracy, however, was obtained when any two of the three
techniques were positive in the same patient. Recommendations
on the use of CMR for myocarditis are summarized in expert con-
sensus documents [55, 57].
In the acute phase, several patterns of LGE have been reported.
Most commonly, LGE is seen in the lateral wall or septum,
involving the mid-​wall and/​or subepicardium (E Fig. 44.10;
z Video 44.4).
CMR can also help to identify patients who have a DCM
phenotype who may have had a previous myocarditis to explain
the aetiology of the DCM. In patients with an overt DCM pheno-
type the presence of subepicardial LGE in the basal LV lateral wall
is suggestive of a healed myocarditis.
Differences in sensitivity of CMR techniques presumably are
related to temporal changes of the inflammatory and healing pro-
cess. Histologically, oedema and islets of necrosis are dispersed

(a) (b)

Fig. 44.9  Short-​axis late gadolinium

enhancement images of two patients
with heart failure, dilated LV, and poor
EF. (a) A patient with DCM; a small
rim of subtle intraseptal mid-​wall
hyperenhancement that is observed
in one-​third of patients with DCM,
indicating replacement fibrosis. (b) A
patient with coronary artery disease;
a bright subendocardial pattern of
hyperenhancement, typical of ischaemic
origin due to coronary artery disease.
 U si n g i m ag i n g to detect i den ti fia b l e cau se s   of   D C M
(a) (c)
(b) (d)
throughout the myocardium in the acute and subacute phase
of inflammation and ongoing healing of the myocardium.
Depending on the time window after onset of inflammation,
oedema-​sensitive T2-​weighted signal, or necrosis and fibrosis
sensitive LGE signal may both concur or one of the two may pre-
vail. After healing, LVEF and dimensions often restore, and the
areas of hyperenhancement almost completely resolve. Similar
to the shrinkage of myocardial infarct size in the chronic phase,
shrinkage of the islets of fibrotic areas to sizes smaller than the
dimensions of a voxel has been suggested as an underlying mech-
anism of the resolution of hyperenhancement. However, in some
patients in whom LV dysfunction and dilation persists, a small
remnant mid-​wall rim of subtle hyperenhancement may be ob-
served that was shown to be associated with biopsy proven ac-
tive and borderline myocarditis according to the Dallas criteria.
This mid-​wall rim is more often found in patients with idiopathic
DCM and may reflect patchy areas of replacement fibrosis after
sustained myocarditis, but has also been associated with in-
creases depositions of myocardial interstial fibrosis associated
with progressive LV dilation, in the absence of signs of persistent
inflammation. Importantly, the presence of LGE in patients
with suspected myocarditis has shown to be a strong prognostic
marker for major adverse cardiovascular events (hazard ratio for
671
Fig. 44.10  A patient presenting with
clinical signs of acute myocarditis.
(a) Late gadolinium enhancement
(LGE) image of a three-​chamber view
demonstrating a slightly dilated LV and
focal, subepicardial enhancement of
the inferolateral wall, indicating fibrosis
or oedema, see arrowheads. (b) The
same three-​chamber view showing
that the hyperenhanced myocardial
areas on the LGE image also have a
high signal intensity on a T2-​weighted
image indicating oedema as a result of
active inflammation. (c) LGE short-​axis
view of the same patient with typical
epicardial hyperenhancement. (d)
T2-​weighted short-​axis image of the
same patient with high signal intensity
indicating oedema.
MACE 2.2 with the presence of LGE; septal and mid-​wall LGE
showed strongest associations with outcome) [58]. A normal
CMR study corresponds to low annual MACE (0.8%) and death
rates (0.3%) [58].
SPECT imaging, coupled with imaging agents of chronic in-
flammation or labelled antibodies, may be used in myocarditis
and inflammatory DCM [28]. 67Gallium citrate scintigraphy
has been tested in DCM patients showing that 87% of patients
with histologically proven myocarditis had a positive 67Gallium
scan, while histology was positive only in 1.8% in the negative
scintigraphic group. Indium-​111 radiolabelled antimyosin anti-
bodies have been shown to detect myocardial necrosis in human
myocarditis. Using planar and SPECT cardiac imaging, the sen-
sitivity of antimyosin imaging for the detection of histologically
proven myocarditis is very high (91–​100%) with a high negative
predictive value (93–​100%). By contrast, the specificity and posi-
tive predictive value of this approach are below 50%. However, a
positive antimyosin scan can predict more accurately than myo-
cardial biopsy a subsequent improvement in EF in acute onset
DCM patients. Limitations to this technique include its current
limited availability, radiation exposure, and 48-​hour delays in
obtaining imaging after injection to prevent interference of blood
pool signal (E Figs. 44.11 and 44.12).
672 CHAPTER 44   Dil ated cardiomyopat h y
Fig. 44.11  A patient with sarcoidosis who presented with recurrent
ventricular tachycardia (VT). Echocardiography showed proximal septal
thinning and akinesia. It also showed very echogenic myocardium, likely
suggestive of scar. The distal septum and apex were contracting normal.
DCM and Chagas’ disease
Chagas’ disease is an inflammatory infectious disease caused by
the parasite Trypanosoma cruzi and is endemic in South America.
The clinical course of the disease can be subdivided into three
stages: an acute stage with fever and headache, an indeterminate
(a)
Fig. 44.12  Late gadolinium
enhancement (LGE) in patient with
cardiac sarcoidosis. (a) LGE two-​
chamber view image showing multiple
focal areas of hyperenhancement
observed in the epicardium and mid-​
wall, which partially become confluent
and transmural. (b) LGE four-​chamber
view image of the same patient
demonstrating the extent of scarring also
present in the lateral wall and septum.
phase in which patients are asymptomatic, and a chronic phase
in which the heart is the most frequently affected organ, resulting
in heart failure and the onset of potentially life-​threatening ven-
tricular arrhythmias. This cardiac involvement develops in 30–​
40% of patients, sometimes decades after the initial infection.
DCM is the most severe manifestation of the disease. The prompt
use of cardiac imaging is required to detect this and other com-
plications, however most patients with this disease live in regions
with limited access to advanced imaging modalities.
Echocardiography in Chagas’ disease
Echocardiography therefore remains the mainstay imaging inves-
tigation to diagnose complications and risk stratify patients with
Chagas disease [59].
In the early stage of disease, echocardiography may identify
regional wall motion abnormalities (commonly in the basal in-
ferior and inferolateral walls and the apex). Speckle tracking
echocardiography may have particular value in identification of
these regional wall motion abnormalities. In addition to standard
2D echocardiography, 3D echocardiography may permit better
visualization of the LV apex for detection of apical aneurysms.
Together with contrast echocardiography, this may also permit
detection of apical thrombus. Right ventricular impairment is not
uncommon, but often occurs later in the disease course.
Nuclear imaging in Chagas’ disease
Radionuclide functional imaging with equilibrium radionuclide
ventriculography (ERNV) and perfusion imaging by SPECT may
detect LV regional wall motion abnormalities and perfusion de-
fects in the absence of epicardial CAD, particularly in patients
with limited acoustic windows but contraindications to CMR.
Cardiovascular magnetic resonance imaging in
Chagas’ disease
Localized aneurysm formation can be detected using SSFP cine
imaging with predilection sites at the apex and basal inferolateral
wall, which are difficult to evaluate with echocardiography (see
z Video 44.5).
(b)

(a) (b)
Myocardial fibrosis is a striking feature of Chagas cardiomyop-
athy. Using LGE imaging, areas of predominantly subendocardial
LGE can be observed within these regions in 20% of seropositive
patients within the indeterminate phase of the disease, 85% with
clinical Chagas’ cardiomyopathy, and 100% with Chagas’ cardio-
myopathy and ventricular tachycardia (E Figs. 44.13 and 44.14)
[60]. The late enhancement pattern is indistinguishable from the
(a)
(b)
D CM a n d Chag as’ di se ase 673
Fig. 44.13  Chronic stage of Chagas’
disease with cardiac involvement.
(a) SSFP two-​chamber view cine
image. The aneurysms at the apex
and inferior wall result from recurrent
episodes of inflammatory disease.
(b) Late gadolinium enhancement
four-​chamber view image. Within the
apical aneurysm a subendocardial
rim of hyperenhancement due to
fibrosis is visible.
ischaemic pattern, and predilection sites are thought to be ter-
minal portions of the microcirculation, which are most vulner-
able to become ischaemic in recurrent episodes of inflammatory
disease and subsequent vasodilatation. Myocardial fibrosis might
have a role in risk stratification of patients with Chagas disease
[59]. Also, early gadolinium imaging allows visualization of
thrombus formation that may develop within the aneurysms.
Fig. 44.14  (a) A perfusion 13N-​
NH3 PET study performed at rest
(upper row of images) and during
dipyridamole stress (lower row of
images) in a patient with an active
phase of Churg–​Strauss disease. A
perfusion defect involving the basal
portion of the lateral wall is evident
in both conditions, while a stress-​
induced perfusion defect is present
in the middle and apical portions of
the anterior wall of the LV. (b) The
resting 13N-​NH3 perfusion images are
compared with 18F-​FDG metabolic
images. The tracer is injected after
oral glucose loading on another day
in a typical viability study. Extensive
‘mismatch’ pattern (blue segments)
indicating ischaemia is evident in
the anterolateral wall of the LV with
some ‘match’ areas (red segments)
indicating myocardial necrosis.
674 CHAPTER 44   Dil ated cardiomyopat h y
DCM in neuromuscular disorders
In addition to conduction disorders, cardiac muscle involve-
ment leading to progressive DCM is common in neuromus-
cular disorders and occurs in up to 90% and 70% of patients with
Duchenne (DMD) and Becker muscular dystrophy (BMD), re-
spectively. Cardiomyopathy has become the main cause of death
in these patients, even though clinically overt heart failure may
be absent. Female carriers of DMD are largely asymptomatic but
may develop DCM.
Echocardiography in neuromuscular disorders
In patients with Duchenne muscular dystrophy, and presumably
other familial forms of DCM, tissue Doppler imaging (TDI) can
be employed to detect early LV dysfunction, prior to any clinical
manifestation of heart failure [61]. This may have therapeutic im-
plications while early treatment might prevent LV remodelling.
TDI may be used to detect regional or global myocardial dysfunc-
tion, particularly in patients with normal LV dimensions. Early
ventricular dysfunction affects predominantly the longitudinal
function of the left ventricle, which can better be assessed from
apical projections. TDI is ideally suited to assess the LV longi-
tudinal function by measuring mitral annular velocities, as well
as myocardial velocity gradients or LV strain and strain rate.
Doppler-​based strain imaging has found only limited access into
clinical practice due to several limitations, including angle de-
pendency, a low signal-​to-​noise ratio, limited spatial resolution,
and potential interactions by cardiac translational motion and
tethering.
Tracking of acoustic markers (speckles) from frame-​ to-​
frame on the basis of 2D-​echocardiography can now accurately
Fig. 44.15  Apical four-​chamber
view from a patient with DCM.
Using speckle tracking, it is possible
to quantify the longitudinal strain in
every segment and express it as global
longitudinal strain (dotted line). In this
case, strain is markedly reduced.
determine regional and global LV function. This novel technique
overcomes most of the limitations of conventional Doppler-​based
strain imaging (E Fig. 44.15).
Cardiovascular magnetic resonance imaging in
neuromuscular disorders
In addition to quantification of LV volumes and function, CMR
is useful in the detection of oedema in cardiomyopathy associ-
ated with neuromuscular disorders. This can be done qualita-
tively with oedema imaging such as STIR or quantitatively with
T2 mapping. A hallmark of early DMD is subepicardial fibrosis
in the inferolateral wall of the LV. This can often be found early in
the disease process in the presence of preserved LV function [62].
Myocardial fibrosis in DMD patients is associated with impaired
LVEF on follow-​up [63].
DCM and cardiotoxic agents
Alcohol and the heart
A variety of substances can affect the heart leading to DCM,
though there are no distinguishing features of these toxins on
echocardiography and the clinical history and other investiga-
tions are required to discriminate these aetiologies. Perhaps the
commonest toxin is alcohol. Macrocytosis is a useful indicator of
chronically high alcohol consumption, even in the absence of ab-
normal liver function. A raised gamma-​glutamyltransferase may
be an indicator of only recent rather than long-​term alcohol in-
take, whereas raised levels of other liver enzymes may be due to
chronic alcohol hepatitis.
There is an individual susceptibility to the adverse effects
of alcohol on the myocardium, which may well be genetically

(a) (b)
predisposed [64]. The heart is typically markedly dilated with
global ventricular dysfunction and it may show dramatic im-
provement after a patient has stopped excessive alcohol consump-
tion [65]. Therefore, evaluation of LV dimensions and function is
recommended 6 months after alcohol abstinence. Alcoholic car-
diomyopathy has a better prognosis than idiopathic DCM [66].
Chemotherapy and the heart
Cardio-​oncology is an emerging field, dedicated to the assess-
ment and management of cardiovascular disease in patients with
cancer. Cardiac imaging, and in particular, echocardiography,
plays an essential role in the baseline and serial assessment of
cardio-​oncology patients. The cardiotoxic effect of LV dysfunc-
tion is particularly relevant to the phenotype of DCM.
Cancer therapeutics-​related cardiac dysfunction (CTRCD)
is defined as a drop in LVEF of ≥5% in symptomatic patients
or a drop in LVEF of ≥10% to an EF of <53% in asymptomatic
patients [67].
Anthracyclines such as doxorubicin, daunorubicin, idarubicin,
and epirubicin, are widely used for treatment of malignancies
and have a dose-​related cardiac toxicity. Type 1 CTRCD is a
largely irreversible, dose dependent toxicity usually secondary to
anthracyclines. Clinically, patients present with a DCM pheno-
type. Patients can present within the first year of treatment, or
develop a late-​onset progressive phenotype that can present even
1–​2 decades after treatment.
The incidence of congestive heart failure is less than 5% with
cumulative anthracycline exposure of less than 250 mg/​m2; ap-
proaches 10% at doses between 250 mg/​m2 and 600 mg/​m2; and
exceeds 30% for doses higher than 600 mg/​m2 for survivors of
childhood cancer [68]. In addition, mediastinal irradiation, young
age at exposure, female sex, and genetic susceptibility are known
risk factors for the development of anthracycline cardiotoxicity.
Type 2 CTRCD is largely reversible and not dose dependent,
and is most often associated with trastuzumab cardiotoxicity
(commonly used in the treatment of breast cancer) and, to a lesser
extent, other agents such as lapatinib, pertuzumab, imatinib,
sorafenib, sunitinib, bevacizumab, and bortezomib.
D CM a n d Chag as’ di se ase 675
Fig. 44.16  Late gadolinium
enhancement (LGE) imaging in
a patient with Becker’s muscular
dystrophy. (a) LGE three-​chamber
view. (b) LGE short-​axis view.
Hyperenhancement is predominantly
apparent in the basal lateral wall
and to a lesser degree in the
interventricular septum.
The risk of cardiotoxicity to the myocardium is higher in the
presence of multiple risk factors such as pre-​existing cardio-
vascular disease (CAD, heart failure, and arrhythmias), cardio-
vascular risk factors (age, hypertension, diabetes mellitus, and
hyperlipidaemia), drug choice, and delivery, and other concur-
rent drugs such as cyclophosphamide and paclitaxel [69].
A comprehensive baseline echocardiogram with strain imaging
prior to chemotherapy and regular surveillance echocardiography
during chemotherapy are recommended [67]. The European and
American guidelines recommend assessing GLS as a routine com-
ponent of clinical echocardiograms in patients at risk for type 1 or
type 2 cardiotoxicity, due to its ability to detect subclinical cardiac
dysfunction (indicated by a relative percentage decrease in GLS
>15%; 8–​15% is a grey zone; <8% relative change suggests no sub-
clinical LV dysfunction) [67].
Echocardiography is recommended as the first-​line imaging
modality for serial assessment of LVEF in patients undergoing
chemotherapy due to its widespread availability. 3D echocardiog-
raphy gives more accurate estimations of LV volumes and func-
tion than 2D echo but it is not as widely available as 2D echo and
requires additional training. Stress echocardiography is indicated
for the evaluation of inducible ischaemia in patients at risk or
with high pretest probability of CAD.
For multimodality assessment of LVEF, CMR, and gated
SPECT and radionucleotide ventriculography can also be used
[70]. As well as providing highly accurate and reproducible meas-
ures of LVEF, CMR has the additional benefit of providing infor-
mation on myocardial fibrosis including concomitant myocardial
infarction. CMR is also useful for detailed tissue characterization
using T1 and T2 mapping, evaluation of cardiac masses, as well
as assessment of the pericardium [71]. Pericardial constriction is
a rare but noted side effect of cancer treatment. The downside of
CMR globally is limited access due to cost and availability. The
downside of nuclear techniques in this context is the radiation
exposure. Whichever modality is selected at baseline should be
used for subsequent serial assessments. Any deterioration in LV
function during chemotherapy requires prompt evaluation by a
cardiologist, ideally with expertise in cardio-​oncology. The goal
676 CHAPTER 44   Dil ated cardiomyopat h y
of monitoring is to detect early toxicity to enable prompt in-
stitution of heart failure medications and for review/​cessation
of chemotherapeutic agents. In the case of Type 2 CTRCD, the
offending agent can often be reintroduced when LV function has
normalized.
DCM associated with pregnancy and
parturition
Peripartum cardiomyopathy is an idiopathic cardiomyopathy
presenting with heart failure secondary to LV systolic dysfunc-
tion towards the end of pregnancy or in the months following
delivery, when no other cause of heart failure is found [72]. The
majority of patients who are diagnosed during pregnancy de-
velop heart failure in the third trimester. In the United States,
its incidence has been estimated at between one in 900 and 1 in
4,000 live births [73]. Because of the low incidence, limited data
is available on the aetiology of disease. It is currently thought
that peripartum cardiomyopathy (PPCM) develops in a ‘two hit’
model of a vascular insult caused by antivascular or hormonal
effects of late pregnancy and the early postpartum period on a
background of underlying susceptibility, such as genetic predis-
position [74]. It is more common in black women and increased
maternal age is an independent risk factor. Other reported
risk factors include hypertension, anaemia, substance misuse,
asthma, autoimmune disease, pre-​eclampsia or eclampsia, and
multiple gestation [73].
Approximately 50–​80% of women with PPCM recover to normal
range left ventricular systolic function (LVEF ≥50%), with most of
this recovery occurring within the first six months [75, 76].
Echocardiography in peripartum cardiomyopathy
The echocardiographic findings can be of a dilated or a non-​dilated
left ventricle with global hypokinesia (increased end-​systolic di-
mensions). LV thrombus needs to be excluded, as this will carry a
high risk for embolization and requires anticoagulation therapy.
LV size and EF at the time of diagnosis most strongly predict LV
recovery [76].
(a)
Fig. 44.17  A patient with isolated
left ventricular non-​compaction
cardiomyopathy demonstrating
a meshwork of trabeculae
predominantly in the apex. The
end-​diastolic non-​compacted to
compacted ratio exceeds 2.3. (a) SSFP
cine short-​axis view. (b) SSFP cine
two-​chamber  view.
Cardiovascular magnetic resonance imaging in
peripartum cardiomyopathy
Although non-​contrast CMR is probably safe during pregnancy
[77], it should only be used when acoustic windows do not allow
sufficient image quality with echocardiography. Gadolinium con-
trast should be avoided in pregnancy but can be used if potential
benefit outweighs risk, this is however likely to be a rare scen-
ario. Unlike in idiopathic DCM, mid-​wall fibrosis is much less
common (~5% in the IPAC and other series [76, 78]) and its sig-
nificance in PPCM is uncertain, with limited data suggesting it
may hinder recovery.
Isolated left ventricular non-​compaction
As genetic evidence emerges, there is no consensus on whether
left ventricular non-​compaction (LVNC) is a separate cardiomy-
opathy, or merely a congenital or acquired morphological trait
shared by many phenotypically distinct cardiomyopathies [52].
Apical hypertrabeculation is increasingly detected in patients
with DCM, particularly with improved visualization of the apex
afforded by CMR. The clinical conundrum is distinguishing what
is within the spectrum of normal versus what represents a distinct
entity of LVNC.
It is macroscopically characterized by an extensive layer of non-​
compacted myocardium aligning a compact layer of myocardium
and is typically located in the apical and lateral regions of the left
ventricle. Patients with isolated LV non-​compaction often suffer
from heart failure as first symptom of disease, but are also prone
to thromboembolic events, since the hypertrabecularization is be-
lieved to be a risk factor for cardiac thrombus formation. Isolated
LV non-​compaction may be present in neonates and children, but
also in young adults. It is rarely diagnosed for the first time in
middle or advanced ages.
Echocardiography in non-​compaction cardiomyopathy
The diagnosis is made by echocardiography in the vast majority of
patients by the combination of the clinical presentation of breath-
lessness or palpitations and the echocardiographic appearance
(b)

(a)
Fig. 44.18  Myocardial crypts in the inferoseptal wall as observed in genetically proven carrier of a hypertrophic cardiomyopathy mutation without overt
hypertrophy. The appearance is clearly distinct from hypertrabecularization in non-​compaction cardiomyopathy (see Fig. 44.17). (a) SSFP end-​diastolic cine
short-​axis view with a dashed line through a bright, blood containing triangle in the inferoseptum indicating the transsection of modified two-​chamber view to
best visualize the crypts. (b) In the SSFP cine end-​diastolic modified two-​chamber view, the crypts are clearly visible in the inferoseptum, see arrow heads.
of a coarsely trabeculated left ventricle, often localized towards
the apex and presenting with subendocardial recesses. Jenni et al.
proposed the following criteria: (1) no coexisting abnormalities;
(2) a two-​layered myocardial structure with a thin compacted
epicardial band and a thick non-​compacted endocardial layer of
trabecular meshwork with deep endomyocardial spaces with a
non-​compacted/​compacted ratio of 2.0 in end-­​­systole; (3) non-​
compaction predominantly in the mid-​lateral, mid-​inferior, and
apical segments; (4) colour Doppler evidence of deep-​perfused
intertrabecular recesses [79]. This is best visualized in the apical
four-​chamber and parasternal short-​axis views. Because of the
limitations of 2D-​echocardiography to visualize the cardiac apex,
the use of transvenous contrast agents will improve the visualiza-
tion of apical recesses. With the dissemination of transthoracic
three-​dimensional echocardiography the cardiac apex can also be
better identified and the myocardial recesses better visualized.
Nuclear imaging in non-​compaction cardiomyopathy
PET with 13N-​NH3 has been shown to demonstrate restricted
myocardial perfusion and decreased flow reserve in these myo-
cardial areas in children. The myocardial perfusion defects may
contribute to myocardial damage and possibly to cause arrhyth-
mias and pump failure.
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RE F E RE N C E S 677
(b)
Cardiovascular magnetic resonance imaging in
non-​compaction cardiomyopathy
With the advent of high-​resolution imaging techniques such as
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stricter criteria for diagnosis of non-​compaction than the previ-
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between CMR images of patients with several forms of cardiomy-
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compacted to compacted ratio >2.3 in end-​diastole has been pro-
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9 For additional multimedia materials please visit the online version of the book at M oxfordmedicine.com/esccvimaging3
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Contents
Arrhythmogenic right ventricular
cardiomyopathy (ARVC)  681
Introduction and definitions  681
Criteria for diagnosis of ARVC  681
Echocardiography  682
Cardiac magnetic resonance  682
Functional evaluation  682
Morphological evaluation  684
Delayed enhancement  685
CMR limitations  685
Other imaging techniques  685
Histological demonstration of fibro-​fatty
replacement of myocardium  686
Repolarization and depolarization/​
conduction abnormalities  686
Family history  687
Conclusions  687
Left ventricular non-​compaction
(LVNC)  688
Introduction  688
Aetiology  688
Clinical presentation  688
Diagnostic criteria  688
Treatment  689
Takotsubo cardiomyopathy (stress
cardiomyopathy)  689
Introduction and definitions  689
Diagnosis  689
Echocardiography  689
Cardiac magnetic resonance  691
Conclusions  691
CHAPTER 45
Other genetic and acquired
cardiomyopathies
Kristina Haugaa and Perry Elliott
Arrhythmogenic right ventricular
cardiomyopathy (ARVC)
Introduction and definitions
Arrhythmogenic right ventricular cardiomyopathy is an inherited, progressive cardio-
myopathy associated with high risk of ventricular tachycardia associated with right-​sided
structural disorders. More recent reports have shown that although the right ventricle
(RV) is most often affected, the left ventricle (LV) is also commonly involved [1]‌. This has
led to the more recent term arrhythmogenic cardiomyopathy (AC).
Men are more frequently affected than women and it is usually diagnosed between
the second and fourth decade of life. The most common presentation is ventricular ar-
rhythmia, specifically ventricular tachycardia originating from the RV with a character-
istic left bundle-​branch block (LBBB) morphology. ARVC is also an important cause of
sudden death in individuals <30 years of age and has been found in up to 20% of sudden
deaths in young individuals [2]‌. Furthermore, ARVC is more common in athletes and
disease expression is associated with high intensity exercise [3–​5].
ARVC is a genetic trait disease with variable penetrance and incomplete expression.
The first gene mutations were identified in a recessive, syndromic variant of ARVC
known as Naxos disease caused by variants in the gene encoding plakoglobin [6, 7], a
component of cell-​to-​cell junctions. This discovery led to the identification of disease-​
causing mutations in other genes encoding desmosomal proteins in the more common
autosomal dominant forms of ARVC [8]‌. Latterly, very similar clinical phenotypes have
been identified in patients with mutations in non-​desmosomal genes, including titin [9],
desmin [10], and lamin [11].
ARVC is characterized by replacement of myocardial tissue in the right ventricular
wall by adipose tissue and fibrosis that starts on the right ventricular subepicardium and
progresses to the endocardium with replacement of myocytes and thinning of the wall
(E Fig. 45.1).
When the LV is also involved, the fibro-​fatty replacement can affect both the septum
and left ventricular free wall.
Criteria for diagnosis of ARVC
The non-​specific nature of most clinical findings and the absence of a single diagnostic
test make the diagnosis of ARVC extremely challenging. In 1994 an International Task
Force guideline proposed standardized diagnostic criteria based upon the identifica-
tion of structural, morphological, electrocardiographic (ECG), and arrhythmic features
682 CHAPTER 45   Other genet ic and ac qu ired ca rdi o m yopathi es
Fig. 45.1  Left panel: Apical four-​chamber demonstrating the discrete aneurysm at the apex (arrow).
Right panel: Apical four-​chamber view from ARVC patient demonstrating the markedly dilated RV and with normal LV size. The colour Doppler demonstrating
the presence of severe tricuspid regurgitation secondary to the marked dilatation of the tricuspid annulus. Notice the low velocity flow as seen by the deep blue
colour of the velocity jet.
and the evaluation of families [12]. These criteria were updated
in 2010 (E Box 45.1) using the same basic scheme, and adding
quantitative values for cardiac function and volumes [13]:
The diagnosis of ARVC is considered based on the following
criteria:
◆ Definite: two major, or one major and two minor, or four
minor criteria from different diagnostic categories.
◆ Borderline diagnosis: one major and one minor or three minor
criteria from different diagnostic categories.
◆ Possible diagnosis: one major or two minor criteria from dif-
ferent diagnostic categories.
Echocardiography
Echocardiography is the most used method to diagnose and
follow patients with ARVC. However, the RV is difficult to
image using echocardiography because of its proximity to the
anterior chest wall and its complex shape and orientation.
Echocardiography should be performed with specific focus on
the RV, carefully assessing dimensions and function including
the RV inflow and outflow views [14]. Strain echocardiography
can identify subtle RV and LV abnormalities and help detec-
tion of early structural changes in ARVC disease (E Fig. 45.2).
Subtle RV free wall dysfunction can be detected in early dis-
ease together with an increased mechanical dispersion [15].
Furthermore, the regional dysfunction in the RV inflow tract
can be detected by strain echocardiography showing a systolic
stretch in the RV basal segment [16, 17]. Strain echocardiog-
raphy may help risk stratification for ventricular arrhythmias in
early phases of ARVC disease [18].
At more advanced disease stages, the more obvious and path-
ognomonic abnormalities are those of localized aneurysmal re-
gions in the form of systolic bulging (E Fig. 45.1). In the most
advanced stage of ARVC, extended areas of RV free wall may be-
come thin and akinetic, which, together with RV dilatation, will
form the ‘typical’ pattern of ARVC. Ultimately, the whole of the
RV will be thinned, dilated, and hypokinetic.
The LV can be involved at any stage of the disease and left dom-
inant forms are reported. In left dominant forms, the phenotype
can mimic dilated cardiomyopathy and is often accompanied
by severe and frequent ventricular arrhythmias. The differential
diagnosis with pulmonary hypertension is assisted by estimation
of the RV systolic pressures.
Cardiac magnetic resonance
Cardiovascular magnetic resonance overcomes some of the dif-
ficulties of echocardiography by providing three-​ dimensional
visualization of the heart and other thoracic structures. It also
provides a method for detecting fat and fibrosis using tissue char-
acterization, but since the RV wall is very thin, partial volume ef-
fects can affect the image and differentiation between pericardial
fat, and fatty infiltration of the RV can be difficult. First reports
[19, 20] included T1-​weighted spin echo images showing bright
signal intensity corresponding to RV free wall fatty infiltration.
After a period of initial enthusiasm that almost gave cardiac mag-
netic resonance (CMR) the same value as histology for the detec-
tion of fat replacement [21, 22], the role of CMR in the detection
of fat was redefined. Since fat infiltration has been described in
normal hearts and given that CMR tissue of fat signals (particu-
larly in the thin walled RV) is often difficult, the clinical and diag-
nostic utility at present is limited [23].
CMR abnormalities described in patients with ARVC
(E Table 45.1) can be divided into two groups: functional ab-
normalities and morphological changes.
Functional evaluation
As with echocardiography, among functional abnormalities de-
scribed by CMR in ARVC, dilatation and RV systolic dysfunc-
tion are most commonly found in patients who meet Task Force
 Arrh y thmo g en i c ri g ht ven tri cu l a r ca rdi o m yopat h y   ( A RVC ) 683

Box 45.1  2010 Task Force criteria for the diagnosis of ARVC
I  Global and/​or regional dysfunction and structural alterations
MAJOR
By 2D echo: Regional RV akinesia, dyskinesia, or aneurysm and one of the following (end-​diastole):
—​PLAX RVOT ≥ 32 mm (corrected for body size [PLAX/​BSA] ≥19 mm/​m2)
—​PSAX RVOT ≥36 mm (corrected for body size [PSAX/​BSA] ≥21 mm/​m2)
—​or fractional area change ≤33%
By MRI: Regional RV akinesia or dyskinesia or dyssynchronous RV contraction and one of the following:
—​Ratio of RV end-​diastolic volume to BSA ≥110 ml/​m2 (male) or ≥100 ml/​m2 (female)
—​or RV ejection fraction ≤40%
By RV angiography: Regional RV akinesia, dyskinesia, or aneurysm
MINOR
By 2D echo: Regional RV akinesia or dyskinesia and 1 of the following (end-​diastole):
—​PLAX RVOT ≥29 to <32 mm (corrected for body size [PLAX/​BSA] ≥16 to <19 mm/​m2)
—​PSAX RVOT ≥32 to <36 mm (corrected for body size [PSAX/​BSA] ≥18 to <21 mm/​m2)
—​or fractional area change > 33% to ≤40%
By MRI: Regional RV akinesia or dyskinesia or dyssynchronous RV contraction and one of the following:
—​Ratio of RV end-​diastolic volume to BSA ≥100 to <110 ml/​m2 (male) or ≥90 to <100 ml/​m2 (female)
—​or RV ejection fraction > 40% to ≤45%
II  Tissue characterization of walls
MAJOR
Residual myocytes <60% by morphometric analysis (or <50% if estimated), with fibrous replacement of the RV free wall
myocardium in ≥1 sample, with or without fatty replacement of tissue on endomyocardial biopsy
MINOR
Residual myocytes 60% to 75% by morphometric analysis (or 50% to 65% if estimated), with fibrous replacement of the
RV free wall myocardium in ≥1 sample, with or without fatty replacement of tissue on endomyocardial biopsy
III  Repolarization abnormalities
MAJOR
Inverted T-​waves in right precordial leads (V1, V2, and V3) or beyond in individuals >14 years of age (in the absence of
complete right bundle-​branch block QRS ≥120 ms)
MINOR
Inverted T-​waves in leads V1 and V2 in individuals >14 years of age (in the absence of complete right bundle-​branch
block) or in V4, V5, or V6
Inverted T-​waves in leads V1, V2, V3, and V4 in individuals >14 years of age in the presence of complete right bundle-​branch block
IV  Depolarization/​conduction abnormalities
MAJOR
Epsilon wave (reproducible low-​amplitude signals between end of QRS complex to onset of the T wave) in the right pre-
cordial leads (V1 to V3)
MINOR
Late potentials by signal-​averaged electrocardiography (SAECG) in ≥1 of 3 parameters in the absence of a QRS dur-
ation of ≥110 ms on the standard ECG: filtered QRS duration (fQRS) ≥114 ms; duration of terminal QRS <40 µV (low-​
amplitude signal duration) ≥38 ms; root-​mean-​square voltage of terminal 40 ms ≤20 µV
Terminal activation duration of QRS ≥55 ms measured from the nadir of the S wave to the end of the QRS, including R’,
in V1, V2, or V3, in the absence of complete right bundle-​branch block
V  Arrhythmias
MAJOR
Non-​sustained or sustained ventricular tachycardia of left bundle-​branch morphology with superior axis (negative or in-
determinate QRS in leads II, III, and aVF and positive in lead aVL)
MINOR
Non-​sustained or sustained ventricular tachycardia of RV outflow configuration, left bundle-​branch block morphology
with inferior axis (positive QRS in leads II, III, and aVF and negative in lead aVL) or of unknown axis
> 500 ventricular extrasystoles per 24 hours (Holter)
684 CHAPTER 45   Other genet ic and ac qu ired ca rdi o m yopathi es

Box 45.1 Continued
VI  Family history
MAJOR
ARVC confirmed in a first-​degree relative who meets current Task Force criteria
ARVC confirmed pathologically at autopsy or surgery in a first-​degree relative
Identification of a pathogenic mutation categorized as associated or probably associated with ARVC in the patient under
evaluation
MINOR
History of ARVC in a first-​degree relative in whom it is not possible or practical to determine whether the family member
meets current Task Force criteria RVC/​D confirmed pathologically or by current Task Force criteria in second-​degree
relative

criteria. Other abnormalities include regional wall motion ab-
normalities (hypokinesia or akinesia) and focal aneurysm with
persistent diastolic bulging (E Box 45.1). CMR allows the evalu-
ation of RV volumes as well as global and regional function.
ECG-​gated breath-​hold gradient echo sequences (steady-​state
free-​precession) achieve an excellent contrast between blood and
myocardium with good delineation of RV endocardial borders.
Image planes include classical long-​axis cardiac views, as well as
RV outflow tract (RVOT), short-​axis and axial images from the
level of the RVOT to the diaphragm RV volume and systolic func-
tion are calculated from serial short-​axis cine loops tracing end-​
diastolic and end-​systolic areas. RV volumes and ejection fraction
(EF) should be matched according to age, sex, and body surface
area. Wall motion abnormalities are subjectively assessed in order
to detect localized aneurysms defined as akinetic or dyskinetic
regions of the RV wall showing diastolic bulging. Since normal
variations of RV regional function are frequently seen in healthy
subjects, especially on axial planes and near moderator band
insertion [24], the significance of their presence should be inter-
preted with caution.
Morphological evaluation
Morphological abnormalities include focal wall thinning,
moderator band or trabeculae hypertrophy, RVOT enlarge-
ment, and intramyocardial fibro-​fatty infiltration. Although
a first approach to wall thickness and RVOT diameter can
be done using previously described ECG-​gated fast gradient
echo sequences, a better spatial resolution is achieved by the
use of black-​blood spin echo sequence. Current black-​blood
sequences use a breath-​hold fast spin echo with a dual mag-
netization preparation pulse (double inversion-​ recovery),
which provides end-​diastolic T1-​weighted images for detailed
morphological analysis. Fat infiltration is also evaluated with
this sequence; since signal intensity of fat on T1-​weighted im-
ages is high (bright), much higher than normal myocardium,
the presence of a bright focal or diffuse area within the right

Fig. 45.2  Mechanical dispersion as predictor of ventricular arrhythmias in two patients with ARVC. Left panel: strain curves from three different
echocardiographic views of a healthy individual. All strain curves show a uniform coordinated contraction and relaxation pattern. The bullseye plot shows
homogeneous timing of contraction in all LV segments (green colour). Right panel: strain curves of an ARVC patient with ventricular arrhythmias. The strain
curves show non-​uniform contraction leading to increased dispersion of contraction (mechanical dispersion). The bullseye plot shows heterogeneous timing of
LV segmental peak shortening (yellow and red coloured segments).
 Arrh y thmo g en i c ri g ht ven tri cu l a r ca rdi o m yopat h y   ( A RVC )
Table 45.1  CMR findings on ARVC
Task Force criteria
Major
Functional abnormalities
Severe RV dilatation +
RV severe systolic dysfunction without +
LV involvement
Localized RV aneurysm (akinetic, +
dyskinetic areas with diastolic bulging)
Severe segmental RV dilatation +
Mild global RV dilatation
Mild RV ejection fraction reduction
Mild segmental dilatation RV
Regional RV hypokinesia
Morphological abnormalities
RV free wall thinning
RV moderator band or trabeculae
hypertrophy
RVOT enlargement
RV fat infiltration
Delayed enhancement (intramyocardial
fibrosis)
CMR = cardiac magnetic resonance; ARVC = arrhythmogenic right ventricular
cardiomyopathy; RV = right ventricle; LV = left ventricle; RVOT = right ventricular
outflow tract.
or left ventricular myocardium is suggestive of fat infiltration.
However, high signal intensity on T1-​weighted images is not
specific of fat; proximity to surface coil, motion-​related arte-
facts, and other technical issues may cause projection of high
signal intensity onto the myocardium causing the false diag-
nosis of fatty infiltration. Along with T1-​weighted images, a fat-​
suppressed sequence should always be performed. The presence
of a bright signal spot within the myocardium on T1-​weighted
images that darkens or disappears on fat-​suppressed images is
diagnostic of fatty infiltration (E Fig. 45.3).
High spatial resolution on spin echo images is mandatory
[25]. Even though fat detection with CMR is not a Task Force
criterion for the diagnosis of ARVC, most CMR protocols in-
clude T1-​weighted and T2-​weighted short tau inversion recovery
(STIR) (fat suppression) images on axial and short-​axis planes.
Importantly, planning of both sequences should be the same, so
the very same image can be seen without and with fat suppression.
This approach has proved to increase interobserver agreement
and confidence in diagnosis and evaluation of intramyocardial
fatty infiltration in patients suspected of having ARVC [26]. Fat
RV infiltration detected with cine CMR has also been described
in patients without any other ARVC abnormalities [27] and its
presence should be evaluated with caution (E Fig. 45.4).
685
Minor None
+
+
+
+
Fig. 45.3  Cardiac magnetic resonance imaging from a patient with ARVC.
Note the clarity of the thinned RV free wall (arrow) and the dilation of the
+ RV cavity.
+
+
Delayed enhancement
+ Delayed enhancement imaging in the CMR evaluation of pa-
tients with ARVC for detecting fibrosis has gained acceptance
+
but is not included in Task Force criteria due to high variability
between centres. Studies have shown that delayed enhancement
can be detected in biopsy-​proven ARVC patients in areas with wall
thinning and regional dysfunction [28]. Fibro-​fatty infiltration
is more common in ARVC patients than fatty infiltration alone.
Detection of fibrotic tissue using delayed enhancement may be
more important than the detection of fat replacement alone
(E Fig. 45.5). However, prognostic implications and its clin-
ical utility for diagnosis and prognostic purposes are not
defined yet.
CMR limitations
Despite the excellent image quality and reproducibility, CMR has
some disadvantages: the data acquisition and analysis require ex-
pertise and is rather time-​consuming, without clear, validated,
and standardized protocols. Furthermore, availability of CMR
scanners, constitute a limitation of this technique.
Other imaging techniques
Recently, multidetector computed tomography (MDCT) was
used in the evaluation of patients suspected of having ARVC.
Also, patients with a pacemaker and cardioverter-​defibrillators
can be studied using MDCT, which at present cannot be imaged
with CMR. Further studies are warranted to ensure the accuracy
of MDCT in the detection of ARVC [29].
The recent development of radionuclide blood-​pool SPECT
imaging allows also regional assessment of the left and right
ventricular function. In one prospective study it was found that
detecting localized dysfunction by gated SPECT was accurate in
686 CHAPTER 45   Other genet ic and ac qu ired ca rdi o m yopathi es

Fig. 45.4  (a) Fat spin echo T1-​

weighted image showing high signal
intensity suggestive of fat infiltration
in the septum (arrow). (b) Same image
as (a) with fat suppression. Septal
high signal intensity has disappeared,
confirming the diagnosis of fat
infiltration in this patient diagnosed
with arrhythmogenic cardiomyopathy.

the detection of ARVC (sensitivity 100%, specificity 81%) [30]
but obviously more studies are needed to assess the value of this
technique in this setting.
Histological demonstration of fibro-​fatty
replacement of myocardium
The histological demonstration of fibro-​fatty replacement of
myocardium by endomyocardial biopsy represents a major
Task Force criterion for the diagnosis of ARVC. However,
Fig. 45.5  Delayed gadolinium enhancement from a patient with ARVC.
Short-​axis projection demonstrating the scar in the inferior-​basal portion of
the RV but also extending into the LV.
Reproduced from Gerull B, Heuser A, Wichter T, et al. Mutations in the desmosomal
protein plakophilin-​2 are common in arrhythmogenic right ventricular cardiomyopathy
[published correction appears in Nat Genet. 2005 Jan;37(1):106]. Nat Genet.
2004;36(11):1162–​4. doi:10.1038/​ng1461 with permission from Springer Nature.
endomyocardial biopsy in patients with ARVC is associated
with risk of perforation due to thin walls. Furthermore, in its
earlier stages of the disease progression the fibro-​fatty replace-
ment has a patchy distribution, thus limiting the value of myo-
cardial biopsy. (E Fig. 45.6).
Repolarization and depolarization/​conduction
abnormalities
The ECG is central in the diagnosis of ARVC. One of the key fea-
tures of ARVC is the presence of T-​wave inversion in right pre-
cordial leads in absence of complete right bundle brunch block
(RBBB), which is considered specific enough to be a major ab-
normality [13]. LV involvement is reflected in the repolarization
criteria, which include the presence of T-​wave inversion in lateral
leads V4, V5, or V6 (typically seen in cases of LV involvement)
(E Fig. 45.7). Epsilon waves are small-​amplitude electrical po-
tentials that occur at the end of the QRS complex and at the be-
ginning of the ST segment detected in the right precordial leads.
They are thought to represent areas of delayed activation in the
RV as a consequence of fibrous and/​or fibro-​fatty replacement of
RV myocardium and are considered a major criterion but occurs
at late stage disease. Late potentials detected by signal-​averaged
ECG are reflect delayed RV activation and considered a minor
criterion in the 2010 Task Force criteria.
Ventricular arrhythmias are common in patients with ARVC
and are often the initial presentation of the disease. Sustained and
non-​sustained ventricular tachycardia and ventricular ectopics
typically have a LBBB morphology reflecting their RV origin.
When LV involvement is present, ventricular arrhythmias with
RBBB morphology may be observed. The RVOT is also the site
of origin for idiopathic RVOT ventricular tachycardia, which is
usually a benign condition occurring in patients with structur-
ally normal hearts. Differential diagnosis can be challenging in
early stages of ARVC [31]. The new ARVC criteria take this into
 Arrh y thmo g en i c ri g ht ven tri cu l a r ca rdi o m yopat h y   ( A RVC )
account by considering VT with LBBB morphology and an in-
ferior axis as a minor criterion, but VT with LBBB configuration
and a superior axis as a major criterion. The presence of more
than 500 ventricular ectopics in 24-​hour Holter ECG is a minor
criterion.
Family history
Perhaps the most significant major diagnostic criterion is the
presence of familial disease confirmed at necropsy or surgery
or the presence of likely pathogenic variant associated or prob-
ably associated, with ARVC in an individual with clinical sus-
picion of the disease. It is important to adhere to conventional
rules for assignment of pathogenicity to genetic variants since
variation in desmosomal genes is relatively common in normal
individuals.
Fig. 45.7  ECG from a patient with ARVC (50 mm/​s). Note the T-​wave inversion in the precordial leads from V1 to V5 indicating LV involvement.
687
Fig. 45.6  Left panel: Diffuse
intramyocardial septal delayed
enhancement in a patient with ARVC
(short-​axis view) (arrows). Right
panel: Septal intramyocardial delayed
enhancement (4-​chamber view)
(arrow).
Because of the genetic basis of ARVC, it is important to offer
screening to all first-​degree relatives. This can be performed non-​
invasively by routine ECG and echocardiography.
Conclusions
ARVC has been recognized as an important cause of sudden death
in association with exercise and athletic participation. Physicians
should consider this condition in young subjects with exercise
induced ventricular arrhythmias or in patients with unexplained
cardiac arrhythmias. Diagnosis relies predominantly on imaging
using echocardiography and CMR, which are complementary and
should be evaluated by experts. Management involves suppression
of malignant arrhythmias with antiarrhythmic medication and the
correct timing of an implantable cardioverter defibrillator as the
most effective treatment to prevent sudden cardiac death.
688 CHAPTER 45   Other genet ic and ac qu ired ca rdi o m yopathi es
Left ventricular non-​compaction
(LVNC)
Introduction
The term non-​compaction (NC) is used to describe the appear-
ance of excessive trabeculations and deep recesses within the
LV and sometimes RV myocardium that result from abnormal
intrauterine cardiac development and persistence of the foetal
myocardial meshwork [32, 33]. Typically, there is an increase
in the relative thickness of the trabeculated layer of the ven-
tricular wall compared to the compact layer (E Fig. 45.8). In
some patients, NC is associated with LV dilatation and systolic
dysfunction.
Aetiology
LVNC occurs in association with numerous congenital heart
defects including atrioseptal and ventriculoseptal defects, con-
genital aortic stenosis and aortic coarctation [34]. Isolated LVNC
is a rare disorder with prevalence rates ranging from 0.05% to
0.24% of the general population [35, 36].
Familial disease occurs in 18% to 50% of adults with isolated
LVNC, mostly with an autosomal dominant mode of inheritance
[37]. Numerous mutations in genes encoding cardiac sarcomere
proteins have been reported, including ß-​myosin heavy chain
(MYH7) cardiac troponin T (TNNT2), and alpha-​cardiac actin
(ACTC1), as well as calcium-​handling genes and other cardiomy-
opathy genes such as LMNA, LDB3, and Tafazzin. Many of the
genetic mutations that cause LVNC also cause hypertrophic, di-
lated, and restrictive cardiomyopathies [38]. Disease expression
varies even within families and differential diagnoses can be chal-
lenging [39]. Prominent trabeculations are also reported in the
RV in some patients with ARVC [40]. The implication of these
findings is that LVNC is often a non-​specific manifestation of an
underlying familial myocardial disorder.
Fig. 45.8  CMR apical four-​chamber view (left) and parasternal short-​axis view (right) from a patient with LV non-​compaction. Note the deep trabeculations in
the distal part of the ventricle also seen in the short-​axis view below the papillary muscle level.
Some reports have suggested that isolated LVNC may appear
during adult life in patients with muscular dystrophy [41], or as
a transient phenomenon during myocarditis or pregnancy but it
may be more appropriate to label such cases as ‘hypertrabeculation’
rather than NC, accepting that it may be impossible to distinguish
the two entities using imaging alone.
Clinical presentation
Presentation with heart failure, arrhythmias, and systemic
thromboembolism occurs at all ages and, in general, complica-
tions mirror the severity of LV dilatation and systolic dysfunc-
tion [38, 42]. Several studies have suggested that patients with
LVNC have poor LV function and a high incidence of ventricular
arrhythmias and systemic emboli, but recent reports suggest a
much lower incidence of death, stroke, or sustained ventricular
arrhythmia, probably reflecting the identification of preclinical or
mild cases [43].
Diagnostic criteria
LVNC is a clinical diagnosis based on the appearance of prom-
inent and excessive trabeculae on echocardiography or CMR but
there is no single diagnostic standard.
Several criteria are in current use but all share an emphasis on
prominent trabeculation at the LV apex [44–​48]. All were estab-
lished from retrospective analyses of small populations of patients
presenting with LV dysfunction and there are few data on tra-
becular patterns in normal individuals.
The most widely used echo criteria are those described by
Jenni et al., which require a 2:1 ratio of non-​compacted to com-
pacted myocardium and colour Doppler evidence of deep per-
fused intertrabecular recesses. Strictly applying imaging criteria
leads to overdiagnosis of LVNC, particularly in those with sys-
tolic heart failure and in people of Afro-​Caribbean origin [49].
Therefore, careful evaluation of symptoms, family history, and LV
function must accompany imaging investigations.
 Ta kotsu b o ca rdi o m yopathy ( stres s ca rdi o m yopat h y )
Treatment
There is no specific clinical management for LVNC. Heart failure
is treated with standard pharmacotherapy. Anticoagulation is
recommended in the presence of LV dilatation and systolic dys-
function (LVEF<40%) to avoid embolism of thrombi from the
hypertrabeculated LV. Arrhythmias should be managed using
antiarrhythmic agents or implantable cardiac defibrillators ac-
cording to guidelines.
Takotsubo cardiomyopathy (stress
cardiomyopathy)
Introduction and definitions
Takotsubo cardiomyopathy (TC) is a syndrome of transient LV
apical dysfunction occurring with excess catecholamine during
periods of stress, most prevalent among postmenopausal women.
The original description arises from the shape of the Japanese
octopus trap in the early 1990s [50]. It has important implications
because its clinical presentation mimics that of an acute coronary
syndrome.
Diagnosis
The diagnosis is often made following an emergency admis-
sion simulating an acute coronary syndrome with ECG changes
in the form of acute ST segment elevation or depression, a di-
lated cardiac apex (apical ballooning) during ventriculography
(E Fig. 45.9) but unobstructed coronary arteries [51, 52].
Usually, levels of creatine kinase-​MB and troponin T are mildly
elevated, out of proportion to the extensive LV dysfunction.
Echocardiography typically demonstrates a large apical aneurysm
with hypercontraction of the basal segment. However, the final
diagnosis lies in the reversibility of the apical ballooning over a
relatively short period between 1 and 3 weeks.
The syndrome of transient apical ballooning and stress car-
diomyopathy has been well documented in the last two decades.
689
However, the mechanism that ultimately results in reversible
myocardial dysfunction with inflammatory infiltrate on biopsy,
as opposed to myocardial necrosis with acute infarction, remains
unclear.
Several mechanisms have been proposed, such as multivessel
epicardial spasm with regional myocardial stunning [50],
catecholamine-​ excess toxicity mediated by intracellular Ca2+
overload [53], and neurogenic pathways enhancing catechol-
amine toxicity [54].
Enhanced sympathetic activity appears to play a very important
role in the pathophysiology of TC [55]. Triggering factors, such as
intense emotional stress, are frequently seen in patients with this
syndrome and excessive levels of catecholamines have been ob-
served in patients with TC (E Box 45.2).
Although some cases of basal ballooning have been reported,
it is the cardiac apex that is typically involved [56]. The reason
for this is unclear but several hypotheses have been put forward
that make the apex more sensitive to catecholamine surge: (1) the
apex does not have a three-​layered myocardial configuration that
makes it structurally vulnerable; (2) it has a limited elasticity re-
serve; (3) it can easily become ischaemic as a consequence of its
relatively limited coronary circulation; and (4) it is more respon-
sive to adrenergic stimulation.
Echocardiography
Echocardiography is the imaging modality of choice. It shows a
large LV apical aneurysm with full-​thickness myocardium (E
Fig. 45.10). The basal portion of the LV is often contracting vigor-
ously, and it may be accompanied by a high outflow tract gradient,
systolic anterior motion of the mitral valve, and mitral regurgita-
tion. Patients are usually very ill with severe heart failure at onset
but subsequently they recover completely. Often within days, the
LV function improves with resolution of the apical aneurysm.
Complications may include the formation of an apical thrombus
(E Fig. 45.11), and the presence of pericardial effusion. Contrast
echocardiography will delineate the LV apex better and may show
some apical hypoperfusion (E Fig. 45.12).
Fig. 45.9  Left ventriculography from
a 65-​year-​old female who presented as
a primary angioplasty call showing a
typical apical ballooning with dynamic
proximal ventricular contraction. This
patient had normal coronaries. On the
right, a picture of a Japanese fishing
pot (takotsubo) with a narrow neck
and wide base that is used to trap
octopus.
690 CHAPTER 45   Other genet ic and ac qu ired ca rdi o m yopathi es

Box 45.2  Basic findings in patients with Takotsubo

cardiomyopathy

A
◆ preponderant occurrence of the syndrome in elderly or
postmenopausal females
◆ Onset consequent to acute emotional stress or an acute
medical condition
ST segment elevation or depression, or T-​wave changes
◆

A prolonged QT interval
◆

A mild increase in cardiac enzymes

◆

Typical akinesis of the apical and distal anterior wall together

◆

with hypercontraction of the basal wall

The occasional presence of transient intracavitary pressure
◆

gradients in some patients

A need for acute haemodynamic support in some cases
◆

Complete resolution of the apical wall motion abnormality

◆

and the depressed left ventricular systolic function

Fig. 45.11  Apical four-​chamber view from a patient with Takotsubo

cardiomyopathy and an apical thrombus (arrow).

Fig. 45.10  Two-​dimensional echocardiography apical four-​chamber view in

end-​systole from a patient with Takotsubo cardiomyopathy. There is typical
apical aneurysm (arrows) with dynamic basal septal contraction. Note the
small pericardial effusion at the back of the right atrium. Fig. 45.12  Myocardial contrast echocardiography showing apical
LA = left atrium; RA = right atrium. hypoperfusion reduced opacification of the apex (arrow).

Fig. 45.13  Cardiac magnetic resonance imaging demonstrating apical
ballooning.
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 SECTION 8

Peri-​myocardial disease

46 Pericardial effusion and cardiac tamponade  697

Allan Klein, Bernard Cosyns, and Aldo L. Schenone
47 Constrictive pericarditis  707
Alida L.P. Caforio, Maurizio Galderisi†, Massimo Imazio, Renzo Marcolongo, Yehuda Adler,
and Ciro Santoro
48 Myocarditis 715
Ali Yilmaz, Heiko Mahrholdt, and Udo Sechtem
49 Cardiac masses and tumours  731
Teresa López-​Fernández and Peter Buser

Contents
Introduction  697
Pathophysiology of pericardial effusion and
cardiac tamponade  697
Classification of pericardial effusion  698
Clinical presentation  699
Cardiac tamponade  699
Imaging evaluation of pericardial
effusion  700
Chest X-​ray  700
Echocardiography  700
Cardiac CT  701
Cardiac MRI  702
Other imaging modalities  703
Imaging evaluation of cardiac
tamponade  703
Management of pericardial effusions and
cardiac tamponade  705
Conclusion  706
CHAPTER 46
Pericardial effusion and
cardiac tamponade
Allan Klein, Bernard Cosyns, and
Aldo L. Schenone
Introduction
Pericardial effusion (Peff) is defined as an excessive accumulation (>50 cc) of fluid within
the pericardial space [1]‌. Its true incidence remains unknown, but available reports esti-
mate a gross annual incidence of 3–​9% that is expected to vary based on geography and
patient population studied [1, 2]. It can present either silent or symptomatic with cardiac
tamponade in a life-​threatening presentation [3]. An early and accurate characterization
of Peff is crucial, and cardiovascular imaging is key to a timely detection and therapeutic
management. This chapter aims to provide a state of the art review of Peff and cardiac
tamponade with emphasis on the utility of multimodality imaging.
Pathophysiology of pericardial effusion and
cardiac tamponade
The pericardium is flask shaped that encases the heart that consists of an external fibrous
sac (fibrosa), internally lined by a mono-​layer of mesothelial cells called parietal pericar-
dium, and a visceral layer, that coats the epicardium (visceral pericardium). The virtual peri-
cardial space is enclosed between the two serosal layers and normally contains less than
50 cc of fluid (average 20–​25 ml) [4, 5]. The fluid is a plasma ultra-​filtrate with a lympho-​
monocytic cell predominance [6]‌. Any process that increases the production (inflammation,
post-​thoracotomy syndrome) and/​or limits the drainage (disrupted lymphatic drainage or
elevated systemic venous pressures) would lead to the formation of Peff [1]. The composition
of the Peff varies depending on the underlying process and ranges from transudate, exudate,
haemopericardium, pyopericardium, and chylopericardium [4].
As the Peff accumulates, the normal pericardium stretches to accommodate the fluid
without major changes in intrapericardial pressure (pericardial reserve volume). As the
Peff accumulation continues, the pericardial compliance is eventually spent causing a
prominent increase in intrapericardial pressure [4, 7] (E Fig. 46.1). The volume at which
the pericardial compliance is exhausted is a moving target and depends on the interplay
between the intrinsic properties of the pericardium in question (lower with thickened
pathologic pericardium) and the rate of Peff accumulation (lowest at faster rates) [1, 4].
The transmission of intrapericardial pressures to the cardiac chambers eventually
equalizes the pericardial pressure and the end-​diastolic pressures across the four car-
diac chambers (E Fig. 46.2). This forces the heart to work under a reduced and fixed
volume which greatly alters the cardiac filling dynamics forcing the right (RV) and
left ventricle (LV) to compete for such volume, causing an exaggerated ventricular
interdependence [8]‌. During inspiration, there is preferential filling of the RV, albeit
698 CHAPTER 46   Pe ric a rdial ef f u sion and ca rdiac ta m p ona de

the LV end-​diastolic pressures leading to a reduction in the pul-

Acute Peff Chronic Peff monary vein-​to-​LV end-​diastolic pressure gradient. As a conse-
quence, there is a leftward excursion of the septum, later mitral
valve opening, longer isovolumic relaxation times and reduced
Critical Tamponade
early mitral inflow velocities compared to expiration or apnoea
Pressure

Pericardium
Compliance Limit
Volume
Fig. 46.1  Pericardial pressure-​volume curve. Pericardial pressure-​volume
curves are shown. The red curve (left) represent a rapidly accumulating
pericardial effusion (Peff) which quickly exhaust the pericardial reserve
volume at low volumes and then exceed the limit of pericardial compliance
causing an steep rise in intrapericardial pressure which translate into
critical tamponade. The blue curve (right) denotes a chronic and slowly
accumulating Peff which allows for higher pericardial reserve volume before
exceeding the stretch limit and subsequent critical tamponade.
Reproduced from Klein AL, Abbara S, Agler DA, et al. American society of
echocardiography clinical recommendations for multimodality cardiovascular imaging
of patients with pericardial disease: Endorsed by the Society for Cardiovascular
Magnetic Resonance and Society of Cardiovascular Computed Tomography. J Am Soc
Echocardiogr. 2013. doi:10.1016/​j.echo.2013.06.023 with permission from Elsevier.
reduced compared to normal, at the cost of reduced filling of
the LV. This is the result of a greater transmission of the nega-
tive intrathoracic pressure to the pulmonary veins in relation to
[9]. This can lead to an inspiratory drop in stroke volume and sys-
tolic blood pressure clinically known as pulsus paradoxus [8, 10].
During expiration, this whole phenomenon reverses causing re-
duction in the tricuspid inflow velocities and RV filling with res-
toration of LV filling [4]. Although the stroke volume is reduced
during tamponade physiology, the cardiac output is initially main-
tained by an increase in heart rate. Accumulation of fluid further
impairs cardiac filling, rendering compensatory mechanisms in-
sufficient, thus causing haemodynamic instability [2, 8, 11].
Classification of pericardial effusion
A Peff can be classified based on aetiology, size, chronicity,
distribution, composition, and haemodynamic compromise
(E Boxes 46.1 and 46.2). Regarding aetiology, the most common
cause in developed countries remains idiopathic pericarditis,
while tuberculosis (>60%) remains the dominant aetiology in
developing countries [11, 12]. It is important to note the rising in-
cidence of pericarditis and pericardial effusion due to pericardial
injury from cardiac intervention [10].
Large and chronic effusions without haemodynamic compro­
mise are commonly idiopathic, while neoplastic and infectious

Normal Tamponade

Expiration Inspiration Expiration Inspiration

RV LV RV LV RV LV RV LV

Ventricular Interdependence Ventricular Interdependence

PV +20
Pressure

Pressure

∆ PV-LV +15
LV

+10 PV +10
∆ PV-LV ∆ Pleural-LV +5
+5 LV
∆ Pleural-LV 0
0 Pleural Space
–5
–5

Mitral Inflow

Time

Fig. 46.2  Respirophasic changes in intrathoracic and intracardiac pressures during cardiac tamponade. The left panel presents the normal changes in pressures
during with respiration. Note the similar proportional decrease in both intrathoracic and intracardiac pressure that follows the drop in intrapleural pressure
during inspiration. As a consequence, the gradient (∆) between the pulmonary vein (PV) and left ventricle (LV) remains unchanged allowing proper diastolic
filling of LV throughout the respiratory cycle demonstrate by a spared mitral inflow and normal ventricular interdependence. In contrast, the right panel
demonstrate a case of cardiac tamponade with associated elevation in LV end-​diastolic pressure. During tamponade, the intrathoracic but not the intracardiac
pressures are affected by negative change in pleural pressures during inspiration. Such dissociation in the transmission of pleural pressure during the respiratory
cycle results in inspiratory reduction of the PV-​LV gradients. As a result, there is a marked reduction in the mitral inflow velocities during inspiration along with a
leftward shift of the ventricular septum signalling an exaggerated ventricular interdependence.
Reproduced from Oh JK, Seward JB, Tajik AJ. Pericardial diseases. In: The Echo Manual. 3rd ed. Philadelphia: Lippincott Williams &​Wilkins, c2006; 2006.
 Cl i n i ca l pre se n tat i on 699

Box 46.1  Causes of pericardial effusion Box 46.2  Classification of pericardial effusions should we
include trivial and very large
Idiopathic (50%)
Infections (15–​30%) Size
Viral infections Enteroviruses (Coxsackie B, echoviruses),
◆ Trivial (seen only in systole)
◆

adenovirus, herpesviruses (EBV, CMV, VZV, HH-​6), Parvo-​B Mild (50–​100 ml)—​Echo-​free space <10 mm
◆

virus, hepatitis C virus, Influenza, HIV virus Moderate (100–​500 ml)—​Echo-​free space 10–​20 mm
◆

Bacterial–​ Coxiella burnetti, Staphylococcus sp., Streptococcus

◆ Large (>500 ml)—​echo-​free space >20 mm
◆

sp., Haemophilus influenzae, Salmonella sp., Neisseria sp. Very large—​echo-​free space >20 mm
◆

Tuberculosis (>60% in developing countries)

◆ Chronicity
Fungal Histoplasma sp. (immunocompetent patients),
◆ ◆ Acute (<3 months)
Candida sp. (immunosuppressed patients), Aspergillus sp., ◆ Chronic (>3 months)
Blastomyces sp. Distribution
Protozoal Echinococcus sp., Toxoplasma sp.
◆ Localized
◆
Neoplastic (10–​25%) Circumferential
◆
Primary Mesothelioma, teratoma, fibroma, and sarcomas
◆ ◆ Loculated
Metastatic Breast cancer, lung cancer, lymphoma, leukaemia,
◆ Composition
and melanoma ◆ Transudate (hydropericardium)
Pericardial injury (10–​20%) Exudate
◆
Post-​pericardiotomy syndrome
◆
● Inflammatory

Percutaneous cardiac interventions (percutaneous coronary

◆
● Purulent

intervention and cardiac ablations) ● Haemorrhagic

Delayed post-​myocardial–​pericardial injury syndromes

◆
● Chylous

Perforation of the heart by indwelling catheters

◆
Haemodynamic impact
Autoimmune and autoinflammatory disorders (5–​15%) ◆ None
Rheumatic fever, systemic lupus erythematosus, ankylosing
◆
◆ Tamponade
spondylitis, rheumatoid arthritis, scleroderma
◆ Effusive-​constrictive pericarditis
Polymyositis, dermatomyositis,
◆
Source data from Griffin BP, Callahan TD, Menon V, Wu WM, Cauthen CA,
Polyarteritis nodosa, granulomatosis with polyangiitis (GPA),
◆
Dunn JM. Manual of Cardiovascular Medicine.; 2014. doi:10.1016/​B978-​0-
giant cell arteritis (GCA) ​7020-​5401-​3.00005-​9.
Sarcoidosis, amyloidosis,
◆

Inflammatory bowel disease, Whipple’s disease, Behçet’s syn-

◆
hypertension, or low albumin from nephrotic syndrome or liver
drome, Reiter’s syndrome, FMF
dysfunction [1, 11, 12].
Metabolic
Uraemia, myxoedema, hypoalbuminemia
◆

Haemodynamics
Heart failure, pulmonary hypertension
◆
Drugs and drug hypersensitivity
Hydralazine, minoxidil, heparin, warfarin, phenytoin,
◆ ranging from an asymptomatic to full blown cardiac tamponade
phenylbutazone, cromolyn sodium, dantrolene, methysergide,
doxorubicin, procainamide, penicillin colony-​stimulating
factor, interleukin-​2
Mediastinal radiation
Dissecting thoracic aneurysm
Source data from Griffin BP, Callahan TD, Menon V, Wu W m., Cauthen CA,
Dunn JM. Manual of Cardiovascular Medicine.; 2014 doi:10.1016/​B978-​0-
​7020-​5401-​3.00005-​9.
processes are more likely to cause tamponade. Loculated ef-
fusion are commonly secondary to infectious causes or post-
operative haemorrhagic effusions [11]. Exudative effusions can
be idiopathic, purulent, haemorrhagic, or chylous due to altered
lymphatic drainage. Meanwhile, transudative effusions results
from third spacing in the setting of heart failure, pulmonary
Clinical presentation
Patients with a Peff have a wide variety of clinical presentations
or effusive-​constrictive pericarditis. The underlying aetiology, the
volume and the rate of fluid accumulation are the major determin-
ants of the accompanying symptoms [11]. When the Peff is haemo-
dynamically significant, low output symptoms prevail with severe
fatigue, dyspnoea, drowsiness or agitation, and syncope, when not
severe enough to cause full blown haemodynamic collapse from car-
diac tamponade [11, 13]. In 2–​16% of cases of Peff with tamponade
physiology, the right atrial (RA) pressure remains elevated (fails to
decrease by at least 50% or to less than 10 mmHg) due to persistent
inflammation of visceral pericardium despite pericardiocentesis with
ensuing constrictive physiology and associated symptoms [14, 15].
Cardiac tamponade
Cardiac tamponade can be classified as acute, subacute, or
chronic and remains a clinical diagnosis based on the presence of:
700 CHAPTER 46   Pe ric a rdial ef f u sion and ca rdiac ta m p ona de
(1) hypotension (systolic blood pressure <90 mmHg), but blood
pressure may be only slightly reduced in subacute, or chronic
tamponade; (2) resting tachycardia (>100 bpm); (3) elevated
jugular venous pressure with prominent X descent but blunted Y
descent; and (4) pulsus paradoxus defined as a >10 mmHg drop
in blood pressure with inspiration.
Conversely, cardiac tamponade physiology comprises a wide
haemodynamic spectrum from asymptomatic to full cardiac
collapse characterized by a reduction in cardiac filling and an
enhanced ventricular interdependence with or without dia-
stolic cardiac chamber inversion, or collapse resulting from the
increased intrapericardial pressure due to fluid accumulation.
Other forms of cardiac tamponade physiology include focal
tamponade due to loculated Peff, intrapericardial thrombi after
cardiac surgery, and low pressure tamponade, which presents
with severe restriction on diastolic filling but the equalized end-​
diastolic pressure is normal (<10 mmHg) [4]‌.
Imaging evaluation of pericardial
effusion
Dedicated cardiac imaging is warranted whenever a pericardial
effusion is suspected based on clinical evaluation. In general, car-
diac imaging to screen for effusion is advised for patients pre-
senting with pericarditis symptoms, acute aortic syndrome as
well as for those with sudden haemodynamic instability after
myocardial infarction or invasive cardiac procedure. In addition,
imaging is recommended in those patients with presence of ele-
vated jugular venous pressure who suffer from a systemic con-
dition known to cause pericardial effusion or when chest X-​ray
suggests the presence of a pericardial effusion.
Pericardial imaging in the assessment of pericardial effusion
follows a staged, multimodality approach [16, 17]. The goals of
cardiac imaging include: (1) determine the presence, stability,
and potential recurrence of a Peff; (2) characterize effusion in
an attempt to discern underlying aetiology; (3) determine the
best approach for drainage if indicated; (4) define the haemo-
dynamic significance of the Peff; and (5) ascertain the presence
of underlying pericardial inflammation to guide the use of anti-​
inflammatory therapy. Echocardiography is the imaging mo-
dality of choice in the evaluation of patients with or suspected
of having Peff, the use of imaging multimodality (cardiac CT
and cardiac MR) is mainly reserved for patients with concern
for complex, loculated, or very localized effusion or when there
is need to investigate for malignancy or undergoing pericardial
inflammation  [4]‌.
Chest  X-​ray
Patients with Peff often complain of chest pain and/​or dyspnoea
thus chest X-​rays are commonly obtained for these patients as
first-​line imaging modality. The strengths of the chest X-​ray are:
its wide availability, low cost, wide field of view to pick up alter-
native or related pathology, such as chest infection or neoplasia,
and the ability to detect pericardial calcification. Nonetheless,
this technique lacks accuracy to make a definitive diagnosis of
Peff [4, 18]. Moderate to large Peffs might produce an outsized
globular heart on chest X-​ray, while the presence of a double
density along the cardiac border or a posterior bulge on the lat-
eral film strongly suggests the presence of Peff [10, 13]. An echo-
cardiogram should be always obtained if pericardial effusion is
suspected on chest X-​ray [4]‌.
Echocardiography
Transthoracic echocardiography (TTE) remains the first-​ line
imaging modality in the evaluation for known or suspected Peff.
This technique is readily available in multiple settings at low cost
with no radiation exposure and offers enough spatial and tem-
poral resolution to accurately assess size, location, and haemo-
dynamic impact of a Peff [18, 19].
Transudative effusions often appear as an anechoic space be-
tween the visceral and parietal pericardium [13]. The presence
of an echo-​free space within the pericardial sac that is only visu-
alized during systole is considered a normal or trivial finding. A
persistent echo-​free space throughout the cardiac cycle defines
the presence of a clinically significant Peff (>50 ml in the pericar-
dial fluid) [4]‌. The size of the Peff is determined by the dimension
of the echo-​free space at end-​diastole as follows: trivial (seen only
in systole), small <10 mm, moderate 10–​20 mm, large >20 mm,
and very large >2.5 cm [4] (E Fig. 46.1 and z Video 46.1).
Small Peffs are commonly seen posteriorly to the LV or around
the RA, while large effusions are commonly circumferential often
exhibiting heart swings. An isolated anterior Peff is very rare and
must be differentiated from an epicardial fat that appears as echo-​
space with higher density than myocardium following the cardiac
cycle movements [18]. It is also important to discriminate be-
tween pericardial and pleural effusions. In a parasternal long axis
view, a Peff is located posterior to the myocardium and anterior
to the descending aorta, while a pleural effusion is visualized pos-
terior to the descending aorta [18] (E Fig. 46.3).
Exudative effusions might have a heterogeneous appearance
with internal debris and septa rather than the classic anechoic
look of simple transudative effusion [11] (z Videos 46.1 and
46.2). Fibrinous strands can form in chronic effusion, while the
presence of nodular echodensities that seem to penetrate the
myocardium increase the suspicion of malignant cause. The pres-
ence of intrapericardial thrombus appears as a snake-​like mobile
echodensity, while a fluid-​filled sac around the RA must trigger
the thought of pericardial cyst [13] (E Fig. 46.4).
Every Peff must be evaluated in multiple views to define local-
ization, size, and appearance as a single view might be misleading.
The feasibility of a percutaneous drainage must be assessed for
moderate–​large Peffs, along with a full haemodynamic interro-
gation, to rule out tamponade physiology (discussed in the next
section). The adjunctive use of 3D echocardiography might be
useful allowing a more accurate characterization of the pericardial
effusion with better estimations of size, location, and spatial rela-
tionship with surrounding structures than 2D echocardiography

(a) *.
PLAX
Pleural off *.
Ao
*.
PSAX
*.
*.
Subcostal
*.
Small effusion
(<10mm)
Fig. 46.3  Sizing of pericardial effusion on echocardiography. (a) Small and circumferential pericardial effusion (*) with concomitant pleural effusion (pleural
eff.) located posterior to the plane of the aorta (Ao). (b) Moderate pericardial effusion (*) with largest pocket anterior to right atrium and right ventricle. Again,
the plane of the aorta (Ao) and the visible pericardium helps recognize the presence of a pleural effusion (pleural eff.). (c) Large pericardial effusion (*) located
anteriorly. The three presented cases represent simple free-​flowing pericardial effusions based on echocardiographic assessment.
PSAX = parasternal long axis; PSAX = parasternal short axis.
[20]. 3D TTE appears particularly useful when evaluating a com-
plex Peff since it provides an enhanced visualization of the com-
plex network of intrapericardial adhesion as well as the extent
and attachments of the pericardial strands [20, 21]. When the
classic projection on TTE fails to identify a Peff, but the suspicion
remains high, off-​axis views should be acquired searching for
loculated effusions. Transoesophageal echocardiography (TEE)
is recommended when TTE provides suboptimal and inconclu-
sive images or the concern for tamponade remains high, despite
a negative surface study, especially after cardiac surgery when a
focal tamponade occurs due to intrapericardial clot causing local
compression [4]‌(E Fig. 46.4).
Cardiac CT
Cardiac CT offers a high-​spatial resolution with the advantage
of an off-​line multiplaner reconstruction. It provides enhanced
tissue delineation and characterization of both cardiac and
extracardiac structures, based on Hounsfield Units (HU), and
better visualization of the pericardial layers. Cardiac CT is the
gold standard technique when evaluation for pericardial calcifica-
tion is warranted. All these benefits come at the cost of exposure
to ionizing radiation, use of iodinated contrast, and limited func-
tional evaluation. Non-​gated cardiac CT tends to overestimate the
size of the effusion, suffer from motion artefacts, and does not
I m ag i n g eva luati on of peri ca rdia l e f f usi on 701
Size of Effusion
(b) (c)
*. *.
*.
Pleural off Ao
*. *.
*.
*. *.
Moderate effusion Large/Very large effusion
(10–20mm) (>20mm / >25 mm)
provide functional assessment. Retrospectively gated cardiac CT
offers a more accurate quantification of Peff and allows the evalu-
ation for tamponade physiology [18, 19, 22].
The normal pericardial layers are seen as a thin grey line less
than <2 mm in thickness. In the presence of simple Peff, the peri-
cardial fluid usually has the attenuation characteristics of water
(HU <10) encased within the pericardial layers that might or
might not be thickened (>4 mm) [4]‌. In addition, the uptake of
contrast within the pericardium signals the presence of ongoing
pericardial inflammation [4]. Peffs with higher attenuation values
(HU>60) are typically haemorrhagic, while those with inter-
mediate attenuation values (20–​60 HU) are most likely exudative
effusions [4, 18] (E Fig. 46.5). Haemorrhagic effusions exhibit
interval reduction of attenuation values with heterogeneous ap-
pearance due to thrombus formation.
The role of cardiac CT in the evaluation of Peff is restricted to
the following scenarios. First, it might be helpful in stable pa-
tients with high suspicion for Peff, when echocardiography offers
poor quality images or fails to detect a Peff [18]. This is particu-
larly useful when differentiation between Peff and epicardial fat
remains equivocal (E Fig. 46.5), in anterior or superior Peff
where an echocardiographic evaluation is often challenging or in
post-​surgical cases when localized intrapericardial thrombi if sus-
pected [4]‌. Second, CT is very useful in the assessment of complex
702 CHAPTER 46   Pe ric a rdial ef f u sion and ca rdiac ta m p ona de

(a) (b) (c) (d)

Fig. 46.4  Complex pericardial effusion detected by echocardiography. (a) Parasternal long axis and short axis echocardiographic projections reveals presence of
a moderate size pericardial effusion located anterior to right ventricle containing a large, organized thrombus (*). This patient with haemopericardium presented
with a type A aortic dissection (note the dilated ascending aorta). (b) Complex and loculated pericardial effusion (*) with adhesion lateral to left ventricle in a
case of purulent effusion. (c) Loculated effusions located posterior to LA (*) and lateral to RA (*) causing some degree of extrinsic compression. (d) This patient
had open heart surgery and developed haemodynamics instability without apparent cause of surface echocardiography. Transoesophageal echocardiogram
(TEE) reveals a focal intrapericardial haematoma adjacent to right atrium (RA) and right ventricle (RV) causing extrinsic compression of RA leading to
tamponade.

or loculated effusion with precise quantification, distribution, and
tissue characterization, while providing a wide thoracic field of
view useful for screening for related extracardiac pathology and
surgical planning (E Fig. 46.5) [18, 19].
It is crucial to bear in mind that in cardiac CT, it might be diffi-
cult to differentiate small effusions from pericardial thickening or
discriminate between Peff and pericardial thickening when they
share the same attenuation. Pericardial thickening is favoured
when in the presence of nodular areas of increased attenuation,
a thickened anterior pericardium, lack of imaging change with
decubitus position and/​or presence of contrast enhancement of
pericardium  [4]‌.
Cardiac MRI
Similar to cardiac CT, Cardiac MRI offers an unrestricted number
of planes of view with a wide thoracic field of view and a superior
fluid/​tissue characterization of Peff and surrounding structures
based on T1 and T2 characteristics. In addition, this modality
provides concomitant anatomic and functional assessment of the
heart with the capacity to assess for ongoing pericardial and/​or
myocardial inflammation using late gadolinium enhancement
imaging. However, the use of cardiac MRI is time consuming
and restricted by cost and availability. In addition, this modality
cannot be completed in patients with non-​MRI compatible pace-
makers, arrhythmias significantly reduce quality of images, and
the use of gadolinium is precluded by a glomerular filtration rate
<30 ml/​min [19].
Cardiac MRI depicts normal pericardium as a thin dark line
due to low-​intermediate signals on T1 and T2 sequences delin-
eated by the high-​intensity signals from the epicardial and me-
diastinal fat layers which provide great contrast definition [23].
For this reason, the pericardium is less well visualized on the
lateral wall of the LV where fat is scarce [23]. Cardiac MRI can
readily discriminate epicardial fat from Peff using fat suppression
sequences. Regarding effusion sizing, a Peff with circumferential
distribution and a fluid-​space width anterior to the RV <4 mm is
regarded as small, while those >5 mm are considered large [4]‌.
Transudative Peffs have low signals on T1-​weighted images but
high signals on T2-​weighted Fast-​Spin Echo (FSE) and Steady-​
State Free Precession (SSFP) images. In contrast, exudative and
haemorrhagic effusions exhibit high signals on T1-​weighted im-
ages, intermediate signals on T2-​weighted images and lower signal
intensity on SSFP imaging as the T2/​T1 signal ratio decreases (E
Fig. 46.4). Fibrinous strands and intrapericardial thrombi in com-
plex Peffs can be seen on SSFP imaging, while inflammatory or
protein rich material in the effusion might an heterogeneous and
patchy signal intensity [23]. Finally, the use of double-​inversion
recovery in FSE sequences differentiates transudative Peff with
no signal from complex effusion that exhibits intermediate-​high
signals [23].
The MRI characteristics of haemorrhagic Peffs and pericardial
haematomas varies with timing in response to the breakdown
of haemoglobin. Acute haemorrhagic effusions usually depict
low intensity on gradient echo images. In contrast, pericardial
 I m ag i n g eva luati on of ca rdiac ta m p ona de 703

Hounsfield units
(a) (b) (c)
*
Fat
Fat

* *

Fat

*
* *

Fat

Circumferential/Transudative Focal/Exudative Haemorrhagic

(<10 HU) (20–60 HU) (>60 HU)

Fig. 46.5  Pericardial effusions on cardiac CT. (a) Large transudative (9 HU) circumferential pericardial effusion (*) demonstrated in the four-​chamber projection
(upper panel) and short axis (lower panel) projection. (b) Focal pericardial collection (27 HU) of heterogeneous appearance adjacent to the lateral wall of the left
ventricle (*) consistent with abscess that appears to extent into left anterior chest wall (circle) demonstrated in four-​chamber (upper panel) and short axis (lower
panel) projection. (c) Haemopericardium (*) presenting as heterogeneous pericardial effusion (62 HU) located anteriorly demonstrated on four-​chamber (upper
panel) and short axis projection (lower panel). Epicardial fat (fat) is easily differentiate from pericardial effusion (*) with the use of CT.

haematomas in the subacute phase present with heterogeneous
high signals on both T1 and T2 weighted images. In the chronic
phase, they present surrounded by a dark rim with internal low
signals and dark foci representing calcifications [4, 23].
Similar to cardiac CT, cardiac MRI allows detection of Peffs
when echocardiography fails, provides a detailed assessment of
complex and/​or loculated effusions and offers the advantage of
screening for related extracardiac pathology. Although this tech-
nique is inferior to cardiac CT for the detection of pericardial
calcification, it offers the advantage over CT to readily differen-
tiate small Peffs from pericardial thickening. Effusion can be dif-
ferentiated by the presence of smooth margins that change with
decubitus position along with the presence of signal void on black-​
blood sequences and high signal intensity on SSFP and gradient
echo images [23]. Finally, an enhanced pericardium on late gado-
linium images further differentiates a thickened and inflamed
pericardium from the underlying Peff; in addition, it provides ob-
jective description of pericardial inflammation and guides the use
of anti-​inflammatory therapy [23, 24] (E Fig. 46.6).
Other imaging modalities
The detection of a Peff on fluoroscopy is very difficult, as the car-
diac silhouette is not clear enough to make this determination
due to the ‘windowing’ used. Rarely, subtle changes in the mo-
tion and/​or shape of the cardiac silhouette might occur during
percutaneous cardiac interventions (cardiac ablations or per-
cutaneous coronary interventions). The development of an iat-
rogenic pericardial effusion after coronary intervention is more
evident when there is contrast extravasation into the pericardium.
Imaging evaluation of cardiac
tamponade
Echocardiography is the gold standard imaging technique in the
evaluation of patients with suspected cardiac tamponade. When
conducting an echocardiogram to assess for Peff, the use of re-
spiratory tracing is mandatory in order to accurately assess the po-
tential respirophasic cardiac changes that could signal tamponade
physiology. As mentioned before, when TTE provides inconclu-
sive images or fails to detect a Peff in a patient with high suspicion
for tamponade, an urgent TEE is strongly recommended to better
assess and rule out focal tamponade [18].
Cardiac imaging can describe the presence of tamponade physi-
ology; however, it needs clinical correlation to secure the diagnosis
of cardiac tamponade. Nevertheless, the presence of tamponade
physiology in large effusions might be interpreted as a sensitive
predictor of progression to clinical tamponade and may indicate
pericardiocentesis even in the absence of clinical tamponade.
Once a Peff, or in rare cases, an intrapericardial thrombi, mass, or
704 CHAPTER 46   Pe ric a rdial ef f u sion and ca rdiac ta m p ona de

(a) (c)
IR (e)

*
*
* *

SSPF BB Fat Sup

(b) (d) (f)

* *
*

SSPF IR PSIR

Fig. 46.6  Pericardial effusions on cardiac MRI. Large circumferential effusion (*) is demonstrated in SSPF-​Cine sequence in both four-​chamber (a) and short
axis (b). The effusion exhibits high signal (bright) in this sequence, which inform about a transudative nature. (c) On black-​blood (BB) sequence, the free-​flowing
pericardial effusion (*) is either voided of signal or exhibits low signal. In contrast, loculated effusion might exhibit high signal in this sequence. (d) The transudative
nature of the pericardial effusion (*) is suggested by the lack of signal on inversion recovery (IR) sequence. (e) Fat suppression sequences allow better delineation
of the pericardial effusion (*) and pericardial layers by subtracting signal from adjacent epicardial fat. (f) The presence of mild delayed gadolinium enhancement
(arrows) informs about the presence of pericardial inflammation as the potential mechanism behind pericardial effusion.

even air have been identified, the key echocardiographic findings
supporting cardiac tamponade include the presence of (1) cardiac
chambers collapse; (2) an exaggerated ventricular interdepend-
ence; and (3) plethoric inferior vena cava (IVC) (E Fig. 46.7). The
physiologic processes behind these findings have been described
in section II. In addition, all echocardiographic evaluations for
cardiac tamponade physiology should determine the feasibility of
a percutaneous drainage. Enough accumulation of fluid in an an-
terior location must be identified in any projection including off-​
axis for pericardiocentesis to be feasible.
During tamponade physiology (z Video 46.1), the normally
rounded RA contour comes to an abrupt and transient inversion
during early systole (near peak R wave) when the atrial volume
and pressure are the lowest. This RA inversion can be seen best
in the subcostal view, but other projections such as parasternal
short axis at the level of great vessel and apical four-​chamber
using 2D echo. This is a highly sensitive findings with a lower
specificity that is enhanced by a longer duration of inversion
(>1/​3 of cardiac cycle) [25]. Right ventricular collapse can also
be seen in tamponade physiology and is regarded as the most
specific (100%) finding. It occurs during the isovolumetric relax-
ation of the RV near the T wave when RV volume and pressure
are the lowest. RV collapse is best visualized on 2D echo using
a subcostal, parasternal long axis, or apical four-​chamber views.
The use of M-​mode across the free wall of the RV on either para-
sternal long axis or subcostal can be helpful in the detection of
subtler RV inversion given its superior temporal resolution.
During the echocardiographic evaluation of cardiac tamponade,
it is important to remember that both inversions might be falsely
absent in the presence of high RV filling pressures such in signifi-
cant tricuspid regurgitation or pulmonary hypertension [18, 25].
Finally, left-​sided collapse is very rare given their higher pressure
(z Video 46.1), but might be seen with focal tamponade after
cardiac surgery [25].
The presence of exaggerated respirophasic variation on
transmitral (>30%) and transtricuspid (60%) E wave velocities
serves as the echocardiographic evidence of pulsus paradoxus
[4]‌. The peak E wave velocities are measured during the first beat
after inspiration and expiration using pulsed wave Doppler at
both mitral and tricuspid inflows. The variation percentage is cal-
culated as expiration-​inspiration/​inspiration with trans-​tricuspid
resulting in negative values. The variation in inflows time vel-
ocity integral (VTI) portrays similar relevance. The reciprocating
changes in LV and RV dimensions throughout the respiratory
cycle detected using M-​mode are another surrogate echocardio-
graphic finding of pulsus paradoxus [25, 26] (Fig. 46.7).
The identification of a dilated IVC (>2.1 cm) with minimal or
no respiratory collapse (<50%) is the most sensitive echocardio-
graphic finding of cardiac tamponade. The absence of a plethoric
IVC should call into question the diagnosis of cardiac tamponade,
unless in the presence of low pressure tamponade or focal tam-
ponade involving the left-​sided chambers [11, 18]. Other ancillary
 Managemen t of peri ca rdia l effu si on s a n d ca rdiac ta m p ona de 705

(a) (c) (e) (g)

* RV
MV inflow variability ~ 40%

E exp

RA E insp

(b) (d) (f) (h)

* TV inflow variability ~ 50%

* E insp
Exp
RV E exp
RA D
<50% collapse Insp

D
S
S

Fig. 46.7  Echocardiographic signs of cardiac tamponade physiology. (a) Very large and circumferential (4 cm) pericardial effusion (*). (b) Plethoric ICV
measured at 2.5 cm. (c) RA wall inversion during early systole (near peak of R wave) due to a high pericardial to RA pressure gradient in atrial diastole
(arrows), this is a very sensitive sign of tamponade physiology. (d) RV collapse during ventricular diastole (near T wave) due to high pericardial to RV pressure
during ventricular diastole, this is a very specific sign of tamponade physiology. (e) Prominent respirophasic variability on the mitral E’ wave velocities due to
exaggerated ventricular interdependence, note the decrease during inspiration. (f) Prominent respirophasic variability on the tricuspid E’ wave velocities due to
exaggerated ventricular interdependence, note the increase during inspiration. (g) M-​mode across RV outflow track and LV in PLAX projection demonstrate
diastolic RV collapse (circle) and the exaggerated ventricular interdependence with notable respirophasic changes in ventricle dimension (arrows) and septum
position. (h) Pulsed-​Doppler at hepatic veins demonstrating a more prominent diastolic flow reversal during expiration compared to inspiration (arrow).
Reproduced from Klein AL, Abbara S, Agler DA, et al. American Society of Echocardiography clinical recommendations for multimodality cardiovascular imaging of patients with
pericardial disease: Endorsed by the Society for Cardiovascular Magnetic Resonance and Society of Cardiovascular Computed Tomography. J Am Soc Echocardiogr. 2013. doi:10.1016/​
j.echo.2013.06.023 with permission from Elsevier.

findings on echocardiography include the presence of septal
fluttering on M-​mode known a septal notching due to competi-
tive filling waves of the two ventricles. The septum may exhibit a
leftward excursion during inspiration and rightward shift during
expiration. Finally, the presence of dilated hepatic veins with ex-
piratory blunting or reversal of diastolic flow support the pres-
ence of cardiac tamponade [4]‌(E Fig. 46.7).
The use of advanced imaging modalities such as cardiac CT and
MRI should be reserved for stable patients with subacute presen-
tations where high suspicion for regional tamponade remains des-
pite inconclusive initial imaging with surface and transoesophageal
echocardiography [11]. The use of ECG-​gated CT allows the ac-
curate identification of any loculated effusions or focal thrombi,
while the acquisition of 4D cine images could detect focal chamber
compression or even evidence of ventricular interdependence such
as respirophasic abnormal septal motion and reciprocating changes
in ventricular dimensions. Similarly, cine images of cardiac func-
tion and free-​breathing sequences on cardiac MRI allow similar
determination of focal effusion or clot with or without chamber
collapse and/​or ventricular interdependence. If any of these find-
ings are noted to be present during cardiac CT, cardiac MRI, or
fluoroscopy, then urgent referral for treatment is warranted.
Finally, fluoroscopy plays an important role as a surveillance
method during percutaneous cardiac procedures. The interval
development of an immobile cardiac silhouette should prompt
evaluation for cardiac tamponade with immediate clinical correl-
ation and emergent surface echocardiography.
Management of pericardial effusions
and cardiac tamponade
Patients with Peff in the absence of cardiac tamponade should
receive treatments that targets the underlying cause as described
elsewhere [12]. The detection of late gadolinium enhancement
on cardiac MRI, conducted in an otherwise idiopathic Peff,
should prompt the initiation of anti-​inflammatory therapy [24].
Diagnostic pericardiocentesis is rarely of incremental value in the
management of Peff [18]. The indication for drainage in patients
with large effusion without signs of tamponade is not clear and
must be individualized. In contrast, any Peff with signs of cardiac
tamponade warrants drainage along with concomitant targeted
medical management [18].
Echocardiography is the modality of choice for an imaging-​
guided pericardiocentesis. Echo-​guided pericardiocentesis per-
formed by experienced operators has a high rate of technical
success (97%) with low complication rate (1.2%). Although the
classic teaching recommends subcostal or apical projections,
in real practice, any echocardiographic window, including off-​
axis ones, that identifies a pocket fluid of enough size and direct
706 CHAPTER 46   Pe ric a rdial ef f u sion and ca rdiac ta m p ona de

path clear of vital structures can be used to guide the percutan-

eous drainage. When there is no safe window for percutaneous
drainage or when effusion is likely to recurs such in malignant
effusion, a pericardial window is favoured [18].

Conclusion
Peffs are commonly encountered in clinical practice either inci-
dentally or as drivers for clinical presentations. A wide variety of
conditions are associated with Peffs in response to the disruption
of pericardial fluid production-​reabsorption equilibrium. Cardiac
imaging plays an important role in the diagnosis, risk stratifica-
tion, and management of Peffs. Echocardiography is the modality
of choice in the evaluation of Peff as well as the guide during peri-
cardiocentesis. The adjunctive use of advanced imaging including
TEE, cardiac CT and/​or cardiac MRI is useful in complex cases
with high suspicion for focal effusion or tamponade when TTE is
unrevealing. Medical treatment targeting the underlying cause is
recommended for effusion without haemodynamic compromise,
while the identification of cardiac tamponade warrants emergent
pericardiocentesis.
 References
1. Imazio M, Adler Y. Management of pericardial effusion. Eur Heart J 2013; 34: 1186–​97.
2. Hoit BD. Pericardial effusion and cardiac tamponade in the new millennium. Curr Cardiol Rep
2017; 19: 57.
3. Adler Y, Charron P, Imazio M, et al. 2015 ESC Guidelines for the diagnosis and management of
pericardial diseases. Eur Heart J 2015; 36: 2921–​64.
4. Klein AL, Abbara S, Agler DA, et al. American Society of Echocardiography clinical recom-
mendations for multimodality cardiovascular imaging of patients with pericardial disease: en-
dorsed by the Society for Cardiovascular Magnetic Resonance and Society of Cardiovascular
Computed Tomography. J Am Soc Echocardiogr 2013; 26: 965–​1012.e15.
5. Adler Y, Charron P, Imazio M, et al. 2015 ESC Guidelines for the diagnosis and management of
pericardial diseases. Eur Heart J 2015; 36: 2921–​64.
6. Ben-​Horin S, Shinfeld A, Kachel E, Chetrit A, Livneh A. The composition of normal peri-
cardial fluid and its implications for diagnosing pericardial effusions. Am J Med 2005; 118:
636–​40.

transvalvular flow velocities studied by Doppler echocardiography. J Am Coll Cardiol 1988;

7. Vasquez A, Butman SM.
11: 1020–​30
Pathophysiologic mechanisms in peri-
10. Shabetai R, Oh JK. Pericardial effusion and compressive disorders of the heart: influence of
cardial disease. Curr Cardiol Rep 2002;
new technology on unraveling its pathophysiology and hemodynamics. Cardiol Clin 2017;
4:  26–​32.
35:  467–​79
8. Hoit BD. Pathophysiology of the peri-
11. Griffin BP, Callahan TD, Menon V, Wu WM, Cauthen CA, Dunn JM. Manual of Cardiovascular
cardium. Prog Cardiovasc Dis 2017;
Medicine. Philadelphia, PA: Wolters Kluwer Health/​Lippincott Williams & Wilkins; 2014.
59:  341–​8.
12. Soler-​Soler J, Sagristà-​Sauleda J. Pericardial disease. In: Camm AJ, Lüscher TF, Serruys PW, edi-
9. Appleton CP, Hatle LK, Popp RL.
tors. The ESC Textbook of Cardiovascular Medicine, 2nd edition. Oxford: Oxford University Press;
Cardiac tamponade and pericar-
2009: Chapter 19.
dial effusion: respiratory variation in
13. Azarbal A, LeWinter MM. Pericardial effusion. Cardiol Clin 2017; 35: 515–​24.
14. Kim KH, Miranda WR, Sinak LJ, et al. Effusive-​constrictive pericarditis after pericardiocen-
tesis: incidence, associated findings, and natural history. JACC Cardiovasc Imaging 2018: 11:
534–​41.
15. Klein AL, Cremer PC. Ephemeral effusive constrictive pathophysiology. JACC Cardiovasc
Imaging 2018; 11: 542–​5.
16. Yared K, Baggish AL, Picard MH, Hoffmann U, Hung J. Multimodality imaging of pericardial
diseases. JACC Cardiovasc Imaging 2010; 3: 650–​60.
17. Schairer JR, Biswas S, Keteyian SJ, Ananthasubramaniam K. A systematic approach to evalu-
ation of pericardial effusion and cardiac tamponade. Cardiol Rev 2011; 19: 233–​8.
18. Vakamudi S, Ho N, Cremer PC. Pericardial effusions: causes, diagnosis, and management. Prog
Cardiovasc Dis 2017; 59: 380–​8.
19. Xu B, Kwon DH, Klein AL. Imaging of the pericardium. Cardiol Clin 2017; 35: 491–​503.
20. Veress G, Feng D, Oh JK. Echocardiography in pericardial diseases: new developments. Heart
Fail Rev 2013; 18: 267–​75.
21. D’Cruz IA, Minderman D, Dockery BK. Three-​dimensional imaging of intrapericardial adhe-
sions within a large pericardial effusion. Can J Cardiol 2009; 25: 366.
22. Young PM, Breen JF. CT imaging of the pericardium. Curr Cardiovasc Imaging Rep 2013; 6:
259–​67.
23. Rajiah P. Cardiac MRI: part 2, pericardial diseases. AJR Am J Roentgenol 2011; 197: W621–​34.
24. Cremer PC, Kumar A, Kontzias A, et al. Complicated pericarditis. J Am Coll Cardiol 2016; 68:
2311–​28.
25. Appleton C, Gillam L, Koulogiannis K. Cardiac tamponade. Cardiol Clin 2017; 35: 525–​37.
26. Oh JK, Seward JB, Tajik AJ. Pericardial diseases. In: Oh JK, Seward JB, Tajik AJ, editors. The
Echo Manual, 3rd edition. Philadelphia, PA: Lippincott Williams &​Wilkins; 2006: p. 330.

9 For additional multimedia materials please visit the online version of the book at M
oxfordmedicine.com/esccvimaging3

†
  In beloved memory of our great friend Professor Maurizio Galderisi.
708 CHAPTER 47   Pe ric a rdial ef f u sion and ca rdiac ta m p ona de

Table 47.1  Major published series on constrictive pericarditis. As for acute pericarditis, most cases are idiopathic in developed
countries with a low prevalence of tuberculosis, while tuberculosis is the most important cause in developing countries

Feature Cameron et al. Ling et al. Bertog et al. Mutyaba et al.

Institution Stanford University Mayo Clinic Cleveland Clinic Groote Schuur Hospital
Country USA USA USA South Africa
Years 1970–​85 1985–​95 1977–​2000 1990–​2012
Patients 95 135 163 121
Cause
Idiopathic 40 (42%) 45 (33%) 75 (46%) 6 (5%)
Post-​radiation 29 (31%) 17 (13%) 15 (9%) 0 (0%)
Post-​surgery 10 (11%) 24 (18%) 60 (37%) 0 (0%)
Post-​infectious 6 (6%) 26 (20%) 7 (4%) 110 (91%)*
Connective tissue disease 4 (4%) 10 (7%) 5 (3%) 0 (0%)
Other 6 (6%) 13 (10%) 1 (1%) 5 (4%)
*36 patients (29.8%) had proven tuberculosis, and 74 patients (61.2%) had presumed tuberculosis.

LV
RV

Fig. 47.1  Echocardiographic evidence of ventricular septal motion to the left

in early diastole during inspiration ‘Septal bounce’.
 C on c lusi on 709

Table 47.2  Multimodality imaging to differentiate RCM from constrictive pericarditis

Constrictive pericarditis RCM

Chest  X-​ray +++ Rare
Pericardial calcification
2D and M-​mode echocardiography
Abrupt septal movement (‘notch’) in early diastole +++ 0
Septal movement towards left ventricle in inspiration +++ 0
Left atrial enlargement + +++
Thick pericardium +++ 0
Pulsed-​wave Doppler
Respiratory variation in mitral and tricuspid flow velocity >25% <15%
Diastolic flow reversal in expiration within the hepatic vein +++ +
TDI
Mitral medial annulus velocities e’>8 cm/​s, E/​e’<15 e’<8 cm/​s, E/​e’>15
0 0
Deformation imaging
Reduced longitudinal strain 0 ++
Cardiac CT/​CMR 0 0
Thick pericardium (cardiac CT) +++ 0
Pericardial calcifications (cardiac CT) +++ 0
Left atrial enlargement (cardiac CT/​CMR) + +++
Abrupt septal movement (‘notch’) in early diastole (CMR) +++ 0
Septal movement towards left ventricle in inspiration (CMR) +++ 0
Reduced longitudinal strain (CMR) 0 ++
Reproduced from Habib G, Bucciarelli-​Ducci C, Caforio A, et al. Multimodality imaging in restrictive cardiomyopathies. An EACVI expert consensus document.
In collaboration with the ‘Working Group on myocardial and pericardial diseases’ of the European Society of Cardiology. Endorsed by the Indian Academy of
echocardiography. Eur Heart J Cardiovasc Imaging 2017; 18: 1090–​121. doi:10.1093/ehjci/jex034 with permission from Oxford University Press.

CHAPTER 47

Constrictive pericarditis
Alida L.P. Caforio, Maurizio Galderisi†, Massimo Imazio, Renzo
Marcolongo,
Yehuda Adler, and Ciro Santoro

Contents Cardiac CT  711

CMR  711
Definition  707 Constriction vs. restriction  711
Pathophysiology  707
Clinical presentation  708
Differential diagnosis and principles of management  708
Non-​invasive imaging  709
Chest X-​ray  709
Echocardiography  709
Invasive haemodynamics  711
710 CHAPTER 47   C on strictive pericarditis

Fig. 47.2  Transmitral flow with E velocity reduction of more than 25%
during inspiration.
Fig. 47.3  Constrictive pericarditis in patients with mild pericardial effusion
(white arrow), severe atrial enlargement, and moderate tricuspid regurgitation.

Definition
picture of fibrosis and scarring on bioptic samples, and the clin-
Constrictive pericarditis is a pericardial syndrome where the
ical presentation are non-​specific.
pericardium becomes relatively rigid and inelastic, may be thick-
In constrictive pericarditis the typical impairment of diastolic
ened and calcified or not, and impairs mid to late diastolic filling.
filling is mid to late diastolic with a suddenly blocked early diastolic
Constrictive pericarditis is the final pathway of several different
filling causing several signs on physical examination (pericardial
diseases or causes, usually causing pericarditis and pericar-
knock) and echocardiography (septal notch on M-​mode, 2D echo
dial effusion, and progressing towards pericardial fibrosis and
recordings). In addition the fibrotic evolution of the pericardium
calcification  [1–​4].
is responsible for the obliteration of pericardial space with dis-
sociation of intrathoracic pressures from intracardiac pressures as
in cardiac tamponade [1–​3]. On this basis the overall pericardial
Pathophysiology volume becomes fixed and the increase of the size of one ventricle
(e.g. right ventricle during inspiration due to increased venous
Constrictive pericarditis is commonly the final evolution of
return) can only occur with the decrease of the other (e.g. left ven-
any type of pericarditis and pericardial effusion. The risk of
tricle). This causes an exaggerated interventricular interdepend-
developing such evolution is especially related to the aetiology.
ence with inspiratory decrease of the left ventricle volume and
The risk of progression is especially related to the aetiology: low
flows and contemporary increase of right ventricle volume and
(<1%) in viral and idiopathic pericarditis, intermediate (2–​5%)
flow with septal bulging that can be seen on echocardiography
in immune-​ mediated pericarditis and neoplastic pericardial
(E Fig. 47.1).
diseases, and high (20–​30%) in bacterial pericarditis, especially
purulent pericarditis [4]‌.
There few series of constrictive pericarditis reported by ter-
tiary referral centres after pericardiectomy (Stanford, Mayo
Clinic, Cleveland Clinic, and Groote Schuur Hospital) (E Table
47.1)  [5–​8].
The most common reported causes were idiopathic or viral
(42–​49%), post-​cardiac surgery (11–​37%), post-​radiation therapy
(9–​31%), mostly for Hodgkin’s disease or breast cancer, con-
nective tissue disorder (3–​7%), post-​infectious (tuberculous or
purulent pericarditis in 3–​6%), and miscellaneous causes (ma-
lignancy, trauma, drug-​induced, asbestosis, sarcoidosis, uremic
pericarditis in less than 10%) in developed countries. However,
tuberculosis is a major cause all over the world, especially because
of developing countries, where tuberculosis is endemic [1, 8].
In final stages, when constriction is chronic and permanent,
it may be difficult to distinguish the initial cause, since the final
Fig. 47.4  Longitudinal parasternal view with specific setting (low gain) to
detect partial thickening of the pericardium (double arrows).

Fig. 47.5  Reduced longitudinal strain of the basal and middle segment of
the lateral wall with relatively preserved function of the remaining segments.
Clinical presentation
The typical presentation of a patient with constrictive pericarditis
includes signs and symptoms of right heart failure, usually with
preserved right and left ventricular function in the absence of
previous or concomitant myocardial disease or advanced forms
[1]‌. Patients complain about dyspnoea, fatigue, peripheral oe-
dema, breathlessness, hepatomegaly, pleural effusions, ascites,
and abdominal swelling. The delay between the initial pericar-
dial inflammation and the onset of constriction is variable and it
is possibly a direct evolution from subacute/​chronic pericarditis
to constrictive pericarditis. In specific forms as in tuberculous
pericarditis or effusion the evolution usually occurs within 3 to
6 months [4].
In advanced cases, pericardial fibrosis and scarring may ex-
tend into the myocardium, thus causing myocardial fibrosis and
dysfunction [9]‌. In specific forms (e.g. radiation pericarditis), the
same aetiological agent (radiation) affecting the pericardium, also
affects the myocardium (as well as valves and coronary arteries),
thus causing ventricular dysfunction as well.
(a) (b)
N on - i n vasi v e i m ag i n g 711
Differential diagnosis and principles
of management
In constrictive pericarditis there is chronic constriction, defined
as persistent constriction after 3–​6 months [1]‌. The mainstay of
management is pericardiectomy, medical therapy is palliative and
reserved for advanced cases or high risk of surgery or mixed forms
with concomitant myocardial involvement [1, 10]. Typically, in
some cases it is necessary to differentiate constrictive pericarditis
from restrictive cardiomyopathy [11]. To this end, multimodality
imaging is helpful (E Table 47.2) [11].
Constrictive pericarditis also needs to be differentiated from
transient constriction, e.g. a reversible pattern of constriction
following spontaneous recovery or a 2–​3-​month course of em-
piric anti-​inflammatory medical therapy [1]‌. Last but not least,
constrictive pericarditis has to be distinguished from effusive-​
constrictive pericarditis, defined as failure of the right atrial
pressure fall by 50% or to a level below 10 mmHg after pericardio-
centesis, which is also diagnosed by non-​invasive cardiac imaging
[1]. In effusive-​constrictive pericarditis, current European Society
of Cardiology (ESC) guidelines recommend pericardiocentesis
followed by medical therapy; surgery remains an option for per-
sistent cases [1].
Non-​invasive imaging
Cardiac imaging plays a pivotal role in diagnosing constrictive
pericarditis. Chest X-​ray, echocardiography, cardiac computed
tomography (CT) and cardiovascular magnetic resonance (CMR)
are the most relevant diagnostic tools to investigate the pericar-
dium and its diseases. Lately cross-​sectional cardiac imaging,
supplemented by haemodynamic catheterization, became an es-
sential approach to overcome the diagnostic challenges of con-
strictive pericarditis [2]‌.
Chest  X-​ray
Pericardial calcification at chest radiography can be seen in the
27% of the cases of constrictive pericarditis, in areas where tu-
berculosis is not endemic [12]. In most cases unspecific find-
ings of cardiovascular overload (e.g. pleural effusion, pulmonary
Fig. 47.6  (a) Transmitral Doppler filling
velocities suggestive restrictive pattern
expression of elevated left ventricular
filling pressure and (b) inferior vena cava
plethora (double arrows) expression of
elevated right atrial pressure. (asterisks)
pleural effusion.
Fig. 47.7  Axial CT images:
Generalized thickened and non-​
calcified pericardium with localized
pericardial effusion (red box). Bilateral
pleural effusion, severe on the right
side. Complete atelectasis of the
middle lobe.
CT and CMR images in a patient with
constrictive tuberculous pericarditis.

Fig. 47.8  CMR images: Axial

cine SSFP images (left) and T1-​TSE
images (right) that show pericardial
thickening (4 mm) most pronounced
over the right heart side with localized
pericardial effusion.
CT and CMR images in a patient with
constrictive tuberculous pericarditis.

Fig. 47.9  LGE images show diffuse

pericardial enhancement suggestive of
residual inflammation. Mild pericardial
effusion is also noted.
CT and CMR images in a patient with
constrictive tuberculous pericarditis.

Fig. 47.10  Real-​time cine CMR

during respiration showing septal
flattening suggestive of respiratory-​
related ventricular coupling (or
ventricular interdependence).

vascular congestion) and mild cardiomegaly, with atrial rather
than ventricular dilation, can be detected.
Echocardiography
Transthoracic echocardiography (TTE) represents the first
imaging modality to assess the pericardium thanks to its high
availability [13]. TTE examination can promptly rule out other
causes of heart failure, such as valve heart disease, left ventricular
(LV), or right ventricular (RV) dysfunction. When constrictive
pericarditis is suspected the following benchmarks should be
pursued: the motion of the ventricular septum, respiratory vari-
ation in the mitral inflow velocity and in the hepatic vein pro-
file, and tissue Doppler assessment of mitral annular velocities
[14]. During inspiration, increased venous return to the right
heart and reduced LV filling cause expansion of RV volume at
the expense of LV, shifting the interventricular septum towards
the left (E Fig. 47.1). The opposite occurs during the expiratory
phase, with higher venous return to the left chamber moving the
septum back towards the right. Thus, echocardiographic evidence
of ventricular septal motion to the left in early diastole during
inspiration (septal bounce) should rise suspicion of pericardial
constriction.
The ventricular interdependence may be pointed out also ana-
lysing transmitral Doppler pattern. An increment of more than
25% of transmitral E velocity during expiration is strongly sug-
gestive of constriction (E Fig. 47.2). Nevertheless, respiratory
variation in mitral inflow velocities may not be evident in al-
most 50% of patients with constriction. In fact, this finding may
be influenced by atrial arrhythmias and hypovolemic condition
due to marked diuresis, and induced therapeutically to reduce
intrathoracic and intracardiac pressure. Accordingly, even in
presence of significant systemic venous congestion, the absence
of respiratory transmitral E velocity variation does not exclude
the diagnosis of constrictive pericarditis [15].
Reduced venous return to the right chamber during expiration
can also be identified by observing the hepatic vein flow, with a
prominent inversion in late diastole.
Assessment of tissue Doppler mitral annular velocities is an
essential element for diagnosing constrictive pericarditis, being
the only pathologic condition in which high diastolic filling pres-
sure are concomitant with preserved or supranormal relaxation
velocities [16]. Furthermore, due to restricted motion of lateral
myocardium because of pericardial tethering, the relaxation pro-
file known as ‘annulus reversus’ may occur. In fact, unlike physio-
logical condition, the lateral e’ velocity results higher than the
medial e’.
When constriction is suspected additional echocardiographic
evidence should be sought. Pericardial thickening or effusion
and/​or information on LV systolic and diastolic function may
RE F E RE N C E S 713
provide relevant information that can facilitate diagnosis of peri-
cardial constriction.
Pericardial effusion is uncommon in chronic constrictive
pericarditis, but it may co-​exist with constriction in some spe-
cific condition (e.g. effusive-​constrictive pericarditis) (E Fig.
47.3). Even though pericardial thickening exceeding 3–​5 mm
is suggestive of constrictive pericarditis (E Fig. 47.4), con-
striction can also develop in the absence of echocardiographic
evidence of thick pericardium. LV systolic function is usually
preserved in constrictive pericarditis, as demonstrated by high
mitral annular systolic velocities and preserved myocardial
strain and strain rate [17]. Occasionally, longitudinal strain ana-
lysis shows a distinct regional pattern of reduced strain of LV
lateral segments and preserved medial, secondary to the teth-
ering effects of the constrictive pericardium on this free LV
wall [18] (E Fig. 47.5). Transmitral Doppler filling velocities
suggestive of pseudonormal or restrictive pattern (i.e. E/​a ratio
>0.8) and inferior vena cava plethora are expression of elevated
left atrial and right atrial pressure respectively, caused by peri-
cardial constriction [15] (E Fig. 47.6).
TTE is yet affected by several limitations, mainly related to
the inability to evaluate the entire pericardium [19]. Three-​
dimensional echocardiography (3DE) can potentially image
the entire pericardium in different planes overcoming 2D TEE
limits, helping to quantify and follow-​up pericardial mass or
effusion [20].
Invasive haemodynamics
Haemodynamic catheterization may be necessary when con-
strictive pericarditis diagnosis is difficult. Indeed, respira-
tory Doppler velocity variation may also be related to higher
intrathoracic pressure due to respiratory diseases such as chronic
obstructive lung disease, right ventricular infarct, sleep apnoea,
asthma, and pulmonary embolism. Invasive cardiac catheteriza-
tion allows to measure right and left intracardiac pressures in
order to assess several findings that are indicative of constrictive
pericarditis. Elevated central venous pressure is frequent when
constriction occurs. Biventricular end-​diastolic pressure equal-
ization and rapid early diastolic filling of the RV with abrupt
cessation due to pericardial constraint (square root sign) are
characteristic of this condition. RV systolic pressure lower than
50 mmHg may indicate constrictive pericarditis rather than re-
spiratory diseases. Moreover, contemporary measurement of pul-
monary wedge and LV pressure can reveal dissociation between
intrathoracic and intracardiac pressures that occurs when in-
spiratory fall in intrathoracic pressure is not followed by LV pres-
sure reduction due to the stiff pericardium [21].

CMR
CMR is a valuable additional test, espe-
cially when concomitant involvement
of the surrounding structure is sus-
pected (e.g. myocardium), providing
information about tissue character-
ization by using black blood T1-​and
T2-​weighted spin-​echo CMR (EFigs.
47.8–​47.10). Pericardial thickening
>4 mm assessed by breath-​hold ECG-​
gated fast spin-​echo segmented black
Cardiac CT
Its high temporal resolution and short time of acquisition make the cardiac CT an ex-
cellent modality to assess all cardiac structures including the pericardium (E Fig. 47.7).
Particularly, CT is highly accurate to detect thickening and calcification of the pericar-
dium and to obtain functional information about atrial and vena cava enlargement that
usually occurs in presence of pericardial constriction [22]. However, since the CT attenu-
ation of pericardium is similar to that of myocardium, pericardium can be well visualized
when is deployed by other structure (i.e. pericardial fat, pericardial effusion, or tumour
extension) from the myocardium.
blood T1-​weighed imaging is strongly suggestive of constrictive pericarditis [23]. Late
gadolinium enhancement (LGE) can point out signal enhancement of the pericar-
dium when pericarditis occurs, eventually with associated myocardial inflammation
(myocarditis). Occasionally, adhesions between the pericardial layers and the adjacent
myocardium can be seen especially by CMR tagging, revealing lack of myocardial sliding
during the cardiac cycle. Hence, CMR is used also in the therapeutic work up when peri-
cardiectomy is planned to exclude myocardial atrophy or myocardial fibrosis [24].
Constriction vs. restriction
In case of elevated ventricular filling pressure cross-​sectional cardiac imaging is neces-
sary for the differential diagnosis between constrictive pericarditis and restrictive car-
diomyopathy. Frequently, the patient’s clinical history (i.e. history of acute pericarditis,
tuberculosis infection, or previous surgery) helps to address the diagnosis. Besides spe-
cific restrictive cardiomyopathies such as cardiac amyloidosis, which shows peculiar
echocardiographic findings, differential diagnosis between constrictive pericarditis and
other cause of restrictive cardiomyopathies (i.e. post-​radiotherapy, sarcoidosis, haemo-
chromatosis, endomyocardial fibroelastosis, and primary restrictive cardiomyopathy)
can be defying. Some echocardiographic evidence should suggest the presence of peri-
cardial constriction such us the ‘septal bounce’, which does not occurs in case of restric-
tion (E Table 47.2). Tissue Doppler imaging (TDI) comes very helpful to differentiate
constrictive pericarditis from restrictive cardiomyopathies. Indeed, an e’ cut-​off value of
>7 cm/​s indicate a higher probability of constrictive pericarditis [17]. In fact, E/​e’ ratio is
usually low in constrictive pericarditis, despite elevated LV filling pressure. Myocardial
infiltration that occurs in restrictive physiology, usually causes detrimental effect on LV
function. Late gadolinium enhancement (LGE)-​CMR may give precious information on
both myocardial infiltration and LV function, thus it is often necessary resort to this
imaging technique when differential diagnosis is complicated [25].
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(c)
Fig. 48.1  2D-​echocardiographic
images of a patient presenting with
fulminant myocarditis: an increased
thickness of the interventricular
septum is seen at acute onset in the
long-​(a) and short-​axis (b) views.
Five days after presentation the
thickness of the septum has already
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(d)
 N on - i n vasi v e i m ag i n g 717

(a) (b) (c)

Fig. 48.2  Antimyosin scan of a healthy patient with normal findings (a). Significant myocardial antimyosin uptake in a patient with myocarditis (b) with the
corresponding right ventricular endomyocardial biopsy (c) demonstrating lymphomononuclear cell infiltrate diagnostic of myocarditis.
Reprinted by permission of the Society of Nuclear Medicine from Martin et al., J Nucl Med 2004;45:429–​37, Figure 1.

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718 CHAPTER 48   C on strictive pericarditis

(a) (b)

(c)

(d) (e)

Fig. 48.3  A 42-​year-​old woman with a medical history of dyslipidaemia presenting with sudden onset of substernal chest discomfort 5 days after an episode of
acute pharyngitis. There is minor concave upward ST-​segment elevation in leads I, aVL, and V5–​V6 (a). Laboratory test results revealed elevation of troponin-​I
and C-​reactive protein. Multidetector computed tomography (MDCT) coronary angiography showed normal coronary arteries (b). Mild pericardial effusion was
noted. A delayed acquisition performed 5 min after contrast injection (c) showed, on thick multiplanar reformation images, subepicardial delayed enhancement
of the lateral wall (red arrows), suggesting myopericarditis. Contrast-​enhanced CMR confirmed the delayed enhancement findings seen on MDCT with
an excellent topographic match (d). T2-​weighted cardiac magnetic resonance images (e) demonstrated a lateral subepicardial layer of high-​intensity signal
consistent with regional oedema (white arrow)
Reproduced from Ferreira ND, Bettencourt N, Rocha J, et al. Diagnosis of acute myopericarditis by delayed-​enhancement multidetector computed tomography. J Am Coll Cardiol.
2012;60(9):868. doi:10.1016/​j.jacc.2012.01.079 with permission from Elsevier.
 Imaging modaliti es other tha n ca rdiac m ag n eti c res ona nc e i m ag i n g 719

Pre contrast Post contrast

Fig. 48.4  T1-​weighted cross-​sectional views at the midventricular level of

a patient with myocarditis. The left panel displays a view obtained before
gadopentetate dimeglumine (Gd-​DTPA). The right panel depicts the same
view after the administration of 0.1 mmol/​kg Gd-​DTPA. Note diffuse signal
enhancement in the left ventricle.
Reproduced from Friedrich MG, Strohm O, Schulz-​Menger J, Marciniak H, Luft FC,
Dietz R. Contrast media-​enhanced magnetic resonance imaging visualizes myocardial
changes in the course of viral myocarditis. Circulation. 1998;97(18):1802–​9. doi:10.1161/​
01.cir.97.18.1802 with permission from Wolters Kluwer.

CHAPTER 48

Myocarditis
Ali Yilmaz, Heiko Mahrholdt,
and Udo Sechtem

Contents As clinical tools such as history taking, physical exam-

Introduction  715 ination, blood tests, the ECG and the chest X-​ ray are not
Imaging modalities other than cardiac magnetic resonance imaging  715 sufficient to ascertain the diagnosis of myocarditis [1]‌ ,
Echocardiography  715
Myocardial scintigraphy  716 additional information from cardiac imaging techniques, or
Multidetector computed tomography  717 endomyocardial biopsy are necessary to confirm or exclude the
Hybrid imaging techniques  717
disease. In daily clinical routine however, the use of biopsy is
CMR imaging  718
Anatomic and functional abnormalities  719 limited to severely ill patients with reduced left ventricular func-
Tissue characterization  719 tion due to its invasiveness and potential complications. Thus,
Follow-​up of patients with myocarditis by CMR  726 this chapter reviews how non-​invasive cardiac imaging tech-
CMR or endomyocardial biopsy?  727
Clinical recommendations  727 niques can be used in clinical practice to diagnose myocarditis.

Introduction Imaging modalities other than

The symptoms and signs of myocarditis are non-​specific. Thus,
cardiac magnetic resonance imaging
myocarditis is a differential diagnosis in many patients with heart Echocardiography
complaints. As myocarditis may accompany common viral in-
Echocardiography still represents the first-​choice imaging mo-
fections of the upper respiratory and gastrointestinal tracts, and
dality in patients with a clinical suspicion of myocarditis, since
mild ECG changes are not uncommon in such patients, the diag-
it offers the acquisition of comprehensive anatomic and func-
nosis needs to be considered in large patient cohorts. Establishing
tional data very quickly at the bedside of the patient. Especially
the correct diagnosis is of importance as the disease may lead to
in haemodynamically unstable patients in whom their clinical
sudden cardiac death or dilated cardiomyopathy.
720 CHAPTER 48  Myo c ardit is

Table 48.1  Sensitivity and specifity of global relative enhancement (T1 spin-​echo) in myocarditis

SENSITIVITY n Sensitivity SPECIFICITY n Specificity

Friedrich et al. [8]‌ 19 84% Friedrich et al. [1]‌ 34 90%
Abdel-​Aty et al. [14] 25 80% Abdel-​Aty et al. [6]‌ 23 74%
Abdel-​Aty et al. [14] 25 80% Abdel-​Aty et al. [6]‌ 23 74%
Laissy et al. [*] 20 85%
Laissy et al. [**] 24 100% Laissy et al. [**] 7 100%
Gutberlet et al. [15] 48 63% Gutberlet et al. [15] 35 86%
Total 136 79% 99 86%
* Laissy JP, Messin B, Varenne O, et al. MRI of acute myocarditis: a comprehensive approach based on various imaging
sequences. Chest 2002; 122(5): 1638–​48.
** Laissy JP, Hyafil F, Feldman LJ, et al. Differentiating acute myocardial infarction from myocarditis: diagnostic value of early-​
and delayed-​perfusion cardiac MR imaging. Radiology 2005; 237(1): 75–​82.

state precludes the application of other, potentially more accurate
imaging modalities such as cardiac magnetic resonance imaging,
echocardiography is the most helpful imaging tool.
In the last years, new developments have broadened the arma-
mentarium of echocardiographic methods: apart from traditional
M-​mode and two-​dimensional echocardiography, new techniques
such as tissue Doppler, strain-​rate imaging, or contrast-​enhanced
echocardiography have become available for evaluation of pa-
tients with clinical symptoms suggestive of myocarditis. Recently,
longitudinal and circumferential strain parameters (measured
by two-​ dimensional speckle-​ tracking echocardiography) were
shown to be not only of diagnostic but also prognostic value in
young patients with suspected acute myocarditis [2, 3]: deterior-
ation of left ventricular (LV) function and overall event-​free sur-
vival were significantly related to these measurements. However,
the additional value of these new echocardiographic imaging
techniques compared to established non-​invasive imaging mo-
dalities such as cardiovascular magnetic resonance (CMR) in pa-
tients with myocarditis is yet unknown and echocardiographic
data in larger patient groups are not available. Using M-​mode and
two-​dimensional echocardiography in patients with histologically
proven myocarditis, a multitude of different echocardiographic
patterns comprising dilated, hypertrophic, restrictive, or even is-
chaemic cardiomyopathy can be detected, but these echocardio-
graphic features are non-​specific in comparison to biopsy results.
However, echocardiography may help to differentiate between
fulminant and non-​ fulminant acute myocarditis. While ful-
minant myocarditis is characterized by a rapid onset of illness
with severe haemodynamic compromise, non-​fulminant acute
myocarditis is believed to have a less distinct presentation with
less severe haemodynamic compromise but with a greater likeli-
hood to progress to dilated cardiomyopathy. Using echocardiog-
raphy, normal LV diastolic diameters combined with an increased
thickness of the interventricular septum (E Fig. 48.1) and/​or an
impaired right ventricular systolic function at initial presentation
are more suggestive of fulminant myocarditis [4]‌.
Myocardial scintigraphy
Two scintigraphic methods, gallium-​ 67 scintigraphy [5]‌and
indium-​111 radiolabelled antimyosin imaging [6] (E Fig. 48.2)
have been used in the past for diagnosis and evaluation of prog-
nosis in patients with clinical suspicion of myocarditis. These

Table 48.2  Sensitivity and specifity of T2-​weighted imaging in myocarditis

SENSITIVITY n Sensitivity SPECIFICITY n Specificity

Rieker et al. [*] 11 100%°
Abdel-​Aty et al. [6]‌ 25 84%° Abdel-​Aty et al. [1]‌ 23 74%°
Laissy et al. [**] 20 62%°
Laissy et al. [***] 24 61%°
Gutberlet et al. [15] 48 67%°° Gutberlet et al. [15] 35 69%°°
Total 128 71% 58 71%
* Rieker O, Mohrs O, Oberholzer K, Kreitner KF, Thelen M. [Cardiac MRI in suspected myocarditis]. Rofo Fortschr Geb
Rontgenstr Neuen Bildgeb Verfahr 2002; 174(12): 1530–​6.
** Laissy JP, Messin B, Varenne O, et al. MRI of acute myocarditis: a comprehensive approach based on various imaging
sequences. Chest 2002; 122(5): 1638–​48.
*** Laissy JP, Hyafil F, Feldman LJ, et al. Differentiating acute myocardial infarction from myocarditis: diagnostic value of
early-​and delayed-​perfusion cardiac MR imaging. Radiology 2005; 237(1): 75–​82.
° Sensitivity and specificity to detect inflammation as defined by clinical picture.
°° Sensitivity and specificity to detect inflammation as defined by immunohistochemistry.
 Imaging modaliti es other tha n ca rdiac m ag n eti c res ona nc e i m ag i n g 721

SAX LAX Trichrome Macrophages

Patient 6

Fig. 48.5  Late gadolinium-​enhanced (LGE) CMR images

and histopathology of typical patients in whom biopsies
Patient 14 were obtained from the area of contrast enhancement. The
panels show cases of active myocarditis with myocyte damage
as well as infiltration of macrophages. Note that contrast
enhancement is often located in the subepicardial region of the
posterolateral wall.
Reproduced from Mahrholdt H, Goedecke C, Wagner A, et al.
Patient 7 Cardiovascular magnetic resonance assessment of human myocarditis:
a comparison to histology and molecular pathology. Circulation.
2004;109(10):1250–​8. doi:10.1161/​01.CIR.0000118493.13323.81 with
permission from Wolters Kluwer.

techniques have a high sensitivity but data are only available from
patients with severely impaired LV function (indicating severe
forms of myocarditis), and the gold standard against which the
sensitivity of the techniques was evaluated was endomyocardial
biopsy without immune histology, which itself suffers from a low
sensitivity. Gallium-​67 is a non-​specific marker of inflammation.
Gallium imaging should be performed 72 hours after the injec-
tion of the tracer to avoid false positive results from remaining
gallium circulating in the blood. In clinical practice, owing to this
disadvantage, gallium scintigraphy is rarely used today.
The disease process of myocarditis is histologically characterized
by myocardial inflammation with accumulation of immune cells
leading to myocardial damage with necrosis of cardiomyocytes.
Since necrotic cardiomyocytes lose the integrity of their cell mem-
branes, intracellular proteins such as myosin are exposed to the
extracellular space. Indium-​111 labelled antimyosin is able to lo-
calize and visualize those myocardial areas. In practice, antimyosin
antibodies are coupled with indium-​111 and administered intra-
venously. Scintigraphic imaging (single photon emission com-
puted tomography, SPECT) is performed 48 h after intravenous
administration of the radionuclide. Qualitative or (semi-​) quantita-
tive analysis of the scans is then performed. The semi-​quantitative
calculation of the heart-​to-​lung ratio may be used to objectively

Ischaemic Non-ischaemic

• Idiopathic dilatative • Myocardial Amyloid • Hypertrophic Cardiomyopathy (HCM)

Cardiomyopathy (DCM) Right ventricular pressure overload

• Sarcoid
• Myocarditis
• Anderson-Fabry
• Chagas
• Other infiltrative
disorders

Fig. 48.6  Late gadolinium enhancement patterns that one may encounter in clinical practice. If hyperenhancement is present, the endocardium should be
involved in patients with ischaemic disease. Isolated mid-​wall or epicardial hyperenhancement strongly suggests a ‘non-​ischaemic’ aetiology.
Reproduced from Mahrholdt H, Wagner A, Judd RM, Sechtem U, Kim RJ. Delayed enhancement cardiovascular magnetic resonance assessment of non-​ischaemic cardiomyopathies.
Eur Heart J. 2005;26(15):1461–​74. doi:10.1093/​eurheartj/​ehi258 with permission from Oxford University Press.
722 CHAPTER 48  Myo c ardit is

ACUTE HEALED

K Gd K K K K K K K K K K K

Gd K Gd Gd K Gd K K Gd K K K
Gd
Gd Gd
K Gd K Gd K K K K K K K K

K K Gd Gd K K K K K K K K
Gd Gd

K Intact myocyte (K+ inside) Gd Necrotic myocyte (Gd chelates inside)

Gd Gadolinium chelate Fibrocytes & collagen fibers

(can not penetrate intact myocytes) (=enlarged extracellular space)
Fig. 48.7  Mechanism of contrast enhancement in the setting of acute and healed myocarditis. Upper images show LGE images using inversion recovery
gradient echo images, bottom images show a schematic view of contrast enhancement. Just as in infarcts, acute necrosis in the setting of myocarditis is
characterized by ruptured sarcolemmal membranes and surrounding interstitial oedema, allowing the contrast agent to accumulate in the interstitium
as well as to diffuse into the intracellular space. Thus, the general mechanism of hyperenhancement in myocarditis is the same as in infarction. During
healing some amount of interstitial oedema persists and necrotic myocytes are slowly replaced by fibrous tissue, comparable to small chronic infarcts. Thus,
hyperenhancement will remain present during this phase of the disease. However, when healing is completed, oedema has resolved while scars shrink and
remodel over time. Consequently, voxels may now contain so many previously bordering surviving myocytes that hyperenhancement in these voxels may
not be visible any longer, resulting the area of hyperenhancement to decrease significantly. This effect is likely magnified by the patchy distribution of scars in
myocarditis and the fact that interstitial oedema mainly occurs in areas of myocardial necrosis. Thus, all areas of visible hyperenhancement may disappear in
some cases after healing, just leaving minimal diffuse signal enhancement.

assess the extent of antimyosin-​ coupled indium-​ 111 labelled
radionuclide accumulation in the myocardium.
The strength of indium-​111 scintigraphy in the work-​up of
myocarditis is based on many studies suggesting that a positive bi-
opsy result (indicative of myocarditis) is almost always associated
with a positive scintigraphic result, while a negative scintigraphic
result is excluding a biopsy-​based diagnosis of myocarditis with a
high degree of reliability. However, the specificity (31–​44%), and
the positive predictive value (28–​33%) of indium-​111 scintig-
raphy are quite low [6]‌. In consideration of this limited specificity,
the radiation burden, and the practical difficulties of performing
myocardial scintigraphy, scintigraphic techniques are very rarely
applied today to make the diagnosis of myocarditis.
Multidetector computed tomography
The diagnostic capacity of multidetector computed tomography
(MDCT) has tremendously increased with recent technological
advancements. MDCT-​based coronary angiography is becoming
increasingly popular for non-​invasive evaluation of coronary ar-
tery disease. Hence, MDCT coronary angiography is increasingly
used in low-​and intermediate-​risk patients presenting with chest
pain suggestive of coronary artery disease. As myocarditis may
be a differential diagnosis in these patients, myocardial tissue
information from MDCT images would be helpful to also estab-
lish the diagnosis of myocarditis once coronary artery stenoses
were excluded.
Delayed enhancement (DE)-​ MDCT images acquired 5–​ 10
min after contrast injection with a lower tube current and voltage
compared to MDCT coronary angiography reduce radiation dose
and may also increase signal-​to-​noise ratio [7]‌. The combination
of MDCT coronary angiography and DE-​MDCT can be used to
differentiate ischaemic from non-​ischaemic causes of chest pain
(E Fig. 48.3): ischaemic myocardial damage is characterized by
subendocardial or transmural delayed enhancement, while non-​
ischaemic forms are characterized by epicardial or intramural
patterns of DE [7, 8]. Diagnostic agreement of appropriately per-
formed MDCT with contrast-​enhanced CMR in patients with
suspected myocarditis is excellent [9]. However, prospective com-
parative studies do not exist.
A combined procedure of MDCT coronary angiography and
DE-​MDCT could become attractive for the diagnosis of acute
myocarditis in the emergency department, since it allows the ac-
quisition of comprehensive data in a single study within 15 min
[8, 10]. However, such a combined procedure has a slightly higher
radiation exposure than coronary imaging alone [10]. This could
become relevant in the often young patients who present with
 Imaging modaliti es other tha n ca rdiac m ag n eti c res ona nc e i m ag i n g 723

Table 48.3  Sensitivity and specifity of LGE-​CMR in myocarditis

SENSITIVITY n Sensitivity SPECIFICITY n Specificity

Rieker et al. [*] 11 45%° Rieker et al. [*] 10 100%°
Mahrholdt et al. [10] 32 88%°° Roiditi et al. [**] 8 100%°
Abdel-​Aty et al. [14] 25 44%° Abdel-​Aty et al. [6]‌ 23 100%°
Hunold et al. [*****] 6 100%
Laissy et al. [******] 24 79%° Laissy et al. [***] 31 97%°
Ingkanisorn et al. [****] 21 100%°
DeCobelli et al. [12] 23 84%
Gutberlet et al. [15] 48 27%°° Gutberlet et al. [15] 35 80%°°
Mahrholdt et al. [11] 87 95%°°
Yilmaz et al. [#] 71 46%°°
Total 348 68% 107 93%
* Rieker O, Mohrs O, Oberholzer K, Kreitner KF, Thelen M. [Cardiac MRI in suspected myocarditis]. Rofo Fortschr Geb Rontgenstr
Neuen Bildgeb Verfahr 2002; 174(12): 1530–​6.
** Roditi GH, Hartnell GG, Cohen MC. MRI changes in myocarditis-​-e​ valuation with spin echo, cine MR angiography and contrast
enhanced spin echo imaging. Clin Radiol 2000; 55:
752–​58.
*** Laissy JP, Hyafil F, Feldman LJ, et al. Differentiating acute myocardial infarction from myocarditis: diagnostic value of early-​and
delayed-​perfusion cardiac MR imaging. Radiology 2005;237(1): 75–​82.
**** Ingkanisorn WP, Paterson I, Calvo KR, et al. Cardiac magnetic resonance appearance of myocarditis caused by high dose IL-​2:
similarities to community-​acquired myocarditis. J Cardiovasc Magn Res 2006; 8: 353–​60.
***** Hunold P, Schlosser T, Vogt FM, et al. Myocardial late enhancement in contrast-​enhanced cardiac MRI: distinction between
infarction scar and non-​infarction-​related disease. AJR Am J Roentgenol 2005; 184: 1420–​6.
****** Laissy JP, Messin B, Varenne O, et al. MRI of acute myocarditis: a comprehensive approach based on various imaging sequences.
Chest 2002; 122(5): 1638–​48.
# Yilmaz A, Mahrholdt H, Athanasiadis A, et al. Coronary vasospasm as the underlying cause for chest pain in patients with PVB19
myocarditis. Heart 2008; 94: 1456–​63.
° Sensitivity and specificity to detect inflammation as defined by clinical picture.
°° Sensitivity and specificity to detect inflammation as defined by immunohistochemistry.

Post-Gd Pre-Gd
T1 T1 2000

(ms)

0
1/T1 1/T1

R1 R1 ∆R1 0.004 ECV 100

* (1–hct)
(ms–1) = (%)
∆R1blood 32
20
0 0

Fig. 48.8  A flow chart describing the process of generating a composite quantitative extracellular volume fraction (ECV) image of a midventricular short-​axis
slice through the left ventricle. The top row shows two quantitative T1 maps generated from modified look-​locker inversion-​recovery images acquired 15 min
after (Post-​Gd) and before (Pre-​Gd) administration of a gadolinium (Gd)-​based extracellular contrast agent. Both T1 maps are displayed with the same grey
scale. The reciprocal of each pixel value is taken to generate R1 maps (bottom-​left two images labelled R1). The Pre-​Gd R1 map pixel values are subtracted
from the Post-​Gd R1 map to generate a DR1 map. The R1 maps and the DR1 map are all displayed with the same grey scale. In the DR1 map, the DR1 value
of the left ventricular blood pool is measured in a region of interest (black oval). The DR1 map pixel values are then multiplied by one minus the haematocrit
(hct) and divided by the mean of DR1 value of the blood pool (DR1blood) in order to get the composite extracellular volume fraction image, ranging in
values between 0 and 100%.
Reproduced from Ugander M, Oki AJ, Hsu LY, et al. Extracellular volume imaging by magnetic resonance imaging provides insights into overt and sub-​clinical myocardial pathology.
Eur Heart J. 2012;33(10):1268–​78. doi:10.1093/​eurheartj/​ehr481 with permission from Oxford University Press.
724 CHAPTER 48  Myo c ardit is

infarct-​like myocarditis. The lower image quality as compared to may be found adjacent to the myocardial region most affected by
LGE-​CMR may also result in a lower sensitivity of detecting small myocardial inflammation [13].
areas of myocardial damage.
Tissue characterization
Hybrid imaging techniques The following three tissue features potentially associated with
Emerging hybrid PET/​CT and PET/​MRI techniques may have myocardial inflammation may be assessed by CMR:
considerable potential for future cardiovascular inflammation 1. following gadolinium administration (elevated global relative
imaging because they combine PET, a highly sensitive and quan- enhancement [gRE]);
titative modality to detect even low grade inflammation, with
2. tissue oedema, which may result in elevated T2 relaxation
CT or MRI that enable non-​invasive assessment of cardiovas-
times and signal on T2-​weighted magnetic resonance (MR)
cular anatomy with excellent spatial resolution. PET performed
images;
with e.g. fluorine-​18-​fluorodeoxyglucose (FDG) has the unique
ability to depict metabolically active regions. Use of FDG-​PET/​ 3. and myocardial necrosis or scarring, as indicated by the pres-
CT is well established for the diagnosis and management of ma- ence of late gadolinium enhancement (LGE).
lignancies, however, also well suited for assessing infectious and
inflammatory processes of the myocardium [11]. Larger studies Hyperaemia CMR (early myocardial gadolinium
evaluating the diagnostic value of PET/​CT in patients with acute enhancement ratio)
myocarditis are still missing. The myocardium in patients with the clinical manifestations of
Integrated PET/​MRI shows good agreement between FDG-​ acute myocarditis shows hyperenhancement relative to skeletal
PET and CMR [12]. However, it remains unclear whether this muscle on T1 weighted contrast-​enhanced images in the early
form of multimodality imaging has diagnostic or prognostic ad- wash-​out period (E Fig. 48.4) [14]. Scanning is started imme-
vantages over CMR alone. Moreover, FDG-​based PET assessment diately following the first pass of contrast media, such as gado-
of myocardial disease can be challenging [12] because FDG may linium diethylenetriamine penta-​acetic acid (Gd-​DTPA), using
also accumulate in normal myocardium and techniques to pre- a standard fast spin-​ echo pulse sequence with sufficient T1
vent this are required. Novel PET tracers that specifically targetweighting, and is completed at 5 minutes after the injection [15].
monocytes/​macrophages are being tested in preclinical studies The mechanism of signal increase related to tissue hyperaemia
and could overcome these limitations in the future. in the myocardium remains unclear. Tissue hyperaemia may
lead to faster distribution of contrast medium into the interstitial
space. However, it is also conceivable that the increased T1 signal
is caused by the same mechanism of tissue destruction, which ex-
CMR imaging plains the LGE effect. Whatever the exact cause, an increased T1
Due to its non-​invasiveness, the lack of radiation exposure, its signal can be observed during the first minutes after injection of
image quality which helps assessing and quantifying cardiac the contrast agent. It is usually difficult to visually appreciate the
function, and its high tissue contrast, which can be modified diffuse rise in signal intensity on these images and thus quantifi-
using various pulse sequences, CMR has become an important cation of signal changes is necessary. As spin-​echo imaging often
technique for evaluating patients with suspected myocarditis. In yields low contrast between inflamed and normal myocardium
many institutions CMR is now routinely applied clinically in such and suffers from image artefacts it turned out to be advantageous
patients and many reports confirmed the feasibility and diag- to relate the signal increase in the myocardium to that observed
nostic accuracy of CMR protocols. in neighbouring skeletal muscle [14]. Thus, relative enhance-
ment depends on the assumption that skeletal muscle is normal
Anatomic and functional abnormalities which may be erroneous if the inflammation also involves skeletal
For just depicting anatomic and functional abnormalities in muscles. Although early gadolinium enhancement ratio suffers
patients with suspected myocarditis CMR has few advantages from several artefacts, several studies confirm the diagnostic use-
as compared to echocardiography. It is mainly in patients with fulness of this parameter (E Table 48.1). Nevertheless, this pulse
a suboptimal ultrasound window, in those in whom a three-​ sequence is infrequently used today and its value in diagnosing
dimensional visualization of the ventricles is needed to detect acute myocarditis has recently been questioned [16].
subtle abnormalities of regional anatomy and function, and in Oedema imaging by CMR
those in whom details of the right ventricle are of interest that
Acutely inflamed tissue shows an increase in water content due to
CMR should be employed for this purpose only.
oedema formation. Isolated oedema usually indicates reversible
Similar to echocardiography, CMR detects an increase in myo-
myocardial injury. However, oedema also accompanies necrosis
cardial mass in patients with fulminant myocarditis, and is able
as shown in myocardial infarction. Once myocarditis has healed
to document normalization of mass with disappearance of myo-
oedema should disappear.
cardial oedema. CMR is more sensitive than echocardiography in
T2-​weighted CMR [15] today is usually performed by short
depicting small and often localized pericardial effusions, which
inversion time recovery (STIR) pulse sequences. These pulse
 CMR i m ag i n g 725

'Conventional' CMR methods 'Novel' CMR methods

Cine-CMR LGE-CMR T2w-CMR T1 map ECV map

Fig. 48.9  Images of the initial CMR study comprising cine (first column), late gadolinium enhancement (second column)—​and T2w oedema images (third
column) as well as native T1—​and extracellular volume (ECV) maps (fourth and fifth column). Black arrows indicate myocardial areas with increased native T1
suggestive of myocardial inflammation.
Reproduced from Bietenbeck M, Florian A, Shomanova Z, Klingel K, Yilmaz A. Novel CMR techniques enable detection of even mild autoimmune myocarditis in a patient with
systemic lupus erythematosus. Clin Res Cardiol. 2017;106(7):560–​3. doi:10.1007/​s00392-​017-​1100-​7 with permission from Springer Nature.

sequences are sensitive to the long T2 of water protons to gen- or fibrotic myocardium in patients with myocarditis as bright
erate images with a higher signal intensity of oedematous myo- areas and provide high contrast between diseased and normal
cardial tissue as compared to non-​inflamed muscle tissue in the myocardium. Imaging is performed at about 5–​10 minutes after
vicinity. Depending on the distribution of oedema within the contrast injection (LGE). The mechanism by which contrast
LV myocardium there may be visible regional signal differences
within an image. Regions with a signal intensity of more than two Table 48.4  Descriptive statistics of currently available evidence
standard deviations above the mean of normal appearing myo- comparing the diagnostic performance of CMR markers for the
cardial tissue within the same slice are regarded as indicative of detection of acute myocarditis (see also E Fig. 48.1)
regional oedema. One has to be careful not to look at too small CMR criteria Median AUC* Number of Total
regions as signal inhomogeneity on T2 images in normal persons (total range) published number
may be considerable. However, the often diffuse nature, especially studies of cases
in less aggressive inflammation, makes quantitative analysis of the Individual
signal of the entire slice of myocardium superior to visual ana-   T2w imaging 73 (58–​100) 13 981
lysis. Signal intensity of the myocardium is normalized to that of
  EGE 73 (62–​93) 10 711
nearby skeletal muscle and ratios of 1.9 or higher are regarded
as indicative of oedema. However, this cut-​off ratio is based on   LGE 83 (53–​96) 14 1,073
small-​sized studies and every centre is advised to establish its own   T1 mapping 89 (71–​99) 9 682
cut-​off  value.   T2 mapping 80 (73–​86) 6 449
An obvious drawback of this type of analysis is the depend-   Extracellular volume 74 (59–​82) 7 555
ence on absence of inflammation in the skeletal muscle, which
Combinations
is not uncommon in systemic viral illness. Another shortcoming
  Original Lake Louise Criteria 84 (57–​90) 8 630
of T2-​weighted CMR is that in patients with arrhythmias or mo-
tion artefacts from breathing image quality may not allow reliable   T2w + LGE 76 (71–​89) 3 191
visualization or quantification of oedema. Moreover, in studies   T2w + EGE 75 1 45
looking at the diagnostic value of T2 oedema imaging it is usually   EGE + LGE 70 1 45
not specifically mentioned how the diagnosis was made (visually   T2 mapping + LGE 90 (83–​97) 2 120
or by quantification or by both methods). The results of several
  T2 mapping + T1 mapping 86 1 36
studies are shown in E Table 48.2.
  T2w + T1 mapping 84 (73–​95) 2 176
Necrosis and fibrosis imaging by CMR (LGE)   T1 mapping + LGE 96 (82–​97) 5 350
The more severe forms of myocarditis may result in tissue ne- AUC* = estimated area under the curve, calculated as the average of the sensitivity
crosis, which is often focal in nature just as the disease itself. and specificity reported for each combination in published studies (this allowed direct
comparison of various combinations even for studies which did not provide the actual
New contrast-​enhanced CMR techniques employing inversion AUC); CMR = cardiac magnetic resonance; EGE = early gadolinium enhancement;
pulses to null the signal of normal myocardium were initially LGE = late gadolinium enhancement; T2w = T2-​weighted imaging.
developed for infarct imaging. However, they also show necrotic
726 CHAPTER 48  Myo c ardit is

2018 Lake Louise Criteria CMR Image Examples

Regional or global increase Regional or global increase

of native T2 of T2 signal intensity

Myocardial oedema or
(T2-mapping or T2W images)

Main
Regional or global increase Regional or global Regional LGE
Criteria of native T1 increase of ECV signal increase

Non-ischaemic myocardial injury or or

(Abnormal T1, ECV, or LGE)

Fig. 48.10  2018 Lake Louise Criteria.

Reproduced from Ferreira VM, Pericardial effusion Regional or global hypokinesis
Pericarditis
Schulz-​Menger J, Holmvang G, et al. (Effusion in cine images or
Cardiovascular Magnetic Resonance in abnormal LGE, T2 or T1)
Nonischemic Myocardial Inflammation: Supportive
Expert Recommendations. J Am Coll Criteria Systolic LV dysfunction
Cardiol. 2018;72(24):3158–​76. doi:10.1016/​ (Regional or global wall
j.jacc.2018.09.072 with permission from motion abnormality)
Elsevier.

enhancement can be explained is as follows: when serious
membrane damage has occurred in early necrosis gadolinium
molecules enter the intracellular space. This results in an in-
creased volume of distribution for the contrast agent within a
voxel of tissue with an associated increase in signal intensity. In
the chronic stage of myocarditis, areas of scar are histologically
characterized by abundant loose connective tissue with a few
fibrocytes. Again, voxels within such areas of myocardium ex-
hibit a higher concentration of contrast medium as compared
to normal myocardial tissue. In contrast to necrotic or fibrotic
tissue, densely packed myocytes forming most of the normal
myocardium are not accessible to gadolinium compounds.
Hence, the volume of distribution and the concentration of the
contrast agent within a voxel remain low.
When such inversion recovery gradient echo-​techniques are
used in patients with clinically suspected myocarditis (history
of respiratory or gastrointestinal symptoms with 8 weeks of ad-
mission in combination with fatigue/​malaise, chest pain, dys-
pnoea, or tachycardia plus ECG changes such as conduction
block, ST abnormalities, supraventricular tachyarrhythmia,
or ventricular tachycardia) LGE is found in up to 90% of the
patients [17]. The regions of LGE have a patchy distribution
throughout the left ventricle. They are frequently located in the
lateral free wall (E Fig. 48.5), and originate from the epicar-
dial quartile of that wall. Another frequently seen pattern is
the mid-​wall stria pattern in the basal interventricular septum
in patients with chronic myocarditis (E Fig. 48.6, middle of
lower row) [18]. LGE-​CMR also has a good sensitivity in pa-
tients with a more chronic form a myocarditis by clinical cri-
teria [19]. However, in this series of biopsy confirmed patients
with chronic myocarditis, borderline myocarditis—​the less se-
vere form of the disease by the DALLAS criteria—​was less often
associated with LGE than active myocarditis by the DALLAS
criteria [19].
If scarring occurs in acute myocarditis it will usually remain
visible on LGE images when the acute inflammation has long sub-
sided. However, chronic scar following acute myocarditis is often
significantly smaller than in the acute stage due to scar shrinking.
When the initial areas of scarring are just large enough to be vis-
ible, scar shrinking may lead to disappearance of LGE in some
patients (E Fig. 48.7).
LGE-​CMR is the most widely used approach in the diagnosis
of myocarditis and this is reflected in the literature. E Table
48.3 shows the results of published studies including the average
weighted sensitivity and specificity.
Novel mapping techniques for the diagnosis of
myocarditis
In principle, MR images are reconstructed after sampling of MR
data from the predefined imaging plane based on the respective
MR pulse sequence chosen. The sampled MR data originate
from tissue, environment, and MR hardware, as well as pulse-​
sequence-​ dependent measurements of T1 and T2 relaxation
times (relaxivities). Conventional CMR methods such as the ones
discussed earlier (T1w early gadolinium enhancement (EGE),
T2w oedema imaging or T1w LGE) do not directly measure the
local ‘absolute’ tissue T1 and T2 relaxivities on a pixel-​by-​pixel
level. Especially signal intensities in LGE images reflect ‘rela-
tive’ changes/​differences in T1 and T2 relaxivities within the
target tissue by increasing the difference in signal intensity be-
tween healthy and diseased myocardium by additional use of a
gadolinium-​based contrast agent.
In order to overcome the limitations of those conventional
‘indirect’ CMR methods used for tissue characterization so far,
novel CMR mapping techniques have been developed within
the last years and promising clinical results have already been
obtained regarding e.g. detection of myocardial inflammation in
patients with suspected myocarditis [20, 21]. These novel T1 and

(b) Kaplan–Meier survival curves: cardiac death
1
Cumulative survival
0.8
0.6
0.4
p-log-rank < 0.001
0.2
LGE present
0
0 365 730 1095 1460
(c) Kaplan–Meier survival curves: sudden cardiac death
1
Cumulative survival
0.8
0.6
0.4
p-log-rank < 0.001
0.2
LGE present
0 Reproduced from Grün S, Schumm J, Greulich S, et al. Long-​term follow-​up of
0 365 730 1095 1460
Days after CMR
T2 mapping techniques permit measuring absolute T1 and T2
relaxation times on a pixel-​by-​pixel level and the obtained data
are routinely displayed as colour maps reflecting the respective
T1 or T2 relaxation time(s). These T1 and T2 maps in turn allow
to assess whether local and/​or global T1 and T2 relaxation times
are within normal range or rather increased or decreased, thereby
suggesting the presence of pathological tissue changes. Moreover,
the acquisition of T1 maps prior to (native T1) and after admin-
istration of a gadolinium-​based contrast agent (post-​contrast T1)
allows to calculate ‘extracellular volume’ (ECV) maps (E Fig.
48.8) if the haematocrit value is known [22]. Hence, novel map-
ping techniques do not only promise to detect both local as well as
diffuse and subtle myocardial tissue changes but also to visualize
both intra-​and extracellular pathologies and to allow for elegant
quantitative measurements using absolute values (further details
regarding the MR protocol and appropriate application of map-
ping techniques can be found elsewhere in [23, 24]).
However, it should be emphasized that myocardial mapping
protocols are still in the process of development, standardiza-
tion and optimization, and clinical users of mapping proto-
cols are asked to individually test and thereafter set their local
normal values prior to reporting pathological findings based on
mapping techniques. Even slight differences in MR hardware
and/​or software configuration between different MR centres
(even if using the same MR scanner) may result in relevant dif-
ferences regarding mapping results. Since mapping is based on
quantification of absolute T1 and T2 relaxation times, prede-
fined cut-​offs are used for the assessment of pathological results.
Hence, missing method validation as well as standardization
and/​or overinterpretation of mapping findings may result in ra-
ther more clinical confusion than diagnostic support—​in par-
ticular in patients with suspected myocarditis. Therefore, it may
be prudent to compare maps acquired with one’s own CMR
CMR i m ag i n g 727
No LGE
1825 2190 2555 2920
Fig. 48.11  Kaplan–​Meier survival curves with regard to cardiac
mortality (upper panel) and sudden cardiac death (bottom panel) of
patients with biopsy-​proven myocarditis. Note that no patient without
No LGE the presence of LGE suffered an event.
1825 2190 2555 2920 biopsy-​proven viral myocarditis: predictors of mortality and incomplete recovery.
J Am Coll Cardiol. 2012;59(18):1604–​15. with permission from Elsevier.
mapping protocol with those acquired using the protocol of an-
other experienced centre (this can usually be obtained through
your vendor). Testing should be done in normal persons and in
patients with stable cardiomyopathy, for instance with cardiac
amyloidosis. Only if these tests indicate reproducible and con-
sistent results should mapping (T1, T2, ECV) be introduced for
routine clinical work-​up.
So far, mapping data in patients with suspected and/​or proven
myocarditis were mostly obtained in single centre studies with
important differences in the respective study design. For ex-
ample, Ferreira et al. [25] studied 50 patients with suspected
acute myocarditis manifesting itself as acute chest pain and ele-
vated troponin levels (infarct-​like myocarditis) yet preserved left
ventricular ejection fraction (LV-​EF) of 63 ± 12%. Compared to
their control group, patients with suspected myocarditis demon-
strated a higher mean myocardial T1 value (1,010 +/​–​65 ms vs.
941 +/​–​18 ms, P <0.01). Myocardial injury suggestive of acute in-
flammation was defined as T1 ≥ 990 ms. Using this definition, the
diagnostic sensitivity and specificity of T1 maps for the diagnosis
of acute myocarditis was 90% and 91%, respectively. In com-
parison, LGE imaging in the same patients showed a sensitivity
and specificity of 74% and 97%, respectively. Receiver-​operating
characteristic (ROC) analysis regarding the diagnosis of acute
myocarditis showed an area under the curve (AUC) for T1 map-
ping of 0.95 and for LGE for 0.96. Hence, a convincing superiority
of T1 mapping compared to conventional LGE imaging could
not really be shown in this initial study and the authors carefully
concluded that T1 mapping showed a higher diagnostic sensi-
tivity and that it might be useful in detecting subtle focal disease
when LGE imaging is not feasible. Limitations of this study were
that only a very homogeneous patient population was studied
and that the diagnosis of myocarditis was just clinical without
endomyocardial biopsy. In addition, only one slice of T1-​map
728 CHAPTER 48  Myo c ardit is
per subject was ‘randomly’ preselected and thereafter analysed;
average T1 values were calculated as the average of the T1 values
of all pixels for that slice. Accordingly, only moderate correlations
were observed when T1-​maps were compared with LGE images
(r = 0.49).
In another subsequent study of this group [20], the same study
protocol was applied to 60 patients with suspected acute myo-
carditis (all infarct-​ like clinical presentations) and preserved
LV-​EF. In this study, quantitative analysis of T1 maps was per-
formed in all slices. Using their predefined threshold of T1 ≥990
ms for acute myocardial injury, the authors detected larger areas
of myocardial damage using T1 mapping when compared to
both conventional T2 oedema and LGE imaging. Moreover, they
were even able to detect minor degrees of myocardial injury by
T1 mapping in some patients who were T2-​and LGE-​negative.
Again, the sensitivity and specificity for the detection of acute
myocarditis was 90% and 88% for T1 mapping and 72% and 97%
for LGE imaging. Obviously, T1 mapping diagnoses depend on
the predefined cut-​off threshold of T1 for myocardial injury and
would be substantially different (e.g. lower sensitivity and higher
specificity of T1 mapping in case of a higher T1-​cut-​off value).
Unfortunately, ROC analyses were not performed in this study.
Overall, this study did not convincingly show that mapping out-
performs conventional LGE imaging and will really be helpful in
clinical decision-​making. Nevertheless, it demonstrated that T1
mapping may be used for detection of myocardial injury in those
patients in whom the administration of a gadolinium-​based con-
trast agent is contraindicated.
One of the few studies that combined mapping techniques with
correlation to endomyocardial biopsies (EMB) in patients with
suspected myocarditis was the MyoRacer trial by Lurz et al. [26].
This study included a broader range of clinical presentations com-
patible with a diagnosis of myocarditis. There were 61 patients
with acute symptoms (<14 days) who mainly presented with chest
pain (90%) and a mean LV-​EF of 48%. In addition 68 patients
with chronic symptoms (≥14 days) (chest pain (60%) but more
often symptoms of heart failure) and a reduced LV-​EF of 27%
were recruited. Apart from conventional CMR methods, both T1
and T2 mapping was performed and myocardial ECV values were
calculated. Myocardial inflammation was histologically detected
in 70% in the acute group and in 71% in the chronic group. In the
acute group, the diagnostic sensitivity and specificity for the de-
tection of myocardial inflammation was 88% and 67% for native
T1 mapping (using a threshold of T1 >1.058 ms), 85% and 68%
for T2 mapping (using a threshold of T2 > 58.8 ms), 75% and
72% for ECV measurement, and 66% and 47% for conventional
methods according to former Lake–​Louise criteria (LLC) [15].
Moreover, in the acute group, the best diagnostic performance as
defined by the AUC of ROC analysis was obtained for T1 map-
ping (AUC = 0.82) followed by T2 mapping (0.81), ECV (0.75),
and LLC (0.56). Unfortunately, the authors neither mentioned
individual diagnostic values for LGE imaging per se, nor per-
formed a comparative segment-​based analysis. Compared to the
aforementioned studies of Ferreira et al. [20, 25], a much different
Box 48.1  Indications for CMR in myocarditis
Suspected myocarditis based on various combination of clinical
symptoms such as fatigue, palpitations, arrhythmias, unexplained
dyspnoea, unexplained chest pain in the absence of coronary
artery disease or any other structural heart disease, and/​or ab-
normal resting ECG.
Clinical presentation with acute coronary syndrome in the ab-
sence of coronary artery disease or culprit lesion.
Clinical presentation with successful resuscitation after sudden
cardiac death in the absence of coronary artery disease or any
structural heart disease.
Clinical presentation with new onset of heart failure in the ab-
sence of coronary artery disease or any structural heart disease.
CMR guidance of endomyocardial biopsy to increase sensitivity.
Follow-​up of known myocarditis.
Follow-​up of known myocarditis after antiviral or immuno-
suppressive treatment.
T1 threshold (defining acute myocardial injury) was used (990
ms vs. 1.058 ms)—​illustrating the aforementioned need for opti-
mized standardization of mapping techniques and for individual
method validation. Furthermore, the obtained diagnostic sensi-
tivity and specificity values for native T1 mapping (88% and 67%)
are substantially lower than those in the studies of Ferreira et al.
and the (quite low) respective values for conventional LLC (66%
and 47%) are in strong contrast to previous studies that were used
to define those LLC in the past. Issues get even more complex
and difficult to interpret when the results of the chronic group
are analysed in more detail. In these patients in whom the clinical
question was whether LV dysfunction was caused by myocardial
inflammation only T2 mapping had an acceptable diagnostic per-
formance. This indicates that T1 mapping may mostly be useful
for confirming the diagnosis of myocarditis in younger patients
with an infarct-​like presentation. Such patients were exclusively
studied by Ferreira et al. and comprised most of the acute patients
in the MyoRacer trial.
Taken together, T1 and T2 mapping techniques promise a more
sensitive and sophisticated diagnosis of myocardial tissue changes
in case of acute and chronic myocarditis compared to conven-
tional techniques (E Fig. 48.9). Looking at individual case re-
ports and small-​sized single centre studies [21, 27, 28], there are
data supporting this notion [29]. However, when looking carefully
at individual study details and in particular at study limitations
and discrepancies, one should currently be cautious regarding the
additional diagnostic yield of mapping techniques compared to
conventional methods (in particular to LGE imaging). Moreover,
there are no outcome studies demonstrating a superior value of
mapping techniques with respect to guiding therapy or predicting
prognosis. Finally, it is not yet clear how mapping techniques per-
form in patients who do not present with the infarct-​like form of
myocarditis [30].
Nevertheless, the aforementioned LLC were recently revised
to include the results of CMR mapping into the diagnostic

process [31]. The authors performed a descriptive statistical
meta-​ analysis (somewhat blanking essential differences in
individual study design) and assessed the overall diagnostic
performance of T1 mapping with an AUC of 89%, of T2 map-
ping with an AUC of 80% and of ECV measurement with an
AUC of 74%. Combining T1 mapping with LGE imaging re-
sulted in an AUC of 96% (E Table 48.4). In a challenging
approach to unite previous data that formed the basis of the
initial LLC criteria with novel mapping data, the authors pro-
pose that the CMR-​b ased diagnosis of acute myocardial in-
flammation suggestive of myocarditis is appropriate if the
CMR scan demonstrates the combination of myocardial oe-
dema with other CMR markers of inflammatory myocardial
injury (E Fig. 48.10). Thus, the diagnosis of myocarditis re-
quires at least one T2-​b ased criterion (global or regional in-
crease of myocardial T2 relaxation time or an increased signal
intensity in T2-​weighted CMR images), with at least one T1-​
based criterion (increased myocardial T1, ECV, or LGE). The
authors of this recommendation paper further explain that
having only one positive CMR marker (i.e. T2-​based OR T1-​
based) may still support the diagnosis of acute myocardial
inflammation if the clinical scenario is appropriate, but with
less diagnostic specificity.
Given the paucity of available data regarding the CMR-​based
diagnosis of acute myocardial inflammation, the lack of stand-
ardized multicentre studies and the absence of outcomes data re-
lated to different diagnostic criteria, the new LLC 2018 [31] with
their two-​by-​two approach and a rather broad armamentarium of
CMR techniques allowing the diagnosis of acute myocarditis are
conceivable and appropriate. These criteria will permit that each
CMR centre can continue using their current CMR sequences/​
methods while adopting and validating novel mapping tech-
niques. However, future large-​size (multicentre) outcome studies
are needed in order to show which of the current techniques will
have the highest diagnostic yield in every day clinical routine and
the highest clinical benefit regarding clinical decision-​making.
In this context, the superiority of mapping techniques that are—​
just as conventional pulse sequences—​prone to artefacts caused
RE F E RE N C E S 729
by arrhythmia, cardiac and respiratory motion, partial volume
effects, suboptimal B0-​shimming, presence of cardiac devices,
surrounding tissue composition (and others) compared to the ro-
bust and well established LGE technique needs to be particularly
shown in future studies. Therefore, a CMR scan showing only
the presence of (characteristic) LGE as a positive CMR marker—​
without an additional T2-​based criterion (e.g. due to artefact
problems with T2-​based sequences)—​does still support the diag-
nosis of acute myocardial inflammation with sufficient specificity
if the clinical scenario is appropriate and if other causes for LGE
presence are unlikely.
Follow-​up of patients with myocarditis
by CMR
Clinical improvement of myocarditis patients is paralleled by
normalization of gRE and oedema ratio in many patients [32].
Serial assessment of the relative T2 signal, gRE ratio, and LGE at
initial presentation and after 18 months in 36 patients diagnosed
with acute myocarditis by clinical criteria showed a decrease of
the mean T2 signal ratio from 2.4 to 1.9, a decrease of the gRE
signal ratio from 7.6 to 4.4 and a decrease of the amount of LGE
from 38% to 22% of LV mass. These findings are in line with pre-
vious publications describing the individual time courses of each
of those CMR parameters [33, 34] in myocarditis patients. Hence,
the CMR approach combining a contrast-​enhanced T1 weighted
pulse sequence, a T2-​ weighted sequence, plus a LGE pulse
sequence may be capable of differentiating reversible and healing
(elevated T1 gRE ratio and T2 oedema ratio which normalizes
over time) myocarditis and irreversible myocardial damage with
or without ongoing inflammation (persistent LGE with or without
accompanying elevations of T1 gRE ratio and T2 oedema ratio)
non-​invasively.
In patients with ongoing cardiac symptoms, the clinical ques-
tion is often whether the acute inflammatory process has healed.
If none, or just one of T2 or gRE ratios is elevated, this constella-
tion may have a very high negative predictive value for excluding
ongoing active myocarditis in living patients [32].

in 4.7 years, and that the presence of
LGE was the best independent pre-
dictor of all-​cause and of cardiac mor-
tality. Importantly, no patient without
LGE suffered cardiac or sudden cardiac
death during follow-​up despite biopsy-​
proven myocarditis (E Fig. 48.11). In
a population of patients with clinically
suspected myocarditis (consecutive all
comers) a normal CMR (defined as LV-​
EF ≥ 60% and LV-​EDV≤180 ml and no
LGE) has a very low risk for death or
other adverse cardiac events [37].
However, data on the value of CMR in identifying healed from ongoing active myocar-
ditis are far from being conclusive. The largest study examining patients with clinically
suspected chronic myocarditis by CMR and endomyocardial biopsy [35] found absence
of T2 elevation in 33%, and no elevated gRE ratio in 37% of those shown to have inflam-
mation by histology. Hence, there is a sizeable subgroup of chronic myocarditis patients
with persisting inflammation who will have elevation of only one of these two CMR
parameters.
Another important clinical question is risk stratification of patients with myocarditis
and suspected myocarditis with regard to mortality and major adverse cardiac events.
Grün et al. recently evaluated the long-​term mortality in patients with viral myocarditis,
to establish the prognostic value of various clinical, functional and CMR parameters [36].
They concluded that among their population with a wide range of clinical symptoms,
biopsy-​proven viral myocarditis was associated with a long-​term mortality of up to 19.2%
CMR or endomyocardial biopsy?
Biopsies obtained from the area of LGE show acute or borderline myocarditis [17] in a
higher percentage than reported from biopsies taken randomly (usually from the right
ventricle) in some reports. These findings may be explained by the fact that more LGE
may be associated with more intense ongoing inflammation in patients with an acute
presentation permitting the operator to direct the bioptome towards the area of max-
imum injury. Myocarditis was found less consistently in patients in whom the biopsy
could not be obtained from the region of contrast enhancement [17]. However, the
data on CMR guided biopsy remain controversial. Yilmaz et al. reported that a pref-
erential biopsy in regions showing LGE on CMR did not increase the number of posi-
tive diagnoses of myocarditis [38]. However, they did not distinguish EMB yield with
respect to the clinical presentation of the patients. Irrespective of the precise location
of biopsy taking the available data show (1) biventricular biopsies have a higher diag-
nostic yield compared to selective biopsies; and (2) that LV biopsies give a higher diag-
nostic yield compared to right ventricular biopsies, while having a lower risk for minor
complications [38].
When managing patients with inflammatory heart disease today, it should be kept in
mind that endomyocardial biopsy remains the only technique that can directly assess the
presence and intensity of myocardial inflammation in vivo. Therefore, it is the technique
of choice if clinically indicated to differentiate between active and healed myocarditis.
Endomyocardial biopsy also provides information on the underlying cause of inflamma-
tion, such as viral or bacterial infection of the myocardium, or myocardial autoimmune
processes, on the presence of giant cells, or Churg Strauss syndrome [39]. This infor-
mation cannot be obtained by CMR imaging but is essential for patient management
decisions. One has to keep in mind, however, that the currently used criteria for diag-
nosing borderline myocarditis only require a number of activated macrophages (and/​or
lymphocytes) >14/​high power field [40]. As many intramyocardial processes other than
viral myocarditis may lead to increased number of macrophages [41] this may potentially
result in an overdiagnosis of (viral) myocarditis by EMB.
Clinical recommendations
The optimal CMR approach for diagnosing myocarditis likely depends on the clinical
presentation of the patient. The patient with less impressive symptoms may be more
likely to have pathologic hyperaemia and oedema imaging with normal LGE. Recent
expert consensus suggests that CMR should be performed in patients who are symp-
tomatic, have clinical evidence suggesting myocarditis, and in whom CMR will likely
affect clinical management [31]. A positive diagnosis of myocarditis may result in a
732 CHAPTER 48  Myo c ardit is

Table 49.1  Differential diagnosis of cardiac masses are more severe. In these patients clinical symptoms may be ab-
sent, and the mere presence of an abnormal ECG should trigger a
Benign cardiac Rhabdomyoma
request of performing CMR (E Box 48.1).
tumours Cardiac myxoma
Papillary fibroelastoma In most centres only two sets of images (T2 oedema and LGE)
Haemangioma are acquired whereas myocardial global relative enhancement is
Cardiac fibroma not measured due to the fact that T1 weighted spin-​echo images
Lipoma are often of poor quality. When all three sets of images are ac-
Cystic tumour of the AV node
quired myocarditis is defined to be present when at least two of
Malignant cardiac Angiosarcoma the three sets of images show pathologic results. Other centres
tumours Myofibrosarcoma
Rhabdomyosarcoma
feel that LGE is the most stable pulse sequence with the fewest
Osteosarcoma number of artefacts, and they rely on the result of this set of im-
Liposarcoma ages alone. This approach may result in some underdiagnosis
Undifferentiated pleomorphic sarcoma of myocarditis but has a good specificity. Acquisition of T1
Cardiac lymphomas and T2 maps is still not routine in all institutions using CMR
Metastatic tumours
for diagnosing myocarditis. These different approaches at dif-
Non-​neoplastic Cardiac thrombi ferent centres reflect the fact that there are still not enough data
cardiac masses Lipomatous hypertrophy of the atrial septum
Abscess available at the moment, especially in patients who also had
Vegetation endomyocardial biopsy, to give final recommendations on CMR
Anatomic variants (crista terminalis . . . ) in patients with suspected myocarditis.
Focal myocardial hypertrophy
Pericardial tumours Pericardial cyst
Solitary fibrous tumour
Malignant mesothelioma
Metastatic pericardial tumours

recommendation to refrain from exercise, betablockade may be

instituted in patients with arrhythmias, and clinical follow-​up
may be scheduled. Some patients may require additional follow-​
up by echocardiography or CMR. In patients with occupations as-
sociated with strenuous exercise the indication to perform CMR
should even be broader as the consequences of having the disease

Table 49.2  CMR characteristics of cardiac masses: typical signal intensities on T1-​weighted (T1)
and T2-​weighted (T2) images and late gadolinium enhancement (LGE)

T1 T2 LGE
Primary benign cardiac tumours
Myxoma Isointense High Heterogeneous
Lipoma Higha Higha No uptake
Rhabdomyoma Isointense Isointense/​High No/​minimal uptake
Fibroma Isointense Low Hyperenhancement
Primary malignant cardiac tumours
Angiosarcoma Heterogeneous Heterogeneous Heterogeneous
Undifferentiated sarcoma Isointense Hyperintense Heterogeneous/​variable
Lymphoma Isointense Isointense No/​minimal uptake
Metastasis b Low High Heterogeneous
Pseudotumours
Thrombus Low if recent Low if recent No uptake
Pericardial cyst High High No uptakec
a
similar to surrounding fat signal and characterized by marked suppression with fat saturation prepulse; b the exception is
metastatic melanoma which has a high T1w* and a low T2w*; c best seen on early gadolinium enhancement imaging.
 CMR i m ag i n g 733

(a) (b) (c)

Fig. 49.1  Large left atrial myxoma with typical origin at the basal interatrial septum. (a) Transthoracic echo three chambers view; (b, c) Transoesophageal
echocardiographic imaging shows the myxoma as a highly mobile mass of heterogeneous texture and isodensity relative to the myocardium. Large myxomas
can occlude the mitral valve during diastolic filling causing functional mitral stenosis.

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CMR i m ag i n g 735
Fig. 49.4  A 60-​year-​old male
with history of two recent cerebral
embolic strokes Transoesophageal
3D echocardiographic reveals a
histologically proven mitral papillary
fibroelastoma, attached to the
endocardium on the left atrial side
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736 CHAPTER 49  Myo c ardit is

(a) (c) (e)

(b) (d) (f)

Fig. 49.5  A 40-​year-​old otherwise healthy female patient with the incidental echocardiographic finding (a, b) of a hyperintense mass in the interventricular
septum (yellow arrow). On CMR, cardiac fibroma appears as a mural hypointense mass (c). Cardiac fibromas do not show enhancement during first-​pass
perfusion, suggesting a low vascularity (d). 10 minutes after contrast administration, intense late gadolinium enhancement was observed (e, f).

(a) (b)

Fig. 49.6  Lipomatous hypertrophy of the interatrial septum is defined as ‘any deposit of fat in the atrial septum which exceeds 2 cm in transverse dimension’
is caused by an increase in the number of adipocytes, spares the fossa ovalis, and does not represent a true cardiac neoplasy. (a) TTE image can simulate a right
auricular mass, however, the TEE (b) confirms the diagnosis.
 Epi dem i ol o g y a n d cl as si f i c at i on 737

(a) (b)

Fig. 49.7  Typical tissue signal

intensities with different CMR
sequences of a lipoma located within
the interventricular septum. (a) T1-​
(c) (d) weighted image shows hyperintense
signal of the lipoma which is similar
to subcutaneous fat; (b) T1-​weighted
image with preparation pulse for
fat saturation shows hypointense
signal of the lipoma relative to
myocardium. Similar signal loss of
subcutaneous fat; (c) cine TRUFI
image shows isointense signal of the
lipoma relative to myocardium; (d)
T1-​weighted image with preparation
pulse for fat saturation after contrast
administration shows no contrast
enhancement of the lipoma.

CHAPTER 49

Cardiac masses and tumours

Teresa López-​Fernández and Peter Buser

Contents Epidemiology and classification

Epidemiology and classification  731
Benign cardiac tumours  731 Cardiac masses include tumours, thrombi, cysts, calcific lesions,
Rhabdomyoma  731
Myxoma  732 vegetations, and other rare conditions [1]‌. Cardiac tumours rep-
Papillary fibroelastoma  733 resent a rare but important cause of morbidity and mortality in
Haemangioma  734 clinical cardiology and are often challenging in diagnostic car-
Fibroma  735
Lipoma  735 diac imaging. The classification of cardiac tumours has recently
Cystic tumour of the atrioventricular node  736 been updated by the World Health Organization: cardiac tu-
Malignant cardiac tumours  737 mours include benign tumours, tumour-​like lesions, malignant
Angiosarcoma  737
Miscellaneous sarcomas (myofibrosarcoma, rhabdomyosarcoma, liposarcoma, tumours, and pericardial tumours (E Table 49.1) [2]. Primary
undifferentiated pleomorphic sarcoma)  737 cardiac tumours are rare with an estimated prevalence between
Cardiac lymphoma  738
Cardiac metastases  739
0.001% and 0.3% [3] and are found in 1 of 2,000 autopsies [1,
Cardiac thrombi  740 2]. Secondary cardiac tumours, including metastases from distant
Conclusions  742 malignomas or local invasion from neoplasms in the chest, are at
least 20 times more common [1, 4]. The vast majority (>80–​90%)
of primary cardiac tumours are benign. Of those, the majority
are myxomas, followed by papillary fibroelastomas, lipomas, and
738 CHAPTER 49   C ardiac masses and tumou r s

(a) (b) (c)

Fig. 49.8  Right atrium angiosarcoma involving the pericardium. TTE (a) showed an inhomogeneous mass with hypodense areas, located in the right atrium
with pericardial infiltration and severe pericardial effusion with cardiac tamponade criteria on admission. After pericardiocentesis on CMR cine image (b) shows
heterogeneous signal intensity with diffuse late contrast enhancement (c).

haemangiomas. In paediatric patients, rhabdomyomas and fi-

bromas are the most common benign primary cardiac tumours
[5]. Of the malignant primary cardiac tumours, 95% are sarcomas,
and the more common types are undifferentiated pleomorphic
sarcomas, angiosarcomas, leiomyosarcomas, and osteosarcomas
[1, 2, 6]. Common sources of metastatic lesions are melanoma,
thyroid cancer, breast cancer, renal carcinoma, lung cancer, oe-
sophageal cancer, and hepatocellular carcinoma [1, 2]. Clinical
presentation (asymptomatic, embolic phenomena, cardiac ar-
rhythmias, obstruction) depends on location, size, shape, mo-
bility, and rate of growth.
The present chapter will cover benign and malignant tumours
as well as cardiac masses from the imaging diagnostic perspec-
tive. Although echocardiography is generally the first imaging
tool used, tissue characterization by cardiac magnetic resonance
(CMR) can be particularly helpful for differential diagnosis (E
Table 49.2).
Benign cardiac tumours
Rhabdomyoma
Rhabdomyomas are the most common primary cardiac tumour
in children. Cardiac rhabdomyomas comprise 90% of heart tu-
mours diagnosed prenatally [7]‌. Most frequently, rhabdomyomas
are located in the myocardium of both ventricles and the size of
the tumours may vary considerably. They tend to disappear spon-
taneously and conservative management is common in asymp-
tomatic children, although surgical resection may be necessary in
selected cases. Pharmaceuticals that inhibit the mTOR signalling
pathway (e.g. everolimus) have been shown to hasten regression
in some cases [8].
The diagnosis of suspicion by echocardiography is established
in the presence of an echodense homogeneous intracardiac mass,
more frequently lobulated in shape and ventricular in origin [9]‌.
About 80% of children with cardiac rhabdomyomas have clin-
ical, radiologic, or family history of tuberous sclerosis complex

(a) (b) (c)

Fig. 49.9  Large rhabdomyosarcoma (*asterisk) first detected by transthoracic echocardiography (a) in an 83-​year-​old female patient with signs of progressive
dyspnoea. The tumour that fills out the entire dilated left atrium in echocardiography appears of heterogeneous texture with hypodense zones of necrosis and
hyperdense sclerotic spots. Cardiac MR (b) revealed a large rhabdomyosarcoma (7.0 = 13.1 cm) with cystic areas and strong contrast agent uptake in border regions,
as well as with extensive infiltration of the left lung and less infiltration of the right lung, but no metastases. Cardiac CT 1 month after cardiac MR (c) reveals rapid
progression of tumour size now being 9.1 × 14.3 cm with progressive building of a wall around the left lung hilus and compression of the oesophagus.
LV = left ventricle.
 B en i g n ca rdiac t umour s 739

(a) (b)

(c) (d)

Fig. 49.10  (a, b) TTE shows an inhomogeneous

mass located in the right atrium (RA). The origin of
RA mass is a leiomyosarcoma located at the inferior
cava vein (c, d).

[7]. Nearly two-​ thirds of patients will have multiple cardiac
rhabdomyomas, usually located intramurally, as a circumscribed
left and/​or right ventricular wall thickening [9].
On CMR examination, and compared to the normal
myocardium, rhabdomyomas show a homogeneous isointense
signal on T1-​ weighted images and on T2-​ weighted images,
hyperintense signal is observed within the mass [10, 11]. Perfusion
imaging shows complete opacification of the full thickness of the
mass with almost immediate opacification of the central portion.
Early gadolinium uptake is more intense compared to the sur-
rounding myocardium, and abnormal late gadolinium enhance-
ment may be observed sometimes across the entire thickness of
the mass [12].

(a) (b) (c)

Fig. 49.11  A 52-​year-​old woman with a primary cardiac lymphoma. (a, b) TTE shows a polypoid heterogeneous mass in the right atrium with a pericardial
effusion and infiltration of the right AV area and the tricuspid annulus. Cardiac CT reveals a large hyperintense mass with pericardial and pleural effusion.
740 CHAPTER 49   C ardiac masses and tumou r s

(a) (c) (d)

(b) (e)

Fig. 49.12  Cardiac metastasis of a primary renal tumour. (a, b) TTE showed a large irregular and inhomogeneous mass at the right ventricular outflow tract.
Cardiac CT (c–​e) shows invasion of the myocardial wall with irregular areas of peripheral mass perfusion.

Myxoma Due to the various histologic components, myxomas appear

with heterogeneous signal intensity on every CMR sequence.
Approximately 50% of primary benign cardiac tumours are myx-
Occasionally, they can appear heterogeneous on both T1-​weighted
omas. They typically arise from the left side of the interatrial
and T2-​weighted images due to the presence of haemorrhage,
septum or the fossa ovalis, although they can arise from any endo-
necrosis, and calcification [16]. On steady-​ state free preces-
cardial area. Of myxomas, 75% are located within the left atrium,
sion (SSFP) cine sequences, they are usually hyperintense with
20% in the right atrium, and rarely in the ventricles [1]‌. Myxomas
hypointense foci as compared to myocardium and hypointense as
typically are attached to the endocardium by a narrow pedicle.
compared to the blood pool. To some degree, contrast enhance-
Internally myxomas may contain cysts, necrosis, haemorrhage, or
ment on first-​pass perfusion and heterogeneous late enhancement
calcifications [13] and their surface may partially be covered by
can be observed [17, 18]. With cardiac CT, myxomas usually have
organized thrombi, increasing the risk of thromboembolic events.
heterogeneous low attenuation reflecting gross pathologic fea-
In echocardiography, myxomas usually present as a single
tures and calcifications can be found frequently (E Fig. 49.3).
homogeneous mass, isodense to the myocardium, and typic-
ally located at the interatrial septum. Differentiation between Papillary fibroelastoma
myxoma and thrombus can be difficult because sometimes myx-
Papillary fibroelastomas (PFEs) are usually small tumours
omas can present inhomogeneous aspect due to intratumour
(<1 cm). 90% occur on valve surfaces, and they are slightly
haemorrhage, necrosis, or calcification [7]‌(E Fig. 49.1,
more common on the ventricular side of the aortic valve and
z Videos 49.1a, 49.1b, 49.1c). Morphology and mobility do
on the auricular side of the mitral valve. On histopathology,
not provide reliable discrimination between them; however,
it is a papillary mass with a short narrow pedicle and mul-
detection of flow, by colour Doppler, within the mass makes
tiple non-​vascular fronds of dense connective tissue lined by
thrombus less likely. Transoesophageal echocardiography (TEE),
endothelium [13].
particularly three-​dimensional (3D) TEE, has a higher sensitivity
In echocardiography, PFEs typically present as small highly
in detecting small myxomas compared to transthoracic echo
mobile masses. They tend to exhibit a stalk with a ‘frond-​like’
(TTE). 3D TTE provides accurate information regarding size and
shimmering area near the edges. Due to their small size, PFEs
shape of the masses and their relationship with adjacent struc-
are rarely detected by TTE. Even with TEE, PFEs are usually inci-
tures. 3D TEE is highly recommended before cardiac surgery
dental findings. Depending on the clinical context, a differential
to define the exact location of the pedicle and the true extension
diagnosis must be made either with Lambl’s excrescences or in-
of the myxoma in relation to neighbouring cardiac structures
fectious vegetations [19] (E Fig. 49.4; z Video 49.4).
[14, 15] (E Fig. 49.2, z Video 49.2).
 B en i g n ca rdiac t umour s 741

(a) (b) (c)

Fig. 49.13  Cardiac metastasis of a primary renal tumour. Images (a) and (b) show a large mass at the apex of the left ventricle with contrast echo uptake (b).
Cardiac MRI (c) shows late gadolinium enhancement of the mass and invasion to the pericardium.

Due to their small size and hypermobility, the detection with
CMR is rather challenging. They are isointense to the myocardium
on T1-​and T2-​weighted fast-​spin echo (FSE) sequences and on
fat saturation preparation no signal dropout is observed. On
SSFP cine sequences these highly small mobile masses appear
hypointense as compared to myocardium. There is usually no
contrast enhancement with first-​pass perfusion, but uniform late
enhancement reflecting gadolinium-​ accumulation within the
fibroelastic tissue has been described [18, 20].
Haemangioma
Haemangiomas are benign vascular tumours that represent less
than 2% of all cardiac tumours and 5–​10% of benign cardiac
tumours. They are classified according to the size of their vas-
cular channels into capillary, cavernous, or venous haemangi-
omas [21]. They can occur in any cardiac location and arise
from the epicardium, endocardium, myocardium, and peri-
cardium. Cardiac haemangiomas are often clinically insignifi-
cant, exist unrecognized, and are mostly diagnosed incidentally.
Symptoms depend on the location within the heart and the ex-
tent of the tumour. Conduction disturbances, atrioventricular
(AV)-​block, arrhythmias, pericardial effusion, and angina have
been reported [22].
Echocardiographic findings of cardiac tumours suspicious of
being haemangiomas are extremely rare. Tumour size is highly
variable (less than 1 cm to more than 8 cm) with a non-​calcified
but hyperdense appearance. They can occur in any cardiac cavity,
although they are most often attached to the left or right ven-
tricular wall by a thin pedicle [23].
On CMR examination, cardiac haemangiomas show inter-
mediate signal intensity on T1-​weighted images, which is com-
parable to myocardium. On T2-​weighted images, high signal

(a) (b) (c)

Fig. 49.14  Large left atrial thrombus in a patient with moderate rheumatic mitral stenosis. (a) TTE; (b, c) Real-​time 3D echocardiographic imaging reveals the
true extension of the thrombus.
742 CHAPTER 49   C ardiac masses and tumou r s

(a) (b)

(c) (d) (e)

Fig. 49.15  Right atrial thrombus in a patient with active synovial sarcoma of the left lower limb. TTE shows an irregular and high mobile mass that extends
towards the right atrial appendage and prolapses through the tricuspid valve. MR images confirm the diagnosis of thrombus.

intensity is typically observed. Cardiac haemangiomas enhance Fibroma

intensely and very rapidly after administration of contrast media
Cardiac fibroma is a congenital neoplasm and the second most
indicating a high vascularity. However, early enhancement after
common cardiac tumour in children. However, 15% of cardiac
gadolinium administration can be inhomogeneous because of
fibromas occur in adolescents and adults. Cardiac fibromas are
interspersed calcifications and fibrous septations within the tu-
typically solitary, circumscribed, firm, and often centrally calci-
mour. Peripheral nodular contrast enhancement and progres-
fied. Cardiac fibromas are usually located within the myocardium
sive centripetal fill appear on late contrast enhancement [24].
of the ventricles and the interventricular septum. The size of the
On unenhanced cardiac CT, haemangiomas are shown as well-​
tumours may vary between 2 and 5 cm [25].
delineated mass heterogeneous to low density. They intensely en-
In echocardiography cardiac fibromas appear as non-​
hance after intravenous contrast administration [24].
contractile solid rounded masses. They most commonly arise
in the ventricular septum followed by the left ventricular free
wall, right ventricular free wall, right atrium, and the left atrium.

Calcification is a common finding in fibromas from patients of all
ages (E Fig. 49.5; z Videos 49.5a and 49.5b).
On CMR, cardiac fibromas may appear as a discrete mural
mass or focal myocardial thickening with heterogeneous signal
intensity. These lesions appear isointense to hyperintense relative
to myocardium on T1-​weighted images and hypointense with
T2-​weighted images, findings which are characteristic for fibrous
tissue. After intravenous administration of gadolinium, contrast
media cardiac fibromas do not show enhancement during first-​
pass perfusion, suggesting a low vascularity. However, 10 minutes
after contrast administration, intense late gadolinium enhance-
ment was observed reflecting an increased extracellular volume of
distribution within the ventricular myocardium [26]. In contrast
to the normal myocardium, no deformation of the mass is seen
with myocardial tagging [27–​29].
Lipoma
Lipomas are encapsulated, homogeneous fatty tumours. They
may arise from the epicardium, from the endocardium, or from
the interatrial septum [30–​32]. They grow as broad-​based, some-
times pedunculated masses into any of the cardiac chambers and
may reach giant sizes and weigh up to 4,800 g [33]. Many patients
are asymptomatic, and the tumour is found incidentally because
of chest X-​ray abnormalities or heart murmur.
In echocardiography, lipomas usually appear as well-​
circumscribed, hypodense masses broadly attached on the epi-
cardial surface. There is neither shadowing nor necrosis nor
intratumour haemorrhage as a discriminating criterion to scler-
otic masses. Lipomatous hypertrophy of the atrial septum refers
to an abnormally large collection of fat within the atrial septum
without further clinical consequences. Characteristic thickening
spares the fossa ovalis (E Fig. 49.6; z Video 49.6). Because
lipomatous hypertrophy is composed of metabolically-​ active
brown fat, it may demonstrate 18F fluorodeoxyglucose avidity
and may be mistaken for a metastasis at positron emission tom-
ography (PET) imaging [34].
Cardiac lipomas are extremely well-​characterized with both
CT and CMR with a high degree of certainty. On T1-​weighted
images, lipomas have a homogeneous increased signal inten-
sity that is comparable to the signal intensity of subcutaneous
fat. Necrosis, haemorrhage, or calcifications are not found. On
T2-​weighted images, they appear with intermediate signal in-
tensity. By application of a fat saturation, preparation pulse with
T2-​weighted sequences signal intensity is decreased parallel to
subcutaneous fat. Cardiac lipomas do not enhance with admin-
istration of contrast media. With lipomatous hypertrophy of the
interatrial septum, the fatty tissue is not encapsulated, but rather
appears as diffuse thickening of the interatrial septum; sparing
the fossa ovalis and extending in the adjacent posterior wall of the
right atrium [17] (E Fig. 49.7). On cardiac CT, lipomas appear
as homogeneous, low-​attenuation masses with approximately 50
Hounsfield units.
RE F E RE N C E S 743
Cystic tumour of the atrioventricular node
Cystic tumour of the atrioventricular node, also known as meso-
thelioma of the AV node, is a congenital tumour, located in the
triangle of Koch. It is the most common primary cardiac tumour
causing sudden death. Cystic tumour of the atrioventricular node
is a diagnosis which is made mostly by chance either at autopsy
or surgery or as an incidental finding while imaging the heart for
other reasons. It may contain cysts filled with protein rich fluid
and may be calcified [13].
Because of the rareness of this tumour, few case reports have
included imaging findings; however, these reports do show that
the most common finding on echo examination is a rounded
echogenic mass located in the lower interatrial septum area [35].
On CMR examination, the tumour is usually hyperintense com-
pared to myocardium on T1-​and T2-​weighted FSE sequences or
isointense with T2-​weighted FSE [36].
Malignant cardiac tumours
Angiosarcoma
Primary cardiac sarcomas by definition are confined to the heart
or pericardium at the time of diagnosis. The most common
types are angiosarcoma (37%), unclassified or undifferenti-
ated sarcoma (24%), malignant fibrous histiocytoma (11–​24%),
leiomyosarcoma (8%), and osteosarcoma (3–​9%) [37].
Echocardiographic imaging helps to differentiate between be-
nign myxomas and malignant tumours. Angiosarcomas are typ-
ically inhomogeneous irregular masses, with hypodense necrotic
and haemorrhagic zones, usually located in the right atrium.
These tumours are often first identified by TTE due to symptoms
of dyspnoea. The use of ultrasonic enhancing agents in TTE may
help to characterize any suspicious cardiac mass. Complete en-
hancement or hyperenhancement of the tumour supports the
existence of a highly vascular tumour, which is most often malig-
nant [38]. Additionally, angiosarcomas invade adjacent structures
including the pericardium and great vessels. Therefore, when a
TTE demonstrates a right atrial echogenic mass, with an asso-
ciated haemorrhagic pericardial effusion, a malignant tumour
should be considered and further imaging with CT or CMR is
required [39, 40] (E Fig. 49.8, z Video 49.8).
On CMR, angiosarcomas are depicted as large, heterogeneous,
invasive masses frequently located within the right atrium with
pericardial involvement and haemorrhagic pericardial effusion.
Cardiac angiosarcomas have a marked heterogeneity of signal in-
tensity on T1-​weighted and T2-​weighted images. Hyperintense
foci in T1-​ weighted images may correspond to intratumour
haemorrhage, whereas hyperintense foci on T2-​weighted im-
ages may represent cystic or necrotic parts of the tumour [41].
Vascular structures within the tumour may appear hyperintense
on cine sequences, which has been described as ‘cauliflower’ ap-
pearance [21]. Cardiac angiosarcomas typically show diffuse and
744 CHAPTER 49   C ardiac masses and tumou r s
intense contrast enhancement that has been described as ‘sunray’
appearance [42].
Miscellaneous sarcomas (myofibrosarcoma,
rhabdomyosarcoma, liposarcoma,
undifferentiated pleomorphic sarcoma)
For the echocardiographic evaluation of the other cardiac sar-
comas, the same rules may be applied as for angiosarcomas.
They appear as large, mobile, and inhomogeneous masses, with
zones of necrosis and haemorrhage, associated with tissue inva-
sion of the surrounding cardiac wall or pericardial structures.
They are indistinguishable from angiosarcomas, except osteo-
sarcomas that shown calcified areas. Location may be the most
encountered frequently. After application of contrast media most sarcomas show heterogeneous enhancement due to intratumour
helpful feature for diagnosis because they typically originate
from the roof of the left atrium unlike myxomas [7]‌. The use
of echo contrast media helps in the differentiation of some tu-
mours from clot.
Rhabdomyosarcomas (E Fig. 49.9 and z Video 49.9),
leiomyosarcomas (E Fig. 49.10) and undifferentiated sarcomas
tend to be isointense as compared to myocardium on CMR T1-​
weighted FSE sequences and isointense or mildly hyperintense
(leiomyosarcoma) on T2-​ weighted FSE. Fibrosarcomas and
liposarcomas are heterogeneous on T1-​and T2-​ weighted
sequences. Liposarcomas rarely contain significant amounts
of macroscopic fat and necrosis and haemorrhage can be seen.
Osteosarcomas tend to be hypointense on T1-​weighted FSE and
hyperintense on T2-​weighted FSE sequences. Calcification can be
 SECTION 9

Aortic disease:
aneurysm and
dissection

50 The role of echocardiography  747

Arturo Evangelista and Gisela Teixidó-​Turà
51 Aortic disease: Aneurysm and dissection—role of CMR  757
Jose F. Rodriguez-​Palomares and Arturo Evangelista
52 Aortic disease: Aneurysm and dissection—​role of MSCT  771
Rocío Hinojar and Raimund Erbel

Contents
Introduction  747
Aortic dilation and aneurysms  747
Transthoracic echocardiography  748
Transoesophageal echocardiography  749
Acute aortic syndrome  749
Diagnosis of aortic dissection  749
B-​Main anatomical and functional
features  750
Diagnosis of complications  752
Intramural haematoma  753
Penetrating atherosclerotic ulcer  753
Echocardiography in the diagnostic
strategy  753
Intraoperative and postoperative echo  754
Conclusions  754
CHAPTER 50
The role of
echocardiography
Arturo Evangelista and Gisela Teixidó-​Turà
Introduction
Aortic diseases are a leading cause of cardiovascular morbidity and mortality and their
diagnosis and follow-​up depend exclusively on imaging techniques. Echocardiography
has become the most commonly used imaging test in the evaluation of cardiovascular
disease and plays an important role in the diagnosis and follow-​up of aortic diseases.
Evaluation of the aorta forms a routine part of the standard echocardiographic exam-
ination. Transthoracic echocardiography (TTE) permits adequate assessment of several
aortic segments, particularly the aortic root and proximal ascending aorta. All scanning
planes should be used to obtain information on most aortic segments [1]‌(E Fig. 50.1).
The suprasternal view depicts the aortic arch and proximal segments of the three major
supra-​aortic vessels (innominate, left carotid, and left subclavian arteries). The distal as-
cending aorta and the entire thoracic descending aorta are not well visualized by TTE.
In contrast, the abdominal aorta is relatively easily visualized from the left of the inferior
vena cava by the sagittal subcostal view to the distal segment of the aortic bifurcation.
Transoesophageal echocardiography (TEE) provides high-​quality imaging of nearly
all the ascending and descending thoracic aorta owing to the close proximity of the oe-
sophagus to the thoracic aorta and the use of high-​frequency transducers. The most im-
portant views of the ascending aorta, aortic root and aortic valve are the high long-​axis
(at 120–​150º) and short-​axis (at 30–​60º) views. A short segment of the distal ascending
aorta, just before the innominate artery, remains unvisualized owing to interposition of
the right bronchus and trachea (blind spot). The descending aorta is easily visualized in
short-​axis (0º) and long-​axis (90º) views from the coeliac trunk to the left subclavian ar-
tery. Further withdrawal of the probe shows the aortic arch. In the distal part of the arch,
the origin of the subclavian artery is easily visualized. In non-​anaesthetised patients, the
origin of the innominate and left carotid arteries is not clearly visualized. The proximal
part of the coeliac trunk is visualized in most cases [2]‌.
Aortic dilation and aneurysms
Normal aortic diameter, in adults, is roughly considered to be under 40 mm in the
aortic root, 37 mm in ascending aorta, and 28 mm in descending aorta. A diameter of
2.1 cm/​m² has been considered the upper normal range in ascending aorta. However,
the upper limit of normal aortic diameter has been defined as 2 SD greater than the
predicted mean diameter. Since aorta enlarges with age, the Z-​score (the number of SD
above or below the predicted mean normal diameter) is a useful way to quantify aortic
748 CHAPTER 50   The role of ech o cardio gra phy
(a)
Fig. 50.1  Transthoracic echocardio­
(c)
graphy. (a) Parasternal long-​axis
view showing aortic root and
proximal ascending aorta. (b) Mid
and distal ascending aorta has to be
imaged by moving the transducer up
one or two intercostal spaces.
(c) Suprasternal view with visualization
of aortic arch and supra-​aortic
branches. (d) Aneurysm of abdominal
aorta with a large circumferential
thrombus surrounding aorta lumen.
AA = ascending aorta; DA = descending
aorta
dilation [3]‌. Furthermore, echocardiography allows us to assess
the presence and severity of aortic valve disease. Aortic aneurysm
is a pathological dilation of the aorta involving one or several seg-
ments. Aortic diameter exceeding 1.5 times the normal value is
commonly considered to be an aneurysm. From a practical point
of view, an aortic aneurysm is diagnosed when these diameters
exceed 50 mm in ascending and 40 mm in descending aortas [1].
Transthoracic echocardiography
TTE is an excellent modality for imaging the aortic root, which
is important for patients with annuloaortic ectasia or Marfan
syndrome. Since the predominant area of dilation is in the prox-
imal aorta, TTE often suffices for screening. This technique has
seen tremendous success in the serial measurement of maximum
aortic root diameters, evaluation of aortic regurgitation, and the
timing of elective surgery. In addition, an aneurysm can arise in
the sinus of Valsalva and is correctly seen both in long-​and short-​
axis views. Several studies have shown the clinical usefulness of
TTE in aortic root measurement in patients with aortic valvular
disease, mainly in bicuspid aortic valve [4, 5].
Aortic root dimensions are assessed in the parasternal long-​
axis view at three levels: annulus, sinuses of Valsalva, supra-​
aortic ridge, and proximal ascending aorta (E Fig. 50.1a). At
the Valsalva sinuses, aorta diameter is obtained from the right
coronary sinus to the posterior (usually non-​coronary) sinus.
Measurements ought to be made perpendicular to the long axis
of the aorta with use of the leading edge method at end-​diastole
[1]‌. Paediatric guidelines recommend inner edge-​to-​inner edge
measurement but in end-​ systole. Differences between both
(b)
(d)
conventions are slight; however, end-​diastolic diameter is less
dependent on changes in blood pressure, heart rate, and car-
diac output. In addition, recent studies showed good agree-
ment between the leading edge-​to-​leading edge convention and
maximum diameters obtained by computed tomography (CT)
or MRI [6]. The upper segment of the ascending aorta has to
be imaged by moving the transducer up one or two intercostal
spaces, and the aortic arch via the suprasternal notch. In several
conditions, such as bicuspid aortic valve patients, aortic root
asymmetry (>5 mm) may be present in over 40% of patients [5].
This aortic root asymmetry, when significant, may be suspected
in the basal parasternal short-​axis view. However, this plane
does not always provide a perfect cross-​sectional plane through
the aortic root. These limitations could be overcome with three-​
dimensional (3D) matrix-​array echo probes using a simultan-
eous biplane modality. Nevertheless, it is advisable to confirm
the maximum aorta diameter by MRI/​CT when it is ≥45 mm
by TTE [7]. The excellent reproducibility of measurements at
this level and information from other parameters such as aortic
regurgitation severity, ventricular function, etc., facilitate ap-
propriate follow-​up by TTE when acceptable intertechnique
agreement (<3 mm has been documented.
Opportunistic screening during an echocardiographic study
has been recommended by the ESC Guidelines [8]‌with class IIa
recommendation in all men >65 years and IIb in women >65
years of age with a history of current/​past smoking. In a recent
nationwide survey in France, the prevalence of AAA screened im-
mediately after TTE was 3.7%, with low extra cost related to the
time necessary for screening [9].

Fig. 50.2  Ascending aorta aneurysm by transoesophageal echocardiography.
LV = left ventricle; Ao = aorta.
Transoesophageal echocardiography
Although CT and MRI are more useful than TEE for assessing
thoracic aorta aneurysms (E Fig. 50.2), TEE plays an important
role in the evaluation of functional aortic regurgitation mech-
anisms. TEE is warranted when the type of surgical treatment
(repair or valve replacement) is considered. The functional clas-
sification of aortic root abnormalities responsible for aortic in-
sufficiency has been suggested [10]. Tethering of the leaflets
is the feature most closely associated with functional aortic re-
gurgitation and depends on sinotubular junction/​annulus mis-
match. This information is useful for planning the best strategy
for aortic valve-​sparing surgery in the setting of ascending aorta
aneurysms. Both TTE and TEE have limitations for adequately
measuring of distal ascending aorta diameters, aortic arch, and
descending aorta. Assessment and follow-​up of descending aorta
and arch aneurysm usually requires other imaging techniques,
such as CT or MRI, with a wider field of view and better measure-
ment reproducibility.
Acute aortic syndrome
Acute aortic syndrome (AAS) is a life-​threatening condition re-
sulting from a lesion on the aorta wall that involves the tunica
(a) (b)
Acu te aorti c sy n dro m e 749
media and entails a risk of aorta rupture. AAS includes three
entities: aortic dissection, intramural haematoma, and penetrating
ulcer. Early medical and surgical treatment are crucial and there-
fore, rapid and accurate diagnostic techniques, which can be ap-
plied in critically ill patients, are essential. Correct diagnosis of
AAS is often challenging owing to the ability of AAS to mimic the
onset of many other diseases, such as acute coronary syndrome,
pericarditis, pulmonary embolism, etc. It is important to iden-
tify the signs and symptoms of the disease to establish an early
diagnosis [8]‌. The diagnosis of AAS can be made with similar
accuracy using different imaging techniques [11]. However, the
decision to use a specific technique depends on two major fac-
tors: availability of the techniques and experience of the imaging
staff. Echocardiography has the advantage of being applicable in
any hospital setting (emergency, intensive care, operating theatre),
without the need to transfer the patient who is often in an unstable
haemodynamic situation, monitored, and with intravenous drugs.
Diagnosis of aortic dissection
Aortic dissections represent more than 80% of acute aortic syn-
dromes, and 65% of them involve the ascending aorta (type A).
Although with significant overlap, aortic dissection without as-
cending aorta involvement (type B) is more frequent in the eld-
erly, with arterial hypertension or atherosclerotic disease [12].
Transthoracic echocardiography
Classically, TTE has been considered limited in the diagnosis
of aortic dissection [13], with 78–​100% sensitivity in ascending
aorta dissection, but only 31–​55% in descending aorta. Specificity
for type A aortic dissection was reported to range from 87% to
96% and 60–​83% for type B [14–​16]. Harmonic imaging im-
proved sensitivity and specificity (E Fig. 50.3) and, with contrast
enhancement (E Fig. 50.4 and z Video 50.1), TTE has similar
accuracy to TEE in the diagnosis of type A aortic dissection al-
though it is more limited in type B, mainly when non-​extended
dissection, intramural haematoma and aortic ulcers are present
[17]. TTE constitutes an acceptable technique for type A dissec-
tion, but not for type B [18]. However, given its availability, rap-
idity, and additional information on cardiac status, TTE should
be used as the initial imaging modality when aortic dissection is
clinically suspected in the emergency room. In patients with acute
Fig. 50.3  Aortic dissection in
transthoracic echocardiography.
(a) Intimal flap in the ascending
aorta (arrow). (b) Intimal flap in the
abdominal aorta (arrows).
AA = ascending aorta; LV = left ventricle;
LA = left atrium.
750 CHAPTER 50   The role of ech o cardio gra phy
Fig. 50.4  Type A aortic dissection diagnosed by contrast transthoracic
echocardiography (arrow).
LV = left ventricle; LA = left atrium; RV = right ventricle; FL = false lumen; TL = true lumen.
chest pain, special attention should be paid to aortic root dilation,
aortic regurgitation, and/​or pericardial effusion during the TTE
exam, since these findings should raise the suspicion of an AAS.
The low negative predictive value of TTE does not permit dissec-
tion to be ruled out, and further tests will be required if the TTE
exam is negative [19]. The value of TTE is also limited in patients
with abnormal chest wall configuration, obesity, pulmonary em-
physema, and in those on mechanical ventilation.
Transoesophageal echocardiography
TEE has constituted a decisive advance in the diagnosis of aortic
dissection (E Fig. 50.5, z Videos 50.2 and 50.3). It can image
the entire thoracic aorta except for a small portion of the distal
ascending aorta near the proximal arch. Since the first works pub-
lished by Erbel et al. [20], several studies have demonstrated the
accuracy of TEE in the diagnosis of aortic dissection, with sen-
sitivity of 86–​100%, specificity 90–​100% and negative predictive
value 86–​100% [21–​24]. The low specificity of the technique
described by Nienaber et al. [25] is explained by the fact that
(a)
Fig. 50.5  Aortic dissection by transoesophageal echocardiography. (a) Ascending aorta dissection by long-​axis view. Arrows show the intimal flap in
the aortic root (z Video 50.2). (b) Descending aorta dissection with an entry tear of 9 mm. Arrow shows a jet from TL to FL through the entry tear
(z Video 50.3).
LV = left ventricle; FL = false lumen; TL = true lumen.
reverberations were diagnosed as intimal flap in the ascending
aorta. In the ascending aorta, particularly when dilated, linear
reverberation images are very common, being observed in 44–​
55% of studies [23]. Artefacts in the aortic root are reverberations
coming from the anterior wall of the left atrium and artefacts in
the middle-​third of the ascending aorta are due to reverberations
from the posterior wall of the right pulmonary artery. Using M-​
mode echocardiography, it can be easily verified that the location
and movement of these reverberations are related to these ana-
tomic structures [23] (E Fig. 50.6 and z Video 50.4).
B-​Main anatomical and functional features
The ideal diagnostic technique in acute aortic dissection should
have high sensitivity and specificity and, furthermore, permit
assessment of the main anatomical and functional aspects of
interest for its management.
Intimal tear location and size
The intimal tear appears as a discontinuity of the intimal flap.
TEE provides a direct image of the tear and permits its meas-
urement. TEE permits identification of the tear in 78–​100%
of cases [26]. Colour Doppler can reveal the presence of mul-
tiple small communications between the two lumina, especially
in the descending aorta (z Video 50.3). Anatomical controls
showed that these images might correspond to the origin of
intercostal or visceral arteries. Pulsed Doppler imaging flow
velocities through the intimal tear reflect the pressure gra-
dient between the two lumina. It is important to differentiate
these secondary communications from the main intimal tear.
The latter is usually identified by two-​dimensional echocardi-
ography, tends to measure more than 5 mm and be located in
the proximal part of the ascending aorta in type A dissections
and immediately after the origin of the left subclavian artery in
type B dissections. On occasions, two-​dimensional echocardi-
ography does not permit visualization of the intimal tear in the
proximal part of the arch. In these patients, contrast-​enhanced
echocardiography can help by revealing contrast flow in the
(b)

(a)
Fig. 50.6  Transoesophageal echocardiography in long axis view showing an intraluminal lineal image in the ascending aorta (arrow). M-​mode
echocardiography evaluating location and mobility of the intraluminal linear image. The image (R) is located at the same distance from the posterior aortic
wall as the latter from the right pulmonary posterior wall. Artefact movement is inverse to that of the right pulmonary artery posterior wall (arrow). These
characteristics meet reverberation criteria.
AA = ascending aorta; LA = left atrium; AP = pulmonary artery.
false lumen coming anterogradely from the proximal arch and
directed towards the distal arch. Location and size of the entry
tear have significant clinical implications since entry tear size
>10 mm has been related to complications during follow-​up
[26]. Three-​dimensional TEE provides additional information
to 2D-​TEE in aortic dissection assessment, particularly in entry
tear size quantification (E Fig. 50.7). Agreement between entry
tear area defined by 3D-​TOE and CT is excellent [27]. Surgeons
should be aware of this feature before planning surgery in order
to choose the best surgical strategy and rule out a large entry
tear in the residual-​distal dissection.
True lumen identification
In certain circumstances, identification of the true lumen is of
special clinical interest. When the aortic arch is involved, the sur-
geon needs to know whether the supra-​aortic vessels originate
from the false lumen. Similarly, when the descending aorta dis-
section affects visceral arteries and ischaemic complications arise,
Entry tear
Acu te aorti c sy n dro m e 751
(b)
it is important to identify the false lumen prior to surgery or
endovascular treatment.
On most occasions, distinction between true and false lumina
is easy. The false lumen is usually larger and has less flow than
the true lumen. M-​mode shows how the intima moves towards
the false lumen at the start of systole by expansion of the true
lumen (E Fig. 50.8). However, in some circumstances the flap
is not mobile or expansion of the true lumen is delayed in end-​
systole and protodiastole. Frequently FL has dynamic smoke-​
like echos with slow swirling movements that are markers of
blood stasis. Thus, a thrombus is frequently observed in the false
lumen. Findings of reduced or absent flow are: absence of signal
by colour or pulsed Doppler; presence of spontaneous contrast;
and thrombus formation. Use of ultrasound contrast may aid
correct identification of the true lumen as long as there is dif-
ferential flow between true and false lumina. Furthermore, con-
trast echocardiography is the best way to analyse false lumen
flow [17, 19, 28].
Fig. 50.7  Three-​dimensional
transoesophageal echocardiographic
study showing the entry tear (left) and
its two orthogonal diameters (right).
752 CHAPTER 50   The role of ech o cardio gra phy
Fig. 50.8  M-​mode transthoracic echocardiography with contrast at
descending thoracic aorta. The true lumen is smaller than the false lumen and
expands in systole.
TL = true lumen; FL = false lumen.
Diagnosis of complications
Appropriate diagnosis of dissection complications during the ini-
tial study may affect therapeutic decisions in acute phase:
Pericardial effusion and periaortic bleeding. Pericardial effu-
sion is not always due to extravasation of blood from the aorta
and may be secondary to irritation of the adventitia produced by
aortic haematoma or small effusion from the wall. In any event,
the presence of pericardial effusion in an ascending aorta dis-
section is a sign of poor prognosis and suggests rupture of the
false lumen in the pericardium [29]. Echocardiography is the best
diagnostic technique for estimating the presence and severity of
tamponade (E Fig. 50.9, z Video 50.5). When acute or subacute
bleeding involves mediastinal haematoma, it is characterized by
an increased distance between the oesophagus and the aorta or
Fig. 50.9  Subcostal transthoracic echocardiographic view that shows a
severe pericardial effusion (arrow) and signs of cardiac tamponade with
compression of the right ventricle (RV). A dilated ascending aorta can also be
visualized.
the posterior left atrial wall. Periaortic haematoma and pleural
effusion are best diagnosed by CT.
Aortic regurgitation is a frequent complication. It occurs in
approximately 40%-​76% of patients. The diagnosis and quantifi-
cation of aortic insufficiency severity can be correctly made with
Doppler echocardiography, both TTE and TEE. Furthermore,
TEE provides information on possible mechanisms that influ-
ence aortic insufficiency, which may greatly aid the surgeon in
deciding to replace or preserve the aortic valve. Several mech-
anisms may determine the onset of significant aortic insuffi-
ciency: (1) dilation of the aortic annulus secondary to dilation of
the ascending aorta; (2) rupture of the annular support and tear
in the implantation of one of the valvular leaflets; (3) in asym-
metric dissections, the haematoma itself may displace a sigmoid
below the coaptation level; (4) prolapse of the intima in the out-
flow tract of the left ventricle through the valvular orifice pre-
vious aortic valvular disease [30]. The first three mechanisms,
characterized by a normal leaflet structure, may benefit from
conservative treatment with surgical valve repair. The last two
mechanisms are independent of dissection and must be treated
by valve replacement if needed.
Involvement of the main arterial vessels of the aorta.
Involvement of aortic branches can account for some symp-
toms secondary to visceral ischaemia. Diagnosis is, therefore,
important and can inform the choice of therapeutic strategy.
Visceral or peripheral malperfusion syndrome and cerebral
vascular accident are complications associated with high mor-
bidity and mortality. The most frequently involved supra-​aortic
trunks are the innominate artery and the left common ca-
rotid artery. The characteristic pattern of dissection propaga-
tion consists of involvement of the left-​sided branches of the
descending thoracic and abdominal aorta. The left kidney is the
organ at greatest risk of ischaemia. The origin of the left sub-
clavian artery is easily observed by TEE. However, emergence
of innominate and left carotid arteries remain inconsistently
detected. In these cases, the TTE suprasternal view appears
very useful. Involvement of coronary arteries in dissection is
considered to be 10–​15%, with the right coronary artery being
most frequently affected. TEE shows the most proximal seg-
ment of the coronary arteries; thus, it can be verified whether
the coronary ostium originates in the false lumen or whether
coronary dissection is present. TEE permits diagnosis of coeliac
trunk involvement, dissection, or compression in 90% of cases,
and superior mesenteric involvement in 64% [1]‌. Visceral or
peripheral malperfusion syndrome is a complication with high
morbidity and mortality. Although echocardiography can be
useful in diagnosing dissection of the supra-​ aortic trunks,
coeliac trunk, and superior mesenteric artery, CT provides
far more precise information. There are two types of circula-
tion disorders of the arterial branches: dissection or dynamic
obstruction of the ostium of the arterial branches leaving the
aorta by the intimal flap. Differentiating the two mechanisms
has important therapeutic implications.

Intramural haematoma
Aortic intramural haematoma (5–​25% of AAS) is a clinical
entity characterized by haemorrhage within the aortic wall in
the absence of an intimal flap or false lumen and a primary in-
timal tear. Haematoma can involve the whole aorta, although
it is more frequent in the descending aorta. It occurs typically
in elderly patients (mean 65–​70 years) with hypertension and
symptoms mimic aortic dissection. The diagnostic hallmark con-
sists of circular or crescentic thickening of >5 mm of the aortic
wall, without evidence of blood flow on imaging examination
(E Fig. 50.10a). Diagnosis is straightforward in typical cases,
but the haematoma may sometimes be mistaken for the presence
of an intraluminal thrombus or a dissection with thrombosed
false lumen. CT and MRI are the techniques of choice. However,
one of the most important limitations of all imaging techniques
in the diagnosis of intramural haematoma is that aortic wall
thickening can be progressive, and detection of this feature can
require more time and imaging tests than classic dissection.
Data from the IRAD registry showed that, in >12% of patients
with intramural haematoma (IMH), the first imaging test was
negative, and the condition was diagnosed in the second study
after some hours or days [31]. On occasions, localized zones of
the haematoma, which break the intima, can be identified giving
rise to saccular images that may be confused with penetrating
ulcers [32]. Evolution of the haematoma is highly dynamic, with
complete reabsorption in more than half the cases or dissection
in 40% being observed in the first six months. For this reason,
closer follow-​up than that undertaken in patients with classical
aortic dissection is advisable.
Penetrating atherosclerotic ulcer
Penetrating atherosclerotic ulcer (PAU) is defined as an ulcer-
ation of an aortic atherosclerotic plaque penetrating the internal
elastic lamina into the media, often associated with a variable de-
gree of intramural haematoma formation (E Fig. 50.10b). Aortic
ulcers are often multiple and may vary greatly in size (ranging
(a) (b)
Acu te aorti c sy n dro m e 753
from 5 mm in diameter and 4–​30 mm in depth). They can occur
at any point throughout the aorta, most commonly in the middle
and lower descending aorta, less frequently in the aortic arch and
abdominal aorta, and rarely in the ascending aorta. Although the
true prevalence of PAU is unknown, it may account for 2–​7% of
all AAS [19].
Typically, patients with PAU are older (>70 years) than those
with aortic dissection and present more often with extensive and
diffuse atherosclerotic disease involving both the aorta and cor-
onary arteries. An asymptomatic lesion may also be identified as
an incidental finding and future research may be helpful to deter-
mine which findings should prompt further testing and/​or man-
agement changes. Among imaging modalities, contrast-​enhanced
CT, including axial and multiplanar reformations, is considered
the diagnostic technique of choice [33]. TEE may provide better
morphological information than CT or MRI for the differential
diagnosis of ulcerated plaques, PAUs, or ulcer-​like projections
secondary to localized dissection in the evolution of IMH. The
prognosis of ulcerated plaques and ulcer-​like projections is more
benign than of symptomatic PAUs.
Echocardiography in the diagnostic strategy
In clinical practice, TTE should be used as the first imaging mo-
dality to evaluate patients with suspected acute cardiovascular
disease and is also useful in the differential diagnosis between
AAS and acute coronary syndromes. TTE is a non-​invasive test,
easily performed at the patient’s bedside, and rapid. However, it
does not make it possible to definitively rule out AAS. A definitive
diagnosis of type A dissection using TTE or contrast-​enhanced
TTE in patients with shock should immediately be followed by
surgery, provided that the diagnosis is confirmed using TEE in
the operating theatre under general anaesthesia. Additionally,
when the diagnosis seems to be definitive using CT. TTE should
always be performed to assess the presence and aetiology of the
aortic insufficiency, and to measure pericardial effusion and ven-
tricular function. In hospitals with cardiac surgery and sufficient
experience, TEE can be performed if the diagnosis by CT is not
Fig. 50.10  Evaluation of descending
aorta by transoesophageal
echocardiography in AAS. (a) aortic
haematoma with typical crescentic
thickening (arrows). (b) Penetrating
aortic ulcer with an intramural
haematoma in the internal part of
the ulcer (*).
Ao = descending aorta; PAU = penetrating
aortic ulcer.
754 CHAPTER 50   The role of ech o cardio gra phy

definitive or if haemodynamic instability renders it inadvisable

Suspected aortic dissection
to transfer a patient to other departments (E Fig. 50.11). TEE is
semi-​invasive, can cause a rise in systemic pressure from gagging,
and requires sedation. Strict control of blood pressure and ad- CT TTE*
equate sedation are mandatory. Ideally, in type A or complicated
type B aortic syndromes, TEE should be performed immediately
Type A Type B Type A Type B
before surgery or endovascular treatment, in the operating the-
atre under general anaesthesia, to avoid a rise in blood pressure
that might cause an aortic rupture. TTE TEE‡
Surgery TEE‡ or
TEE§ CT
After hyperacute phase, before cardiac care unit discharge,
TEE is recommended to evaluate the residual anatomical and Surgery
haemokinetic flows patterns of the false lumen that should be TEE§
considered in the follow-​up and management of patients with re-
Fig. 50.11  Diagnostic algorithm in patients with suspected acute aortic
sidual patent false lumen.
dissection.
* If TTE is the initial test and is negative, further testing might be warranted.
‡ Depending on availability, complications, and examiner experience.
Intraoperative and §
Definitive diagnosis of type A dissection by TTE permits an unstable
haemodynamic patient to be sent directly to surgery. Intraoperative TEE will
postoperative echo be performed before surgery.
TEE = transoesophageal echocardiography; TTE = transthoracic echocardiography.
Echocardiography plays a crucial role in the preoperative,
intraoperative, and postoperative assessment of aortic diseases.
Knowledge of aortic root dimensions, aortic regurgitation severity, applications of transoesophageal echocardiography are to de-
and its mechanisms would enable preoperative selection of the fine entry tear location and size, the mechanisms and severity
best surgical strategy and preparation of an adequately sized graft of aortic regurgitation, and flow dynamics of the two lumina.
tube, repair, or replacement of aortic valve, and shorten surgical Contrast enhancement substantially improves haemokinetic
ischaemic time. Preoperative or intraoperative TEE is essential for information on aortic dissection which may improve prog-
planning surgical treatment of AAS and in deciding whether to nostic assessment and adequate patient management. Three-​
replace the aortic valve, and may help to avoid early reoperations dimensional TEE is highly useful in entry tear size evaluation.
by showing correct connection of the distal part of the graft tube The diagnostic imaging strategy should be individualized ac-
to the true lumen, supra-​aortic vessel involvement, and residual cording to patient’s condition, the relevant diagnostic questions
aortic regurgitation severity. Finally, intraoperative TEE may de- to be answered and local institutional factors, such as expertise
tect complications such as pseudoaneurysm formation, most of and technological availability. TEE should be used in the
which are secondary to a leak in coronary artery reimplantation intraoperative monitoring of surgical and endovascular treat-
to the graft tube, communication of the distal part of the tube to ment of aortic diseases.
the false lumen, significant aortic regurgitation, periaortic haem-
orrhage, or segmental abnormalities in left ventricular contrac-
tion. Intraoperative TEE is also highly useful during endovascular
therapy, especially in type B aortic dissection (E Fig. 50.11, z
Video 50.5). It permits correct guidewire entrance by identifying
the true lumen in aortic dissections, provides additional informa-
tion helpful for guiding correct stent-​graft positioning and iden-
tifies suboptimal results and the presence of leaks and/​or small
re-​entry tears (E Fig. 50.12, z Video 50.6), with much higher
sensitivity than angiography [34, 35]).

Conclusions
Echocardiography is a reference imaging technique for the diag-
nosis and follow-​up of aortic diseases. Its main advantages are
that it is portable, rapid, and does not require irradiation. TTE
Fig. 50.12  Control after thoracic aorta endovascular treatment by contrast
appears to suffice for aortic root and proximal ascending aorta TEE showing a distal type I endoleak (large arrows), owing to lack of correct
assessment and may be useful to establish a rapid diagnosis of apposition of the distal part of the stent (small arrows) with the presence of a
aortic dissection, mainly with the use of contrast. The main thrombus (*).

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Contents
Introduction  757
Magnetic resonance imaging
techniques  757
Cine-​MR sequences  757
Black-​blood sequences  758
Flow mapping  758
Non-​contrast-​enhanced MR angiography
(NCE-​MRA)  759
Contrast-​enhanced MR angiography
(CE-​MRA)  759
Normal aorta and common variants  759
Aortic measures  760
Diagnosis of thoracic aortic diseases  761
Atherosclerosis  761
Aortic aneurysms  762
Acute aortic syndromes  762
Acute aortic syndrome in blunt trauma  767
Aortitis  767
Aortic coarctation  768
Pitfalls and limitations  768
CHAPTER 51
Aortic disease: Aneurysm
and dissection—​role
of CMR
Jose F. Rodriguez-​Palomares and
Arturo Evangelista
Introduction
Diseases of the aorta include a group of cardiovascular disorders such as aortic an-
eurysm, acute aortic syndrome, traumatic aortic disease, arteriosclerotic, inflammatory,
genetic (such as Marfan’s syndrome), and congenital diseases (such as coarctation of the
aorta).
In the last decade, there has been an increase in the overall death rate from aortic an-
eurysms and acute aortic syndromes worldwide with higher rates in males [1]‌. However,
aortic diseases can have a long subclinical period, with acute aortic syndromes or aortic
rupture being the first manifestation of the disease. These presentations require a rapid
diagnosis to guide patient management and improve prognosis.
The diagnosis of aortic diseases focuses on the use of different imaging techniques
such as echocardiography, cardiovascular magnetic resonance (CMR), and computed
tomography (CT). CMR has proven to be a reliable and reproducible imaging modality
owing to its capacity for multiplanar imaging without the use of iodine-​containing con-
trast agents or ionizing radiation and, thus, is becoming one of the first-​line techniques
for the evaluation of thoracic aortic diseases.
Magnetic resonance imaging techniques
Cine-​MR sequences
Cine-​MR images are acquired using steady-​state-​free-​precession (SSFP) sequences
that provide excellent contrast between blood pool and surrounding tissue without the
use of contrast agents. SSFP sequences (TrueFISP, Fiesta, or Balanced FFE) very short
acquisition times since they have very low repetition times. Given the high temporal
resolution of cine-​MR, images of multiple phases of the cardiac cycle can be obtained
and blood flow visualized during both systole and diastole. Non-​contrast single-​shot
SSFP imaging enables us to rapidly rule out aortic dissection and is particularly useful
for patients incapable of breath-​holding or in the setting of suspected aortic syndrome
[2, 3]. SSFP sequences generate images of brilliant blood (z Video 51.1). These im-
ages also show turbulent flow in haemodynamically significant stenosis or valvular
regurgitation that may be useful to detect aortic coarctation or valvular disease. When
evaluating the aorta, which contains areas of turbulent high-​velocity flow, spoiled
gradient-​echo cine sequences can be helpful as they tend to be less prone to flow-​
related artefacts than SSFP.
758 CHAPTER 51   Aortic disease: Aneu rysm a n d di s secti on — rol e of  CM R
Black-​blood sequences
Blood circulating through the aorta is black on conventional
spin-​echo and turbo spin-​echo sequences. In order to optimize
the quality of the aortic images, acquisition is performed with
electrocardiographic (ECG)-​gating, during mid-​to-​late diastole
and during repeated breath-​holds. A slice thickness of 3–​8 mm
and echo time of 20–​30 ms are standard, while repetition time
is determined by the R-​R´ interval of the ECG. ECG-​triggered,
breath-​hold turbo spin echo (TSE) has been the cornerstone of
black-​blood CMR for aortic disease. Rapid black-​blood spin-​echo
sequences such as HASTE or SS-​FSE sequences (Half Fourier
sampling, single-​shot) permit correct morphological assessment
of the aorta with very rapid acquisition times.
These sequences provide excellent morphological informa-
tion on the aortic wall and adjacent structures [4]‌. T1-​or T2-​
weighted images are useful for wall tissue characterization.
Spin-​echo T1-​weighted imaging provides the best anatomic de-
tails of intramural haematoma, intimal flaps (E Fig. 51.1) or
atheroma. T2-​weighted images demonstrate oedema as a high
signal and can provide useful information on the activity of in-
flammatory aortic conditions. Post-​contrast T1 imaging with fat
suppression is useful for diagnosing some entities such as aortitis
or mycotic aneurysms.
Flow mapping
Accurate quantitative information on blood flow is obtained
from modified gradient-​echo sequences with parameter re-
construction from the phase rather than the amplitude of the
MR signal. This is also known as flow mapping or phase con-
trast (PC) or velocity-​ encoded (VENC) cine-​ CMR. VENC
cine-​CMR sequences provide useful functional information
owing to their capacity to quantify flow in different valvular
and aortic diseases. The information is processed using mag-
nitude and phase images. Signal magnitude images display
brilliant flowing blood and offer better anatomical assessment,
while phase images show a map of flow velocities and direc-
tion (z Video 51.2). Quantitative data on flow are estimated by
multiplying the spatial mean velocity and cross-​sectional area
(a)
Fig. 51.1  Axial T1-​weighted turbo spin-​echo sequences in two patients with an aortic dissection: (a) shows the presence of a flap in the proximal descending
aorta (arrow) and (b) shows the presence of a flap in the abdominal aorta (*). The images display the presence of two lumina in the aorta the false lumen being
the one with the bigger size (arrow and *).
of the vessel. Using post-​processing techniques, it is possible
to obtain curves of flow vs. time and peak velocity vs. time. In
this manner, the haemodynamic parameters can be quantified
in different situations such as aortic coarctation or valvular dis-
ease, and in the analysis of flow patterns in the true and false
lumina of aortic dissection.
The main limitation of this sequence is that it permits only
encoding of the velocity in a single direction of the space.
However, pulsatile blood flow through the cavities of the heart
and great vessels is multidirectional and multidimensional. In re-
cent years, three-​dimensional (3D) cine (time-​resolved) PC CMR
with three-​directional velocity encoding has been developed to
achieve more detailed study of intravascular and intracardiac
flows. This sequence, also known as 4D-​flow CMR, refers to a
PC with flow-​encoding in all three spatial directions and time
throughout the cardiac cycle [5]‌(z Video 51.3). It permits flow
volume quantification comparable to 2D cine PC CMR and has
good scan and re-​scan repeatability.
Compared to 2D-​PC CMR, the 4D flow sequence has several
advantages. Using the principle of ‘conservation of mass’ (e.g. the
estimation of the Qp/​Qs within the same data set) it allows us to
investigate the internal consistency of data. A further advantage
is the retrospective placement of different analysis planes at any
location within the acquisition volume (mainly in cases where
multiple 2D cine PC-​CMR scans would be needed).
Recently, the consensus document of experts established that
4D-​flow sequences are clinically useful for studying valvular dis-
eases (stenosis and regurgitation), shunts, and collateral flow,
complex congenital heart diseases, and diseases of the aorta.
Although data remain limited, these sequences can also be con-
sidered in the study of intracardiac flow [6]‌.
Furthermore, 4D-​flow sequences permit the analysis of con-
ventional parameters such as flow volume or regurgitant fraction
or more advanced parameters such as wall shear stress or turbu-
lent kinetic energy [7]‌. It is important to note that the majority of
these in-​vivo haemodynamic measurements cannot be assessed
non-​invasively with any other imaging technique. These complex
parameters are significant for increasing our knowledge of the
pathophysiology of the cardiovascular system; however, further
(b)
 N or m a l aorta a n d c o m mon va ria n ts 759

longitudinal studies should evaluate the real influence of these acquisition techniques, multiphasic time-​resolved 3D MRA im-
parameters in aortic dilation and aortic diseases. ages are obtained with high temporal and spatial resolution. In
these sequences, contrast injection is started at the same time
Non-​contrast-​enhanced MR angiography as image acquisition, using the first set of images as a mask for
(NCE-​MRA) posterior subtraction using post-​processing techniques through
MIP and MPR reconstructions (z Video 51.4). They are very
Three-​dimensional (3D) NCE-​MRA has proved useful in any vas-
useful in the study of aortic dissection and shunts.
cular anatomy throughout the body, owing to the potential risk of
If metallic devices related to the aorta are present (such as
contrast-​induced nephrogenic systemic sclerosis in patients with
stents or adjacent embolization coils), the quality of CMR images
severe renal failure. Different physical mechanisms have been de-
may be limited by off-​resonance artefacts that preclude optimal
veloped for NCE-​MRA sequences (inflow effect, flow-​dependency
evaluation (z Video 51.1).
on cardiac phase, flow-​encoding, spin labelling and relaxation),
which provide high-​quality 3D data including motion-​free im-
ages of the aorta when combined with ECG-​gating and respira-
tory navigation [8, 9] (E Fig. 51.2). The whole data set of the Normal aorta and common variants
thoracic aorta can be acquired in only a few minutes with high
The aorta is the main artery in the body and its size does not
signal-​to-​noise (SNR) and contrast-​to-​noise ratios (CNR), with
exceed 40 mm in healthy adults. In an older paediatric patient,
the pitfall of potential flow artefacts secondary to flow disturb-
comparison with Z-​score (the number of standard deviations
ance and high-​velocity jets. The non-​contrast-​enhanced SSFP
above or below the predicted mean normal diameter) can be
MRA sequences have similar accuracy as contrast-​ enhanced
helpful [11]. This diameter is influenced by age, sex, body size,
MRA [10].
and blood pressure and the normal rate of expansion is approxi-
mately 0.9 mm /​10 years in men and 0.7 mm/​10 years in women
Contrast-​enhanced MR angiography [12]. Thus, normal aortic dimensions should be indexed by body
(CE-​MRA) size and age, and an aortic diameter > 21 mm/​m2 is considered
CE-​MRA images are obtained by T1-​weighted 3D-​gradient-​ abnormal. Progressive aortic dilation in adults is due to ageing,
echo sequences, following intravenous contrast administration higher collagen-​to-​elastin ratio, atherosclerosis, and an increase
through the shortening effect on T1 of gadolinium contrast. in stiffness and pulse pressure. Exercise training per se has only a
These sequences offer important anatomical information on limited impact on aortic remodelling, and the upper limit values
both the aorta and main collateral vessels (E Fig. 51.3). This of the aorta (99th percentile) are 40 mm in men and 34 mm in
technique is suitable for the depiction of abnormalities such women [13].
as penetrating atherosclerotic ulcer, dissection, coarctation, The most common congenital vascular anomaly of the aortic
and aneurysm. The acquired images must be re-​evaluated by arch, occurring in approximately 1% of individuals, is the aberrant
processing maximum intensity projection (MIP) and right subclavian artery arising distal to the left subclavian artery,
post-​
multiplanar reconstruction (MPR) reconstructions. By the coursing to the right and passing behind the oesophagus. A common
application of ultrarapid spoiled gradient-​echo sequences in brachiocephalic trunk, in which both common carotid arteries and
steady-​state free precession and the implantation of parallel the right subclavian artery arise from a single trunk off the arch,

(a) (b) (c)

Fig. 51.2  Non-​contrast-​enhanced MR angiography (NCE-​MRA) with 2D reconstructions in an axial (a), coronal (b), or sagittal (c) plane. The dark left
ventricular cavity (b) is secondary to the presence of a severe aortic regurgitation that induces flow artefacts due to flow disturbance and high-​velocity jet.
760 CHAPTER 51   Aortic disease: Aneu rysm a n d di s secti on — rol e of  CM R
(a)
Fig. 51.3  Contrast-​enhanced MR
angiography of the aorta in a sagittal
view: maximum intensity projection
(MIP) (a) and 3D reconstruction (b).
Note the common take-​off of the
right brachiocephalic trunk and the
left carotid artery (bovine aortic arch)
(arrows).
is the most frequent normal variant of the aortic arch branching.
This so-​called bovine trunk occurs in 10–​22% of individuals; it does
not produce symptoms although it has been postulated that it could
be related to other aortic diseases [14] (E Fig. 51.3). A right-​sided
aortic arch (aortic arch passing to the right of the trachea) is associ-
ated with two principal branching patterns: mirror image branching,
which is associated with a high rate of congenital cardiac anomalies,
and right aortic arch with aberrant left subclavian artery which has
little association with other abnormalities.
Aortic measures
The anatomic locations at which the ascending aorta diameter
has to be measured are: aortic annulus, sinuses of Valsalva, the
sinotubular junction, and the ascending aorta at the pulmonary
trunk. Other measurement sites include the aortic arch between
the brachiocephalic and left subclavian artery, isthmus (just
below the left subclavian artery) and proximal descending aorta
at pulmonary trunk level. Measurements of the abdominal aorta
include those at diaphragmatic level, coeliac trunk, renal arteries
and prior to the iliac artery bifurcation [13].
(b)
Measurements of the aorta can be taken using both CE-​MRA or
NCE-​MRA (E Figs. 51.2 and 51.3). Post-​processing techniques
(MIP, MPR, and rendering volume) facilitate visualization of the
entire aorta and its principal branches and are highly useful when
planning treatment. Furthermore, cine images can be used for
measuring the luminogram of the aorta at an end-​diastolic frame.
However, owing to movement of the valvular plane, aortic root
measurement needs to be taken with cine SSFP sequences since the
resolution and image quality are better compared to angiography
(E Fig. 51.4). Aortic diameters should be assessed in end-​diastole
and using the internal diameter of the aorta. Excellent accuracy has
been observed using this method in CMR compared to CT and
two-​dimensional transthoracic echocardiography [15]. Absolute
measurements are not good predictors of abnormality severity, and
should be considered relative to age, sex, and body surface area [16].
When patients with aortic disease are followed over time it is
necessary to measure the aortic diameters in the same location
and same spatial plane to ensure correct monitoring. Although
the sagittal plane permits a more reproducible evaluation [17],
aortic diameters have to be measured in an imaging plane per-
pendicular to the aorta at the desired level (double oblique tech-
nique) (E Fig. 51.4c).
 Diag n o si s of thor aci c aort i c di se ase s 761

(a) (b) (c)

Fig. 51.4  Aortic root measurements at the level of the sinuses of Valsalva using the cusp-​to-​cusp convention (a) and the cusp-​to-​commissure convention (b)
based on SSFP cine images. Measurements of the ascending aorta and proximal descending aorta at the level of the pulmonary bifurcation (c) from contrast-​
enhancement angiography.

The sinuses of Valsalva are commonly measured by CMR be-
tween the inner edges from commissure to opposite sinus [15, 18].
However, diameters measured using the cusp-​to-​cusp convention
are generally a mean of 2.5 mm larger compared to those measured
by the cusp-​to-​commissure method, present closer agreement with
echocardiographic measurements, and greater feasibility in bicuspid
aortic valves [19, 20]. Perimeter measurements of the annulus, as
used for valvular sizing prior to transcatheter aortic valve replace-
ment, showed good agreement with CT measurements [21]. In the
rest of the aorta, the anteroposterior diameter and one perpendicular
to this one (latero-​lateral) should be performed (E Fig. 51.4).
The presence of aortic root asymmetry should be mentioned.
An asymmetric root is more common in patients with bicuspid
aortic valve (BAV) owing to dilation opposite the commissural
fusion and can also be seen in patients with Marfan syndrome.
An aortic root can be defined as asymmetric when the largest
cusp-​to-​cusp diameter differs ≥5 mm from the smallest. Of note,
underestimation of aortic root diameter by transthoracic echo-
cardiography compared to CMR can be greater in the presence of
an asymmetric root or in BAV patients with fusion of the right-​
to-​non-​coronary sinus. These patients may benefit from a CMR
study to ensure the real largest diameter [20].
CMR has been established as an accurate non-​invasive tool for
the assessment of aortic distensibility and pulse-​wave velocity.
These methods have been used to assess aortic elasticity in pa-
tients with Marfan syndrome, BAV, or aortic aneurysms [22, 23].
They could be of clinical value for the identification of patients at
high risk of aortic complications.
Diagnosis of thoracic aortic diseases
Atherosclerosis
CMR is a non-​invasive imaging modality that can visualize and
characterize the composition of atherosclerotic plaques and dif-
ferentiate tissue structure based on proton magnetic properties
with excellent soft tissue contrast. CMR sequences are highly
useful for the detection of aortic atheroma and offer information
on late repercussions of the plaque in the aortic lumen at an ad-
vanced stage of the disease. Structural alterations occurring in the
aortic wall must be observed for accurate assessment of ather-
omatous plaques. Black-​blood TSE sequences are very useful and
promising for identifying and characterizing aortic plaques and
distinguishing its components in vivo.

(a) (b)

Fig. 51.5  Axial images showing severe atherosclerosis in the proximal descending aorta. The CMR suggests the presence of a fibrocellular plaque being
isointense in T1-​weighted images (a, white arrows and *) and hyperintense in T2-​weighted images (b, yellow arrows and *). Note the presence of a black
circumferential artefact in the descending aorta (b) secondary to the presence of a chemical shift artefact between the atherosclerotic plaque and the not
perfectly nulled blood pool.
762 CHAPTER 51   Aortic disease: Aneu rysm a n d di s secti on — rol e of  CM R
Being composed of cholesterol esters, the lipid nucleus has
a short T2-​and will appear hypointense on T2-​weighted im-
ages; however, in T1-​weighted images, it appears hyperintense.
Fibrocellular components of the plaque are hyperintense in T2-​
and isointense in T1-​weighted images (E Fig. 51.5). Calcium de-
posits can be seen as hypointense regions within the plaque on
T1-​, proton density-​and T2-​weighted images. The fibrous cap,
lipid core, organized or fresh thrombus, calcification, or necrotic
areas have been well-​characterized in studies performed both
in vitro and in vivo. Fayad et al. [24] showed that CMR evalu-
ation of the aorta compared well with transoesophageal echo-
cardiography (TEE) for the assessment of aortic atherosclerotic
plaque thickness, extent, and composition. Furthermore, high-​
resolution, non-​invasive CMR demonstrated regression of aortic
atherosclerotic lesions secondary to lipid lowering by simvastatin
[25]; thus, it can be used to monitor progression and regression of
atheromatous plaques. A very promising aspect is the capability
of CMR to detect inflammatory activity of atheromatous plaque
with the administration of contrast media. Inflammatory phe-
nomena that determine macrophage accumulation can be dem-
onstrated as hyperuptake of gadolinium chelates or ultrasmall
superparamagnetic particles of iron oxides (USPIO) in plaque
[26]. However, in recent years, other methods have been proposed
to study the inflammatory activity of atherosclerotic plaques. On
the one hand, T2-​mapping sequences permit accurate quantifica-
tion of the lipid content in the plaque in a non-​invasive manner.
It has been shown that, compared to asymptomatic plaques, the
lipid concentration is greater in symptomatic plaques despite
both having the same degree of luminal stenosis [27]. On the
other hand, positron emission tomography-​magnetic resonance
imaging (PET-​CMR) has been proposed as a promising imaging
technique to assess atherosclerotic plaque activity. Fluorine-​18
(18F)-​
labelled fluorodeoxyglucose (18F-​FDG) and 18F-​sodium
fluoride (18F-​NaF) PET have been associated with inflammation
and microcalcifications, respectively [28]. A recent study using
PET-​CT demonstrated that fluorine-​18-​NaF may identify disease
activity in patients with abdominal aorta aneurysms and could be
an added predictor of aneurysm growth and future clinical events
[29]. Further studies will demonstrate the real role of PET-​CMR
in the follow-​up of patients with aortic atherosclerosis for evalu-
ating the response to treatment and predicting adverse events.
TEE and CMR are powerful non-​invasive tools for visualizing
aortic atheroma. TEE is the technique of choice in patients with
stroke or peripheral embolism since it affords excellent assess-
ment of complicated plaque size and mobility. Unlike TEE, CMR
can visualize the entire thoracic aorta including the small section
of ascending aorta which is obscured by the tracheal air column.
Cine-​CMR may also permit the assessment of complex plaque
and aortic debris mobility with thrombus formation.
Aortic aneurysms
Thoracic aortic aneurysmal disease usually occurs as a result of
atherosclerotic, inflammatory (such as aortitis), inherited (such
as Marfan’s syndrome) or haemodynamic conditions (such as
aortic valve disease, trauma, or coarctation). Aneurysms are often
incidentally discovered on imaging, with the ascending aorta
most commonly involved [30]. An aneurysm is diagnosed when
the ascending aorta is >5 cm, the descending aorta >4 cm and the
Z-​score ≥2 in the paediatric population [13].
CMR is a robust tool for evaluating aortic aneurysms. Three-​
dimensional CE-​MRA is highly accurate at depicting the location,
extent and precise diameter of an aneurysm and its relationship
with aortic branch vessels (EFigs. 51.3 and 51.4). It is recom-
mended to combine MRA images with spin-​echo black-​blood
images (E Fig. 51.1), which are very useful for detecting alter-
ations in the wall and adjacent structures. In mycotic aneurysm,
T2-​weighted and post-​contrast T1-​weighted images permit iden-
tification of inflammatory changes in the aortic wall and adjacent
fat, secondary to bacterial infection. Periaortic haematoma and
areas of high signal intensity within the thrombus may indicate
aneurysm instability and are well depicted on spin-​echo images.
The capability of CE-​MRA to visualize the Adamkiewicz artery
represents an advance in planning surgical thoracic aneurysm
repair, thereby preventing postoperative neurological deficits
secondary to spinal cord ischaemia [10]. As these sequences are
rapid and simple to perform, they play a major role in efficient
aneurysm follow-​up (E Fig. 51.6).
When the aneurysm affects the ascending aorta, it is recom-
mended to conduct a functional study through the aortic valve
using cine-​CMR and velocity-​encoded sequences to rule out as-
sociated valvular disease. The aortic cusps should be described
as bicuspid (BAV) or tricuspid, which has a significant impact
on tailoring the therapeutic strategy. In recent years, 4D-​flow
sequences have added understanding of aortic dilation patho-
physiology in BAV patients. BAV induces greater rotational flow
which produces abnormal and asymmetric wall shear stress in the
ascending aorta that determines its dilation (z Video 51.3) [7, 31].
The principal predictor of aortic rupture or dissection is aortic
size. In a large retrospective study of patients with thoracic aortic
aneurysms of different aetiologies (excluding genetic disorders),
the 5-​year risk of rupture or dissection was 1.1% in patients with
an aortic diameter of 50 mm, and 2.9% when the aortic diameter
was ≥55 mm [32]. Furthermore, the probability of complications
at follow-​up is similar in patients with BAV compared to TAV if
the aortic diameter is similar [33, 34].
The mean growth rate for all thoracic aneurysms is about 1 mm/​
year. The growth rate is significantly higher for aneurysms of the
descending aorta, 1.9 mm/​year, than those of the ascending aorta,
0.7 mm/​year. In addition, dissected thoracic aneurysms grow sig-
nificantly more rapidly (1.4 mm/​year) than non-​dissected aneur-
ysms (0.9 mm/​year) [30]. In a more recent study, Davies et al.
[16] recommended elective operative repair before the patient
enters the zone of moderate risk of an aortic size index higher
than 2.75 cm/​m2.
Acute aortic syndromes
Acute aortic syndromes include aortic dissection, intramural
haematoma (IMH), penetrating atherosclerotic ulcers (PAU), and

(a) (b)
Fig. 51.6  Contrast-​enhanced MR angiography of the aorta in a sagittal view (3D reconstruction) in a patient with an aneurysm of the ascending aorta and
proximal arch (a), a patient with a bicuspid aortic valve with a dilatation of the aortic root and ascending aorta (b) and a patient with a degenerative aneurysm
in the aortic arch (c).
traumatic partial or total rupture. As they are associated with high
morbidity and mortality rates, their early recognition is vital to
ensure prompt treatment [35].
Aortic dissection
Aortic dissection is characterized by a laceration of the aortic in-
tima and inner layer of the aortic media that allows blood to course
through a false lumen in the outer third of the media. Diagnosis
of aortic dissection is based on demonstration of the intimal flap
separating the true from false lumina (E Fig. 51.1, z Videos
51.2 and 51.4). In the acute phase, the use of CMR is often limited
by poor availability, patient claustrophobia, and time-​consuming
study. A meta-​analysis [36] showed diagnostic accuracy to be
practically the same (95–​100%) for CT, TEE, and CMR. Most
shortcomings are due to user interpretation errors rather than the
technique itself. However, analysis of the International Registry
of Aortic Dissection (IRAD) [35] showed CT to be the most fre-
quently used imaging technique (61%) in acute patients followed
by echocardiography (33%).
In suspected aortic dissection, the standard CMR protocol
should begin with black-​blood sequences (E Fig. 51.1). In type
B dissection, it is important to acquire images with a wide field-​
of-​view that includes the whole aorta from the arch to the aortic
bifurcation. In the axial plane, the intimal flap is detected as a
straight linear structure within the aortic lumen. The true lumen
can be differentiated from the false by anatomical features and
flow pattern: the true lumen shows a signal void, whereas the false
lumen has higher signal intensity (E Fig. 51.7). High signal in-
tensity of pericardial effusion indicates blood components and is
a sign of impending ascending aorta rupture into the pericardial
Diag n o si s of thor aci c aort i c di se ase s 763
(c)
space. Similarly, the presence of pleural effusion is an indicator
of impending aortic rupture. CE-​MRA has proved to be superior
to black-​blood sequences in the assessment of dissection exten-
sion and supra-​aortic trunk involvement. However, owing to the
limitation of this technique in visualizing the aortic wall and ad-
jacent structures, the aortic dissection protocol should include
both sequences [37]. Detailed anatomical information on aortic
dissection must describe dissection extension and branch vessel
perfusion from the true or false lumen. Gradient-​echo sequences
and PC images can help identify aortic regurgitation, entry sites,
and differentiate slow flow from thrombus in the false lumen
(E Fig. 51.8, z Video 51.2). Also, PC sequences have a prom-
ising role in the functional assessment of aortic dissection
through the quantification of flow in both lumina and the pos-
sibility of establishing haemodynamic patterns of progressive
dilation risk. An increased false lumen pressure is an important
factor associated with false lumen enlargement and, thus, aortic
dilation. Indirect signs of high false lumen pressure include true
lumen compression, partial thrombosis of the false lumen or the
velocity pattern of the false lumen flow.
For planning surgery or endovascular repair, it is useful to dem-
onstrate the course of the flap, entry tear location, false lumen
thrombosis, aortic diameter, and main arterial trunk involvement
by post-​processed techniques with MPR reconstructions, MIP,
and volume rendering (E Fig. 51.8). It is mandatory to visualize
the native images from CE-​MRA (2D images) since the flap may
not be seen on the volumetric reconstruction [38]. Time-​resolved
MRA provides additional functional information compared to
conventional MRA, such as the dynamic assessment of blood flow
in entry tears and may help identify the entry and exit points of
764 CHAPTER 51   Aortic disease: Aneu rysm a n d di s secti on — rol e of  CM R

(a) (b) (c) (d)

Fig. 51.7  Aortic dissection: (a) Single-​shot SSFP sequence in a coronal view showing a patient with a type A aortic dissection (black arrows showing the
intimal flap), (b) T1-​weighted turbo spin-​echo sequence in an axial view of the same patient (white * showing the intimal flap in the ascending aorta and red
* showing the intimal flap in the descending aorta), (c) 3D-​MR angiogram of the same patient (black arrow showing the intimal flap), (d) Contrast-​enhanced
MR angiography of the aorta in a sagittal view (MIP reconstruction) in a patient with a type B aortic dissection (red * showing the entry tear in the proximal
descending aorta).
TL = true lumen; FL = false lumen.

the dissection (z Video 51.4). In type A dissection, it is manda-
tory to include cine-​CMR sequences through the left ventricular
outflow tract to rule out valvular regurgitation.
Along with age, signs and/​or symptoms of organ malperfusion,
clinical instability, fluid extravasation into the pericardium, and
periaortic haematoma represent poor prognosis in the acute phase.
After discharge, different variables have been associated with out-
comes after long-​term follow-​up in type B dissection. They include
aortic diameter >40 mm in acute phase [39], false lumen diameter
>22 mm [40], a wide and proximal entry tear [41], and partial false
lumen thrombosis [42]. Although these variables stemmed from
CT studies, they could also be assessed by CMR.
Intramural haematoma (IMH)
Spontaneous acute IMH can be observed with no imaging fea-
tures of intimal flap or penetrating atherosclerotic ulcer, and
may be secondary to vasa vasorum rupture, the capillary net-
work of the adventitia and media [43, 44]. However, IMH may

(a) (b)

(c)
Fig. 51.8  Contrast-​enhanced MR
angiography in a patient with a type
B aortic dissection with an entry tear
distal to the left subclavian artery
(black * at the level of the entry tear)
in a sagittal view (a), coronal view
(b), and axial view (c). The black
arrows show the presence of partial
thrombosis of the false lumen.
TL = true lumen; FL = false lumen.

(a) (b) (c)
Fig. 51.9  T1-​weighted turbo spin echo in a sagittal view (a) and axial view (b and c) of three different patients with an intramural haematoma in the subacute
phase (images c and d correspond to the same patient). The arrows and the * show the presence of signal hyperintensity corresponding to the bleeding region.
A fat suppression technique (c) is applied to differentiate the intramural haematoma from periaortic fat. Post-​contrast T1-​weighted image showing the absence
of communication (black *) between the bleeding region and the aortic lumen (d).
also be secondary to imperceptible microscopic intimal tears with
limited wall dissection in which the false lumen is completely
thrombosed. IMH is associated with hypertension and tends to
occur preferentially in older patients and disproportionately in
the descending aorta [45, 46]. A classic double-​barrelled dissec-
tion in which the lumen is completely thrombosed at the time of
initial imaging is very rare but indistinguishable from an IMH,
and these conditions may have considerable overlap in natural
history and require similar treatment [45, 46]. Although greater
availability and rapidity favour the use of CT in acute diseases,
CMR plays a major role in the diagnosis of IMH. The greater con-
trast among tissues offered by CMR often permits the depiction
of small IMHs, which may go unnoticed on CT [43]. The typ-
ical finding is the presence of thickening of the aortic wall (semi-
lunar or concentric) with a hyperintense signal in T1-​weighted
black-​blood sequences (E Fig. 51.9). In the hyperacute phase,
the haematoma shows an isointense signal in T1-​weighted images
and a hyperintense signal in T2-​weighted images (E Fig. 51.10).
From the first 24–​72 hours, the change from oxyhaemoglobin to
methaemoglobin is responsible for a hyperintense signal in T1-​
and T2-​weighted images. Fat suppression techniques are crucial
to differentiate periaortic fat from IMH (E Fig. 51.9c). Mural
thrombi may present with semi-​lumen morphology that mimics
(a)
(b)
Diag n o si s of thor aci c aort i c di se ase s 765
(d)
the morphology of IMH, rendering the differential diagnosis by
CT or TEE difficult. This differentiation is easier by CMR since
mural thrombosis shows a hypo-​or isointense signal in both T1-​
and T2-​weighted sequences.
The evolution of IMH may result in resorption, aneurysm for-
mation or dissection [47]. IMH may regress completely in 34%
of patients, progress to aortic dissection in 12%, to aneurysm
in 20% and to pseudoaneurysm in 24% (E Fig. 51.11). Given
their wider field-​of-​view, CMR and CT are better than TEE for
defining this dynamic evolution. Also, CMR offers the possibility
of monitoring the evolution of intramural bleeding and depicting
new asymptomatic intramural re-​bleeding episodes.
Penetrating atherosclerotic ulcer
PAU is defined as an atherosclerotic lesion that penetrates the
elastic lamina, usually leading to haematoma within the media,
but also potentially to true dissection or rupture. The diagnosis of
penetrating ulcer by CMR is based on visualization of a crater-​like
ulcer located in the aortic wall. CMR is particularly suitable for
depicting aortic ulcers together with the irregular aortic wall pro-
file seen in diffuse atherosclerotic involvement. The aortic ulcer
is easily recognized as contrast-​filled outpouching of variable
extent with jagged edges (E Fig. 51.12). Black-​blood sequences
Fig. 51.10  T2-​weighted turbo
spin-​echo images in a patient with
an intramural haematoma in the
hyperacute phase (first 48 hours). The
images show the presence of a signal
hyperintensity corresponding to the
acute bleeding (arrow) in a sagittal
view (a) and in an axial view (b).
766 CHAPTER 51   Aortic disease: Aneu rysm a n d di s secti on — rol e of  CM R

(a) (b) (c) (d) (e)

Fig. 51.11  Evolution of a patient with a type B intramural haematoma. Initially, the patient presented a localized dissection (ulcer-​like image or pseudoaneurysm)
as seen in images (a), (b), and (c) (white and black arrows). At follow-​up, the patient progressed to a classical type B aortic dissection (d and e, red arrows).

may show disruption of the intima with extension of the ulcer to
the thickened media that may be associated with IMH. It may be
difficult to differentiate penetrating ulcer from the typical forms
of dissection. The differential diagnosis should be established be-
tween arteriosclerotic ulcers that penetrate the middle layer and
ulcer-​like images that develop from a localized dissection of an
IMH that appears as a pseudoaneurysm located in the area of the
former IMH (E Fig. 51.11).
The natural history of PAU is unknown and several evolutive
possibilities have been described. Many patients with PAU do
not need immediate aortic repair but do require close follow-​up
with serial imaging studies (CMR/​CT) to document disease pro-
gression. Although many authors have documented the propen-
sity of aortic ulcers to develop progressive aneurysmal dilatation
and the possibility of spontaneous aortic rupture, the progres-
sion is usually slow. CMR may be helpful to show incidental and

(a) (b) (e) (f)

(c) (d)

Fig. 51.12  Penetrating atherosclerotic ulcer in a patient presenting with acute chest pain. (a) Axial SSFP single-​shot image showing the presence of a crater-​
like lesion in the aortic wall (arrows). The image also shows the presence of left pleural effusion (*). (b) Axial T1-​weighted image showing the presence of an
outpunching lesion in the aortic wall associated to the presence of an isointense signal of the aortic wall compatible to the presence of an atherosclerotic
plaque. (c) Fat suppression technique to exclude the presence of periaortic fat. (d) Same image after the administration of contrast. (e, f) Contrast-​enhanced MR
angiography showing the penetrating atherosclerotic ulcer in the same patient in different projections (white arrows).

asymptomatic bleeding of aortic ulcers. Some aortic ulcers are an
incidental finding, similar to saccular aneurysms, in these cases,
size and enlargement are the only predictors of complications.
The prognosis of the ulcer-​like images following an IMH or
aortic dissection is variable. Thus, its presence in the acute phase
has a poor prognosis owing to the high risk of aortic rupture
(Hazard Ratio: 24.43). However, if they appear in the chronic
phase, most of them evolve with slow aortic dilatation and
without complications [48].
Acute aortic syndrome in blunt trauma
Thoracic aortic injury is one of the leading causes of death in
major blunt trauma and involves partial or total transection of the
aortic wall [49]. The aortic segment subjected to the greatest strain
by rapid deceleration forces is located just beyond the isthmus,
thus, aortic rupture occurs at this site 90% of times. Other less
common sites are the distal ascending aorta or distal segments
of the descending aorta. The lesion is transverse, involves all
or part of the aortic circumference and penetrates the aortic
layers to various degrees with the formation of a false aneurysm.
Intimal haemorrhage without any laceration has been described
in pathological series but was not easily recognized in vivo be-
fore the advent of high-​resolution imaging modalities. Periaortic
haemorrhage occurs irrespective of the type of lesion. The closed
bore design and long examination time have been the main limi-
tations of CMR in acute aortic diseases and trauma patients. The
potential for CMR to detect the haemorrhagic components of a
lesion by its high signal intensity is beneficial in trauma patients.
On spin-​echo images in the sagittal plane, the longitudinal view
of the thoracic aorta makes it possible to distinguish a partial le-
sion from a lesion encompassing the entire aortic circumference.
This discrimination is of prognostic significance since a circum-
ferential lesion may be more likely to rupture. The presence of
periadventitial haematoma and/​or pleural and mediastinal haem-
orrhagic effusion may also be considered as a sign of instability.
On the same sequence, the wide field-​of-​view of CMR provides a
comprehensive evaluation of chest trauma such as lung contusion
(a) (b)
Fig. 51.13  (a) Axial T1-​weighted turbo spin-​echo images in a patient with an acute aortitis showing the presence of an isointense concentric thickening of the
aortic wall (white arrows). (b) T2-​weigthed images in the same patient showing the presence of concentric signal hyperintensity of the aortic wall confirming
the acute and inflammatory stage of the disease (white arrows). (c) Axial post-​contrast T1-​weighted images in a patient with a chronic aortitis in the descending
aorta showing the presence of hyperenhancement of the aortic wall with a laminar intramural thrombus (yellow arrow).
Diag n o si s of thor aci c aort i c di se ase s 767
and oedema, pleural effusion, and rib fractures. Furthermore,
if delayed surgery is considered, CMR may be used to monitor
thoracic and aortic lesions as it is non-​invasive and repeatable
[50]. MRA provides an excellent display of the aortic lesion and
its relationship with supra-​aortic vessels. However, it does not add
any diagnostic value to spin-​echo CMR, and it cannot supply in-
formation on parietal lesions and haemorrhagic lesions outside
the aortic wall.
Aortitis
Inflammatory diseases of the aorta can be classified into two
major subgroups: aortitis of non-​specific or unknown aetiology
(Takayasu´s aortitis, Beçhet disease, giant cell aortitis, Kawasaki
disease, ankylosing spondylitis), and specific aortitis, in which the
aortitis is the consequence of an inflammatory disease of known
origin (e.g. syphilitic aortitis). Relevant ethnic differences have
been observed in the epidemiological distribution of non-​specific
aortitis and they are more common in Asian countries. Typical
findings are marked irregular thickening of the aortic wall along
with fibrous lesions that are the results of the inflammatory pro-
cess of the media which can lead to stenotic lesions (Takayasu´s
disease), aneurysms of the aorta and its major branches, or
aortic insufficiency because of aortic root dilation. The high spa-
tial and contrast resolution offered by newer CMR techniques
permit the assessment of the aortic wall, and CMR is included
as a routine test in the work-​up of patients with vasculitis af-
fecting large vessels, giant cell arteritis and Takayasu´s arteritis.
Contrast spin echo in black-​blood sequences is useful to iden-
tify the wall thickening in aortitis of various causes. In the initial
stages of Takayasu’s arteritis, short inversion-​ time inversion-​
recovery (STIR) and post-​contrast T1-​weighted sequences are
particularly useful. Inflammatory changes in initial phases are
reflected with contrast uptake and hyperintensity secondary to
the wall oedema in STIR sequences (E Fig. 51.13). Active in-
flammatory disease appears as variable thickening of the aortic
wall and delayed contrast-​enhancement after gadolinium admin-
istration can characterize the degree of inflammation in the aortic
(c)
768 CHAPTER 51   Aortic disease: Aneu rysm a n d di s secti on — rol e of  CM R
wall of patients with Takayasu’s arteritis [51]. In advanced stages
of the disease, CE-​MRA can determine the presence of stenosis
in the aorta and its main branches secondary to chronic fibrous
alterations. Recently, it has been shown the capability of 18F-​FDG
hybrid PET camera combined with CMR to depict early stages of
Takayasu’s aortitis or to diagnose the presence of an infected an-
eurysm [52, 53]. Moreover, CMR can be useful in evaluating the
response to medical treatment by depicting a decrease in arterial
wall thickness.
Aortic coarctation
Coarctation of the aorta causes a more or less severe stenosis at
the junction of the aortic arch and descending aorta and may
be focal or more diffuse. Pseudocoarctation resembles a true co-
arctation but is caused by aortic kinking just distal to the origin
of the left subclavian artery. It is usually not flow-​limiting and
therefore not associated with multiple collaterals. CE-​MRA is
the most useful technique for evaluating stenoses of the thoracic
aorta. Temporally resolved CE-​MRA can depict aortic stenoses,
but it is particularly useful in haemodynamically significant le-
sions such as coarctation, where it demonstrates gradual filling
of chest wall collaterals (E Fig. 51.14). PC CMR can be used to
(a)
Fig. 51.14  Contrast-​enhanced MR
angiography showing a patient with
an haemodynamically significant
aortic coarctation (arrow) associated
with multiple collateral vessels: MIP
reconstruction (a) and 3D volume
rendering reconstruction (b).
measure velocity and flow, both proximal and distal to a stenosis,
and helps assess the significance of a stenosis [54]. In patients
with haemodynamically significant coarctation, an inversion in
the aortic flow pattern has been observed with a higher flow in
the distal thoracic descending aorta compared to the aortic flow
precoarctation. CMR may be very useful in monitoring disease
progression over time. However, it is important to obtain meas-
urements in similar anatomical locations to produce accurate
and consistent results. CMR is also well adapted for serial follow-​
up imaging after surgery of the aortic aorta with no radiation
exposure.
Pitfalls and limitations
The main limitations of CMR imaging include the low avail-
ability 24 hours per day, cost, patient claustrophobia, and the
classical contraindications (pacemakers/​defibrillators, metallic
ocular implants, and cerebral vascular clips). CMR is not contra-​
indicated in patients with mechanical prosthetic valves, but the
valve may induce a signal void artefact which may preclude the
study of the initial portion of the aorta. Big aortic stents often
make the local study of the aorta impossible (mainly the cobalt
or stainless steel ones). Although in some cases, depending on
(b)

the paramagnetic properties of the stent the evaluation is feas-
ible (z Video 51.1). In acute aortic diseases, CMR is limited
by lesser availability and is more time-​consuming. For unstable
patients, TEE or CT are better options. The use of gadolinium
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Contents
Introduction  771
The normal aorta  771
Computed tomography imaging
protocol  772
Aortic aneurysm  773
Inflammatory aortic diseases  774
Acute thoracic syndromes  775
Aortic dissection (AD)  776
Intramural haematoma (IMH)  777
Penetrating atherosclerotic ulcer  777
Limitations of MSCT  779
CHAPTER 52
Aortic disease: Aneurysm
and dissection—​role
of MSCT
Rocío Hinojar and Raimund Erbel
Introduction
Multislice computed tomography (MSCT) is currently the preferred modality for diag-
nosis and complete characterization of aortic pathology because of its widespread
availability, rapidity, excellent spatial resolution, and excellent accuracy for all aortic seg-
ments and different aortic diseases. Aortic disease often remains undiagnosed until a
life-​threatening complication occurs or the disease is an unexpected finding on imaging
studies performed for other purposes. MSCT allows the measurement of the aortic wall
and dimension and the evaluation of morphologic features and surrounding structures,
even in very sick or unstable patients.
The normal aorta
The thoracic aorta has its origin at the aortic annulus and extends to the diaphragmatic
hiatus. The thoracic aorta is divided in the aortic root, ascending aorta, the aortic arch,
and the descending aorta. Electrocardiographic (ECG) gating MSCT is preferable for
the ascending aorta to avoid aortic motion. CT and MSCT data are available for the
ascending and descending thoracic aorta (E Table 52.1). Diameter measurements on
MSCT should be provided at standard landmarks for serial comparisons, including the
sinuses of Valsalva, sinotubular junction, mid-​ascending aorta, proximal arch, mid-​arch,
proximal descending thoracic aorta, mid-​thoracic descending aorta, and aorta at the dia-
phragm (E Fig. 52.1).
The aortic root is the most proximal portion of the thoracic aorta and is located be-
tween the aortic annulus and the sinotubular junction. It is composed of the three sinuses
of Valsalva (right, left, and non-​coronary). The normal aortic root diameter is typically
less than 3.9 cm. The tubular segment of the ascending aorta extends from the sinotubular
junction to the brachiocephalic artery origin. Mean diameters of the ascending aorta at
the level of the right pulmonary artery are 3.45 ± 0.4 cm for women and 3.71 ± 0.4. cm
for men derived from non-​contrast CT (E Table 52.1) [7].‌
The aortic arch passes from the proximal ostium of the brachiocephalic trunk to the
distal ostium of the left subclavian artery. This is followed by the isthmus, which is at-
tached to the ligamentum arteriosum. The aortic arch is usually 3.0 cm or less, with the
isthmus often slightly smaller in diameter than the proximal descending aorta. Typically,
there are three branches arising from the aortic arch: the brachiocephalic trunk or ar-
tery (or innominate artery), the left common carotid artery, and the left subclavian ar-
tery. The bovine arch is the most common variant of the aortic arch, and occurs when
the brachiocephalic artery shares a common origin with the left common carotid ar-
tery. Additional common variants include a left vertebral artery arising directly from
772 CHAPTER 52   Aortic disease: Aneu rysm a n d di s secti on — rol e of  M S CT

Table 52.1  Normal aortic dimensions. Studies on mean aortic diameters by MSCT

Author (ref) Sample size (n) Age range Anatomic landmark of the Ascending thoracic aorta Descending thoracic aorta
(years) aorta diameter diameter
Aronberg et al. [1]‌ 102 21–​61 Caudal to the aortic arch 3.5 cm 2.6 cm
Hager et al. [2]‌ 70 17–​89 Caudal to the aortic arc 3.1 ± 0.4 cm 2.5 ± 0.4 cm
‘at maximal size’
Kaplan et al. [3]‌ 214 24–​87 Pulmonary artery level 3.4 ± 0.5 cm n.a.
Lin et al. [4]‌ 103 51 ± 14 Pulmonary artery level 3.0 ± 0.3 cm 2.3 ± 0.2 cm
Mao et al. [5]‌ 1,442 55 ± 11 Pulmonary artery level 3.4/​3.6 cm (females/​males) n.a.
Wolak et al. [6]‌ 2,952 26–​75 Pulmonary artery level 3.3 ± 0.4 cm 2.4 ± 0.3 cm
Kälsch et al. [7]‌ 4,129 45–​75 Pulmonary artery level 3.45 ± 0.4/​3.71 ± 0.4. cm 2.54 ± 0.3 /​2.82 ± 0.3 cm
(females/​males) (females/​males)
Reproduced from Kälsch H, Lehmann N, Möhlenkamp S, et al. Body-​surface adjusted aortic reference diameters for improved identification of patients with thoracic aortic
aneurysms: results from the population-​based Heinz Nixdorf Recall study. Int J Cardiol. 2013;163(1):72–​8. doi:10.1016/​j.ijcard.2011.05.039 with permission from Elsevier.

the arch and the ductus diverticulum, which represents the re-
sidual of the ductus arteriosum. This often appears as a focal
bulge along the inner curvature of the isthmus and may resemble
a pseudoaneurysm from traumatic aortic transection. The ductus
diverticulum is characterized by smooth contour and obtuse an-
gles. This must be distinguished from aortic transection, which
more commonly creates acute angles with the aortic wall.
The descending thoracic aorta includes from the aortic isthmus
to the diaphragmatic crura. Normal diameter of the descending
thoracic aorta is 2.5 cm or less. Vessels branching from the
descending thoracic aorta supply intrathoracic muscles and or-
gans and include bronchial, spinal, intercostal, and superior
phrenic arteries, in addition to smaller branches supplying the
oesophagus and pericardium.
The aortic diameters increase over time. Gender and age de-
pendent percentile distribution of diameters of the ascending
and descending aorta showed within three decades from 45 to
75 years an increase from 2.4 cm/​m2 to 2.7 cm/​m2 for females
and 2.3 cm/​m2 to 2.5 cm/​m2 for males.
In addition to the aortic diameter, the increase in wall thickness
has to be taken into account related to the ageing process and
development of atherosclerosis. Minimal intimal thickening and
extensive intimal thickening are regarded as grade I and grade II
aortic sclerosis [8]‌
Computed tomography imaging protocol
Correct protocolling is essential for generating high-​ quality
MSCT images. As the aorta is a dynamic structure, ECG gating
is crucial for reducing motion artefact, particularly in the aortic
root, ascending aorta, and proximal arch. Often, non-​contrast
imaging is performed prior to contrast-​enhanced imaging, as the
former can help to detect some pathology such as acute intra-
mural haematoma [9, 10]. Iodinated contrast agent is adminis-
tered as a rapid bolus and images must be acquired when the aorta
is well opacified. An inadequately opacified aorta may reduce the
accuracy of MSCT in acute aortic syndromes. To maximize sen-
sitivity for branch-​vessel involvement of acute aortic pathology,
the field of view should include the aortic arch branch vessels and

(a) (b)

6
5

4
Fig. 52.1  Volume rendering
7
3
reconstruction (a) and curved 2
multiplanar reconstructions (b) of a
thoracic aorta. Standard landmarks 1
include the aortic annuli (1) sinuses of 8
Valsalva (2), sinotubular junction (3),
mid-​ascending aorta (4), proximal arch
(5), distal arch (6), mid-​descending
thoracic aorta (7), and aorta at the
diaphragm (8).
 Aorti c a n e urysm 773

extend distal to the femoral arteries. In patients with acute chest

Box 52.1  Causes of thoracic aortic aneurysm
pain, MSCT can be useful in both excluding aortic and non-​aortic
aetiologies. The triple rule-​out protocols—​aortic dissection, pul- Causes of thoracic aortic aneurysm
monary embolism, and obstructive coronary artery disease—​
Atherosclerosis
have gained increasing interest in the emergency setting given its
Aortic dissection
high negative predictive value to rule out life-​threatening sources
Medial degeneration (genetic)
of acute symptoms.
Marfan syndrome
Ehlers–​Danlos syndrome
Outside influences (acquired)
Aortic aneurysm Trauma
A thoracic aortic aneurysm is defined as a localized dilation of Syphilis
an artery with a ≥50% increase in diameter relative to the ex- Mycosis (infection)
pected normal diameter of the vessel. However, the size of the Noninfective aortitis
normal thoracic aorta varies with age and body size, and usually Rheumatic fever
a threshold of the ascending aorta diameter ≥2.1 cm/​m2 is em-
Rheumatoid arthritis
ployed to detect aortic aneurysm in adult patients. Different to
Ankylosing spondylitis
the normal aorta, aortic aneurysms grow more rapidly at about
Giant cell arteritis
1 mm per year. Current American and European guidelines for
management of thoracic aortic disease highlight the importance Relapsing polychondritis
of the maximum diameter of aneurysm and rate of diameter in- Takayasu arteritis
crease in determining the optimal moment for intervention [11, Reiter syndrome
12]. MSCT provides not only accurate and highly reproducible Systemic lupus erythematosus
aortic measurements but also the evaluation of the wall and con- Scleroderma
tents of an aneurysm, including thrombus, and surrounding Psoriasis
structures. Ulcerative colitis
Atherosclerosis is the most common cause of thoracic aortic Radiation
aneurysms; however, it is usually presented as a more diffuse pro- Behçet disease
cess and usually involves the ascending and descending thoracic
Congenital aneurysm (rare)
aorta. Using MSCT the aortic wall can be imaged and signs of ath-
Source data from Moll FL, Powell JT, Fraedrich G, et al. Management of
erosclerotic plaque formation can be detected, which are reported abdominal aortic aneurysms clinical practice guidelines of the European
in five grades by echocardiography and also used by MSCT (E Society for Vascular Surgery. Eur J Vasc Endovasc Surg. 2011;41 Suppl 1:S1–​
Table 52.2). S58. doi:10.1016/​j.ejvs.2010.09.011.
Concomitant abdominal aortic aneurysm occurs in almost
30% of patients with thoracic aortic aneurysms, and therefore ini-
tial evaluation should include the entire thoraco-​abdominal aorta small aorta, the individual risk is very low. Current European
[13]. A list of alternatives causes of thoracic aortic aneurysms is Society of Cardiology (ESC) guidelines recommend interventions
presented in E Box 52.1 [14]. on ascending aortic aneurysms with maximal ascending aortic
The main complication of aortic aneurysm is aortic rupture or diameters of ≥55 mm for patients with no elastopathy. Lower
dissection. According to the law of Laplace, wall tension increases thresholds are recommended for patients with Marfan syndrome
with the diameter of the aorta and consequently aortic rupture or patients with bicuspid valve and risk factors (≥45 and ≥50 mm,
risk increases with the size of the aorta. There is a rapid increase respectively) [12]. Particularly important is to monitor the size of
in the risk of dissection or rupture when the aortic diameter is aneurysms with MSCT annually; accelerated annual growth can
>60 mm for the ascending aorta and >70 mm for the descending constitute an indication of surgery on its own [15].
aorta [14]. Although dissection may occur in patients with a Although thoracic aortic aneurysms are usually asymptomatic,
they can produce symptoms by compressing adjacent structures
when reaching significant aortic size. MSCT allows visualization
Table 52.2  Atherosclerotic plaque grades of potential vulnerable structures such as superior vena cava (su-
perior vena cava syndrome), airway compression resulting in
Grade I Minimal intimal thickening stridor or dyspnoea, or recurrent laryngeal nerve or oesophageal
Grade II Extensive intimal thickening compression causing hoarseness or dysphagia, respectively [16]
Grade III Aortic atheroma (E Fig. 52.2).
Abdominal aortic aneurysm (AAA)—​ almost exclusively
Grade IV Protruding atheroma
infrarenal—​is usually defined as a diameter ≥30 mm. Although
Grade V Mobile atheroma
the main cause is degenerative, it is also commonly associated
774 CHAPTER 52   Aortic disease: Aneu rysm a n d di s secti on — rol e of  M S CT

Fig. 52.2  Right-​sided aortic arch, aberrant left subclavian artery, and aneurysm at the origin of the aberrant artery (Kommerell aneurysm). Upper panel: Axial
MSCT images with contrast. Lower panel: volume rendered images. AA = aortic arch; KA = Kommerell aneurysm; LSA = origin of the aberrant left subclavian
artery. Right-​sided aortic arch is a rare anatomical variant present in about 0.1% of the adult population and half of the cases are associated with an aberrant left
subclavian artery. Aneurismal dilatation usually at Kommerell’s diverticulum may occur causing compression of adjoining structures.

with atherosclerotic disease. The reported average growth rate
of AAAs between 30 and 55 mm ranges from 0.2 to 0.3 cm per
year [17]. Similarly to thoracic aortic aneurysm, maximum
size (>55 mm), symptoms, or fast growing (>10 mm/​year)
are current indications for AAA intervention (E Fig. 52.3).
Preoperative assessment of abdominal aneurysms includes
the measurement of their maximal transverse perpendicular
diameter and the relationship of the aneurysm to the renal ar-
teries. Their lengths, as well as diameters, angulations, and tor-
tuosity, are particularly important for endovascular aneurysm
repair [12].
Inflammatory aortic diseases
Aortitis is a general term that refers to a broad category of in-
fectious or non-​infectious conditions in which there is ab-
normal inflammation of the aortic wall. The most common
causes of aortitis are non-​infectious inflammatory vasculitis
such as Takayasu arteritis and giant cell arteritis (GCA). It is
also seen in other collagen vascular disorders such as rheuma-
toid arthritis and ankylosing spondylitis. Infectious aortitis
may be secondary to tuberculosis, syphilis, or infection due to
Salmonella, Staphylococcus, mycobacteria or other bacterial or
viral pathogens [18].
Imaging in general and MSCT in particular allows early diag-
nosis, identifying the pattern of aortic involvement and the pres-
ence aortic wall changes. Nuclear medicine imaging with fluorine
18
fluorodeoxyglucose (FDG) positron emission tomography
(PET) is helpful in assessment of inflammatory activity and its
combination with MSCT allows the evaluation of morphologic
changes. Any FDG uptake in the aorta is considered abnormal,
and in active aortitis, FDG uptake is higher in the aortic wall than
in the liver [19, 20]. Given the limited spatial resolution of PET
alone, PET imaging performed in conjunction with MSCT al-
lows for more precise localization of inflammatory lesions. MSCT
findings in Takayasu arteritis include concentric thickening of the
vessel wall, thrombosis, stenosis, and occlusion (E Fig. 52.4).
Other associated findings include vessel ectasia, aneurysms,
and ulcers. Arterial wall calcification can develop in chronic
 Acu te thor aci c sy n dro m e s 775

Fig. 52.3  Large infrarenal abdominal aortic aneurysm (AAA) of

9.6 × 10 cm., with signs of contained rupture (high density fluid and
stranding of retroperitoneal fat).

cases, typically after several years of inflammatory involvement.

Aortic wall calcification is typically linear and usually spares the Acute thoracic syndromes
ascending aorta.
Acute aortic syndromes (AAS) including thoracic aortic dissec-
On the other hand, aortic involvement occurs in 15% of GCA
tion (TAD), intramural haematoma (IMH), and penetrating ath-
patients usually manifests as annuloaortic ectasia or as an as-
erosclerotic ulcer (PAU) are emergency conditions with similar
cending aortic aneurysm that can extend into the aortic arch,
clinical characteristics involving the aorta that requires accurate
which can lead to aortic dissection, or rupture. Aortic involve-
and prompt diagnosis and management (E Fig. 52.5). MSCT is
ment can also manifest as aortic valve insufficiency, or AAA.
the preferred modality for diagnosis and complete characteriza-
MSCT can detect thickened aortic wall or luminal changes such
tion of AAS because of its widespread availability, rapidity, excel-
as stenosis, occlusion, dilatation, aneurysm formation, calcifica-
lent spatial resolution, and accuracy for ascending and descending
tion, and mural thrombi [21].
aortic pathology.

(a) (b)

(c) (d)

Fig. 52.4  Concentric thickening

of the aortic wall in a patient
with Takayasu arteritis. Significant
thickening was found at the origin of
the supra-​aortic trunks (a), aortic arch
(b) and the proximal portion of the
descending thoracic aorta and in the
abdominal aorta distal to the celiac
trunk (c and d).
776 CHAPTER 52   Aortic disease: Aneu rysm a n d di s secti on — rol e of  M S CT

Dissection Intramural haematoma Penetrating aortic ulcer

Fig. 52.5  Acute aortic syndromes can have overlapping features that include dissection, penetrating aortic ulcer, and intramural hematoma. These three
conditions can occur with overlapping clinical, radiological, and anatomic features.
Reproduced from Oderich GS, Kärkkäinen JM, Reed NR, Tenorio ER, Sandri GA. Penetrating Aortic Ulcer and Intramural Hematoma. Cardiovasc Intervent Radiol. 2019;42(3):321–​34.
doi:10.1007/​s00270-​018-​2114-​x with permission from Springer Nature.

Aortic dissection (AD) There are two classifications of AD: De Bakey and Stanford.
Both are based on the origin of the intimal tear and the extent
AD is the most common AAS and defined by disruption of the
of aortic involvement. The Stanford classification is the most
medial layer provoked by intramural bleeding, resulting in sep-
often used in clinical routine and determines the treatment ap-
aration of the aortic wall layers and subsequent formation a true
proach. Type A dissection involves the ascending aorta regard-
and a false lumen separated by an intimo-​medial flap with or
less of the origin of the intimal tear or the extent of the dissection
without communication [12, 22–​24]. In most cases, an intimal
(E Fig. 52.6) and requires urgent surgical repair. Type B dis-
tear is the initiating process, causing an inflow of blood into the
section affects only the descending aorta and is usually man-
media. This process is followed either by an aortic rupture in the
aged conservatively with antihypertensive medication. It may
case of adventitial disruption or by a re-​entering into the aortic
be complicated by dilatation and rupture of the false lumen,
lumen through a second intimal tear.

Fig. 52.6  Type A and B aortic dissection in a patient with a previous Bentall’s Procedure. Extensive dissection of thoracoabdominal aorta that originates
immediately distal to the aortic valve in the ascending aorta, and that extends distally to the iliac arteries.

end-​organ ischaemia, and progression to type A dissection.
Complicated type B dissection can be managed by endovascular
repair.
MSCT is the most common imaging modality in AD with a
sensitivity of 95% for AD [24]. The main finding on contrast-​
enhanced images is the intimal flap separating the true and false
lumens, which is observed in around 70% of the studies. The
false lumen is usually larger in diameter, has slower flow, and
may contain thrombus; the true lumen can be identified by its
continuity with an unaffected segment of the aorta. The convex
face of the intimal flap is usually towards the false lumen that
surrounds the true lumen. In type A AD, the false lumen is most
commonly located along the right anterolateral wall of the as-
cending aorta and extends distally, in a spiral fashion, along the
left posterolateral wall of the descending aorta. In most cases,
the lumen that extends more caudally is the true lumen. In add-
ition, MSCT allows a comprehensive assessment of the entire
aorta, including aortic diameters, shape, and the extent of aortic
involvement. It can detect the entry point, signs of rupture, ex-
tension into the aortic valve or aortic branches, presence and lo-
cation of true and false lumen, involvement of vital vasculature,
and distance from the intimal tear to the vital vascular branches.
Particularly important is the ability of MSCT to detect signs of
emergency and signs of ongoing aortic penetration or rupture
including periaortic haematoma, mediastinal bleeding, pericar-
dial effusion, and pleural effusion. Acute and chronic haema-
toma can be differentiated based on differences in Hounsfield
density.
Multiplanar reconstruction images are a particular advantage
of MSCT imaging, determining the extent of involvement and the
involvement of aortic branch vessels.
Intramural haematoma (IMH)
Intramural haematoma occurs after bleeding of the vasa vasorum
in the medial layer of the aorta without intimal tear. The resulting
haematoma can lead to infarction of the aortic wall, which may
contribute to the development of an AD or aortic aneurysm.
IMH is diagnosed in the presence of a circular or crescent-​shaped
thickened aorta (>5 mm) in the absence of detectable blood flow
(and therefore absence of contrast) [25, 26].
(a) (b)
Acu te thor aci c sy n dro m e s 777
Unenhanced MSCT acquisitions are crucial for the diag-
nosis and allow the differential diagnosis with an atheroscler-
otic thrombus. A high-​attenuation crescentic thickening of the
aortic wall, extending in a longitudinal, non-​spiral fashion, with
no enhancement after contrast is the hallmark of this entity
(E Fig. 52.7). The aortic lumen is commonly not affected and
no intimal flap is seen after contrast. However, given the simi-
larities with AD, IMH are also categorized according to the
Stanford classification.
Penetrating atherosclerotic ulcer
PAU is an ulceration of an atheromatous plaque that disrupts
the intimal layer of the aortic wall with subsequent extension
of blood into the media [27]. PAUs can remain stable or enlarge
and develop aortic aneurysms (E Fig. 52.8). Progression of
the ulcerative process may lead to IMH, or rarely progress into
AD, pseudoaneurysm, or even aortic rupture if the ulcer breaks
through the adventitia.
Contrast-​enhanced MSCT shows typically a localized ulcer-
ation penetrating through the aortic intima in the mid-​to distal
third of the descending thoracic aorta. PAU can be multiple, and
vary greatly in size and depth within the vessel wall. Focal thick-
ening or high attenuation in the adjacent aortic wall suggests
associated IMH.
Blunt and iatrogenic aortic injury
MSCT is the modality of choice for the assessment of thoracic
aorta emergencies after blunt and iatrogenic trauma. These in-
clude incomplete and complete aortic rupture; traumatic or iatro-
genic AD; traumatic intramural haematoma or pseudoaneurysm
after endovascular repair.
Optimized protocols are essential in maximizing the yield of
diagnostic information for the most complete and accurate as-
sessment. Thin collimation and triggered intravenous contrast
material injection is absolutely mandatory.
Blunt traumatic thoracic aortic injuries are commonly located
at the aortic isthmus [28]. Clinical practice guidelines from the
Society of vascular surgery classifies blunt aortic injuries in four
grades based on the severity (E Fig. 52.9) [29, 30]. These include:
grade 1, intimal tear; grade 2, intramural haematoma; grade 3,
Fig. 52.7  Intramural haematoma.
Non-​contrast (left) and contrast
(right) axial CT images show a high
density crescent-​shaped thickened
descending aorta (8 mm) and the
absence of contrast outlying to intimal
calcifications.
778 CHAPTER 52   Aortic disease: Aneu rysm a n d di s secti on — rol e of  M S CT

Fig. 52.8  Saccular dilatation with thrombosis in

the anterior wall of the descending thoracic aorta,
which correspond to a pseudoaneurysm as the
evolution of a penetrating ulcer.

aortic pseudoaneurysm with transection of the aortic wall; and
grade 4, free aortic rupture. While grade I can be managed conser-
vatively with careful monitoring, surgery or endovascular treat-
ment is indicated in grade II, III, and IV. Evidence showed that
most grade I injuries healed spontaneously, although close follow-​
up is necessary to detect late aortic related complications [29].
Iatrogenic AD may occur in the setting of catheter-​ based
coronary procedures, cardiac surgery, as a complication of
endovascular treatment of aortic coarctation, aortic endografting,
peripheral interventions, intra-​aortic balloon counterpulsation,
and during transcatheter aortic valve implantation. Classical in-
timal flaps or patent false lumen are visualized less often suggesting

Fig. 52.9  Classification system for traumatic aortic

injury.
Reproduced from Azizzadeh A, Keyhani K, Miller CC 3rd,
Coogan SM, Safi HJ, Estrera AL. Blunt traumatic aortic
injury: initial experience with endovascular repair. J Vasc
Surg. 2009;49(6):1403–​8. doi:10.1016/​j.jvs.2009.02.234 with
permission from Elsevier.

that iatrogenic AD may occur in the form of IMH and produces
a more localized injury [31]. Resources of the International
Registry of Aortic Dissection showed aortic iatrogenic AD in 5%
of all patients included with aortic dissection, 76% had Stanford
type A, and 24% had type B. Proximal iatrogenic AD most often
followed cardiac surgical procedures and distal dissections were
more likely to follow cardiac catheterization.
The diagnosis of iatrogenic AD is usually challenging given its
atypical presentation and the relative lack of classic signs of AD on
imaging studies. The mortality for iatrogenic AD is high, and in cases
of type B iatrogenic AD, may exceed that of spontaneous dissection.
Postoperative imaging
MSCT is essential in the follow-​up of patients after emergent or
elective thoracic aortic intervention or surgery. Interpretation
of MSCT findings can be confusing and knowledge of sur-
gical details is of paramount importance prior to interpret-
ation. Protocols should be tailored according to the type of
surgery performed. Complications that should be detected in-
clude haematoma, pseudoaneurysm, mediastinal fluid collec-
tion, pneumomediastinum, grafts dehiscence or infection, and
progression of residual aneurysm or dissection, as well as stent
complications or deformation in cases of thoracic endovascular
aortic repair [32, 33]. Endoleak is a unique complication of
endovascular repair and defined as the presence of contrast en-
hancement outside the stent-​graft. Depending on the source of
blood flow there are four types of endoleaks: type I, leak at the
attachment site; type II, leak from a branch artery; type III, graft
defect; and type IV, graft porosity (E Fig. 52.10). Identification
of the correct type of endoleak has important treatment im-
plications. While type 1 and type 3 endoleaks are repaired
L i m i tati on s of   M S C T 779
immediately, type 4 endoleaks are self-​limited and require no
treatment, and commonly resolve with normalization of the
patient’s coagulation status. The management of type 2 endoleak
is controversial, and requires individualized assessment. Lastly,
aneurysm expansion without endoleak is known as endotension
or type 5 endoleak. The exact cause of endotension is unknown.
Current recommendations in postoperative imaging include
predischarge or 1-​month postoperative assessment after thor-
acic aortic surgery, followed by reimaging at progressively longer
intervals with the aim to confirm stability and efficacy of surgical
or interventional techniques.
Limitations of MSCT
Although MSCT holds a high diagnostic accuracy for aorta path-
ology when applying ECG triggering and slice thickness below 2
mm, theses protocols are more time consuming and not always
applied. In non-​triggered MSCT data sets, small AD and PAU
may be unnoticed due to motion artefacts. In critical emergency
setting, motion artefacts may simulate increased wall thickness
or mimic a dissection flap. On the other hand, MSCT can pro-
duce false negative results in AASs when the aorta is inadequately
opacified. This may occur if the contrast bolus is administered too
slowly or if the patient has low cardiac output.
One major limitation of MSCT is the potential for development
of contrast-​ induced nephropathy with iodine-​ based contrast
agents. In patients with high risk of nephropathy, hydration, or an
alternative imaging modality (often transoesophageal echocardi-
ography (TEE) in acute setting or MRI in stable patients) should
be considered [34].
Fig. 52.10  Infrarenal abdominal aortic aneurysm
treated by aortoiliac endoprosthesis. A small type
II endoleak at the lumbar artery is observed in the
posterior portion of the aneurysm.
780 CHAPTER 52   Aortic disease: Aneu rysm a n d di s secti on — rol e of  M S CT
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correlations. Ann Vasc Surg 1986; 1: 15e23.
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Engl J Med 2008; 359: 1708–​16.
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Estrera AL. Blunt traumatic aortic injury: initial experience with
endovascular repair. J Vasc Surg 2009; 49: 1403–​8.
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 SECTION 10

Adult congenital
heart disease

53 The role of echocardiography in adult congenital heart disease  783

Lindsay A. Smith, Mark K. Friedberg, and Luc Mertens
54 The role of CMR and MSCT  809
Giovanni Di Salvo and Francesca R. Pluchinotta

Contents
Introduction  783
Overview of the main non-​invasive imaging
modalities  783
Describing abnormal cardiovascular
connections  784
The role of echocardiography in different
congenital defects  784
Atrial septal defects (ASD)  784
Ventricular septal defects (VSDs)  786
Atrioventricular septal defects (AVSDs)  787
Patent ductus arteriosus  789
Coarctation of the aorta  790
Right ventricular outflow tract obstruction
(RVOTO)  791
Left ventricular outflow tract
obstruction  792
Ebstein’s anomaly  793
Congenital mitral valve anomalies  794
Tetralogy of Fallot and tetralogy of Fallot with
pulmonary atresia  795
Transposition of the great arteries  797
Congenitally corrected transposition of the
great arteries  799
The functionally univentricular heart  801
Eisenmenger syndrome  803
Special topics in adult congenital
imaging  804
Echocardiography in the pregnant woman
with congenital heart disease  804
Echocardiography in patients with infective
endocarditis and congenital heart
disease  805
Tissue Doppler, strain, and strain rate in
congenital heart disease  805
Three-​dimensional echocardiography in
congenital heart disease  805
Stress echocardiography in patients with
congenital heart disease  805
Acknowledgement  805
CHAPTER 53
The role of
echocardiography in adult
congenital heart disease
Lindsay A. Smith, Mark K. Friedberg,
and Luc Mertens
Introduction
Congenital malformations of the heart affect at least 1% of newborn infants. Without
intervention, the prognosis for more complex forms is poor. Over the last few decades
advances in paediatric cardiology and cardiac surgery have significantly improved pa-
tient management, and the majority of patients now survive into adulthood [1–​3]. This
has led to new challenges as increasing numbers of adult patients with congenital heart
disease transition into the care of adult cardiac services. Caring for these patients requires
expert knowledge and a new subspecialty of adult congenital heart disease (CHD) has
emerged. This patient population also has specific imaging requirements due to vari-
ability in morphology and haemodynamics.
Overview of the main non-​invasive imaging
modalities
The different non-​invasive modalities are, to a large extent, complementary. More than
one modality is likely to be needed to address all the relevant clinical questions, particu-
larly in the more complex cases.
Chest  X-​ray (postero-​anterior ± lateral) provides an inclusive overview of the heart,
mediastinum, pulmonary vessels, lung fields, and thoracic skeleton. It remains a valu-
able and inexpensive modality, with only a low dose of ionizing radiation, for the serial
comparison of heart size, pulmonary vascularity, and peripheral lung fields in adults
with CHD.
Transthoracic echocardiography (TTE) is generally the first-​ line cardiovascular
imaging modality because of its convenience, availability, real-​time acquisition, safety,
and relatively modest cost. Its usefulness is, however, operator dependent, particularly
in adults with CHD. Limited echocardiographic acoustic windows and the suboptimal
penetration of ultrasound represent important limitations in adults after cardiovascular
surgery.
Transoesophageal echocardiography (TOE) has the advantage of clear access to more
posterior parts of the heart, particularly for 3D visualizations of valves and the atrial
septum. A disadvantage, however, is its invasive nature, generally requiring sedation or
anaesthesia, making it less acceptable than cardiac magnetic resonance (CMR) for serial
investigation. The field of view provided by TOE also is relatively narrow, with limited
access to extracardiac structures, and the alignment of the Doppler beam with unusually
oriented flow jets can be challenging. Perioperative TOE is an essential tool and is used
784 CHAPTER 53   The role of ech o cardio gra phy i n a du lt c on g en i ta l hea rt di sease
routinely in the operating room for assessing the surgical result
immediately after cardiopulmonary bypass. TOE is also used for
guiding interventional procedures in the cardiac catheterization
laboratory (e.g. for interventional closure of atrial septal defects).
Cardiovascular magnetic resonance (CMR) is not restricted
by body size or poor acoustic windows and is versatile, offering
a repertoire of velocity mapping and tissue contrast options,
without any ionizing radiation. CMR is widely regarded as the
gold standard for measurements of right as well as left ventricular
volumes, although analysis takes time and requires rigorously
consistent methods of acquisition and measurement that may
be hard to maintain in practice. It also provides flow quantifica-
tion and tissue characterization, which can be important in adults
with CHD.
Multislice computed tomography (MSCT) also offers ro-
bust spatial localization, plus excellent spatial resolution in
much shorter investigation times than CMR. It is well suited for
imaging the epicardial coronary arteries and aortopulmonary
collateral arteries, and for the investigation of parenchymal lung
disease, if present. ECG-​gated cine MSCT allows measurements
of biventricular size and function, albeit at a lower temporal reso-
lution than CMR, and subject to adequate opacification of the
intraventricular blood volumes. In patients with a pacemaker or
ICD, CT provides an alternative to CMR. The main drawback of
MSCT is exposure to ionizing radiation, albeit at lower dose with
advancing technology, and the need of contrast media. Other
drawbacks compared with CMR include less versatile tissue con-
trast and an inferior ability to evaluate cardiovascular physiology.
The role of CMR and MSCT in adult CHD is described in more
detail in Chapter 54 of this textbook.
Describing abnormal cardiovascular
connections
For the description of anatomy a common methodology can be
used by all imaging techniques. This is called the segmental ap-
proach [4]‌. The heart is viewed as consisting of certain segments
(the systemic and pulmonary veins, the atria, the ventricles, and
the great vessels) which are defined by unique morphological
characteristics. The segments need to be identified and the con-
nections between the segments are to be described. These are the
venoatrial connections, the atrioventricular connections, and the
ventriculoarterial connections.
Segmental analysis begins by defining the cardiac position and
atrial arrangement (situs). The cardiac position may be levocardia,
dextrocardia, or mesocardia. The atrial situs is ‘usual’ (situs solitus,
i.e. a right atrium (RA) on the right and a left atrium (LA) on the
left), or ‘inverted’ (situs inversus) or there can be bilateral duplica-
tion of one type of atrium known as right or left atrial ‘isomerism’.
Isomerism is generally associated with accompanying malforma-
tions. Atrioventricular (AV) and ventriculoarterial connections
are described as concordant (e.g. RA to right ventricle [RV], or
left ventricle [LV] to aorta), discordant [e.g. LA to RV], double
inlet [e.g. double inlet LV] or single inlet [left AV-​valve atresia].
This requires identification of the ventricular chambers as mor-
phological left or right ventricles, which is based on unique mor-
phological characteristics for each ventricle. A RV typically has
coarser apical trabeculations, has a tricuspid valve at the inlet,
has a moderator band and the inlet and outlet are separated by
an infundibulum. Afterwards the great vessels are identified and
the ventriculoarterial connections are described. These connec-
tions can be concordant (normal), discordant (transposition of
the great arteries), double outlet (double outlet RV) or single
outlet (pulmonary atresia, common arterial trunk). Finally com-
munications between the left and right side need to be described
(ventricular septal defect, VSD; atrial septal defect, ASD; patent
ductus arteriosus, PDA).
The role of echocardiography in
different congenital defects
Atrial septal defects (ASD)
ASDs are common also in the adult population. When diagnosing
patients with ASDs, the following questions should be addressed:
Type and location of the ASD
◆ Secundum ASD (70%). The defect is localized centrally in the
interatrial septum (E Fig. 53.1, z Video 53.1a and 53.1b). There
can be multiple defects and the defect can be fenestrated.
◆ Primum ASD (11%). This belongs to the spectrum of atrioven-
tricular septal defects. This is always associated with an abnormal
left atrioventricular valve (‘cleft’ AV valve) (E Fig. 53.2, z Video
53.2a and 53.2b).
◆ Sinus venosus ASD (SVC 5.3–​10%, IVC 2%). This defect is lo-
cated outside the limbus of the fossa ovalis, on the right septal
surface adjacent to the drainage site of the superior (or inferior)
vena cava (E Fig. 53.3, z Video 53.3). This is commonly asso-
ciated with partially anomalous venous return of the right upper
pulmonary vein.
◆ Coronary sinus ASD. This defect is in the wall that separates the
coronary sinus from the left atrium (LA). It may be fenestrated
or completely absent. An enlarged coronary sinus with a drop out
between the LA and the coronary sinus is seen. This is best visu-
alized in a posteriorly tilted four-​chamber view (E Fig. 53.4).
Haemodynamic effects
The atrial left-​to-​right (L→R) shunt can cause right heart dilata-
tion and can be associated with pulmonary hypertension. Signs of
a haemodynamically significant ASD are:
◆ RA and RV dilatation.
◆ Abnormal ‘paradoxical’ septal motion.
◆ Elevated RV pressure (rare)
◆ The right to left (L→R) shunt can be quantified using the con-
tinuity equation (RV outflow tract VTI × RV outflow tract area/​
Th e role of echo ca rdi o g r a phy i n di fferen t c on g en i ta l de f e c ts 785

Fig. 53.1  Large secundum ASD. There is a large central

defect with secondary right atrial and right ventricular
dilatation. The arrow points to the secundum ASD.
The colour Doppler image on the right shows the
left-​to-​right shunt through the ASD (arrow).
RA = right atrium; RV = right ventricle; LA = left atrium;
LV = left ventricle.

Fig. 53.2  Large primum defect. The defect is located low in the
atrial septum just above the atrioventricular junction (arrow). The
left and right AV valves are inserted at the same level and this is
associated with abnormal left AV valve anatomy (‘cleft’ mitral valve).
The right atrium and right ventricle are dilated.
RA = right atrium; RV = right ventricle; LA = left atrium; LV = left ventricle.

Fig. 53.3  Sinus venosus defect. Subcostal view on the atrial septum
(sagittal plane) A defect is noted in the superior part of the atrial
septum (arrow). Typically there is overriding of the superior vena
cava over the defect. There is a left-​to-​right shunt caused by the
defect as shown on the colour image.
786 CHAPTER 53   The role of ech o cardio gra phy i n a du lt c on g en i ta l hea rt di sease
Fig. 53.4  Coronary sinus ASD. This is a posteriorly directed apical
four-​chamber view. In this view a defect is shown in the area where the
coronary sinus drains into the right atrium (arrow) with a left-​to-​right
shunt from the left atrium (LA) through the coronary sinus into the right
atrium (RA).
LVOT VTI × LVOT area) and a Qp:Qs > 1.5:1 is generally con-
sidered to be haemodynamically significant.
Associated anomalies
A full segmental analysis needs to be performed as nearly any
congenital anomaly can be associated with an ASD [5]‌. It is
important to exclude pulmonary venous anomalies and inter-
rupted inferior vena cava (IVC) before interventional closure of
secundum defects.
Most ASDs can be diagnosed using TTE. However, if right
heart dilatation is found without identifying an ASD and without
another cause, additional imaging including TOE or CMR is indi-
cated to exclude a sinus venosus defect or anomalous pulmonary
venous connections.
Imaging is important during interventional closure of
secundum ASDs. Currently, interventional closure is monitored
either by TOE or by intracardiac echocardiography (ICE) [6]‌.
Before device closure, adequacy of the ASD rims needs to be de-
fined. Three-​dimensional echocardiography (3DE) allows an en-​
face view of the defect with a more accurate assessment of its size
and morphology as well as the morphology of surrounding struc-
tures [7, 8].
Imaging post surgery or intervention
Post surgery or intervention, echocardiographic follow-​up should
focus on the following aspects:
◆ Residual atrial shunt through the patch/​device
◆ Position of the patch or device relative to other cardiac structures
◆ Complications related to device implantation, e.g. erosion of the
aorta or atrial roof, thrombosis, infectious endocarditis, and de-
vice embolization
◆ Residual RA and RV dilatation
◆ Presence of pulmonary hypertension (PHT)
◆ AV-​valve regurgitation (especially after ASD primum repair)
Role of other imaging techniques
Generally ASDs can be imaged fully using transthoracic echo-
cardiography but in case of poor transthoracic windows, TOE
is a very useful additional diagnostic technique. In case there
is still uncertainty regarding the location (especially sinus ven-
osus defects can be difficult to image by echocardiography in
adults), or associated congenital abnormalities (particularly
pulmonary vein abnormalities), CMR can be performed. Apart
from the detailed anatomical imaging, CMR also allows a more
accurate quantification of the systemic and pulmonary blood
flow and calculation of Qp/​Qs, which is helpful for therapeutic
decision-​making.
Ventricular septal defects (VSDs)
In the newborn period, VSDs are one of the most common struc-
tural abnormalities diagnosed due to the high prevalence of small
muscular VSDs in this population. As most of the small muscular
defects close spontaneously and since large defects are treated
surgically or percutaneously during childhood, VSDs are less
common in the adult population.
The type and location of the VSD
◆ Perimembranous VSDs (60%) are localized in the membranous
part of the septum and are characterized by fibrous continuity
between the leaflets of the atrioventricular and arterial valve
(E Figs. 53.5a and 53.5b, z Video 53.4a–​c). These defects may
have inlet, trabecular, or outlet extensions. Anterior deviation
of the outlet part of the septum can cause RV outflow tract ob-
struction (tetralogy of Fallot). Posterior deviation can cause LV
outflow tract obstruction and can be associated with aortic arch
anomalies (coarctation, interrupted aortic arch).
◆ Muscular VSDs (20%) are localized in the muscular septum. The
muscular VSDs can be divided into the inlet, trabecular, or outlet
types. There may occasionally be multiple defects.
◆ Doubly committed VSDs (5%) are localized just below the aortic
and pulmonary valve and are characterized by fibrous con-
tinuity between the aortic and pulmonary valve (z Videos 53.5
and 53.6).
Assessment of defect size and haemodynamic
significance
◆ The size of the VSD should be measured in at least two dimen-
sions. A VSD is small (<5 mm), moderate (5–​10 mm), or large
(>10 mm). 3DE by allowing an en-​face visualization of the defect
allows an accurate assessment of its size and morphology [9]‌.
◆ The L→R shunt can cause LA and LV dilatation. LA size, volume,
and LV dimensions should be measured. There can be associated
secondary mitral regurgitation due to LV dilatation. Associated
structural abnormalities of the mitral valve are possible and
should always be excluded.
 Th e role of echo ca rdi o g r a phy i n di fferen t c on g en i ta l de f e c ts 787

(a) (b)

Fig. 53.5  (a) Perimembranous VSD as shown on a parasternal short-​axis view (arrow). The size is measured from this view. Typically the VSD is adjacent to the
septal leaflet of the tricuspid valve. There is fibrous continuity between the aortic and tricuspid valve. (b)
Perimembranous VSD. Colour flow demonstrates left-​to-​right shunting during systole (arrow).

◆ A VSD can be unrestrictive (with no significant pressure differ-
ence between both ventricles) or restrictive due to small size or
tissue partially covering the VSD.
◆ A VSD can be associated with PHT. RV pressures should be as-
sessed based on calculating the VSD pressure Doppler gradient
or tricuspid regurgitant jet. Obstructive PHT can develop
and result in R→L shunting across the VSD (Eisenmenger
syndrome).
◆ The shunt can be calculated and a Qp:Qs >1.5:1 is considered as
haemodynamically significant.
Associated anomalies
Any congenital heart defect can be associated with a VSD. A full
segmental analysis is therefore crucial. Commonly associated
lesions are:
◆ Prolapse of the right coronary leaflet with progressive AR.
◆ Development of double chambered RV due to the presence of
hypertrophic RV muscle bands.
◆ Development of LV outflow tract obstruction due to the develop-
ment of a fibromuscular ridge or subaortic membrane, or due to
the presence of posterior malalignment of the outlet septum.
◆ Anterior malalignment of the outlet septum can cause right ven-
tricular outflow tract obstruction and aortic override (tetralogy
of Fallot).
Imaging post surgery or interventions
Most large VSDs will have been surgically closed during child-
hood. Percutaneous device closure of certain perimembranous
and muscular VSDs is possible. Post-​surgical or device closure of
a VSD, the following needs to be assessed:
◆ Residual VSDs due to patch leaks or additional VSDs
◆ The development of subaortic stenosis (membrane or fibromus­
cular ridge)
◆ The development of right ventricular muscle bundles causing
right ventricular outflow tract obstruction
◆ Aortic regurgitation
◆ Tricuspid regurgitation (after perimembranous VSD closure),
pulmonary regurgitation (after surgical closure of doubly
committed VSD)
◆ Residual PHT
Role of other imaging techniques
Most VSDs can be imaged using TTE. Rarely, TOE or other
imaging modalities may be indicated. CMR can help quantify the
Qp/​QS. Where there is uncertainty regarding the pulmonary vas-
cular resistance or the presence of obstructive PHT, cardiac cath-
eterization may be indicated.
Atrioventricular septal defects (AVSDs)
Most AVSDs are diagnosed and will have been treated surgi-
cally in childhood. In adulthood, unoperated AVSDs with large
ventricular components are associated with obstructive PHT
(Eisenmenger syndrome). Isolated septum primum septum de-
fects or intermediate AVSDs can be diagnosed in adulthood.
Types of AVSDs and morphologic description
The essential morphological feature of an AVSD is the presence
of a common atrioventricular (AV) junction with a common AV
valve at the entrance of both ventricles [10, 11]. When imaging,
the following features are important:
◆ Variable shunting across the AVSD. Different relationships
between the bridging leaflets and the atrial and ventricular
septal components determine different levels of shunting. In
a complete defect, shunting is present at the level of the atrial
septum (primum defect) and the inlet ventricular septum
(E Fig. 53.6a, z Video 53.7a). If the bridging leaflets attach
788 CHAPTER 53   The role of ech o cardio gra phy i n a du lt c on g en i ta l hea rt di sease
(a) (b)
Fig. 53.6  (a) Complete atrioventricular septal defect. There is a single AV valve at the entrance of both ventricles. There is a large atrial primum component
(upper arrow) and a large inlet ventricular septum defect (lower arrow). There is a single AV valve at the entrance of both ventricles. (b) Subcostal ‘en-​face’ view
on the AV valve. There is a single AV valve at the inlet of both ventricles. This valve has five leaflets: superior bridging leaflet (SBL), mural leaflet (ML), inferior
bridging leaflet (IBL), right anterior leaflet (RAL), right inferior leaflet (RIL).
to the crest on the interventricular septum, they can close the
VSD, and shunting can be present only at atrial level (primum
defect). If the bridging leaflets are attached to the underside
of the atrial septum, shunting can only be present at the ven-
tricular level (inlet VSD). The bridging leaflets can close all
septal defects resulting in a common AV junction with no atrial
or ventricular communication (E Fig. 53.4).
◆ The common AV valve at the entrance of the ventricles is ab-
normal and is made up of five leaflets (E Fig. 53.6b, z Video
53.7b). It differs from a normal mitral and tricuspid valve. There
is a variable degree of functional AV-​valve abnormalities as-
sociated with this lesion. This is mainly left or right AV-​valve
regurgitation with valve stenosis being more uncommon. Three-​
dimensional echocardiography can be helpful in defining the
AV-​valve morphology and determining the mechanisms of AV-​
valve regurgitation.
The left ventricular outflow tract (LVOT) is elongated in the
◆
parasternal long axis. This is due to the presence of a single AV
junction and unwedging of the aorta. LVOT obstruction can be
present.
◆ Most defects have balanced ventricular chambers with dilatation
of the RV mainly related to the atrial shunt. Unbalanced AVSD
with RV or LV dominance can be present, however.
Haemodynamic assessment
◆ Variable degrees of atrial and/​or ventricular shunting can be
present. These shunts can result in atrial as well as ventricular
dilatation.
◆ PHT can be present mainly related to the presence of an
unrestrictive VSD or more rarely related to the primum ASD.
◆ AV-​valve regurgitation severity needs to be assessed and the
mechanism described.
◆ If uncorrected, AVSD with large VSD components will give rise
to obstructive PHT and Eisenmenger syndrome.
Associated lesions
Any associated congenital heart defect can be present and a full
segmental analysis is essential. Commonly associated lesions are:
◆ Additional secundum ASD and additional muscular VSDs
◆ Associated PDA which can be difficult to detect in case of PHT
◆ Anterior deviation of the outlet septum can result in RV outflow
tract obstruction (AVSD + tetralogy of Fallot)
◆ LVOT obstruction can be present and this can be associated with
aortic coarctation or interrupted aortic arch
◆ AVSD can be associated with more complex situs anomalies
(isomerism)
Post-​surgical imaging
Surgical repair typically consists of closing the atrial and ven-
tricular communications and involves variable interventions on
the atrioventricular valve dependent on a variable degree of atrio-
ventricular valve regurgitation. Typically, the ‘cleft’ in the left AV
valve is closed surgically. Residual lesions include:
◆ Residual atrial and/​or ventricular shunts.
◆ Left and right AV-​valve regurgitation or stenosis. Left AV-​valve
regurgitation is common and often is due to the presence of
a residual ‘cleft’. Other mechanisms related to AV-​valve dys-
plasia may be present. The description of the severity and as-
sociated AV-​ valve stenosis is important. Three-​ dimensional
 Th e role of echo ca rdi o g r a phy i n di fferen t c on g en i ta l de f e c ts
echocardiography can be helpful in determining the mechanisms
contributing to residual AV-​valve regurgitation.
◆ LVOT obstruction can be present, often related to the develop-
ment of subaortic obstruction.
◆ PHT can be present postoperatively.
Role of other imaging techniques
Generally, echocardiography should be able to describe the ana-
tomical and haemodynamic features of patients with AVSD pre
and post-​operatively. In case of poor transthoracic windows, TOE
can be helpful. In adults, aortic arch imaging and imaging of a
PDA can be challenging and CMR or MSCT might be needed if
clinically indicated. For patients with suspicion of elevated pul-
monary vascular resistance, cardiac catheterization may be re-
quired to determine pulmonary vascular resistance.
Patent ductus arteriosus
A PDA is not an uncommon lesion in adulthood. The L→R shunt
causes left LV volume overload. If large, it may cause progressive
obstructive PHT and Eisenmenger syndrome.
Morphology of the PDA
In a left aortic arch, the duct is usually located between the
descending aorta and the left pulmonary artery. If the arch is right
sided, the duct can be present between the descending aorta and
the right pulmonary artery, but other locations like between the
left subclavian artery and the left pulmonary artery are possible.
This variability in location of the duct makes the echocardio-
graphic diagnosis sometimes difficult. Colour flow Doppler can
be helpful in identifying the duct location (E Fig. 53.7a).
Haemodynamic consequences of a PDA
For the haemodynamic assessment of a PDA, the size of the duct,
the presence of restriction to pressure, the direction of shunting,
(a)
Fig. 53.7  (a) Patent ductus arteriosus. Colour flow Doppler demonstrating aortic-​to-​pulmonary flow in the short-​axis view. The red colour represents the
diastolic flow though the arterial duct. (b) Patent ductus arteriosus. There is continuous left-​to-​right shunting from the aorta to the pulmonary artery through
the duct. The high velocity across the duct excludes the presence of significant pulmonary hypertension.
789
and the pressure and/​or volume loading caused by the PDA need
to be assessed. The shunt size and direction can be assessed by
2D echocardiography, colour Doppler, pulsed Doppler, and con-
tinuous wave Doppler (E Fig. 53.7b). If the pulmonary vascular
resistance (PVR) is normal, the flow is left to right (L→R) and
continuous. Flow velocity is high in a restrictive PDA. The peak
and mean gradient between the aorta and pulmonary artery can
be measured. With increasing PVR, flow becomes bidirectional
with R→L flow in systole and L→R shunting in diastole. With
progressive pulmonary vascular disease, the shunt can be exclu-
sively R→L. The L→R shunt will cause an increase in pulmonary
blood flow and can result in LA and LV dilatation caused by LV
volume loading. In case the duct is unrestrictive, PHT will be pre-
sent causing pressure loading to the RV.
Associated anomalies
In the adult population, an isolated PDA is the most common
presentation, but associated congenital anomalies need always be
excluded. As for any congenital defect, a full segmental analysis
is required.
Imaging post surgery or intervention
A PDA can be closed surgically or interventionally by placement
of a coil or a duct occluder [12]. After PDA closure, the following
should be evaluated:
◆ Residual shunting through the duct
◆ Residual PHT
◆ Residual LV dilatation and mitral regurgitation
◆ Obstruction on the left pulmonary artery after coil/​
device
placement
Role of other imaging techniques
A PDA can usually be diagnosed using TTE. Rarely, CMR or
MSCT might be required especially if the origin of the duct is
(b)
790 CHAPTER 53   The role of ech o cardio gra phy i n a du lt c on g en i ta l hea rt di sease

unusual. In case of PHT, cardiac catheterization may be required

to assess the PVR and its responsiveness to pulmonary vasodila-
tors may be helpful in therapeutic decision-​making.

Coarctation of the aorta
In classic coarctation there is a narrowing of the aorta located
distal to the origin of the left subclavian artery in proximity to
the level of insertion of the arterial duct [13]. The morphology of
the narrowing is variable but typically is discrete with variable de-
grees of hypoplasia of the isthmus and the transverse aortic arch.
The more extreme form is interruption of the aortic arch, which
obviously is extremely rare to be diagnosed in adulthood. The
diagnosis should be clinical with arterial hypertension associated
with poor or absent femoral pulses and an arm-​leg blood pres-
sure gradient. Typically, large collaterals develop providing blood
supply to the lower part of the body.
Imaging the morphology of coarctation of the aorta
In adults, imaging coarctation of the aorta using echocardiog-
raphy can be challenging due to the limited echocardiographic
penetration and often limited visualization of the descending
aorta. The best screening method for diagnosing coarctation of
the aorta is scanning the abdominal aorta in a subcostal long-​axis
view (E Fig. 53.8). If there is a decreased systolic flow with dia-
stolic run-​off, this is suggestive for the presence of a narrowing
of the thoracic aorta. To further identify the location of the nar-
rowing, the suprasternal view should be used but this gives very
often only very limited windows in adult patients (E Fig. 53.9,
z Video 53.8). Colour flow Doppler can be helpful. If the distal
aorta cannot be viewed in the presence of an abnormal abdominal
flow pattern and clinical suspicion, additional imaging by CMR
and MSCT may be required.
Fig. 53.9  Coarctation of the aorta. The coarctation with an obvious
posterior shelve is located just distal to the origin of the left subclavian artery.
There is a localized narrowing in the juxtaductal region with a prominent
posterior shelve.
BA = brachiocephalic artery; LCA = left carotid artery; LSA = left subclavian artery; Asc
Ao = ascending aorta; Desc Ao = descending aorta.
Haemodynamic significance
To determine the haemodynamic significance of the coarctation,
the blood pressure gradient between a limb proximal and distal to
the narrowing has to be measured. Continuous wave Doppler can
be used to interrogate the gradient across the narrowed segment.
The coarctation is significant if high velocities and anterograde
diastolic flow is seen (diastolic run-​off due to continued pressure
gradient in diastole) (E Fig. 53.10). The CW Doppler gradient
may be misleading due to different factors: (1) the presence of
a PDA or the development of arterial collaterals may reduce the
gradient across the coarctation; (2) the simplified Bernoulli equa-
tion is less accurate for long segment lesion or segments with
multiple stenoses; (3) often multiple obstructive lesions in series
are present (such as hypoplasia of the transverse arch) that lead

Fig. 53.8  Coarctation of the aorta. Abdominal aortic flow in aortic

coarctation. Typically there is a continuous flow pattern in the abdominal Fig. 53.10  Coarctation of the aorta. Continuous wave Doppler through
aorta with diastolic forward flow (arrows) instead of the normal pulsatile the coarctation region. The typical ‘saw-​tooth’ pattern is identified with the
pattern. typical diastolic run-​off.
 Th e role of echo ca rdi o g r a phy i n di fferen t c on g en i ta l de f e c ts
to an increased peak velocity proximal to the descending aortic
narrowing. The expanded Bernoulli equation should be used if
the proximal velocity exceeds 1m/​s:
Peak gradient = 4v2max-​coarctation –​4v2max-​pre coarctation.
The arterial hypertension associated with coarctation, can cause
secondary left ventricular hypertrophy (LVH) with increased LV
wall thickness and mass. Secondary LV systolic and diastolic dys-
function can be present.
Associated lesions
Coarctation can be associated with multiple other cardiac defects.
The most common ones include:
◆ bicuspid aortic valve with variable degree of aortic valve sten-
osis or regurgitation
◆ subaortic stenosis due to a small outflow tract or subaortic mem-
brane can be present
mitral valve anomalies such as a parachute-​type mitral valve with
◆ dynamic obstruction in the right ventricular outflow tract (RVOT).
mitral valve stenosis
◆ supravalvar mitral stenosis related to the presence of a supramitral
membrane
◆ VSDs
Imaging post surgery or intervention
After surgery or interventional treatment (balloon dilatation
and/​or stent implantation), follow-​up imaging should focus on
diagnosing residual arch narrowing (aortic arch hypoplasia), re-
sidual narrowing at the coarctation site, detection of aneurysm
formation, and studying the secondary effects on LV mass and
systolic and diastolic function. Especially the detection of an-
eurysm formation can be challenging by echocardiography in
adults and additional imaging using CMR or MSCT is required.
In case of stent implantation, MSCT is the modality of choice.
Early development of coronary artery disease and ischaemic
heart disease is possible and might also require additional
imaging.
Role for additional imaging techniques
In adults with coarctation of the aorta, there is an important
role for CMR and MSCT in the preoperative and postoperative
791
assessment due to the limited visualization of the area of the co-
arctation and aortic arch using echocardiography.
Right ventricular outflow tract obstruction
(RVOTO)
The two most common lesions causing RVOTO are pulmonary
valve stenosis and subvalvar pulmonary stenosis caused by RV
muscle bundles.
Morphology of RVOTO
The most common form of RVOTO is caused by pulmonary valve
(PV) stenosis. The valve can be tricuspid, bicuspid or unicuspid
with variable degree of dysplasia of the leaflets (E Fig. 53.11,
z Video 53.9). There can be tethering of the valve leaflets in the
supravalvar area causing additional supravalve narrowing which
can influence the success of balloon dilatation of the PV. Subvalvar
stenosis is caused by hypertrophy of RV muscle bundles causing
Muscle bundles dividing the RV into a proximal and distal chamber
characterize double chamber RV. Double chamber RV is differenti-
ated from infundibular narrowing in that the obstruction is located
lower within the body of the RV. A concomitant perimembranous
VSD may be identified (E Fig. 53.12, z Video 53.10).
Haemodynamic assessment
RVOT obstruction can generally be well diagnosed using TTE. The
valve morphology can be assessed and, before intervention, the
annulus size can be measured. If the gradient is muscular, it often
has a dynamic component, which is characterized by a high peak
late in systole. Continuous wave Doppler can be used to grade the
severity of the obstruction. RVOT obstruction is considered se-
vere if the Doppler peak gradient measures > 64 mmHg. Different
factors can influence the gradient however: an atrial L→R shunt
can lead to increased velocities and gradient overestimation.
Conversely, RV dysfunction, severe tricuspid regurgitation, atrial
R→L shunting and high pulmonary artery pressures due to a large
PDA all result in a lower Doppler velocity across the stenosis and
can cause underestimation of the severity. There can be secondary
RV hypertrophy (RVH) indirectly reflecting the degree of obstruc-
tion but RVH is very difficult to quantify echocardiographically.
Fig. 53.11  Critical valvar pulmonary stenosis. The
pulmonary valve is thickened (arrow left panel) and there is
limited opening of the valve leaflets with minimal antegrade
flow (arrow right panel).
792 CHAPTER 53   The role of ech o cardio gra phy i n a du lt c on g en i ta l hea rt di sease

Fig. 53.12  Double chambered right ventricle. A

hypertrophied muscle band is noted with flow acceleration
(arrows) in the RV cavity between the RV inflow and
outflow. This patient also had a spontaneously closed
perimembranous ventricular septal defect.

Associated lesions imaging may demonstrate early systolic closure of the aortic valve
Multiple associated lesions can be present. The most common or fluttering of the aortic valve leaflets. Continuous wave Doppler
ones are: should be used to assess the peak and mean gradients across the
lesion. Diagnosis can be made by TTE and only rarely additional
◆ Atrial septal defects imaging modalities are required. Defining the exact location of
◆ Ventricular septal defects the narrowing, describing the mechanism and the relationship to
Imaging post surgery or intervention the aortic valve is the information required for surgical treatment.
3DE can visualize the LVOT en-​face and it allows assessment of
Generally, echocardiography can be used for post-​interventional
the morphology and severity of the obstruction, as well as rela-
follow-​up. After balloon dilatation or surgical valvotomy, residual
tionships with the aortic valve and aortic valve anatomy.
PV stenosis can be present and Doppler can measure the gradient.
Supravalvar stenosis is a rarer form of LVOT obstruction.
Pulmonary regurgitation can be present and the severity can be
The stenosis is typically localized at the level of the sinotubular
evaluated by colour Doppler and continuous wave Doppler. If se-
junction. It can be membranous, hourglass-​shaped, and be as-
vere, this can result in progressive RV dilatation and dysfunction
sociated with hypoplasia of the ascending aorta and also the
as after tetralogy of Fallot repair. After muscle bundle resection,
more distal aortic arch. The coronary arteries may be involved
residual muscular obstruction can be present.
in the supravalvar narrowing which puts these patients at risk
Role of other imaging techniques for ischaemia, especially when arterial pressure decreases (e.g.
with general anaesthesia). In patients with elastin gene muta-
In the majority of patients, the diagnosis of RVOT obstruc-
tions, associated pulmonary branch stenosis is not uncommon.
tion can be made using echocardiography. In case of very poor
Supravalvar stenosis can be secondary to surgery such as after the
transthoracic images, TOE can be helpful defining the level of
arterial switch procedure or Ross operation.
obstruction (valvar, subvalvar, supravalvar). CMR can be used in
the postintervention assessment particularly in patients with se-
vere pulmonary regurgitation (PR) causing RV dilatation. CMR
allows quantification of the pulmonary regurgitant fraction and
regurgitant volume as well as the RV volumes and ejection fraction.

Left ventricular outflow tract obstruction

Congenital abnormalities of the LVOT can be present in the adult
population. This includes congenital aortic stenosis, subvalvar
aortic stenosis, and supravalvar stenosis. The evaluation of con-
genital valve abnormalities does not differ from acquired aortic
valve disease and the reader is referred to the chapters on aortic
valve disease in this book (Chapters 50, 51, and 52).

Morphology of subaortic and supravalvar stenosis

Subaortic stenosis is a narrowing in the LVOT below the aortic
valve (E Fig. 53.13). Three subtypes can be identified: a mem-
branous form, a fibromuscular ridge, and a fibromuscular tunnel.
Colour flow Doppler detects turbulence while pulse wave Doppler Fig. 53.13  Subaortic stenosis. There is a fibromuscular ridge (arrow) in the
helps to localize the origin of acceleration. M-​mode and 2D left ventricular outflow tract below the insertion of the aortic valve.
 Th e role of echo ca rdi o g r a phy i n di fferen t c on g en i ta l de f e c ts 793

Haemodynamic assessment
The haemodynamic assessment of LVOT obstruction includes
measurement of the peak and mean gradients by Doppler tech-
niques. The gradient is best measured from the apical outflow
tract views. For subvalvar stenosis, a peak gradient >50 mmHg
is considered haemodynamically significant. Subvalvar stenosis
can cause damage to the aortic valve resulting in associated aortic
regurgitation. For supravalvar stenosis, the gradient is best meas-
ured from suprasternal windows. The secondary effect on the LV
needs to be assessed including the occurrence of LVH and LV sys-
tolic and diastolic dysfunction.

Associated lesions
In adult congenital patients, subaortic stenosis is typically seen in
patients after VSD closure, after repair of double outlet RV and in
patients with AVSD. It can also be present as an isolated lesion.
Supravalvar stenosis is typically present in patients with elastin
gene mutations and patients with Williams’ syndrome. It is asso- Fig. 53.14  Ebstein’s anomaly. The apical four-​chamber view shows the apical
ciated in these patients with supravalvar pulmonary stenosis and displacement of the tricuspid septal leaflet (arrows) and the normally inserted
anterior leaflet. There is a large atrialized portion the of the RV.
pulmonary artery branch stenosis, hypoplasia of the aortic arch,
arterial hypertension, and coronary artery narrowing.
regurgitation (E Fig. 53.15, z Video 53.12). The severity of
Postoperative evaluation
Ebstein malformation is largely determined by the degree of apical
After surgical intervention, residual outflow tract obstruction displacement and the severity of the tricuspid valve regurgitation
and aortic valve function need to be evaluated. Recurrence of (TR). Significant atrialization of the RV cavity results in a reduction
subvalvar stenosis is common and requires serial follow-​ up. of stroke volume and together with the TR this reduces RV output.
Aortic valve function needs to be monitored, especially for the
presence of progressive aortic regurgitation. Haemodynamic assessment
In the haemodynamic assessment, the evaluation of TR and tri-
Role of other imaging techniques
cuspid valve stenosis is important. Colour Doppler echocardi-
Generally, subvalvar and supravalvular stenosis can be diagnosed ography can be extremely helpful to determine the degree of
using TTE. For subvalvar stenosis, TOE can be helpful in those tricuspid regurgitation. Tricuspid stenosis is uncommon and
cases where the LVOT cannot be visualized well and can help to the evaluation requires alignment with the tricuspid inflow,
determine the mechanism of the obstruction better. In patients
with supravalvular stenosis in the context of elastin gene abnor-
malities, the coronary arteries can be involved in the disease
process. As the origins of the coronary arteries can be extremely
difficult to image using TTE, additional imaging techniques may
be required. These include TOE, CMR, MSCT, or angiography.
These imaging modalities also allow a better assessment of the
entire aortic arch and the pulmonary artery branches.

Ebstein’s anomaly
Ebstein’s anomaly is a relatively rare congenital abnormality that
sometimes can be diagnosed in adulthood.

Morphology
Ebstein’s anomaly of the tricuspid valve is defined by apical dis-
placement of the septal and postero-​inferior leaflets of the tri-
cuspid valve [14] (E Fig. 53.14, z Video 53.11). Typically, the
tricuspid valve orifice is rotated superiorly towards the RV outflow
Fig. 53.15  Tricuspid regurgitation associated with Ebstein’s disease. This is viewed
tract. The anterosuperior leaflet is large and redundant (sail-​like).
from a short-​axis view as typically in Ebstein’s malformation the tricuspid valve
The displacement can be very significant and results in significant opens in the direction of the right ventricular outflow tract. The regurgitant
atrialization of the basal part of the RV reducing the stroke volume. jet generally is best viewed from this view. The arrow indicates the tricuspid
This is associated with variable degrees of tricuspid stenosis and regurgitant jet at valve level.
794 CHAPTER 53   The role of ech o cardio gra phy i n a du lt c on g en i ta l hea rt di sease
which can be challenging. The severity of the stenosis can be
underestimated by a gradient measurement due to the presence
of a patent foramen ovale (PFO)/​ASD.
Associated lesions
An ASD or PFO is often present and can result in R→L shunting
causing desaturation and is associated with a risk for paradoxical em-
boli. There can be associated PV stenosis. Other common associated
lesions include LV non-​compaction cardiomyopathy and VSDs.
Postoperative evaluation
Surgery consists of either a valvuloplasty of the TV or a TV re-
placement in case the valve is not deemed repairable. The recently
introduced cone technique provides an anatomical repair of the
valve. Postoperative evaluation involves assessment of tricuspid
valve function (degree of regurgitation or stenosis), assessment of
RV size and function, and also LV functional assessment.
Role of other imaging techniques
Generally, Ebstein malformation can be diagnosed well by TTE.
In adults with poor echocardiographic windows, TOE can be a
useful additional imaging technique for assessing tricuspid valve
function and to identify the presence of a PFO/​ASD. CMR is
useful to determine RV volumes and function and to quantify
the severity of tricuspid regurgitation. For patients needing sur-
gical repair or replacement of the tricuspid valve, tricuspid valve
function can generally be followed using TTE and no additional
imaging techniques are required.
Congenital mitral valve anomalies
In adults, acquired mitral valve disease is much more common
than congenital abnormalities of the valve. The evaluation of
Fig. 53.16  Isolated cleft in the anterior leaflet of the
mitral valve. Short-​axis view at the level of the valve
leaflets. Typically the cleft is anteriorly oriented.
AML = anterior mitral valve leaflet; PML = posterior mitral
leaflet.
mitral valve stenosis and regurgitation is discussed in Chapter
13 of this book. The same techniques apply to patients with con-
genital valve abnormalities but the mechanisms for valve dys-
function are different.
Morphology of congenital mitral valve abnormalities
Different types of mitral valve anomalies can be distinguished:
Parachute mitral valve. This defect is characterized by an abnor-
mality of the subvalvar apparatus with the support provided
to the anterior and posterior leaflets by a single papillary
muscle (most commonly the posteromedial papillary muscle).
Typically, this results in decreased mobility of the leaflets with
the presence of mitral stenosis. It can be associated with other
left ventricular abnormalities such as subaortic stenosis, aortic
valve disease, and coarctation of the aorta.
Double orifice mitral valve. This is a left AV valve with two orifices
each having their own attachments. The first type is associated
with an AVSD. The second type is a mitral valve with two ori-
fices each having their own chordal attachments and papillary
muscles. The orifices can be stenotic or regurgitant. A short-​
axis view generally is diagnostic although the orifices might be
in different planes.
Isolated cleft in the mitral valve. In an AVSD, the zone of appos-
ition between the superior and the mural leaflets is sometimes
called a ‘cleft’. An isolated cleft in the anterior mitral leaflet
not associated with an AVSD, is a rare lesion that can cause
progressive mitral regurgitation (E Fig. 53.16). While in an
AVSD the cleft is oriented towards the interventricular septum,
in an isolated cleft, the cleft is oriented towards the LVOT.
The morphology of the mitral valve anomaly can generally be well
described using 2-​DE. However, 3DE with an en-​face view of the
 Th e role of echo ca rdi o g r a phy i n di fferen t c on g en i ta l de f e c ts 795

mitral valve from the ventricular perspective will allow a better

definition of the valve anomaly and the subvalvar apparatus.

Haemodynamic assessment
The different anatomic abnormalities can be associated with
variable degrees of mitral valve stenosis and regurgitation. The
evaluation is identical to acquired mitral valve disease but prior
to valve surgery, the surgeon should be aware of the exact mech-
anism causing valve dysfunction.

Associated lesions
Mitral valve anomalies can be isolated but can be associated with
other types of LV congenital abnormalities. This includes LVOT
obstruction, aortic valve disease, and coarctation of the aorta.
Other congenital defects associated include double outlet RV
(parachute mitral valve).

Postoperative assessment
Postoperative evaluation includes mitral valve function and left Fig. 53.17  Tetralogy of Fallot. Subcostal view demonstrating the anterior
ventricular function. deviation of the outlet septum causing subvalvar obstruction. The arrow
indicates the anterocephalad deviation of the outlet septum, causing right
Role of other imaging techniques ventricular outflow tract obstruction.
LV = left ventricle; RV = right ventricle; VSD = ventricular septal defect; RVOT = right
Generally, TTE provides sufficient imaging but in case of poor ventricular outflow tract; MPA = main pulmonary artery.
windows, TOE may be required. There is a limited role for
other imaging techniques as CMR and MSCT do not image the
leaflets well. ◆ Define the mechanism + severity of RV outflow tract obstruc-
tion: infundibular, valvular and or supravalvular (E Fig. 53.19).
Tetralogy of Fallot and tetralogy of Fallot with ◆ Define whether the pulmonary arteries (PA) are present and con-
pulmonary atresia fluent. Measure the size of the proximal and distal PAs and look
for PA branch stenosis. Exclude the presence of aorta-​pulmonary
Tetralogy of Fallot is the most common cyanotic lesion which is collaterals.
rare to diagnose in adulthood as most of the patients will have
◆ Identify coronary artery abnormalities especially any coronary
been diagnosed and treated during childhood. Most patients in artery crossing the RV outflow tract. This can be an abnormal
the adult congenital clinic are postoperative patients. left anterior descending (LAD) from the right coronary artery
Morphologic description
Tetralogy of Fallot (TOF) is defined as the combination of a large
outlet VSD with overriding of the aorta associated with various
degrees of RV outflow tract obstruction and secondary RV hyper-
trophy. The key anatomical feature of TOF is anterocephalad
deviation of the outlet septum causing various degrees of mus-
cular/​infundibular RV outflow tract obstruction (E Fig. 53.17,
z Video 53.13 a-​c). This is associated with variable degrees of
PV obstruction and hypoplasia of pulmonary artery branches.
TOF with pulmonary atresia can be considered as an extreme
form where no connection is present between the RV and the
pulmonary circulation. The pulmonary perfusion can be duct-​
dependent to central pulmonary arteries or be dependent on
aorta-​pulmonary collaterals [15].
The preoperative assessment of an uncorrected patient with
TOF includes the following:
◆ Define the size and localization of the VSD + degree of aortic
override (E Fig. 53.18): perimembranous to outlet (92%),
doubly committed (5%), inlet VSD or AVSD (2%). If aorta Fig. 53.18  Tetralogy of Fallot. Parasternal long-​axis view demonstrating the
overrides the VSD by more than 50%, this is called a double ventricular septal defect extending to the outlet part of the septum and the
outlet RV. overriding of the aorta over the defect (in this case around 50% override).
796 CHAPTER 53   The role of ech o cardio gra phy i n a du lt c on g en i ta l hea rt di sease

Fig. 53.19  Tetralogy of Fallot. Parasternal

long-​axis view tilted towards the right
ventricular outflow tract. There is flow
acceleration from below the valve, at the
valve level due to the small pulmonary
valve that domes and also tethers at the
supravalvular level.

(RCA), an accessory LAD from the RCA, or a prominent conal
branch from RCA. Typically, the origins of the coronary ar-
teries are clockwise rotated. Before any intervention on the right
outflow tract, including stenting and PV implantation, the re-
lationship of the coronaries to the outflow tract and proximal
pulmonary artery branches needs to be determined.
◆ Determine aortic arch anomalies: TOF can be associated with a
right aortic arch and other arch anomalies. The presence of aorta-​
pulmonary collaterals needs to be determined.
Preoperative haemodynamic assessment
The preoperative haemodynamic assessment mainly includes the
determination of the severity of the RVOT obstruction and iden-
tifying the different levels of obstruction (infundibular, valvar,
supravalvar). Different Doppler techniques need to be combined.
The direction of shunting across the VSD needs to be determined.
Associated anomalies
TOF can be associated with other lesions and, as for any con-
genital defect, a full segmental evaluation is required.
◆ Associated abnormalities like ASDs, left superior vena cava
draining to the coronary sinus, additional VSDs, abnormal pul-
monary venous return
◆ AVSD can be associated if the VSD extends to the inlet part of
the septum
◆ Aortic arch anomalies: right aortic arch, double aortic arch
◆ Aortic root dilatation and progressive aortic regurgitation
Postoperative imaging
Surgical repair of TOF includes closure of the VSD and surgical
relief of RV outflow tract obstruction using different techniques.
If the PV annulus is too small, a transannular patch is required
to relieve the RVOT obstruction, resulting in severe PR. This can
cause progressive RV dilatation and dysfunction.
Postoperative evaluation includes the assessment of:
◆ Residual RV outflow tract obstruction
◆ Pulmonary regurgitation
◆ Residual VSD
◆ RV size and function
◆ Pulmonary artery branch stenosis
◆ Aortic root dilatation and aortic regurgitation
◆ LV function
The most common residual lesion is PR resulting in RV dilatation
and dysfunction (E Fig. 53.20, z Video 53.14 a and b). Timely
replacement of the PV can prevent irreversible damage to the
RV but timing of the valve replacement is still controversial and
seems largely dependent on RV volume. Different imaging tech-
niques can be used for the assessment of RV function in these
patients [16–​18].
Role of different imaging techniques
For the preoperative assessment in children, generally, echocardi-
ography can provide all the necessary information. Only in case
of pulmonary atresia with complex pulmonary perfusion through
 Th e role of echo ca rdi o g r a phy i n di fferen t c on g en i ta l de f e c ts
major aorta-​pulmonary collaterals, additional imaging may be re-
quired to delineate the pulmonary blood supply. CMR and MSCT
both provide excellent images of the pulmonary circulation but
angiography remains the clinical gold standard in the preopera-
tive assessment of this lesion, especially if pressure measurements
are required.
For the postoperative assessment, echocardiography re-
mains the first-​line imaging technique. It allows assessment of
the presence of a residual VSD, residual RV outflow tract ob-
struction, severity of PR, TR, aortic root dilatation, and aortic
regurgitation. In adults, the pulmonary branches can be diffi-
cult to visualize especially more distally. In patients with sig-
nificant PR, RV dimensions and RV functional parameters can
be obtained for serial assessment. We propose to use tricuspid
annular systolic plane annular excursion (TAPSE), fractional
area change, and pulsed tissue Doppler. 3DE can be used to
measure RV volumes and ejection fraction if the windows allow
for a good volumetric data acquisition. Strain imaging is an
emergent technique that can be used to assess RV longitudinal
function but has not found its way yet into the routine clin-
ical practice. Apart from assessing RV function, the assessment
of LV function is very important for this patient population as
progressive LV dysfunction carries a poor prognosis for this pa-
tient population.
Especially in the postoperative evaluation, there is an important
role for the use of CMR mainly for quantifying RV volumes and
ejection fraction, pulmonary regurgitant fraction and volumes
and for better delineating the pulmonary branch anatomy. Timing
of PV replacement may be influenced by measurement of RV vol-
umes with a cut-​off value between 170 and 190 ml/​m2. In patients
with contraindications to CMR, MSCT can be an alternative for
measurement of RV size and function.
Transposition of the great arteries
Transposition of the great arteries (TGA) is generally diagnosed
in the immediate postnatal period as it causes significant cyan-
osis. An increasing number of patients with TGA are diagnosed
during foetal life. Due to the success of the atrial and arterial
switch operations, there is a growing population of patients sur-
viving into adulthood.
797
Fig. 53.20  Tetralogy of Fallot. Postoperative image. Severe
pulmonary regurgitation after tetralogy of Fallot repair. The
left panel shows a diastolic frame with a wide regurgitant
jet at valve level and backflow originating from distally into
the pulmonary branches (red colour in the branches). The
Doppler (arrow) shows the short deceleration time typical
for severe pulmonary regurgitation with flow only in early
and mid-​diastole.
Morphology of TGA and associated anomalies
In TGA, the aorta arises from the morphological RV and the
pulmonary artery from the morphological LV resulting in
ventriculoarterial discordance [19]. In this paragraph we will
discuss ventriculoarterial discordance with atrioventricular con-
cordance. Most commonly in this condition the aorta is posi-
tioned rightward and anterior relative to the position of the
pulmonary artery.
Commonly associated lesions are:
◆ VSD in up to 50% of all patients. The VSD is most commonly
located in the perimembranous area but can be located any-
where in the septum. In case of inlet extension, straddling of
the tricuspid vale may occur.
◆ LVOT obstruction: subpulmonary and pulmonary stenosis
which can preclude an arterial switch procedure.
◆ Coarctation of the aorta can be associated.
◆ Variable coronary artery anatomy. This is important when per-
forming an arterial switch operation, which involves coronary
artery transfer. In TGA, usually the left coronary artery origin-
ates from the right facing sinus (sinus 1) and the RCA from
the left sinus (sinus 2). The most common coronary variant is
the circumflex originating from the RCA from sinus 2 (18%).
A single coronary artery or an intramural course of a coronary
artery can make an arterial switch procedure more challenging
and is important to identify preoperatively.
The preoperative anatomy can generally be accurately diagnosed
by TTE. Additional imaging is nowadays rarely required. The
treatment for TGA has undergone an historical evolution as the
atrial switch procedure (Senning or Mustard operation) was per-
formed until the mid-​80s-​early 90s to be replaced by the arterial
switch operation afterwards [20]. For TGA with VSD and LVOT
obstruction, the Rastelli operation is performed although this was
recently replaced by the Nikaidoh procedure in selected cases.
Postoperative imaging
The postoperative imaging differs according to which type of sur-
gery the patient underwent. For all patients, TTE is the first-​lime
imaging technique. For specific indications, other imaging tech-
niques may be used.
798 CHAPTER 53   The role of ech o cardio gra phy i n a du lt c on g en i ta l hea rt di sease
Evaluation after the atrial switch procedure (Senning or Mustard)
The principle of both surgeries is the same: the systemic venous
return is rerouted to the LV and the pulmonary circulation and
the pulmonary venous return is redirected to the RV and aorta.
This redirects the systemic venous blood to the pulmonary circu-
lation and the pulmonary venous blood to the systemic circula-
tion. In a Mustard operation an intra-​atrial tunnel is constructed
using artificial patch material while in a Senning operation the
intra-​atrial rerouting is performed using native atrial tissue. The
diagnostic imaging performed for both procedures is similar and
requires [21]:
◆ Identifying the venous pathways to rule out tunnel obstruction
or baffle leaks (E Fig. 53.21). Pathway obstruction is the most
common problem, especially after Mustard procedure. The su-
perior vena cava and IVC pathways as well as the pulmonary
venous pathways need to be imaged. This requires multiple
imaging windows and views, which sometimes can be difficult
to image in adults. 3DE can be helpful in visualizing the path-
ways and their spatial relationships. TOE and CMR are needed
when TTE cannot define the pathways well. Contrast echocar-
diography with injection of agitated saline through a peripheral
intravenous cannula can help to detect pathway obstruction
and baffle leaks.
◆ Assessment of systemic RV function and tricuspid regurgita-
tion. Progressive tricuspid regurgitation and systemic RV dys-
function are common problems after the atrial switch procedure
(E Fig. 53.22). Quantification of systemic RV function by
echocardiography remains challenging. For RV functional as-
sessment, we suggest using a combination of different methods
Fig. 53.21  Apical four-​chamber view of patient after the Senning operation.
The pulmonary venous atrium (PVA) is directing the pulmonary venous
blood to the right ventricle. The systemic venous blood is directed through
the systemic venous atrium (SVA) to the left ventricle. The RV becomes the
systemic ventricle after this operation.
for serial follow-​up including TAPSE, fractional area change
and tissue Doppler echocardiography. Strain imaging is emer-
ging but its clinical use for this indication still remains to be
proven. Also, 3DE could be used but generally the image acqui-
sition is challenging with limited image resolution. Progressive
tricuspid regurgitation after the atrial switch is considered a
sign of RV dysfunction and failure. For RV functional assess-
ment, CMR remains the clinical reference technique.
Evaluation after the arterial switch operation
The adult population of patients who underwent the arterial
switch operation is quickly growing as the atrial switch operation
has become obsolete in paediatric cardiac surgery. After the ar-
terial switch operation the following problems may occur:
◆ Progressive neo-​ aortic root dilatation associated with neo-​
aortic valve regurgitation.
◆ In an arterial switch operation, the pulmonary trunk is put in
front of the ascending aorta with the right pulmonary artery to
the right and the left pulmonary artery to the left of the ascending
aorta. Pulmonary branch stenosis can be caused by stretching the
proximal pulmonary artery branches. Imaging the RV outflow
tract and PA is required and can be difficult in postoperative pa-
tients after arterial switch (E Fig. 53.23). Peak velocities ≤2 m/​s
(predicted maximum instantaneous gradient ≤16 mmHg) across
the distal main pulmonary artery and branch PA are within
normal limits after arterial switch procedure. TOE generally
does not help to visualize the anteriorly located PA and MSCT or
CMR might be the only non-​invasive alternative.
◆ Coronary artery stenosis can develop after the coronary transfer
and has been reported to cause coronary artery stenosis in 10–​15%
of all patients. Coronary stenosis and especially kinking can result
in myocardial ischaemia. Monitoring of global and regional myo-
cardial performance is important. Exercise or dobutamine stress
echocardiography can be used to identify perfusion problems.
Direct visualization of the coronaries is possible using cardiac CMR
and MSCT. Coronary angiography should be considered in patients
in whom coronary stenosis or occlusion is highly suspected.
Ventricular size and function: evaluation of LV size and function
◆
is required in every patient after the arterial switch procedure. In
patients with PA branch stenosis, assessment of RV function is
also important.
Evaluation after the Rastelli procedure
In patients who underwent the Rastelli procedure, the VSD has
been closed creating a tunnel between the LV and the aorta and
the RV is connected with a conduit to the PA. Imaging the pa-
tients after the Rastelli procedure involves:
◆ Evaluation of the RV-​ to-​
pulmonary artery conduit and
branch PA by 2DE, colour and spectral Doppler using several
approaches.
Evaluation of the LV-​to-​aortic valve pathway for obstruction and
◆
aortic regurgitation.
◆ Evaluation of LV function as LV dysfunction is a potential late
complication after the Rastelli operation.
◆ Exclusion of residual VSDs.
 Th e role of echo ca rdi o g r a phy i n di fferen t c on g en i ta l de f e c ts 799

Fig. 53.22  Severe tricuspid regurgitation

after the Senning operation. The RV is dilated
and hypertrophied. Notice the broad jet
of regurgitation at the tricuspid valve level
(arrow).

Congenitally corrected transposition of the condition, the ventricles and the interventricular septum are
great arteries oriented in a more vertical plane than usual which requires
vertical rotation of the probe in the parasternal views. In the
Congenitally corrected transposition of TGA (ccTGA), short-​axis view of TGA, the aorta is positioned anterior to the
is defined as atrioventricular discordance associated with left of the pulmonary artery.
ventriculoarterial discordance. This results in ‘physiological
correction’ as the oxygenated pulmonary venous blood enters
the LA which connects through the tricuspid valve to the mor-
phological RV into the aorta [21]. Systemic venous deoxygen-
ated blood enters the RA, which connects, to the morphologic
LV through the mitral valve into the pulmonary circulation.
This can be associated with situs anomalies, VSDs, and tricuspid
valve anomalies. In 20% of cases there is dextrocardia [22]. Any
imaging technique should describe the full anatomy as well the
functional impact (systemic RV function and tricuspid regur-
gitation). Generally, this can be done using TTE, but in adults
TOE or CMR might be required.

Morphology of ccTGA
TTE is the first-​line technique to diagnose ccTGA (E Figs.
53.24–​53.26, z Videos 53.15 and 53.16). In usual atrial situs
arrangement, the tricuspid valve and the RV are located on the
left and the mitral valve and LV are positioned on the right.
This can be easily detected on the apical four-​chamber view
due to the more apical insertion of the tricuspid valve relative
to the mitral valve. As the tricuspid valve is often abnormal Fig. 53.23  The arterial switch operation. Position of the pulmonary
in this condition, with some Ebstein-​like features, the apical arteries after the arterial switch procedure. Due to the commonly used
LeCompte manoeuvre, the pulmonary artery bifurcation is located anterior
displacement of the TV is more obvious. The presence of the
to the aorta.
moderator band and the more heavily trabeculated RV on the MPA = main pulmonary artery; LPA = left pulmonary artery; RPA = right pulmonary
left also provides an imaging sign for ccTGA. Typically for this artery.
800 CHAPTER 53   The role of ech o cardio gra phy i n a du lt c on g en i ta l hea rt di sease

Fig. 53.24  ccTGA. Apical four-​chamber view in a patient

with congenitally corrected transposition of the great arteries
(atrioventricular and ventricular arterial discordance). The left
atrium (LA) connects through the more apically displaced
tricuspid valve to the morphologic right ventricle (RV), situated
on the left. The right atrium (RA) connects through the mitral
valve to the morphologic left ventricle (LV) situated on the right.

Fig. 53.25  ccTGA long-​axis view. Parasternal long-​axis view in a patient with
congenitally corrected transposition of the great arteries. The left atrium (LA)
connects to the anteriorly located right ventricle (RV), which connects to
the anteriorly located aorta (Ao). The pulmonary artery i(PA) s positioned
posteriorly to the aorta.
Fig. 53.26  ccTGA short-​axis view. High parasternal short-​axis view in
a patient with congenitally corrected transposition of the great arteries.
The aorta (AO) is seen anterior and slightly leftward of the pulmonary
artery, which is posterior and branches into the left (LPA) and right (RPA)
pulmonary arteries.
 Th e role of echo ca rdi o g r a phy i n di fferen t c on g en i ta l de f e c ts
Commonly associated anomalies
◆ VSD (~60–​70%). Commonly perimembranous but other loca-
tions are possible.
◆ LV outflow tract and pulmonary stenosis (~40–​70%). Commonly
subvalvular (aneurysmal valve tissue, chords, discrete fibrous ob-
struction) and valvar.
◆ Tricuspid valve abnormalities (~83–​90%). Variable pathology (in-
creased apical displacement of septal leaflet (Ebstein’s like), thick-
ened/​malformed leaflets, straddling). Tricuspid regurgitation is
common and can be progressive.
◆ Mitral valve abnormalities (~50%). Cleft mitral valve is possible
and, if a VSD is present, straddling through the VSD.
◆ ASD (43%).
◆ Other associated lesions: aortic stenosis, aortic coarctation, left
atrial isomerism, coronary artery variants, complete heart block.
Haemodynamic assessment
In any patient with ccTGA, haemodynamic assessment is focused
on the systemic RV function and the severity of TR. Progressive
TR is common in this condition related to the frequent anatom-
ical abnormalities of the TV. This is generally not well tolerated
by the systemic RV and can result in progressive RV dilatation
and dysfunction. Severe TR should be treated surgically be-
fore irreversible RV dysfunction develops although optimal
timing is sometimes difficult to determine. LVOT obstruction
(subpulmonary obstruction) can be present and requires assess-
ment of the severity together with a description of the mechanism
causing the obstruction.
Pre and postoperative assessment
Most of the assessment can be performed by TTE or by TOE
in case of poor imaging windows. Assessment of patients with
ccTGA should focus on:
◆ TR for possible repair or replacement.
◆ Evaluation of RV function.
◆ Assess feasibility of biventricular repair (double switch-​type pro-
cedure) or need for pulmonary artery banding (LV retraining).
◆ After pulmonary artery banding, assess LV function, hyper-
trophy, and tricuspid regurgitation.
◆ After atrial switch and Rastelli procedures, assess leak or obstruc-
tion across tunnels and conduits.
◆ Assess for worsening ventricular function and atrioventricular
valve regurgitation.
Role for other imaging techniques
CMR can be used in case of poor echocardiographic windows and
for quantification of RV volumes and ejection fraction. CMR is
also used for evaluating the effect of pulmonary artery banding
and LV retraining on LV hypertrophy and LV function. CMR al-
lows quantification of systemic and pulmonary blood flows. There
is a role for MSCT in these patients as complete heart block is very
common, pacemakers are frequently needed and these may not
be CMR compatible. In patients with pacemakers who develop
801
systolic dysfunction, the possibility of RV dyssynchrony as a con-
tributing factor to the development of systolic dysfunction should
be considered. Strain imaging to study timing of myocardial
events can be helpful in understanding the mechanisms.
The functionally univentricular heart
This is a wide anatomic spectrum of patients in which one of
the chambers is too small to sustain either the pulmonary or
systemic circulation [23, 24]. The dominant ventricle can be
a RV or a LV. A second smaller ventricle is invariably present.
Sometimes, two adequately sized ventricles are present, but
anatomy prevents septation (such as straddling of the atrio-
ventricular valves). The segmental approach needs to be used
to describe the morphology. This can generally be done using
TTE, although in adults poor echocardiographic windows may
require additional imaging techniques. Most adult patients with
univentricular hearts will have been palliated by the Fontan op-
eration. The principle is that the dominant ventricular chamber
is used for the systemic circulation while the systemic venous
blood is directed to the PA, bypassing the heart [25]. Since its
introduction, the Fontan operation has undergone many modi-
fications. Currently, the total cavo-​pulmonary connection with
the lateral tunnel or the extracardiac conduit is the most com-
monly used. A fenestration is often placed between the systemic
venous pathway and the pulmonary venous atrium. The fen-
estration allows a R→L shunt that decompresses the systemic
venous pathway and maintains adequate cardiac output. In case
of favourable haemodynamics, the fenestration can be device-​
closed. As different types of Fontan connections exist, knowing
the exact surgical technique used is important for any imaging
technique.
Before looking at the Fontan connection, it is important to
know the underlying morphology of the heart. This includes
a description of the atrial situs (solitus, inversus, isomerism),
the AV-​connections (double inlet, single inlet with left/​right
absent connection), common inlet (unbalanced AVSD) (see
E Fig. 53.27–​53.30). It is important to determine ventricular
morphology of the dominant ventricle (left/​right). A small su-
perior and rightward subarterial outlet chamber is typically
a morphologic RV. A small inferior-​ posterior rudimentary
chamber is typically a morphologic LV. The outflow tract to the
aorta should be visualized and should be unobstructive. AV-​
valve and ventricular function should be assessed (z Videos
53.17–​53.19).
Imaging a patient after the Fontan operation should include:
1. Visualizing the Fontan connections. The patency of the con-
nections and absence of obstruction and thrombi should be as-
sessed. This involves:
● Evaluation of the superior cavopulmonary anastomosis
(E Fig. 53.31) as well as the entire IVC to pulmonary artery
connection.
Flow measurements in the superior and IVC should be
●
obtained and the effect of respiration on the flows should be
802 CHAPTER 53   The role of ech o cardio gra phy i n a du lt c on g en i ta l hea rt di sease

Fig. 53.28  Tricuspid atresia. Apical four-​chamber view in patient with

absent right atrioventricular connection (tricuspid atresia). The absent right
atrioventricular connection is seen echocardiographically as an echogenic
border between the right atrium and small right ventricle (arrow). The atrial
communication between the right (RA) and left atria (LA) is widely patent.
The mitral valve and left ventricle (LV) dominate the image. The right ventricle
(RV) is barely seen in this image.

Fig. 53.27  (a and b) Double inlet left ventricle. Apical view of double inlet
left ventricle. (a) In this systolic frame, two separate AV valves connect the
left atrium (LA) and right atrium (RA) to a single ventricle of left ventricular
morphology (LV). The Fontan (F) connection is seen posteriorly. (b) Diastolic
frame from an apical four-​chamber view in a patient with double inlet
left ventricle. The right atrium and left atrium (A) connect via separate
atrioventricular valves (arrows) to the dominant left ventricle (V). The Fontan
circuit (F) is seen behind the right atrial cavity.
Fig. 53.29  Tricuspid atresia. Four-​chamber view obtained at
transoesophageal echocardiography in patient with absent right
studied. In general there is low-​velocity flow with increase in atrioventricular connection (tricuspid atresia). The left atrium (LA) connects
flow velocities with inspiration. through the mitral valve to the left ventricle (LV). No atrioventricular
valve is discernible on the right and the absent connection is seen
Evaluation of the patency and size of the fenestration. The
●
echocardiographically as an echogenic border between the right atrium and
mean gradient across the fenestration provides an estimate small right ventricle (RV). The posterior aspect of ventricular septal defect
of the transpulmonary pressure gradient. (VSD) is seen and is non-​restrictive.
 Th e role of echo ca rdi o g r a phy i n di fferen t c on g en i ta l de f e c ts
Fig. 53.30  Unbalanced AVSD. Apical four-​chamber view in a patient
with unbalanced atrioventricular septal defect. The right atrium (RA)
is considerably larger than the left atrium (LA). The large primum atrial
septal defect is denoted with an asterisk. The common atrioventricular
valve opens preferentially to the right ventricle (RV) which is dominant.
The left ventricle (LV) is small. The ventricular septal defect is seen
as the space between the interventricular septum (S) and the
atrioventricular valve.
● In case of an intracardiac type of connection, baffle leaks
should be excluded.
Flow to both PA should be assessed using colour and spectral
●
pulsed Doppler.
Visualization of the entire conduit might be extremely difficult
and TOE or CMR are excellent non-​invasive alternatives.
Fig. 53.31  Bidirectional cavopulmonary anastomosis (bidirectional Glenn shunt). Suprasternal view. The superior vena cava (SVC) is connected end-​to-​side to
the right pulmonary artery (RPA). The functionally proximal left pulmonary artery can be visualized. With colour Doppler the flow through the connection and
the proximal pulmonary arteries can be imaged.
803
2. Visualizing the pulmonary veins. Pulmonary venous obstruc-
tion should be excluded. All four pulmonary veins should
therefore be identified after the Fontan operation and pul-
monary venous flow should be evaluated using colour and
spectral pulsed Doppler techniques. If pulmonary vein prob-
lems are suspected, additional imaging techniques like MSCT,
CMR, and cardiac catheterization are required.
3. AV-​valve function. Low atrial pressure is a condition for op-
timal Fontan function. AV-​valve stenosis and more commonly
AV-​valve regurgitation should be evaluated.
4. Ventricular function assessment is an important part of post-
operative Fontan evaluation but due to the lack of quantita-
tive techniques it is largely a subjective qualitative approach.
Also, the evaluation of diastolic function is extremely difficult
due to abnormal AV-​valve anatomy and abnormal pulmonary
venous flow.
5. Detection of aortic-​to-​pulmonary collateral flow. An esti-
mated 80% of patients undergoing Fontan-​type operations
already have, or subsequently develop, systemic arterial-​to-​
pulmonary arterial collaterals as a consequence of preopera-
tive, or continued, hypoxemia. Competitive flow from these
aorto-​pulmonary vessels can increase right-​sided pressures,
thereby reducing systemic venous flow to the PA. These col-
laterals can be detected by TTE using suprasternal aortic views
but MSCT, CMR, and angiography are more sensitive tech-
niques for detecting collateral flow.
Eisenmenger syndrome
Eisenmenger syndrome is characterized by irreversible pul-
monary vascular disease as a result of a systemic-​to-​pulmonary
communication (e.g. ASD, non-​restrictive VSD, non-​restrictive
PDA, AVSD, aortopulmonary window, surgical systemic-​ to-​
pulmonary shunt). An initial L→R shunt reverses direction
following an increase in PVR and arterial pressures [26]. The
804 CHAPTER 53   The role of ech o cardio gra phy i n a du lt c on g en i ta l hea rt di sease
Fig. 53.32  Septal flattening in pulmonary hypertension. Parasternal
short-​axis view. The interventricular septum is flat in systole due to the
elevated pulmonary pressures. Due to the flattening (arrows), the LV has the
configuration of a capital ‘D’.
R→L shunt causes systemic desaturation that is progressive
with the increase in PVR. Due to the presence of a shunt, the
RV will never reach suprasystemic pressures and becomes less
dysfunctional compared with patients with primary pulmonary
hypertension.
Follow-​up of these patients involves defining the underlying
structural defect causing the increased pulmonary pressures, the
direction of shunting across the defect, the presence of associated
lesions and RV and LV function. As for the other congenital le-
sions, TTE is the first-​line diagnostic technique. Usually, TTE can
identify:
◆ RV hypertrophy, flattening and bowing of the interventricular
septum in systole (‘D’ sign, see E Fig. 53.32). Diastolic
flattening occurs with disease progression.
◆ Pulmonary artery systolic and diastolic pressures (septal con-
figuration, peak gradient from RV to RA) from tricuspid re-
gurgitation jet using modified Bernoulli equation (RV systolic
pressure mmHg = tricuspid regurgitation peak velocity2 (m/​
s) × 4 + estimated RA pressure). This pressure will be equal to
pulmonary systolic pressure if no gradient exists across the RV
outflow tract.
◆ Mean pulmonary artery pressure estimated from peak early dia-
stolic PR velocity and the diastolic pulmonary artery pressure es-
timated from the end diastolic PR velocity.
◆ Qualitative and quantitative assessment of RV function. With
disease progression, RV enlargement and dysfunction may occur.
◆ LV function (prognostic factor).
◆ Worsening tricuspid regurgitation (increasing afterload, annular
dilatation, and RV dysfunction) and RA enlargement.
◆ Underlying structural defect, coexisting structural abnormalities,
surgical shunts.
◆ Obstruction or aneurysm in main pulmonary artery and prox-
imal branches.
◆ Colour flow Doppler helps define the anatomical defect and
direction of shunting. Increased R→L shunting during supine
bicycle ergometry, although the shunt may be small and diffi-
cult to demonstrate due to a low gradient. Contrast echo can
enhance visualization of the shunt.
Role of TOE
◆ Can be performed relatively safely and is usually well tolerated
(even when baseline oxygen saturation levels are < 80%).
◆ May be useful for detecting ASDs/​PDA and for imaging pos-
terior structures (pulmonary veins).
◆ Should be performed in lung transplant candidates (detect un-
suspected intracardiac defects/​shunts, proximal pulmonary
artery thrombus).
Role of CMR
◆ Not routinely required but may be useful in selected cases
for anatomical definition and to estimate magnitude of R→L
shunt.
Special topics in adult congenital
imaging
Echocardiography in the pregnant woman
with congenital heart disease
Pregnancy is associated with increased blood volume which re-
sults in increased cardiac chamber sizes. There is an increase
in cardiac output related to the increased circulatory volume in
combination with the reduction in systemic vascular resistance
due to the presence of the low resistance placental circulation.
Physiologic pulmonary and tricuspid regurgitation and trivial
mitral regurgitation are common. In patients with CHD, this
increased blood volume and the higher circulatory demand can
cause problems. Careful monitoring of the circulatory adaptation
using imaging may be required [27]. High-​risk patients include
patients with significant aortic stenosis (mean gradient >30–​40
mmHg, valve area <0.7 cm2 before pregnancy), significant aortic
coarctation, significant mitral stenosis (valve area <2 cm2), re-
duced systemic ventricular function (EF <40%), mechanical
prosthetic valve, Marfan syndrome (especially when ascending
aorta diameter >44 mm) and cyanotic heart disease. Pregnancy
is contraindicated in Eisenmenger physiology and significant
PHT. In every woman with CHD, a foetal echocardiogram has

to be performed to rule out CHD in the foetus. Screening foetal
echocardiography in a specialized centre is to be performed
at around 17–​19 weeks. TOE can be performed if TTE win-
dows are not sufficient. CMR is also safe during pregnancy and
can be used for specific indications (RV function, aortic root
dilatation).
Echocardiography in patients with infective
endocarditis and congenital heart disease
The endocarditis risk in patients with CHD, both operated and
unoperated, is substantially higher than in the general popula-
tion and is associated with significant morbidity and mortality.
Antibiotic prophylaxis is currently recommended only for those
with the highest risk of infective endocarditis [28]. A high index
of clinical suspicion and prompt access to evaluation, including
echocardiography are required. Echocardiography may show
vegetations (z Videos 53.20 and 53.21), new or progressive valve
dysfunction, prosthetic valve, or patch dehiscence (z Video
53.21), abscess formation, and haemodynamic consequences
such as ventricular dilatation and dysfunction and pulmonary
hypertension. Where TTE is non-​diagnostic and clinical suspi-
cion remains, evaluation with TOE is required. MSCT and nu-
clear techniques may also be helpful in diagnosis and assessing
response to treatment.
Tissue Doppler, strain, and strain rate in
congenital heart disease
Quantification of ventricular function in patients with CHD can
be very challenging using echocardiography. For the assessment
of RV and single ventricular function, subjective visual assess-
ment of ventricular function (eyeballing) is used most of the
time. Alternative, more quantitative methods should be used for
follow-​up and early detection of ventricular dysfunction. Tissue
Doppler quantifies myocardial velocities and either pulsed or
colour Doppler can be used. The introduction of speckle-​tracking
echocardiography makes strain imaging more easily applicable
in clinical practice. Strain measures myocardial deformation
and strain rate measures the speed of myocardial deformation.
Both reflect myocardial function but are influenced by loading
conditions.
Although still considered emerging techniques for clinical
use, the research data on the clinical applicability and utility
of both tissue Doppler and strain techniques are accumulating
[29–​32].
◆ Tissue Doppler velocities are considered useful for:
Diastolic function assessment
●
Evaluation of dyssynchrony
●
◆ Strain and strain rate imaging are promising techniques for:
Evaluation of global and regional systolic RV function
●
Evaluation of global and regional LV function
●
Evaluation of dyssynchrony
● and Dr Michael Gatzoulis to the first edition of this chapter.
Ack n owl e d g e m e n t 805
Three-​dimensional echocardiography in
congenital heart disease
3DE is useful for anatomical definition and for functional assess-
ment, facilitating spatial recognition of intracardiac anatomy and
thereby enhancing diagnostic confidence. 3DE is an emerging ap-
plication. Full volume data acquisition in a single cardiac cycle
and 3D myocardial strain are now being applied. TOE 3DE facili-
tates perioperative assessment.
Functional assessment
◆ 3DE measurements compare well with CMR for measurement
of LV volumes, ejection fraction and mass [3]‌(z Video 53.22).
◆ RV volumes and EF also compare reasonably with CMR meas-
urements [33]. There is a systemic underestimation of RV vol-
umes by around 25%. There is a growing role of 3DE in the
assessment and management of RV volumes in patients after
TOF repair, atrial switch procedures, and congenitally cor-
rected transposition of the great vessels.
Assessment of valve regurgitation
◆ Allows better understanding of the mechanism of regurgitation.
◆ Allows visualization of the entire regurgitant jet. Orthogonal
planes placed through the jet yield true vena contracta jet area
(z Video 53.23).
◆ Ability to overlay colour Doppler on transparent grey-​scale
image and transient suppression of the colour image facilitates
understanding of regurgitant mechanism.
Assessment of valve stenosis
◆ Allows better understanding of the mechanism of stenosis
(z Video 53.24).
3DE multiplanar reconstruction allows more accurate measure-
◆
ment of valve orifice area (E Fig. 53.33).
Stress echocardiography in patients with
congenital heart disease
Stress echocardiography (SE), using exercise or pharmacological
stress techniques, is increasingly utilized in patients with CHD
and provides important information regarding functional cap-
acity, symptom limitation (which may be unrecognized) and sys-
temic and pulmonary haemodynamic response to exercise. While
more data are required, SE has been used and may be helpful in the
following: obstructive left heart lesions such as congenital aortic
and mitral stenosis, ASD, TOF, repaired coarctation, to exclude
inducible ischaemia in TGA post arterial switch operation or post
Ross operation, systemic RV and univentricular heart [34].
Acknowledgement
We would like to acknowledge the contributions of Dr Edgar Tay
806 CHAPTER 53   The role of ech o cardio gra phy i n a du lt c on g en i ta l hea rt di sease

Fig. 53.33  TTE 3DE valve stenosis assessment. Multiplanar reconstruction enables accurate measurement of mitral valve anatomic orifice area in a patient with
congenital mitral stenosis due to parachute mitral valve.

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Contents
Introduction  809
Complementary roles of cardiac magnetic
resonance and computed tomography  809
Protocols and image analysis  810
Anatomical imaging  811
Functional imaging  811
Clinical applications  812
Future perspectives  819
Conclusions  820
CHAPTER 54
The role of CMR and MSCT
Giovanni Di Salvo and
Francesca R. Pluchinotta
Introduction
Congenital heart disease (CHD) affects 6–​8 per 1,000 of newborn infants [1]‌. As a result
of advances in cardiac surgery and clinical management, survival of patients with CHD
has significantly improved over the last decades. Nowadays, it is estimated that 85% of
children will survive to adulthood [2].
Imaging is a crucial component to the multidisciplinary management of these patients.
Techniques are required both to characterize anatomical structures and their functional
status in order to improve management, evaluate the consequences of interventions, and
help guide prognosis. Therefore, assessment for CHD requires a multimodality approach
where a variety of imaging techniques should be used in a complementary fashion
looking for sensitivity, accuracy, reproducibility, and cost-​effectiveness, while minim-
izing harm to the patients.
Echocardiography continues to play a major role in the evaluation of patients with
CHD. The role of echocardiography in adult CHD is discussed in detail in another
chapter of this textbook (Chapter 53).
Multislice computed tomography (MSCT) has a prominent role in the morphologic
evaluation of CHD patients, providing excellent three-​dimensional (3D) depiction of
cardiovascular anatomic structures. Although MSCT requires ionizing radiation, new
generation MSCT has shown marked reduction in radiation dose and improvement in
temporal resolution which allows to perform exams at higher heart rate and to assess
cardiac function, volume, and mass along with anatomy characterization with acceptable
exposure to ionizing radiation [3, 4].
Cardiac magnetic resonance (CMR) is a powerful tool for CHD management, giving
anatomical and physiological information that echocardiography, cardiac catheterization,
and MSCT alone cannot provide [5]‌. CMR provides highly accurate images of cardiac
and vascular anatomy, and tissue characterization. In addition, it is the gold standard for
the assessment of cardiac volumes and ejection fraction, as well as vascular and valvular
flow assessment.
Complementary roles of cardiac magnetic resonance and
computed tomography
The characteristics of MSCT and CMR are listed in E Table 54.1.
Both CMR and MSCT give almost unrestricted access to intrathoracic structures [6]‌.
Although the radiation dose is a concern in CHD patients that may require repeated
studies, MSCT can cover large anatomic volumes with excellent spatial resolution and
in much shorter study times than CMR. The MSCT short acquisition time and high
810 CHAPTER 54   The role of CMR and MSCT

Table 54.1  The characteristics of MSCT and CMR Compared to MSCT, CMR enables functional and flow analysis
providing accurate non-​invasive hemodynamic data including
MSCT CMR
evaluation of valve regurgitation or shunt quantification.
Spatial resolution High Limited Both CMR and MSCT allow 3D contrast-​enhanced angiog-
Temporal resolution Limited Good raphy. Where MSCT offers the better spatial resolution, CMR
Acquisition time Short Long offers the possibility of ‘dynamic’ angiography visualizing the
sequential opacification of the venous and arterial phases in
Ionizing radiation Present No radiation use
adjacent vascular regions. This technique combines the static,
Possibility of image in any Available Available
multiplanar evaluation of vascular morphology typical of MSCT
desire plane
with a functional assessment of blood flow. While vascular assess-
3D data set Available Available
ment through MSCT requires contrast-​enhanced images, CMR
Unrestricted access to Available Available is fully capable of vascular evaluation and vessel diameter assess-
intrathoracic structures
ment on 3D and 2D images, with the advantages of no need for
Biventricular functional Limited Available contrast administration and no radiation.
assessment
In evaluating a CHD patient, the complement of cardiac diag-
Real-​time images Not available Available nosis is cardiac intervention. Interventional CMR combines the
Flow measurements Not available Available advantages of CMR with the utility of cardiac catheterization as
Myocardial viability Not available Available a diagnostic and therapeutic approach for many CHD lesions.
Evaluation of calcifications High Limited
CMR is attractive for guiding and monitoring interventional
procedures due to its unlimited imaging planes, 3D localization
Stent patency High Limited
system, high intrinsic soft tissue contrast and the possibility to
Coronary artery lumen High Limited measure physiologic parameters like flow and cardiac function
assessment
without radiation exposure. However, the logistical complexity,
Lungs and airways Available Limited a reduced temporal and spatial resolution, and the limited range
Presence of pacemaker or ICD Not a contraindication Limitation of suitable catheters and devices still limit its use to few dedicated
centres.
spatial resolution allow better depiction of small structures such
as aortopulmonary collaterals, fistulas, and coronary arteries Protocols and image analysis
(E Fig. 54.1). Furthermore, MSCT is less susceptible than CMR In a baseline study or in a presurgical assessment it is recom-
to artefacts related to percutaneous devices, pacemaker, or cardiac mended to perform a comprehensive examination to review the
defibrillator (E Fig. 54.2). Eventually, the very short examination ventricular volumes and function, the myocardial structure, the
times allows accurate depiction of anatomy even in uncooperative valves, and the vessels through the heart and mediastinum. In a
or sick patients. Also CMR real-​time cine images may be obtained follow-​up study or when the clinical question is well-​defined the
in just few milliseconds without breath-​holding, but suffer from examination can be focused on what is clinically relevant opti-
decreased temporal and spatial resolution. mizing the acquisition time.

(a) (b) (c)

Coronary fistula

Fig. 54.1  Coronary fistula. MSCT images showing: (a) ectasia of the left coronary artery caused by a giant and aneurysmatic fistula (a and b, asterisks) of the left
anterior descending artery with the coronary sinus; (c) From CT data set a 3D virtual model was created for planning surgery.
 Fu n cti ona l i m ag i n g 811

Anatomical imaging stenosis. An interesting alternative technique to standard ceMRA

is time-​resolved ceMRA [8]‌, which displays progressive vascular
MSCT provides excellent 3D depiction of cardiovascular ana-
filling by rapidly acquiring sequential images. This eliminates the
tomic structures. The multiplanar reconstruction of the 3D data
need to time the contrast bolus, it ensures peak vascular contrast
set facilitates orientation of the images in any plane allowing ac-
is acquired, and provides unique temporal information on the dy-
curate measurements, and the maximal intensity projection is in-
namics of blood flow showing at the same time the arterial and
strumental in evaluation of the great vessels.
venous contrast phase (E Fig. 54.4).
CMR uses a large number of pulse sequences for anatomical
In patients in whom contrast agent is not advised or who
and tissue characterization. The most frequently used are cine im-
cannot hold their breath, CMR 3D steady-​state free precession
ages which allow views in any desired plane and adds qualitative
(SSFP) imaging produces excellent anatomical depiction of the
information about function and valve motion. Image acquisition
great vessels. The sequence shows intrinsically high contrast be-
is usually performed during breath-​holding and cardiac motion is
tween the blood-​pool and the surrounding tissues, and the 3D
usually controlled by means of electrocardiographic (ECG) retro-
data set, acquired free-​breathing, can be reformatted in arbitrary
spective gating. An alternative cine technique in patients who
orientations.
cannot hold their breath is standard real-​time imaging, as it does
3D images acquired either by MSCT and CMR can be used to
not require breath-​holding or ECG triggering [7]‌.
produce 3D-​printed heart models which are particularly useful
CMR spin-​echo imaging pulse sequences (often referred to
when planning interventions on complex CHDs or for percu-
as ‘black-​blood’ sequences) are less commonly used in clinical
taneous pulmonary valve implantation, correction of partial
practice but they remain an essential component of great vessel
anomalous pulmonary venous drainage or stenting of aortic
imaging for evaluation of the lumen, vessel wall and for the medi-
coarctation  [9]‌.
astinum [6]‌. They are particularly good to highlight the relation-
Myocardial scar has been known to reflect prognosis in CHD.
ship of the vessels with the airways and the oesophagus as seen in
The CMR late gadolinium enhancement (LGE) technique has
aortic arch anomalies. Another advantage of spin-​echo sequences
excellent spatial and contrast resolution and allows detection of
is that they are less susceptible to artefacts caused by turbulent
small amounts of scar identified as white areas within the normal
flow and metallic implants.
myocardium which appears black. As for the cine imaging,
Contrast-​enhanced magnetic resonance angiography (ceMRA)
standard DE imaging should be performed in a ventricular
or MSCT angiography are the most valuable techniques for
short-​axis orientation with a stack of contiguous slices to com-
imaging the great vessels. Both have been shown to be accurate in
pletely encompass both ventricles. If LGE is present, imaging of
the assessment of vascular stenosis and dilation. The data set is a
the detected lesions in an orthogonal plane should be acquired to
full volume composed of a stack of contiguous slices that can be
confirm them.
reconstructed in any desired oblique plane (multiplanar reformats
and maximum intensity projection images) or volume-​rendered
in a 3D image (E Fig. 54.3). Compared to ceMRA, MSCT offers
a better visualization of the 3D anatomic relations of the en-
Functional imaging
hanced blood vessels with chest. In addition, in ceMRA signal Both CMR and MSCT allow volumetric analysis of the right and
dropout may occur in regions of flow acceleration or in pres- the left ventricle without geometric assumptions, which is par-
ence of stents or valve prostheses leading to an overestimation of ticularly important given the variability of ventricular shape in a

(a) (b) (c)

Fig. 54.2  Artefacts in CMR. CMR short-​axis SSFP sequence showing extensive dark artefacts caused by an implanted loop recorded (a); CMR axial SSFP
sequence presents marked artefacts caused by multiple clips used to close aortopulmonary collaterals 20 years before (b); MSCT scan of the same patient allows
clear visualization of the vessel anatomy showing no coil-​related artefacts (c).
812 CHAPTER 54   The role of CMR and MSCT
(a)
(c)
Fig. 54.3  Multiplanar reconstruction
CT. Reformatted oblique sagittal (a),
coronal (b), and axial (c) planes of
a MSCT angiography after a single
injection of contrast, which gave
simultaneous opacification of the
right ventricular outflow tract, the
pulmonary arteries, the left ventricle,
the coronaries, and the aorta.
LA = left atrium; LV = left ventricle; PA =
pulmonary artery; Aao = ascending aorta.
dilated right ventricle (RV) or in a functionally single ventricle.
Ventricular volumes and ejection fraction are generally derived
by contouring the endocardial and epicardial borders at end sys-
tole and end diastole in a stack of cine slices covering the en-
tire heart aligned in a ventricular short-​axis or in an axial plane
[10]. The myocardium of the RV is extensively trabeculated,
with only a relatively thin layer of compact myocardium in
the free wall. This makes reproducible delineation of the RV
blood–​muscle boundary challenging. For CMR, the most re-
producible approach is to manually contour the trabeculated
and the compact layers of the myocardium (E Fig. 54.5). In
MSCT, a more rapid and robust semiautomated boundary de-
tection based on attenuation (or signal) differences between
the opacified blood and myocardium is routinely used, which
could potentially be more accurate, although not necessarily
directly comparable with the CMR method. Furthermore the
absence of flows assessment in MSCT does not allow a double
check between the ventricular stroke volumes and the antegrade
flow through the semilunar valves which could lead to a less
accurate volumes estimation. An internal consensus policy re-
garding ventricular segmentation, i.e. inclusion or exclusion of
papillary muscles, trabeculations, and right ventricular outflow
tract aneurysm, should be adopted in each centre to guarantee
(b)
(d)
the reproducibility of the measurements for serial comparisons
of ventricular function,
Flow measurements are potentially unrivalled strength of CMR.
Blood flow volumes and velocity across a vessel can be quantified
by phase-​contrast (PC) cine sequence. Typically, a slice is placed
perpendicular to the vessel of interest. During the post-​processing
analysis, the vessel of interest is contoured and the volume of blood
passing through the plane is calculated as the product of velocity
and cross-​sectional area [11]. Through-​plane velocity mapping of
ascending aortic and main pulmonary artery (PA) flow allows cal-
culations of left-​and right-​sided output and, therefore, of shunting
and of the amount of regurgitation of the outflow valves. PC
sequences can be used to measure peak velocity across stenoses,
and give an estimated pressure gradient [12]. It is important to be
aware that PC accuracy depends on laminar flow, and in regions of
turbulence flow calculations can be inaccurate [13].
Clinical applications
ASD, ventricular septal defect (VSD), and shunt
quantification
Shunt lesions are the most common types of CHD. Their anatomy
ranges from septal defects or arterial ducts to complex lesions
 Fu n cti ona l i m ag i n g 813

(a) (b) (c)

(d) (e) (f)

Fig. 54.4  Time-​resolved contrast-​enhanced magnetic resonance angiography (ceMRA). Early venous phase after contrast injection shows opacification of the
right atrium and right ventricle (a), the two intermediate phases demonstrate the main pulmonary artery and branches (b) and the pulmonary venous return to
the left atrium and left ventricle (d); a later phase shows the presence of contrast in the aorta (e). The brightest signals in the pulmonary artery and aorta allow
3D reconstruction of the right (c) and left (f) sided structures.

with multilevel communication between the pulmonary and
systemic circulations. Compared to MSCT, CMR allows simul-
taneous delineation of the anatomy of the defect and of the asso-
ciated lesions, as well as hemodynamic assessment of the shunt.
Quantification of a shunt is expressed by the amount of blood
flowing into the pulmonary circulation (Qp) and the amount of
blood flowing into the systemic circulation (Qs): a left-​to-​right
shunt increases Qp, while a right-​to-​left shunt increases Qs. PC
CMR acquired in different locations is the non-​invasive gold
standard of Qp and Qs quantification [14] (E Fig. 54.6) and
has been found to show good correlation with invasive cardiac
catheterization [15].
Left ventricular outflow tract (LVOT) obstruction and
aortic regurgitation
LVOT obstruction might occur at different levels: in the area
delineated by the membranous and basal muscular portions of
the interventricular septum below the aortic valve (subvalvular
level); at the level of the aortic valve (valvular level); and in the
ascending aorta beyond the superior margin of the sinuses of
Valsalva (supravalvular level). The most common site of obstruc-
tion is valvular (75%) [16].
Both MSCT and CMR are the preferred technology for imaging
the LVOT and the aorta. They are especially required to assess
814 CHAPTER 54   The role of CMR and MSCT

(a) (b)

Fig. 54.5  Ventricular volumes and function. CMR 2D SSFP short-​axis stack of the ventricles (a); segmentation with commercial software of the epicardium and
endocardium give estimation of ventricular volumes, mass, and function (b).

(a) (b)
600
Qp 6,36 L/min = 98ml/sec
500 Qs 3,88 L/min = 60ml/sec
Qp/Qs = 1,64
400
Flow (ml/sec)

300
200
100
0
–100
0 200 400 600 800
Time (ms)
(c) (d)

Fig. 54.6  Atrial septal defect. Patient

with unrepaired atrial septal defect,
ostium secundum type: CMR 2D SSFP
images showing the defect at the atrial
level (a, arrow). In case of shunts, CMR
is useful to calculate the Qp:Qs ratio.
Phase-​contrast sequence planned
on the pulmonary valve (c) and on
the aortic valve (d) give accurate
estimation of the antegrade flow
through the valves. Flows are used to
calculate the Qp:Qs ratio (b).
AAo = ascending aorta; LV = left ventricle;
PA = pulmonary artery; RV = right ventricle.

dilation of the aorta, which may be a consequence of LVOT
obstruction.
Compared to MSCT, in addition to accurate assessment of the
localization of the LVOT obstruction. CMR cine imaging is able
to determine the mechanism of the stenosis. In case of multiple
levels of obstruction, jet velocity mapping can be valuable in as-
sessing the level(s) of obstruction and establishes the pressure
gradient between the LVOT and the aorta. In addition, left ven-
tricular (LV) function, mass, and myocardial fibrosis are useful
information to quantify the haemodynamic burden of the LVOT
lesion(s).
In case of aortic stenosis, assessment of aortic valve by MSCT
is performed measuring the effective valve area which has been
found to show good correlation with transthoracic echocardiog-
raphy [17]. Any calcification of valve structures can be seen, and
MSCT cardiac gating also allows assessment of valve leaflet mo-
bility through the cardiac cycle. In this setting, Cine CMR may be
limited to signal void caused by high velocity jet flow across the
narrow valvular orifice.
CMR is especially useful to measure the amount of aortic re-
gurgitation through PC images acquired in a plane transecting
the ascending aorta. Although this approach is clinically valuable,
the derived measurements of aortic regurgitation are highly sus-
ceptible to any background phase offset errors, which may need
to be minimized or corrected [18]. For reproducibility and lon-
gitudinal comparison, the plane is probably best located imme-
diately above the sinotubular junction at end diastole in order to
keep the plane clear of any convergent, accelerating diastolic flow
(a) (b)
Fig. 54.7  Aortic coarctation. A patient with unrepaired aortic coarctation: CMR 2D SSFP oblique sagittal image through the aorta shows severe aortic
coarctation involving the aortic isthmus (a, arrow); ceMRA maximum intensity projection image showing multiple collateral vessels (b). After percutaneous stent
implantation the patient underwent MSCT (c) which showed stent patency and excluded procedural complications such as aneurysms formation.
Fu n cti ona l i m ag i n g 815
in the vicinity of a regurgitant orifice. However, upward diastolic
displacement of the aortic root relative to the fixed PC plane tends
to cause underestimation of the regurgitant fraction [18]. In iso-
lated aortic regurgitation, the increased LV stroke volume relative
to that of the RV can also quantify the regurgitation, as long as the
volumes are accurately measured.
Coarctation of the aorta
CMR and MSCT contrast-​enhanced angiography are helpful in
the assessment of native coarctation. Either modality also allows
visualization of complications after repair such as recoarctation
or aneurysm formation. Following stent insertion for coarc-
tation, MSCT better visualizes the stent position and possible
intrastent stenosis due to the signal dropout that may occur with
CMR (E Fig. 54.7).
CMR is the preferred modality to assess associated pathology,
such as stenosis or regurgitation of a bicuspid aortic valve, LV
hypertrophy, or to provide serial measurement of the vascular
diameters to assess dilatation of the ascending aorta. Specifically,
cine imaging of the ventricles in short axis should be performed
for volumetric analysis and to assess for LV hypertrophy by
measuring LV mass [19]. Measurements of aortic diameters in
proximity of the head and neck vessels to the stenosis allow for
planning percutaneous interventions. PC CMR completes the
functional assessment of the aorta: the peak velocity across the
narrowed area can be used to estimate the pressure gradient and
in presence of a significant coarctation the velocity–​time curve
of flow beyond the coarctation showed a diastolic prolongation
(c)
816 CHAPTER 54   The role of CMR and MSCT
of forward flow [20]. Eventually, collateral flow can be quantified
by measuring blood flow in the proximal descending aorta before
the site of coarctation and in the diaphragmatic aorta [21]. CMR
4D flow may be useful to evaluate wall stress and predisposition
to aneurysms [22].
Right ventricular outflow tract (RVOT) dysfunction
As a result of structural and functional changes secondary to sur-
geries of the RVOT, adult CHD patients present different residual
anatomic and hemodynamic abnormalities.
Pulmonary regurgitation is most common in patients where
surgical relief of pulmonary valve stenosis disrupts its func-
tion, such as in patients with tetralogy of Fallot (E Fig. 54.8).
Stenosis may be present at the level of the RVOT or in the pul-
monary arteries causing post-​stenotic dilation. RVOT stenosis is
predominant in case of right ventricle to pulmonary artery (RV-​
to-​PA) conduits surgically placed to repair pulmonary atresia or
tetralogy of Fallot with associated with anomalous course of the
right coronary crossing the RVOT.
In both groups the main contributions of CMR and MSCT lie
in demonstrating the RVOT, pulmonary arteries anatomy, and the
coronary arteries (CT). CMR is the central imaging modality for
serial follow-​up because it is the gold standard for quantification
(a)
(c)
Fig. 54.8  Tetralogy of Fallot. Cardiac MR
horizontal long-​axis view (a) and short-​axis view
(b) showed dilated right ventricle; long-​axis view
of the right ventricular outflow tract (c) showed
the anatomy of the pulmonary valve. The long-​axis
view of the right ventricular outflow tract is used
for planning the imaging plane (c, red line) for the
flow measurement sequence: magnitude image
from the flow measurement sequence shows the
main pulmonary artery in cross-​section, and flow
versus time graph shows showing antegrade systolic
flow and retrograde diastolic flow from severe
regurgitation (d).
of RV volumes, ejection fraction, and pulmonary regurgitation
[23–​26]. In addition, mapping of flow velocities through a plane
transecting the stenotic jet together with visualization of the de-
gree of RV hypertrophy and septal flattening allows an assessment
of the severity of pulmonary stenosis. RV and LV myocardial fi-
brosis, which can be explained by previous surgery, should be as-
sessed by CMR as it has important implications on outcome [27].
While MSCT overlaps with CMR in quantifying ventricular
size and function (at the expense of ionizing radiation), it cannot
measure blood flow and valve regurgitation. On the other hand,
MSCT provides clear visualization of the heart and thoracic
blood vessels and it is particularly useful to define small aorto-​
pulmonary collaterals, to characterize the presence of calcium
which is the most common cause of conduits stenosis in this
population, and to evaluate the relationship between the coronary
arteries and the main pulmonary trunk in the assessment prior
to percutaneous pulmonary valve implantation [28–​29]. MSCT
is superior to CMR for the assessment of pulmonary arteries
anatomy, especially in patients with PA stents.
CMR PC images aligned with respect to the interventricular
septum along with aortic and pulmonary velocity mapping al-
lows identification of residual VSD and measurement of Qp:Qs
to quantifying the shunt.
(b)
(d)
 Fu n cti ona l i m ag i n g 817

(a) (b)

Fig. 54.9  Ebstein anomaly. CMR four-​chamber

(a) and short-​axis (b) views help delineate the
morphology of the tricuspid valve and the typical
features of Ebstein’s. The site of the tricuspid valve
leaflets is marked with asterisks. The septal leaflet
in the four-​chamber view (a) is displaced from the
tricuspid annular plane; this results in separation
of the RV in a basal ‘atrialized’ part and a reduced
distal ‘functional’ part which is the only one that
contributes to the cardiac output.
LA = left atrium; LV = left ventricle; RA = right atrium;
RV = right ventricle.

Ebstein’s anomaly and tricuspid regurgitation made with synthetic material (Mustard operation) or by infolding
Ebstein’s anomaly consists of apical displacement of the tricuspid of the atrial wall (Senning operation) to redirect blood from the
valve from the atrioventricular junction into the RV. This results pulmonary veins into the systemic RV and the aorta and blood
in separation of the RV in a proximal ‘atrialized’ part and a distal from the systemic veins into the subpulmonary LV and the PA,
‘functional’ part, which is the only one that contributes to the car- leaving the discordant ventriculoarterial connections intact and
diac output (E Fig. 54.9). the RV as the systemic ventricle.
CMR and MSCT allow thorough visualization of right atrium CMR or MSCT should assess the atrial pathways and systemic
and RV anatomy, the atrial septal defects if present, tricuspid valve right function. In CMR a stack of contiguous transaxial or cor-
displacement and malfunction, and the size and contractility onal cines or a 3D SSFP sequence may be useful to characterize
of the functional RV. Compared to MSCT, CMR has particular the baffle anatomy and identify any narrowing. PC images aligned
strength in quantifying tricuspid regurgitation and characterizing with respect to systemic and pulmonary venous atrial pathways
the physiology implied by the flow direction of any associated allow identification of stenotic jets and measurement of Qp:Qs
atrial septal defect. in case of leaks. CMR fibrosis imaging of the systemic RV pro-
Transaxial and short-​ axis CMR cines, supplemented by 4-​ vides important information on myocardial performance and
chamber and sagittal RVOT cines, are recommended. Transaxial viability [26].
cines may be used for volume measurements of the functional More recently, born TGA patients will have undergone the
part of the RV, which can be hard to delineate in short-​axis slices. arterial switch operation: the aorta and PA are transected at the
Atrialized RV volume should be measured as it has a strong cor- sinotubular junction, the posterior pulmonary bifurcation is
relation with arrhythmias [30]. Measurements of the LV volumes mobilized anteriorly to the aorta and anastomosed to the pre-
and ejection fraction are important as well as evaluation of dia- vious aortic root, while the anterior aorta is brought posteriorly
stolic compression of the LV by the dilated right heart, which and anastomosed to the previous pulmonary root (the so-​called
can impair ventricular filling and reduce the cardiac output. Lecompte manoeuvre). Coronary ostia are transferred from the
Eventually, multiple views of the tricuspid valve are useful to original aortic root to the neo-​a ortic (pulmonary) root. After sur-
characterize valve morphology for surgical planning. gery the arrangement of TGA, anterior to the aorta, might cause
The severity of tricuspid regurgitation can be assessed using distortion of either the pulmonary trunk or branches and the
CMR PC imaging through a plane transecting the jet on the right aorta itself (E Fig. 54.10).
atrial side of the orifice. A tricuspid regurgitation jet width >8 mm CMR is primarily used postoperatively following arterial
and/​or a calculated regurgitant fraction of 40% or more can be re- switch procedures allowing assessment of any right ventricular or
garded as severe [31]. Aortic and pulmonary velocity mapping are supravalvar pulmonary stenosis, branch PA stenosis, aortic root
used to quantifying shunt through the atrial septal defect (Qp:Qs). dilation, and function of both ventricles and the neo-​aortic valve.
Generally, MSCT is reserved for anatomical evaluation of the
Transposition of the great arteries (TGA) reimplanted coronary arteries, especially when there is ongoing
Complete TGA, also called D-​ loop TGA, describes patients high clinical suspicion of coronary artery abnormality and should
with concordant atrioventricular connections and discordant be followed by functional ischaemia testing [26].
ventriculoarterial junctions: the morphological RV gives rise to A small number of patients with the combination of TGA
the aorta, and the morphological LV is connected to the main PA. with VSD and pulmonary stenosis may have been corrected with
Many contemporary adult TGA patients are survivors of Mustard the Rastelli procedure whereby the VSD is closed with a patch
or Senning operation which is an atrial redirection surgery: it in- to create a tunnel between the LV and the aorta. The pulmonary
volves removal of the interatrial septum and insertion of a ‘baffle’ trunk is divided and an RV-​to-​PA conduit inserted.
818 CHAPTER 54   The role of CMR and MSCT

(a) (b)

Fig. 54.10  Transposition of the great arteries,

arterial switch operation. 3D CMR SSFP axial view
(a) shows stents in both pulmonary arteries in a
patient who presented with severe pulmonary
artery stenosis after arterial switch operation in
infancy; stent patency could not be properly
evaluated due to artefacts. 3D contrast-​enhanced (c) (d)
MR angiography (c) shows signal loss (black holes—​
arrows) inside the stents but well represented
peripheral pulmonary branches. To evaluate the
position and patency of the stent the patient
underwent MSCT, which shows the lumen of the
pulmonary arteries (b); 3D volume rendering of
MSCT angiography data allows 3D reconstruction
of the full anatomy and the stents.
Note as after arterial switch operation, (oblique axial view,
a and b) the pulmonary artery is anterior to the ascending
aorta (Aao) and the right (RPA) and left (LPA) pulmonary
arteries pass either side of the aorta.
Legend: SVC: superior vena cava; Dao: descending aorta.

CMR allows assessment of possible stenosis or incompetence
of the RV-​to-​PA conduit (as previously described for tetralogy
of Fallot patients), of the LVOT, of biventricular function, and of
possible residual shunt through the corrected VSD (Qp:Qs calcu-
lation). In multilevel RVOT obstruction CMR is able to determine
the site of the most hemodynamically significant obstruction, e.g.
at subvalvar, valvar, or supravalvar anatomical level [26]. MSCT
can be especially useful to characterize the conduit stenosis being
less susceptible to artefacts related to high velocity jet, and the
degree of calcification.
Congenitally corrected transposition of the great
arteries (CCTGA)
In CCTGA both the atrioventricular and ventriculoarterial junc-
tions are discordant: the LV receives deoxygenated blood from the
right atrium and directs it to the PA, while the RV receives oxygen-
ated blood from the left atrium and directs it to the aorta. Survival
of CCTGA patients is highly dependent on the presence or absence
of associated lesions and their severity. A CCTGA patient without
associated lesions (most commonly VSD, pulmonary stenosis or
morphological abnormality of the systemic tricuspid valve) and
balanced sized ventricles may remain asymptomatic throughout
adult life. However, the systemic ventricle remains morphologically
right; hence, RV function and tricuspid valve regurgitation remain
major concerns during long-​term follow-​up.
Either CMR or MSCT can demonstrate the abnormal anatomy
and connections well, which can be helpful to confirm the diag-
nosis (E Fig. 54.11). However, CMR is preferred for evalu-
ation of biventricular function, (especially of the systemic RV)
and tricuspid regurgitation. A useful way of distinguishing the
morphologically RV is to compare the two ventricular sur-
faces of the interventricular septum: the left ventricular surface
is relatively smooth, with few trabeculations, in contrast to the
right side which gives rise to the moderator band and multiple
trabeculations in the apical region. CCTGA patients have a high
incidence of conduction disturbances and arrhythmias which fre-
quently require pacemakers and defibrillators. In patients with
CMR non-​compatible devices, CT is preferred over CMR.
The functionally univentricular heart and the Fontan
circulation
Fontan operation is a palliative surgical procedure performed
in children in whom the abnormal cardiac anatomy precludes
biventricular repair. It involves diverting all systemic venous re-
turn directly to the lungs bypassing the ventricle. Earlier proced-
ures incorporated the right atrium between the caval veins and
pulmonary arteries (atrio-​pulmonary Fontan), whereas in recent
years the superior vena cava is directly connected to the pul-
monary arteries in the first stage of the surgical correction (bi-
directional Glenn), and later the inferior vena cava is connected
to the pulmonary circulation via a lateral tunnel or extracardiac
conduit (total cavopulmonary connection) (E Fig. 54.12).
CMR or MSCT allow assessment of the Fontan connections,
branch pulmonary arteries, pulmonary veins (which can be
compressed by a dilated right atrium after an atrio-​pulmonary
connection), the atrioventricular valve(s), the ventricle(s), the
ventricular outflow tract, the (neo-​)aorta and aortic arch, as well
as any residual leaks or collateral vessels. However, considering
the opportunity to delineate both the anatomy and assess the
physiology, CMR is the preferred imaging modality.
 Fu tu re pe r spe c t i v e s 819

(a) (b)

(c) (d)

Fig. 54.11  CMR images of unoperated CCTGA

with ventricular septal defect (b, red arrow) and
mild pulmonary stenosis in a young adult with
dextrocardia and situs inversus (a): side-​by-​side
relationships of the great vessels can be seen
with a subaortic RV (b and c) and subpulmonary
LV (b and d); in-​and-​out view of the systemic
RV (c) and subpulmonary LV (d). The features
of a morphologically RV are seen: note the
more irregular side of the septum (b) and the
discontinuity between the tricuspid valve and the
aortic valve (c).
Aao = ascending aorta; LV = left ventricle; PA =
pulmonary artery; RV = right ventricle; SVC = superior
vena cava; VSD = ventricular septal defect.

Comprehensive coverage using a stack of contiguous transaxial

CMR cines is generally suitable for the identification of any intra-​ Future perspectives
atrial thrombus or suspected stenosis of the cavopulmonary connec-
Today’s CMR and MSCT have revolutionized the approach to
tions. The global and regional function of the single ventricle can be
CHD and have substantially affected prognostic information. For
assessed on a cine short-​axis imaging along with myocardial fibrosis
both technologies there are particular needs for reliable and user-​
which is a common finding and is associated with systolic dysfunc-
friendly postprocessing tools for the analysis of image data. For
tion and non-​sustained ventricular tachycardia [26]. Flow ana-
example, rapid and reproducible segmentation and analysis of
lysis provides accurate non-​invasive hemodynamic data including
biventricular volumes from images of either modality would be
velocity through a suspected narrowing, or to evaluate shunt flow
a major step forward.
through a residual fenestration and presence of any leak, calculate
CMR is an inherently versatile modality and the repertoire
Qp:Qs as well as flow to both lungs and systemic-​to-​pulmonary col-
of sequences to assess cardiac function, anatomy, flow, and via-
lateral flow. The peculiar circulation after Fontan surgery results in
bility will be continuously improved and extended. The most re-
some challenges during angiography, both in CMR and MSCT. As
cently implemented technology is a 4D imaging approach which
flow from the upper body is directed into the pulmonary arteries,
combines 3D data regarding anatomy over time. The 4D CMR
injection from the upper arms opacified the pulmonary branches,
sequence generates isotropic 3D voxels over multiple phases of
and most commonly the right PA which is preferentially perfused
the cardiac cycle in free-​breathing and after contrast injection, of-
by the Glenn. The inferior vena cava, the tunnel, and the left PA may
fering the potential of a 3D data set which can be reformatted
be seen after recirculation of the contrast which does not provide
in customized orientations combined with the advantage of dy-
crisp contrast in the vascular structures at this point. Injection from
namic resolution [32]. Currently, limited sequence availability,
a leg or else non-​contrast CMR 3D SSFP imaging may be preferable.
820 CHAPTER 54   The role of CMR and MSCT

(a) (b)

(c) (d)
Fig. 54.12  Univentricular hearts after Fontan
palliation. A CMR 2D SSFP image showing the
anatomy of an atrio-​pulmonary Fontan (a), note the
severely enlarged right atrium and the hypoplastic
right ventricle; CMR 3D SSFP reformatted plane
allows visualization of the connection between
the atrium and the pulmonary bifurcation (b). A
Fontan with intracardiac tunnel in a CMR 2D SSFP
image (c), note the left atrium, the short-​axis plane
of the intracardiac tunnel and the hypoplastic right
ventricle; CMR 2D SSFP oriented in a different plane
highlights the atrial tunnel from the inferior vena
cava to the pulmonary biforcation (d).
Ao = aorta; LA = left atrium; LPA = left pulmonary artery;
LV = left ventricle; RPA = right pulmonary artery; RV =
right ventricle; SVC = superior vena cava.

long acquisition, and post-​processing times are preventing its
routine clinical use.
Fast innovations have pushed the edge of cardiovascular MSCT
broadening its clinical applications: the increase in detector rows
improves cardiac coverage and allows full angiography with the
possibility of contrast tracking allowing some flow data to be
gained. However, the permanent focus of cardiac MSCT remains
the reduction of radiation dose which has accompanied the tech-
nical progresses. Many of the newest generation of MSCT scanners
allow a 50–​90% reduction in ionizing radiation dose, with the latest
scanners delivering approximately less than 5 MsV for a combined
CT coronary, pulmonary, and aortic angiogram. MSCT continues
to develop rapidly and is likely to remain an important modality
in the assessment of adult CHD, particularly for the assessment
of coronary artery pathology and pulmonary hypertension and if
CMR is unable to be performed or is unavailable locally.
Beyond that, along with the burgeoning of artificial intelligence,
we can predict that in the upcoming future, the clinical demands-​
based big data analysis radiomics will likely be the perspective of
cardiac imaging, which is conducive to preoperative assessment,
treatment plan, risk stratification of major adverse cardiac events,
and prognostic analysis.
Conclusions
MSCT and CMR imaging have revolutionized the management of
patients with CHD. They offer comprehensive insight into cardio-
vascular morphology. However, it remains important to appreciate
the advantages and disadvantages of different imaging modalities
in order to provide the most appropriate and cost-​effective diag-
nostic pathway for each individual patient at the right time.

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 Index
Notes: Abbreviations used in the index can be found on pages xi to xiii.
A American Heart Association/​American College
AAS see acute aortic syndrome (AAS)
abdominal aortic aneurysms (AAA)  773–​4, 775f
abscesses, infective endocarditis  273–​4, 274f
ACC see American Heart Association/​American
College of Cardiology (AHA/​ACC)
acoustic windows, transthoracic
echocardiography 7
acquired ventricular septal defect  291
ACS see acute coronary syndromes (ACS)
acute aortic syndrome (AAS)  749–​4, 762–​7,
775
B-​main anatomical/​functional
features  750–​1
diagnosis  749–​50, 749f, 750f, 751f
acute cardiovascular disease  753–​4, 754f
acute coronary artery disease  399
acute coronary syndromes (ACS)  399,
414–​15
aetiology 438
myocardial viability  551–​3, 551f, 552f
acute thoracic syndromes  775–​79, 776f
AD see aortic dissection (AD)
adenosine 398
cardiac stress testing  405t, 409
adjudicated thin-​cap fibroatheroma
(TCFA) 153
AdreView Myocardial Imaging for Risk
Evaluation in Heart Failure
(ADMIRE-​HF)  570, 572
AdreView Myocardial Imaging for Risk
Evaluation in Heart Failure Extension
(ADMIRE-​HFX)  570–​1
ADVANCE (Assessing Diagnostic Value of
Non-​invasive FFR-​CT in Coronary Care)
Registry  152, 441
AFD (Andersen–​Fabry disease)  651–​2
Agaston method  163
AHA see American Heart Association/​American
College of Cardiology (AHA/​ACC)
akinetic regions, myocardial viability  547, 548f
AL amyloidosis, chemotherapy  648–​49
alcohol, DCM and  674–​5
alcohol septal ablation, HCM  640–​1
Alterra Adaptive Prestent  378–​79, 380f
American Board of Echocardiography,
training 82
American Diabetes Association (ADA)  410
of Cardiology (AHA/​ACC)
calcium score  436
DCM aetiology  662
paravalvular leak intervention  295
valvular heart disease  229
American Society of Echocardiography
(ASE) 92
3D echocardiography  92–​3
competence training  81t
contrast echocardiography  113
right heart recommendations  520
American Society of Thoracic Surgeons
Database 223
AMLs (anterior mitral leaflets)  337
Amplatzer Cribriform occluder  294, 294f
Amplatzer Duct Occluder  298
Amplatzer Muscular VSD Occluder  298
Amplatzer septal occluder (ASO)  290–​1, 292f,
293f, 298
amyloid light-​chain (AL)  646
amyloidosis  645, 646f
Analysis of Coronary Blood Flow Using CT
Angiography: Next Steps (NXT trial)  441
analytical algorithms, SPECT  42
Andersen–​Fabry disease (AFD)  651–​2
angina
aetiology 484
post-​PCI  489
angiography  386–​7
see also multigated radionuclide
angiography (MUGA)
angiosarcoma 732t, 737, 738f
Annexin V  474
anterior mitral leaflets (AMLs)  337
anterograde flow, valvular prostheses  249f,
256–​7t, 259–​60, 261–​2t
anterolateral papillary muscles  200
anthracyclines 675
myocardial disease/​ventricular
dysfunction 614
toxicity of  616
antithrombotic drugs  366–​7
aorta
ascending see ascending aorta
common variants  759–​60, 760f
descending see descending aorta
diameter  747, 760, 761f, 772
measures of  760–​1
normal structure  771–​2, 772f, 772t
transoesophageal
echocardiography  749, 749f
aortic aneurysms  747–​49, 757–​70, 763f,
773–​4
causes of  773b
aortic annulus size
calcific AVS  164
patient selection in TAVI  316, 316, 316t
standard values  39t
aortic arch  771–​2
aortic coarctation  768, 768f
aortic dilation  747–​49
aortic disease  747–​55, 757–​70
black-​blood sequences  758, 758f
contrast echocardiography  114
contrast-​enhanced MR angiography
(CE-​MRA)  759, 760f
flow mapping  758–​59
intraoperative echocardiography  754
mitral stenosis and  340
MRI  758–​59
MSCT  771–​80
non-​contrast-​enhanced MR
angiography  759, 759f
postoperative echocardiography  754, 754f
aortic dissection (AD)  757–​70, 776–​7, 776f
complication diagnosis  752, 752f
aortic intramural haematoma (IMH)  753, 753f
aortic regurgitation (AR)  752
AVS and  175
CMR/​MSCT  813, 815
diagnosis 225t
intraoperative transoesophageal
echocardiography 243
jet width/​area  184
mitral regurgitation and  226–​7
prosthetic valves  265, 265f
TAVI follow-​up  329–​0
aortic root
diameter 38t
normal structure  771
patient selection in TAVI  318–​21
symmetry 761
transthoracic echocardiography  748, 748f
transthoracic echocardiography, long-​axis
parasternal view  8
824 I ndex
aortic stenosis
diagnosis 225t
intraoperative transoesophageal
echocardiography 243
microvascular disease type 2 488
mitral regurgitation and  225–​6, 226f, 227f
mitral stenosis and  226
MSCT 815
rheumatic mitral stenosis and  226, 228f
aortic-​to-​pulmonary collateral flow  803
aortic valve (AV)
3D echocardiography  95
anatomy & function  181
calcification  316, 317f
see also calcific aortic valve stenosis
continuous-​wave Doppler transthoracic
echocardiography 20
CRT  588–​89, 588f, 591
functionally univentricular heart  805
morphology 188t
patient selection in TAVI  316, 317f
post-​intraoperative transoesophageal
echocardiography  244–​5, 245–​6f,
246f, 247–​48
surgery  243–​49, 244f
TAVI  325, 326f, 327t, 328f
transcatheter implantation see transcatheter
aortic valve implantation (TAVI)
transcatheter replacement see transcatheter
aortic valve replacement (TAVR)
transthoracic echocardiography colour-​coded
apical long axis view  16, 22f
transthoracic echocardiography, short-​axis
views  11, 18f
aortic valve area (AVA)
3D echocardiography  95
effective measurement  165–​6t, 168–​70, 168f
transoesophageal echocardiography  164
transthoracic echocardiography  164
aortic valve regurgitation  181–​90
aetiology  181–​2
aortic valve implantation by TAVI  325
cardiac magnetic resonance  187
consequences 186
functional classification  183t
index 325
mechanisms  181, 182–​3, 182f
M-​mode  186
quantitative parameters  185–​6, 185f
semi-​quantitative parameters  184, 184f
severity assessment  183–​4
severity indices  186–​7, 186t, 187f, 188t
two-​dimensional (2D) findings  186
aortic valve replacement (AVR)  164
aortic valve stenosis (AVS)  161–​79
3D echocardiography  95
aetiology  161–​3
anatomically severe  164
asymptomatic severe  175, 176t, 177, 177t
calcific see calcific aortic valve stenosis
cardiac chamber damage  173–​5
concomitant valvular disease  175
congenital  161–​2, 162f
Doppler velocity index vs. velocity ratio  170
echocardiographic parameters of
severity 162t, 164, 165–​6t
haemodynamic severity quantitation  164–​73
integrative management  165–​6t, 175, 176t
low gradient with reduced LV
function  170–​1, 172f
morphology assessment  161–​4
multimodal imaging  165–​6t, 170–​1
multiparameter severity grading  165–​6t, 170
normal-​flow, low-​gradient  171, 173f
paradoxical low-​flow, low-​gradient with
preserved LV function  165–​6t, 171
progression assessment  171, 173
rheumatic  162, 162f
severity measures  163–​4, 165–​6t, 169f, 170
transvalvular jet velocities/​pressure gradients
see transvalvular jet velocities/​pressure
gradients
aortitis  767–​69, 767f
apical 2-​chamber transthoracic
echocardiography  20–​1, 23f
apical 4-​chamber transthoracic
echocardiography  21–​2, 24f, 522
apical three-​chamber (A3C) view  161
apolipoprotein A  646
AQUAMARINE pilot study  472
AR see aortic regurgitation (AR)
arrhythmogenesis 569f, 570
cardiomyopathy  538, 538t, 539f
arrhythmogenic right ventricular
cardiomyopathy (ARVC)  681–​7, 682f
CMR 685
diagnosis  681–​2, 683–​4b
family history  687
functional evaluation  682, 683–​4b, 684
morphological evaluation  684–​5
myocardial fibro-​fatty replacement  686, 687f
repolarization/​depolarization
abnormalities  686–​7, 687f
artificial chord implantation, transcatheter
mitral valve interventions  350, 352, 352f
artificial intelligence, CT  154–​5, 155f
ARVC see arrhythmogenic right ventricular
cardiomyopathy (ARVC)
ascending aorta
dilation & AVS  175
patient selection in TAVI  318–​21, 319f, 320f
transoesophageal echocardiography short-​
axis view  33, 34f
transthoracic echocardiography, long-​axis
parasternal view  8
ASE see American Society of
Echocardiography (ASE)
ASH (asymmetric septal hypertrophy)  637f
ASO (Amplatzer septal occluder)  290–​1, 292f,
293f, 298
Assessing Diagnostic Value of Non-​invasive
FFR-​CT in Coronary Care (ADVANCE)
Registry  152, 441
asymmetric septal hypertrophy (ASH)  637f
asymptomatic severe AVS  175, 176t, 177, 177t
atheroma, intraoperative transoesophageal
echocardiography 235
atherosclerosis
aortic aneurysms  773, 773t
cardiac hybrid imaging  139
coronary artery imaging  468, 469t
definition 467
pathophysiology  467–​68, 468f
PET  473–​575
thoracic artery disease  761–​2
atherosclerotic burden, CAD  423
atherosclerotic plaques
aortic root  320, 321f
characterization & quantification  438
non-​invasive imaging  467–​79
atherosclerotic ulcers, penetrating see
penetrating atherosclerotic ulcer (PAU)
Athlete’s heart  538–​39
HCM vs. 638
atrial arrhythmias, CMR  306–​7
atrial fibrillation (AF)
anticoagulation contraindication  311
CMR 307
LVDD 516
stroke profile and  638–​39
atrial fibrillation ablation, patient selection  307
atrial fibrosis, CMR  306
atrial function, STE  108
atrial septal defect (ASD)  534
closure  290–​1
CMR 814f
CMR/​MSCT  812–​13
diameter  290–​1
echocardiography  784, 785f, 786
post-​surgery imaging  786
transcatheter closure by 3D
echocardiography 96
atrial switch procedure  798, 798f, 799f
atrio-​oesophageal fistulae, post-​procedural
electrophysiology CT  311
atrioventricular dyssynchrony, CRT  578, 578f
atrioventricular node (AVN)  736–​7
atrioventricular node, cystic tumour of  736–​7
atrioventricular septal defects (AVSDs)  787–​9
haemodynamic assessment  788
post-​surgical imaging  788–​89
types  787–​88
atrium
left see left atrium
right see right atrium
attenuation artefact
echocardiography 16t
PET data correction  46
attenuation correction (AC), SPECT  43
Automatic Intelligence, heart models and 3D
echocardiography  99–​100, 99f, 100f
AV see aortic valve (AV)
AVS see aortic valve stenosis (AVS)
A-​wave duration  38t
A-​wave velocity of pulmonary vein  38t
B
balanced steady-​state free procession
(bSSEP)  69, 306, 666
ball-​caged valves  251, 252f
balloon-​expandable pulmonary valve  377–​78,
378f
balloon valvuloplasty
percutaneous pulmonary valve
replacement  386–​7, 388f
pulmonary stenosis  217
Bard Clamshell  293
basal right ventricle  38t, 521
BAV see bicuspid aortic valve (BAV)
beam width artefact  16t
benign cardiac masses  731–​7
beta-​blockers  64
bicaval view, transoesophageal
echocardiography  33, 35, 35f
bicuspid aortic valve (BAV)  161–​2, 761
post-​intraoperative transoesophageal
echocardiography  245, 246f, 247
regurgitation 182
bileaflet-​tilting-​disc valves  251, 252f
Doppler haemodynamic parameters  261t
studies on  256t
bioprosthetic valves  251, 252f, 266
stented see stented bioprosthetic valves
stentless bioprosthetic valves  257t
bite guard  28
Bjork–​Shiley valves  260, 266

black-​blood sequences
anatomical imaging  811
aortic disease  758, 758f
aortic dissection  763, 764f
atherosclerosis 761
penetrating atherosclerotic ulcer  765–​6, 766f
blood flow velocities, transthoracic
echocardiography 10t
blooming artefacts  90, 116
blunt injury, penetrating atherosclerotic
ulcer  777–​78
blurring artefacts  90–​1
bolus tracking, CT  64
breath holding
CT 64
MRI 69
British Society of CMR Valve Consortium  323
bSSEP (balanced steady-​state free
procession)  69, 306, 666
B-​type natriuretic peptide (BNP)  538–​39
C replacement  384, 386, 387f, 388f
CA see cardiac amyloidosis (CA)
CAC see coronary artery calcium (CAC)
CACS (coronary artery calcium score)  410–​11
CAD see coronary artery disease (CAD)
cadmium-​zinc-​telluride (CZT)  50
calcific aortic valve stenosis  162–​3, 162f
MSCT  163–​4
quantification 162t, 163, 163f
calcification
aortic root  320
aortic valve regurgitation  183
calcium score
CAD  435–​6
valvular heart disease  224
canakinumab 470
cancer see cardio-​oncology
cancer therapeutics-​related cardiac dysfunction
(CTRCD)  107, 614–​15, 675
cannula displacement, extracorporeal
support 606f, 608–​9, 609f
carbon-​11(11C)-​labelled acetate  554
carbon-​11(11C)-​labelled hydroxyephedrine
(HED) 49
carbon-​11(11C)-​phenylephrine PET  568
carbon-​11(11C)-​Pitsburgh compound (PiB)  651
cardiac allograft vasculopathy (CAV)  489–​90
cardiac amyloidosis (CA)  617, 618f
HCM vs.  636, 637f, 638
SPECT 47
cardiac catheterization  258, 339
cardiac CT  57–​65
acute cardiovascular disease  753–​4
aortic annulus size  316, 318, 318f, 319f
aortic dissection  763
artificial intelligence  154–​5, 155f
basic principles  57–​58
CAD  421–​2
cardiac tamponade  705
cardio-​oncology  620, 621, 622, 623t
CMR vs.  809–​10
constrictive pericarditis  711, 712f
contrast material  63
coronary artery lesions  150
data acquisition  57
detection row number  57
dual-​energy computerized tomography  62–​3,
62f, 149–​0, 149f
dynamic perfusion  150
ECG synchronized acquisition mode  59–​60,
59f, 60f, 130
ECG-​triggered axial acquisition  147, 148f
electrophysiology  308–​11
equipment changes  146t
fractional flow reserve  151–​2, 151f, 152f
future opportunities  153
HCM  632, 641
historical development  145–​6
image noise  61
improvement possibilities  146–​7
infective endocarditis  279, 280f, 280t
iterative reconstruction  148–​50, 149f
lipoma  735–​6
LV mechanical dysfunction  583
mitral valve stenosis  197
myocardial perfusion imaging  150–​1, 150f,
441, 442f
myxoma  733, 734f
non-​femoral TAVI access  321–​2, 323f
paravalvular leak closure  298
patient selection  63–​4, 63t
percutaneous pulmonary valve
pericardial disease  621
pericardial effusion  701–​2, 703f, 704f
post-​procedural electrophysiology
imaging  311, 312f
prerequisites for  146t
procedural imaging  310–​11, 310f, 311f
pulmonary valve  219
quantitative coronary plaque
evaluation  153–​4, 153f
radiation exposure  63
randomics  154–​5
recent developments  153
scale coverage  60
single-​beam acquisition  147, 147t
spatial resolution  58, 60, 61f
temporal resolution  58, 60–​1, 61f
tricuspid valve  214, 215f, 216
valvular heart disease  620
vascular diseases  622
see also single-​photon emission computed
tomography (SPECT)
cardiac hybrid imaging  129–​37, 130f
CAD 414
clinical impact  135, 137
DCM  670, 670f
dedicated cardiac-​only SPECT scanners  137
future perspectives  139, 139f
image fusion software  131, 133, 133f
imaging protocols  133–​4, 134t
myocardial blood flow
quantification  137, 138f
myocardial perfusion imaging  130
myocarditis  717–​18
novel software  138f, 139
prognostic value  135
radiation safety  134–​5
rationale for  129–​31
scanners  131, 133
studies in  135
cardiac implantable electrical device-​related
infective endocarditis (CIEDIE)  277f, 278,
278b, 280f
cardiac implantable electrical devices
(CIED)  304–​5
cardiac innervation imaging  565–​76, 566f
arrhythmogenesis 569f, 570
CAD  568–​70, 569f
dysautonomias  573–​4
HF 569f, 570–​3
125
I-​MIBG imaging  565–​68
I n de x 825
cardiac lymphoma  732t, 738–​39, 739f
cardiac magnetic resonance (CMR)  471–​3,
809–​21
acute aorta syndrome  767
advantages/​disadvantages  471–​2
angiography 472
angiosarcoma 737
aortic aneurysms  762
aortic annulus size in TAVI  318
aortic dissection  763
aortic valve regurgitation  187, 189f, 815
ARVC  682, 685, 685f, 685t
ASD 814f
atherosclerosis  761–​2
atrial arrhythmias  306–​7
atrial fibrillation  307
atrioventricular septal defects  789
CAD in cardio-​oncology  619
cancer therapeutics-​related cardiac
dysfunction  615, 675
cardiac lymphoma  739
cardiac masses  731, 732t
cardiac metastases  740
cardiac tamponade  705
cardiac thrombi  741
cardio-​oncology  620, 623t
Chagas’ disease  672–​673, 673f
characteristics 810t
clinical applications  305–​6
coarctation of the aorta  791, 815f
congenital heart disease  784, 809, 811f
congenitally corrected transposition of the
great arteries  801
constrictive pericarditis  711, 712f
CT and  766–​7
CTCA vs.  471–​2
CT vs.  809–​10
DCM diagnosis  662
Eisenmenger syndrome  804
electrophysiological procedures  303, 308, 309f
evidence for  472
fibroma 735
Fontan circulation  820f
functional imaging  811–​19, 814f
future directions  472
haemangioma 735
HCM  630, 631f, 633, 638
idiopathic DCM  665–​7
image analysis  810
infiltrative cardiomyopathy  648–​7, 653f, 654f
ischaemia  447–​48
lipoma  735–​6, 737f
LVEF 615
LV non-​compaction  676f, 677, 677f
microvascular disease type 1 and 486–​7
microvascular disease type 2 488
mitral valve regurgitation  208, 208f, 209f
mitral valve stenosis  193, 194f
myocardial perfusion see myocardial
perfusion-​CMR
myocardial viability  555–​59, 556f
myocarditis  670–​1, 716, 718–​28, 720t, 727f
myxoma 733
neuromuscular disorders  674
paravalvular leak closure  298–​9
patent ductus arteriosus  789–​90
penetrating atherosclerotic ulcer  766f
pericardial disease in cardio-​oncology  621,
621f
pericardial effusion  702–​3
peripartum cardiomyopathy  676
pitfalls & limitations  768–​69
826 I ndex
cardiac magnetic resonance (CMR)  (cont.)
pre-​transcatheter mitral valve
interventions 339
protocols 810
pulmonary valve  218–​19, 219f
rhabdomyoma 732
RV/​LV function  504–​5, 504t, 505f
RV outflow tract dysfunction  816
RV outflow tract obstruction  792
RV volume  523
sarcoidosis 655
Takotsubo cardiomyopathy  691, 691f
technical approach  304–​5
tetraology of Fallot  797
tricuspid valve  213–​14, 214f
valvular heart disease  224, 620
valvular prostheses assessment  258–​59, 260f
ventricular arrhythmias  303–​6, 304f
vulnerable plaque  472, 473f
see also magnetic resonance imaging (MRI)
cardiac magnetic resonance spin-​echo imaging
pulse sequences (black blood sequencing)
see black-​blood sequences
cardiac masses  731–​44
benign tumours  731–​7
classification 731
CMR 732t
contrast echocardiography  114, 115f
differential diagnosis  732t
epidemiology 731
malignant tumours  737–​40
myocardial contrast echocardiography  118
cardiac metastases  739–​40, 740f, 741f
cardiac mitral regurgitation (CMR)  552
Cardiac Resynchronization Heart Failure
(CARE-​HF)  588
cardiac resynchronization therapy (CRT)  553,
573, 577–​86
clinical response & reverse remodelling  593
CT contraindications  311
echocardiography & patient selection  579,
581, 583
electrophysiology and  305–​6
follow-​up  591–​4
idiopathic DCM  664
imaging dyssynchrony  578–​3
imaging viability  583
limitations 591
LV diastolic function  593
LV reverse remodelling  593
mitral regurgitation  593
optimization  587–​97, 588f
optimization with imaging  588–​89
patient selection  305, 305f
RCTs  592, 593f
response definition  577–​78
RV function  593
super-​responders  592–​3, 594f, 595f
venous anatomy imaging  584
cardiac stress  404–​5
cardiac tamponade  609, 609f, 697–​706
clinical presentation  699–​700
imaging  703–​5, 705f
management  705–​6
pathophysiology  697–​698, 698f
cardiac thrombi  740–​1, 741f, 742f
cardiac wall deformations  103, 104f, 105
Cardioband devices  350, 365, 372t
Carbomedics bileaflet prostheses  242
cardiomyopathy
dilated see dilated cardiomyopathy (DCM)
infiltrative see infiltrative cardiomyopathy
cardio-​oncology  613–​26, 675–​6
CAD  619–​19
imaging  613–​14, 623t
myocardial disease  614
myocarditis  617–​18
pericardial disease  620–​1
pulmonary hypertension  622
STE 107
valvular heart disease  619–​20
vascular diseases  621–​2, 622f
ventricular function/​volumes/​
mass  614, 615–​16
cardiopulmonary exercise testing (CPET)  381
cardiotoxic agents
DCM and  674–​6
LVEF 616
Cardiovascular RISk Prediction using
Computed Tomography (CRISP-​CT)  444
CARE-​HF (Cardiac Resynchronization Heart
Failure) 588
Carillon Mitral Contour system  350
C-​arm view, echocardiography–​fluoroscopy
fusion imaging  122, 122f
Carpentier’s classification  182
CATCH (coronary atherosclerosis T1-​
weighted Characterization with integrated
anatomical reference)  472, 473f
CAV (cardiac allograft vasculopathy)  489–​90
Cavi device  373t
CBCMR, competence training  81t
ccMRA (contrast-​enhanced magnetic resonance
angiography)  811, 812f, 813f
ccTGA (congenitally corrected transposition
of the great arteries)  799, 800f, 801,
818, 819f
CE-​IR (contrast-​enhanced inversion recovery)
MRI  73–​4, 74f
CE MARC II study  456
CE-​MARC study  456, 457
CE-​MRA see contrast-​enhanced MR
angiography (CE-​MRA)
11
C-​epinephrine PET, postganglionic
presynaptic sympathetic innervation  568
cerium-​doped gadolinium oxyorthosilicate
(GSO:Ce) 46
Certification Board in Nuclear Cardiology  82
Certification Board of cardiovascular computed
tomography 82
CFR see coronary flow rate (CFR)
Chagas’ disease
CMR  672–​673, 673f
DCM and  672–​4
echocardiography 672
nuclear imaging  672
CHD see congenital heart disease (CHD)
chelation therapy, myocardial iron loading  656
chemotherapy, tissue damage  613
chest pain, CAD  430–​2, 431f, 432f
chest X-​ray
congenital heart disease  783
constrictive pericarditis  709
pericardial effusion  700
CHF see congestive heart failure (CHF)
chordae tendinae  200
chronic coronary artery disease  552–​3
chronic coronary syndrome  395
chronic heart failure  497
chronic ischaemic functional mitral
regurgitation  397–​8
chronic kidney disease  486
chronic pulmonary hypertension  537–​8
11
C-​hydroxyephedrine (11C-​HED)  568
CIED (cardiac implantable electrical
devices)  304–​5
CIEDIE (cardiac implantable electrical device-​
related infective endocarditis)  277f, 278,
278b, 280f
cinefluoroscopy  258, 258f, 258t, 259f
cine-​magnetic resonance sequence, aortic
disease 757
circumference strain  105, 635
clinical expertise, training  80
Clinical Outcomes Utilizing Revascularization
and Aggressive Drug Evaluation
(COURAGE) trial  407, 439
CMD see coronary microvascular
dysfunction (CMD)
CMR see cardiac magnetic resonance (CMR)
CMR (cardiac mitral regurgitation)  552
coarctation of the aorta  790–​1, 790f
CMR 815f
CMR/​MSCT  815–​16
transposition of the great arteries and  797
COCATS (Core cardiovascular Training
Statement) 82
cold pressure testing (CPT)  484
collimation, CT  58
colour Doppler echocardiography  3
aortic valve regurgitation severity  183
coarctation of the aorta  790
Ebstein’s anomaly  793–​4
Eisenmenger syndrome  804
optimization 10t
patent ductus arteriosus  789
prosthetic valve obstruction  262, 263f
pulmonic stenosis  536
colour wave Doppler (CWD), pulmonary
valve 217
combined transcatheter mitral procedures  354
comet tail artefact  15t
common atrioventricular valve  788, 788f
competence  80, 82
levels of  80, 81f
multimodality imaging  83
Compton radiation scatter, SPECT  43
computed tomographic coronary angiography
see CT coronary angiography (CTCA)
Computed TomogRaphic Evaluation of
Atherosclerotic DEtermiNants of
Myocardial IsChEmia (CREDENCE)
trial 154
computed tomography (CT)
cardiac see cardiac CT
coronary angiography see CT coronary
angiography (CTCA)
multislice see multislice computed
tomography (MSCT)
CONFIRM registry  471
CONFIRM risk score  439–​40
congenital aortic valve stenosis  161–​2, 162f
congenital heart disease (CHD)  783–​807, 809
abnormal cardiovascular connections  784
echocardiography  784–​804
infective endocarditis and  805
non-​invasive imaging  783–​4
pregnancy and  804–​5
stress echocardiography  805
congenitally corrected transposition of the great
arteries (ccTGA)  799, 800f, 801, 818, 819f
congenital mitral valve anomalies  794–​5
congenital ventricular septal defect  291
congestive heart failure (CHF)  502
cardio-​oncology  675
preserved systolic function and  503

constrictive pericarditis (CP)  707–​13
cardio-​oncology  620
clinical presentation  708
differential diagnosis  708–​9, 709t
invasive haemodynamics  711
LVDD  516–​17
management principles  708–​9
non-​invasive imaging  709–​13, 710f,
711f, 712f
pathophysiology  707–​8, 708f, 708t
restrictive pericarditis vs. 713
Continuous Quality Improvement  82
continuous wave (CW) Doppler
aortic valve regurgitation severity  183, 184
mitral valve regurgitation  202, 204f
patent ductus arteriosus  789
transoesophageal echocardiography/​
transthoracic echocardiography  38
transvalvular jet velocities
measurement 162t, 164, 165–​6t, 166f, 167f
contractile reserve, myocardial viability  547
contrast agents  111–​12
cost-​effectiveness  115–​16
CT 63
MRI 68
safety of  115
contrast echocardiography  111–​21
cancer therapeutics-​related cardiac
dysfunction 615
contrast agents  111–​12
future perspectives  118
imaging modalities  112–​13
LV opacification  113–​14, 113f, 114b
myocardial see myocardial contrast
echocardiography (MCE)
myocardial viability  546f, 548
myocardium see myocardial contrast
echocardiography (MCE)
principles  112–​13, 112f, 114f
stress echocardiography and  114, 115f
contrast-​enhanced inversion recovery (CE-​IR)
MRI  73–​4, 74f
contrast-​enhanced magnetic resonance
angiography (ccMRA)  811, 813f, 813f
contrast-​enhanced MR angiography (CE-​MRA)
aortic aneurysms  762, 763f
aortic disease  759, 761f
aortic dissection  763, 764f
aortic measures  760, 760f
aortitis 768
atrial fibrillation  307
CORE320 study  150
Core cardiovascular Training Statement
(COCATS) 82
Cormier score  195t
coronary arteries  146, 147, 636
coronary artery
atherosclerosis  468, 469t
lesions 150
magnetic resonance angiography  75, 76f
stenosis 798
coronary artery calcium (CAC)  435, 436f
CAD  421–​2
ECG–​CT synchronized acquisition
mode 130
coronary artery calcium score (CACS)  410–​11
coronary artery disease (CAD)  395–​401
calcium score  435–​6, 436f
cardiac hybrid imaging  139
cardiac innervation imaging  569–​70, 569f
cardio-​oncology  618–​19
CMR  447–​65
CT  151, 441–​2, 442f
current guidelines  413–​14, 414t
DCM vs.  662–​3
diagnosis  405–​8
functional assessment  441–​2, 442f
future work  414
imaging cost-​effectiveness  411–​13, 413f
magnetic resonance angiography  75
MDCT see coronary artery disease MDCT
myocardial contrast echocardiography  117–​18,
117f
nuclear cardiology  403–​19
PET see coronary artery disease PET
pretest likelihood & imaging
strategy  404, 404f
prior revascularization with chest pain  430–​2,
431f, 432f
prognosis  408–​11, 409f, 413f
risk stratification  398–​9
SPECT 47
spectrum of  403
stable  426, 427f, 428, 428f, 429f
STE  107, 107f
stress echocardiography  398
symptomatic patient evaluation  429–​30,
429f, 430f, 431f
coronary artery disease MDCT  435–​45
future direction  442–​4, 443f
coronary artery disease PET  409, 422f
atherosclerotic burden  423
patient-​centred clinical applications  424–​32,
424f, 425f
radiopharmaceuticals  422, 422t
technical considerations  421–​2
coronary atherosclerosis T1-​weighted
Characterization with integrated
anatomical reference (CATCH)  472, 473f
coronary computed tomography angiography
(CCTA)  150, 436, 437f
CAD in cardio-​oncology  619
microvascular disease type 1 486
coronary flow rate (CFR)
microvascular disease type 1 485–​6
microvascular disease type 3 488
myocardial contrast echocardiography  117
myocardial viability  554
SPECT 50
systemic hypertension  486
coronary flow reserve (CFR)  482, 484, 486f
CAD PET  423
evaluation of  399
myocardial contrast echocardiography  117
myocardial ischaemia  636
myocardial viability  549
coronary heart disease
assessment  438–​1
low-​attenuation plaques  438–​39, 438f
napkin-​ring sign  439
positive remodelling  439
quantitative plaque assessment  440–​1, 440f
semi-​quantitative plaque burden
assessment  439–​40
spotty calcium  439
TAVI risk stratification  324–​5
coronary microcirculation
anatomy  482, 483f, 484t
pathophysiology  482, 485f
coronary microvascular dysfunction (CMD)  481
coronary flow reserve and  482
PET 48
coronary ostia height  320, 321f
coronary sinus  23, 27f, 31, 32f
I n de x 827
ASD  786, 786f
defects 534
COURAGE (Clinical Outcomes Utilizing
Revascularization and Aggressive Drug
Evaluation) trial  407, 439
CP see constrictive pericarditis (CP)
CPET (cardiopulmonary exercise testing)  381
CPT (cold pressure testing)  484
CREDENCE (Computed TomogRaphic
Evaluation of Atherosclerotic
DEtermiNants of Myocardial IsChEmia)
trial 154
CRT see cardiac resynchronization
therapy (CRT)
CSALVOT 169
CT coronary angiography (CTCA)  146,
339, 468–​1
CAD 403
clinical evidence  470–​1
CMR vs.  471–​2
ECG hybrid imaging  130
future directions  471
myocardial perfusion imaging and  135
paravalvular leak closure  298, 299f
pre-​transcatheter mitral valve
interventions 339
stable CAD  405–​6
vulnerable plaques  469–​70, 470f
CTRCD (cancer therapeutics-​related cardiac
dysfunction)  107, 614–​15, 675
CW Doppler see continuous wave (CW) Doppler
cystic tumour of atrioventricular node  736–​7
D
Danon disease  655
data acquisition
CT 57
transthoracic echocardiography  7–​8, 11–​14,
16, 20–​5
data sets, 3D echocardiography  89–​1, 89f, 90f
daunorubicin 675
DCM see dilated cardiomyopathy (DCM)
DECAAF study  307
DECT (dual-​energy computerized
tomography)  62–​3, 62f, 149–​50, 149f
degenerative calcific aortic valve regurgitation  182
degenerative mitral regurgitation (DMR)  344
degenerative mitral valve stenosis  196–​7
delayed enhancement multidetector computed
tomography (DE-​MDCT)  717, 718f
DENSE (displacement encoding with simulated
echoes) 667
descending aorta
diastolic flow reversal  183–​4
normal structure  772
short-​axis transoesophageal
echocardiography  36, 36f
transthoracic echocardiography, long-​axis
parasternal view  8
Detection of Silent Myocardial Ischemia in
Asymptomatic Diabetes (DIAD)  410
diabetes mellitus
CAD 426
CAD prognosis  410
cardiac innervation imaging in
dysautonomias  573–​4
microvascular disease type 1 and 486
DIAD (Detection of Silent Myocardial Ischemia
in Asymptomatic Diabetes)  410
Diamond and Forrester predictive tables  404
Diamond–​Blackfan anaemia  656, 656f
diastolic dysfunction, cardio-​oncology  614
828 I ndex
diastolic flow reversal  183–​4
diastolic stress testing  514, 515f
dilated cardiomyopathy (DCM)  661–​80
aetiology 662t, 663
CAD vs.  662–​3
cardiotoxic agents and  674–​6
Chagas’ disease and  672–​7
definition 661
diagnosis 661
idiopathic see idiopathic dilated
cardiomyopathy
imaging 306
myocarditis and  668–​1
neuromuscular disorders and  674
nuclear imaging  667–​68, 667f
pregnancy/​parturition and  676
primary valve disease vs. 663
dilated inferior vena cava  704–​5, 705f
dipyridamole stress echocardiography  398,
405t, 548
Direct Observation of Practical Skills (DOPS)
training 80
discordant grading, AVS  166f, 170
displacement encoding with simulated echoes
(DENSE) 667
distal coronary segment lesions  135, 136f
DMR (degenerative mitral regurgitation)  344
dobutamine-​cardiac magnetic resonance
imaging 405t, 448–​2
diagnostic criteria  449, 450f, 451f
diagnostic performance  449, 451t
imaging techniques  448–​49
ischaemia 447
limitations 450
myocardium functional assessment  449–​50
prognostic value  450, 452
protocol  448, 448f, 449f
safety of  450, 452
stress agents  448
dobutamine stress echocardiography
(DSE) 398
cancer therapeutics-​related cardiac
dysfunction 615
LV 93
mitral valve regurgitation  208
myocardial viability  548, 557, 557f
myocardial viability echocardiography  547
dopamine stress echocardiography  553
Doppler 4-​chamber transthoracic
echocardiography  22–​3, 26f
Doppler-​derived diastolic indexes  614
Doppler echocardiography
global systolic function  498
myocardial deformation imaging  396–​7
paravalvular leak closure  295
spectrum brightness  10t
spectrum sharpness  10t
tissue imaging see tissue Doppler
imaging (TDI)
transmitral flow imaging see transmitral
Doppler flow
transthoracic see transthoracic Doppler
echocardiography (TTDE)
tricuspid valve  213
valvular heart disease  224
valvular prostheses data  257, 256–​7t
volumetric method  185–​6, 205
see also tissue Doppler imaging (TDI)
Doppler haemodynamic parameters  261–​2t
DOPS (Direct Observation of Practical Skills)
training 80
double orifice mitral valve  794
doubly committed ventricular septal
defects 786
doxorubicin 675
dropout artefacts  90
DSE see dobutamine stress
echocardiography (DSE)
dual-​chamber pacing, HCM  641
dual-​energy computerized tomography
(DECT)  62–​3, 62f, 149–​50, 149f
dual lumen cannulation  606–​7
dual-​source computed tomography (DSCT)  60
Duke criteria  272–​6, 273b, 280
dynamic exercise, cardiac stress  404–​5, 405t
dynamic perfusion, CT  150
dyslipidaemia 486
dyspnoea on exertion, LVDD  514
E pulmonary artery systolic pressure  533–​4,
e’  509–​10
LVDD diagnosis  513–​14
EACVI see European Association of
Cardiovascular Imaging (EACVI)
EAM (electro-​anatomical mapping)  304
E/​A ratio  509, 510f
constrictive pericarditis  517
standard values  39t
early diagnostic velocity, mitral
annulus  509–​10
Ebstein’s anomaly  793–​4, 793f
CMR/​MSCT  817, 817f
ECG see electrocardiography (ECG)
echocardiography  3–​39
acute CAD  399
acute cardiovascular disease  753–​4
acute coronary syndromes & myocardial
viability  551–​3
angiosarcoma  737, 738f
ARVC diagnosis  682, 682f
ASD  534, 536t, 784, 786
cancer therapeutics-​related cardiac
dysfunction 675
cardiac metastases  740, 740f, 741f
cardiac tamponade  703, 705f
cardiac thrombi  741
cardio-​oncology  614, 619–​20, 620f, 621f
Chagas’ disease  672
colour Doppler see colour Doppler
echocardiography
congenital heart disease  784–​804, 809
constrictive pericarditis  708f, 709–​10,
710f, 711f
contrast see contrast echocardiography
CRT  579, 579f, 580f, 581, 583, 583f, 591
DCM  669–​70, 674, 674f
definition 3
documentation 3
ECG vs. 552
electrophysiological procedures  303
exercise echocardiography see exercise
echocardiography
fibroma  735, 735f
fluoroscopy fusion imaging see
echocardiography–​fluoroscopy fusion
imaging
haemangioma  734–​5
HF imaging  502
idiopathic DCM  663–​5, 663f, 664f, 665f
infective endocarditis  271–​79, 272f
infiltrative cardiomyopathy  646–​48, 647f,
652–​3, 653f
lipoma  735, 736f
LV diastolic function  509–​10
LV filling pressure  510–​11, 511f
LV function  395–​6, 396f, 503–​4
LV non-​compaction  676–​7
M-​mode see M-​mode echocardiography
myocardial contrast echocardiography
see myocardial contrast
echocardiography (MCE)
myocarditis  669–​70, 715–​16, 716f
myxoma  732–​3, 733f
neuromuscular disorders  674, 674f
papillary fibroelastoma  734, 735f
paravalvular leak closure  295, 296f
pericardial disease  620, 620f, 621f
pericardial effusion  700–​1, 701f, 702f
peripartum cardiomyopathy  676
prosthetic valve obstruction  262, 263f
prosthetic valve regurgitation  264–​5
533f
pulsed-​wave Doppler see pulsed-​wave
Doppler (PW) echocardiography
rhabdomyoma 732
right atrial pressure  532–​3, 532t
right atrium  521, 521f
RV 520
RV assessment  540t
RV diastolic function  529–​30
RV hypertrophy  524
RV/​LV function  504t
RV size  521–​2, 522f
RV systolic function  526–​29
sarcomas  737–​38
STE see speckle-​tracking
echocardiography (STE)
Takotsubo cardiomyopathy  689, 690f
three-​dimensional see three-​dimensional
(3D) echocardiography (3DE)
transcatheter mitral valve
interventions  337–​38
transthoracic see transthoracic
echocardiography (TTE)
two-​dimensional see two-​dimensional (2D)
echocardiography
valvular heart disease  619–​20
valvular prostheses assessment  252–​5, 253f
ventricular septal defect closure  294–​5
echocardiography–​fluoroscopy fusion
imaging  121–​5, 122f
left atrial appendage closure  124, 125f
MitraClip procedure  125, 125f
paravalvular leak closure  125, 126f
simultaneous views  122–​3, 123f
TAVI procedure  123, 123f
tracking phase  122
transeptal puncture  124, 289
transoesophageal echocardiography
probe 122
ECMO (extracorporeal membrane
oxygenation) 602t, 605–​7, 605f, 606f, 607f
ECV see extracellular volume (ECV)
ED (effective radiation dose), CT  57
edge-​to-​edge repair, transcatheter mitral
valve 344
EDV (end-​diastolic volume)  69
Edwards SAPIEN valve  378, 378f
E/​e’ ratio
constrictive pericarditis  517
LVDD diagnosis  513–​14
E/​E’ ratio
Doppler 4-​chamber transthoracic
echocardiography  22–​3, 26f
standard values  39t

EF see ejection fraction (EF)
effective orifice area (EOA)
bioprostheses 255
valvular prostheses  251, 252
effective radiation dose (ED), CT  57
effective regurgitant orifice (ERO)  297
effective regurgitant orifice area (EROA)  184,
187, 344
3D echocardiography  95–​6
mitral valve regurgitation  208
eighteen-​segment model, regional LV systolic
function 499
Eisenmenger syndrome  803–​4
ejection fraction (EF)
echocardiography 504t
global systolic function  498
idiopathic DCM  664
MRI 69
elastin 472
electro-​anatomical mapping (EAM)  304
electrocardiography (ECG)
ARVC diagnosis  68124
CTA hybrid imaging  130
CT synchronized acquisition mode  59–​60,
59f, 60f, 130
echocardiography vs. 552
infiltrative cardiomyopathy  646, 647f,
652, 652f
stress ECG  405–​6
Takotsubo cardiomyopathy  689, 689f, 690b
triggered axial acquisition  147, 148f
electrocardiography gating
aortic disease  758
equilibrium radionuclide
ventriculography 505
MDCT  773, 772t
SPECT  42–​3
electrophysiology  303–​14
cardiac CT  308–​11
CMR  310, 309f
CRT device and  305–​6
echocardiology 303
registration with imaging  306
EMB (endomyocardial biopsies)  724–​5
embolism risk, valvular prostheses  282
end-​diastolic volume (EDV)  69
endocarditis  271–​83
infective see infective endocarditis (IE)
valvular prostheses  266–​7, 267f, 268f, 269f
endomyocardial biopsies (EMB)  724–​5
end-​systolic triggering, myocardial contrast
echocardiography 116
end-​systolic volume (ESV)  69
enzyme replacement therapy (ERT)  651–​2
EOA see effective orifice area (EOA)
epicardial arterial flow evaluation  397
epirubicin 675
equilibrium radionuclide ventriculography
(ERNV) 672
ERNV (equilibrium radionuclide
ventriculography) 672
ERO (effective regurgitant orifice)  297
EROA see effective regurgitant orifice
area (EROA)
ERT (enzyme replacement therapy)  651–​2
ESC see European Society of Cardiology (ESC)
ESCel 80
ESV (end-​systolic volume)  69
Eulerian (natural) strain  103
Euro Heart Survey  223
European Association for Cardio-​Thoracic
Surgery, valvular heart disease  229
European Association of Cardiovascular
Imaging (EACVI)  81t
CMR (Level 2)  81t
contrast echocardiography  113
CT (Level 2)  81t
EACTA transoesophageal
echocardiography 81t
Euro-​Filling study  515
Expert Consensus Paper (2019), RV size  526t
Recommendations for Cardiac Chamber
Quantification 520
transthoracic echocardiography  81t
European Association of Echo (2003)  82
European Cardiovascular Magnetic Resonance
(EuroCMR) registry  457
European Society of Cardiology (ESC)
acute coronary syndrome guidelines  414, 415
aortic aneurysms  773
aortic valve replacement  164
CAD likelihood  404
CRT 577
DCM diagnosis  662
ischaemia detection guidelines  448
mitral valve stenosis  193
myocardial perfusion-​CMR  457, 458–​59t
valvular heart disease  229
Working group of Nuclear Cardiology and
Cardiac CT  410
European Union (EU), training models  82
Evaluation of Integrated CAD Imaging in
Ischemic Heart Disease (EVINCH)  424
EVEREST criteria  344, 344t
EVINCH (Evaluation of Integrated CAD
Imaging in Ischemic Heart Disease)  424
E’-​wave velocity  38t
exercise echocardiography
CAD 398
LVDD diagnosis  514
mitral valve regurgitation  207–​8
mitral valve stenosis  193
myocardial viability  548
exercise testing
cancer therapeutics-​related cardiac
dysfunction 615
pre-​transcatheter mitral valve
interventions 339
valvular heart disease  224
extracellular volume (ECV)
contrast-​enhanced inversion recovery
MRI 73f, 74
interstitial fibrosis  666
extracorporeal cardiac support  600t,
601t, 604–​8
echocardiographic detected
complications  608–​10
Impella  604, 604f
Impella RP  604
peripheral VA-​ECMO  606, 607f, 608f
TandemLife ProtekDue  605, 605t
VA-​ECMO  602t, 605–​7, 605f, 606f, 607f
ventricular assist devices  602t, 607–​08
extracorporeal membrane oxygenation
(ECMO) 602t, 605–​7, 605f, 606f, 607f
extracorporeal support  599–​12
diagnosis requirements  600, 600t, 601t
diagnostic factors  599–​600
echocardiography
contraindications  600, 602t
indications  599, 600t
respiratory support  602–​4, 602f
underlying pathology  600, 601f
exudative pericardial effusion  700
I n de x 829
F
Fabry cardiomyopathy  652
FAC see fractional area change (FAC)
family history
ARVC 687
LV non-​compaction  688
fast (turbo) spin echo MRI  68
fat attenuation index (FAI)  443
FDG-​PET  49, 131, 473–​4, 475
acute coronary syndromes & myocardial
viability  551, 552f
aortitis 768
atherosclerosis 762
fusion imaging  131
inflammatory aortic disease  774–​5, 775f
myocardial hibernation  546
myocardial viability  554
myocarditis  717–​18
sarcoidosis  655–​6, 655f
femoral artery, patient selection in TAVI  320–​1,
322f
FFR see fractional flow reserve (FFR)
fibrinogen 646
fibroma 732t, 735, 735f
fibrosis
LGE-​CMR images  307
myocarditis  720–​2, 721f, 722f
Fick method  339
field of view (FOV), CT  58
filtered back-​projections
CT 61
SPECT 42
fistulae, infectious endocarditis  276f
five-​chamber transoesophageal
echocardiography  28, 32f
AVS 161
five-​chamber transthoracic
echocardiography  23–​4, 27f
flow mapping, aortic disease  758–​59
fluorine-​18(18F)-​florbetaben  651
fluorine-​18(18F)-​florbetapir infiltrative
cardiomyopathy 651
fluorine-​18(18F)-​fluciclatide  474
fluorine-​18(18F)-​flumetamol  651
fluorine-​18(18F)-​fluorocholine
11C-​PK11195  474
fluorine-​18(18F)-​fluorodopamine PET  568
fluorine-​18(18F)-​flurpiridaz  422, 422t
fluorine-​18(18F)-​labelled-​fluorodeoxyglucose
PET (FDG-​PET) see FDG-​PET
fluorine-​18(18F)-​labelled PET perfusion
tracers 48
fluorine-​18(18F)-​labelled-​sodium fluoride-​PET
(18F-​NaF-​PET)  474
fluorine-​18(18F)-​sodium fluoride PET  762
fluoroscopy
cardiac tamponade  705
echocardiography fusion imaging see
echocardiography–​fluoroscopy fusion
imaging
pericardial effusion  703
transcatheter mitral valve interventions  348
during transcatheter mitral valve
interventions 339
transeptal puncture  288
FMR see functional mitral regurgitation (FMR)
focal coronary artery stenosis  423
focused wide sector ‘zoom’ mode, 3D
echocardiography 88
Fontan circulation
CMR 820f
CMR/​MSCT  818–​19
830 I ndex
Fontan operation  801
FORECAST clinical trial  152
FORMA device  373t
forward flow (FF), aortic valve
regurgitation 187
forward stroke volume, mitral stenosis  341
fossa ovalis (FO)  288
PFO and  290, 291f
4-​chamber transoesophageal
echocardiography  28, 32f
4D flow sequence, aortic disease  758–​59
fractional area change (FAC)
RV area  522–​3
tricuspid annular plane systolic
excursion 524t, 527f, 528
fractional flow reserve (FFR)
CAD 403
CTCA 471
reference standard as  456
fractional flow reserve computed tomography
(FFRCT)  151–​2, 151f, 152f
CAD  441–​2, 442f
Frequent Optimization Study Using the
QuickOpt Method (FREEDOM) trial  591
full-​volume mode, 3D echocardiography  88
functional coronary artery disease
assessment  441–​2, 442f
functional-​gated SPECT  42–​3, 44f
functionally univentricular heart  801–​3,
803f, 803f
CMR/​MSCT  818–​19
functional mitral regurgitation (FMR)  344
pathogenesis  397–​398, 398f
fusion imaging  121–​28
3D echocardiography  98–​99, 98f
echocardiology–​fluoroscopy see
echocardiography–​fluoroscopy fusion
imaging
future perspectives  127, 127f
paravalvular leak closure  299, 299f
percutaneous pulmonary valve
replacement  387, 389f
during transcatheter mitral valve
interventions 340
G hydroxyapatite 474
gadolimium-​68(68Ga)-​DOTATATE PET
tracers 474
gadolinium
MRI contrast agents  68
myocardial perfusion-​CMR  460
gain artefacts, 3D echocardiography  92
gastric cancer  617f
gastric fundus  33, 35, 37f
general anaesthesia, intracardiac
echocardiography 127
genetics
DCM 662
LV non-​compaction  688
systemic amyloidosis  646
Gianturco coils  293
global left ventricular function  395–​6
global longitudinal strain (GLS)  105, 106–​7,
498–​499
cardio-​oncology  614
infiltrative cardiomyopathy  652
global systolic function  498–​499, 500
GLS see global longitudinal strain (GLS)
glycogen storage disease (GSD)  655
Gorlin formula  192, 227
gradient-​echo pulse sequences, MRI  68
GSD (glycogen storage disease)  655
H ICDs see implantable cardioverter-​defibrillators
haemangioma  734–​5
haemodynamics
ASD  784, 786
atrioventricular septal defects  788
AVS  164–​73
coarctation of the aorta  790–​1, 790f
congenitally corrected transposition of the
great arteries  801
congenital mitral valve anomalies  795
Ebstein’s anomaly  793–​4
LV outflow tract obstruction  793
mitral valve regurgitation  201
MRI 534
patent ductus arteriosus  789
RV outflow tract obstruction  791–​2
tetralogy of Fallot  796
valve deterioration in TAVI follow-​up  327–​28,
328t, 329f
valvular prostheses  255
haemolysis, valvular prostheses  268, 269f
Harlequin syndrome  606
harmonic imaging, contrast
echocardiography  112–​13
heart disease see multiple valvular heart
disease (MVHD)
heart failure (HF)
cardiac innervation imaging  569f, 570–​3
chronic CAD and  552–​3
HCM  638–​39
imaging of  502–​3
heart failure with preserved ejection fraction
(HFpEF)  487, 487f, 515
heart rate variability (HRV), HF & cardiac
innervation imaging  571–​2
heart-​to-​mediastinum ratio (HMR), 125I-​MIBG
cardiac innervation 566, 568, 568f
helical acquisition, CT–​ECG synchronized
acquisition mode  59, 59f
heterograft bioprosthesis,
echocardiography  253, 253f
HFpEF (heart failure with preserved ejection
fraction)  487, 487f, 515
Housefield Units (HU)  57
hybrid imaging see cardiac hybrid imaging
hyperaemic cardiac magnetic resonance
imaging  719, 719f, 720t
hypertensive heart disease, HCM vs. 638
hypertrophic cardiomyopathy (HCM)  629–​43
anatomy assessment  630–​4
clinical profile imaging  638–​39
differential diagnosis  636, 638
dual-​chamber pacing  641
future perspectives  641
imaging  629–​30, 630b, 639–​1
intraventricular obstruction  632–​3, 632f, 633f
LVDD 516
LV diastolic function  635–​6, 635f
medical treatment  633f, 639–​40, 640f
microvascular disease type 2 487–​88
myocardial function  634–​6
STE 107
surgical myectomy  640
tissue characterization  633–​4
see also myocardial ischaemia
hypokinesis 547
I echocardiography  25, 30f
iatrogenic penetrating atherosclerotic
ulcer  777–​78
ICA see invasive coronary angiography (ICA)
(ICDs)
ICE see intracardiac echocardiography (ICE)
ICONIC (Incident COroNary Syndromes
Identified by Computed Tomography)  154
idarubicin 675
idiopathic dilated cardiomyopathy  663–​7
CMR  665–​7
complication detection  665, 665f
echocardiography  663–​5, 665f
real-​time three-​dimensional
imaging  664–​5
STE 664
IE see infective endocarditis (IE)
iliac artery size  320–​1
images
analysis in CMR/​MSCT  810
CT 146
CT matrix  58
formation in MRI  67
fusion software  131, 133, 133f
myocardial perfusion-​CMR  455, 455f, 456f
myocardial viability echocardiography  547
noise in CT  61
transthoracic echocardiography  7, 8f,
9–​10t, 9f
imaging-​guided pericardiocentesis  705–​6
IMH (intramural haematoma)  762, 764–​5,
765f, 766f, 775, 777, 777f
immune checkpoint inhibitors (ICIs)  617–​18
Impella  604, 604f
Impella RP  604
implantable cardioverter-​defibrillators
(ICDs)  549–​0
CAD 398
HF & cardiac innervation imaging  572
MRI contraindications  68
patient selection  305
implants, MRI contraindications  68
IMT (intima-​media thickness)  621–​2
Incident COroNary Syndromes Identified
by Computed Tomography (ICONIC)  154
infarct-​related-​artery (IRA) lesions  415
infectious aortitis  774
infective endocarditis (IE)
3D echocardiography  278–​79, 279f
abscesses  273–​4, 274f
congenital heart disease and  805
CT  279, 280f, 280t
definition 271
Duke diagnostic criteria  272–​6, 273b
echocardiography  271–​79, 272f, 277–​78
fistulae  274, 276f
leaflet aneurysm  276f
MRI  279, 280f
PET  279–​81
post-​percutaneous pulmonary valve
replacement  379–​80
pseudoaneurysms  274, 275f
SPECT  279–​1
transoesophageal echocardiography  280t
valve perforation  275, 276f
valvular prostheses dehiscence  275–​6
vegetations  272–​3, 273f
inferior vena cava (IVC)  519
diameter 38t, 532
dilation of  704–​5, 705f
subcostal Doppler transthoracic
infiltrative cardiomyopathy  645–​59
aetiology 645
cardiac nuclear imaging  649, 651–​2, 651f

cardiovascular magnetic resonance  648–​7
CMR  653–​2, 653f, 654f
ECG  646, 647f, 652, 652f
echocardiography  646–​48, 647f, 652–​3, 653f
nuclear cardiac imaging  654
see also amyloidosis
inflammation
18
F-​FDG PET assessment  131, 132f
vulnerable plaque CTCA  469–​70
inflammatory aortic disease  774–​5
inflammatory myocardial injury  725–​6, 726f
inlet ventricular septal defect (type 3)  292, 292t
Inoue balloon catheter  341
intensive care unit (ICU) see extracorporeal
support
interarterial shunt  534–​5, 534f
interatrial communication defects  24–​5,
28f, 29f
interatrial septum anatomy  287–​88, 288f
internal orifice diameter (IOD)  251
International Organization for Standardization
(ISO) 252
International Registry of Aortic Dissection
(IRAD) 763
interstitial fibrosis  666
interventricular dyssynchrony  578–​79, 578f
interventricular septum  520
intimal tear, aorta  750–​1, 751f
intima-​media thickness (IMT)  621–​2
intracardiac echocardiography (ICE)  125–​7,
126f, 127f
transcatheter mitral valve interventions  340
transeptal puncture  288, 288f, 289
intramural haematoma (IMH)  762, 764–​5,
765f, 766f, 775, 777, 777f
intraoperative echocardiography, aortic
disease 754
intraoperative transoesophageal
echocardiography (IOTEE/​IOTOE)  233–​
50, 234–​5f, 236f
aortic valve repair  244–​5, 245–​6f,
246f, 247–​48
aortic valve surgery  243–​49, 244f
atheroma 235
bicuspid aortic valve repair  245, 247
LV outflow tract obstruction  235
mitral regurgitation  234–​5, 236
mitral valve repair  236–​41, 236f, 237f, 238f
myocardial ischaemia  235
tricuspid aortic valve repair  245, 247, 248f
tricuspid regurgitation  236, 249, 249f
intraventricular dyssynchrony, CRT  578f, 579,
579f, 580f
intraventricular obstruction, HCM  632–​3,
632f, 633f
invasive coronary angiography (ICA)  130
CAD 403
fractional flow reserve CT  152
in-​vivo effective orifice area, valvular
prostheses  254–​5
IRAD (International Registry of Aortic
Dissection) 763
IRA (infarct-​related-​artery) lesions  415
iron overload  656–​7
ischaemia
angiographic CAD  424–​6, 425f, 426f, 427f
CMR  447–​48
ischaemic cascade  404, 404f
ischaemic heart disease, STE  107–​8, 107f
ischaemic mitral regurgitation  553–​4
ISO (International Organization for
Standardization) 252
I n de x 831
isolated cleft, mitral valve  794, 794f dobutamine stress echocardiography  93
isovolumic relaxation time (IVRT)  509, 510f dysfunction  106, 174
iterative reconstruction early diagnostic strain rate  510
algorithms 61 echocardiography  503–​4, 504t
CT  148–​49, 149f Eisenmenger syndrome  804
ivabradine 64 ejection fraction see left ventricular ejection
IVRT (isovolumic relaxation time)  509, 510f fraction (LVEF)
end-​diastolic diameter  38t
K end-​diastolic pressure see left ventricular
knowledge acquisition in training  80 end-​diastolic pressure (LVEDP)
end-​diastolic volume see left ventricular end-​
L diastolic volume (LVEDV)
LAA see left atrial appendage (LAA) end-​systolic volume  577
Lagrangian strain  103 forward stroke volume  201
Lambl excrescences  273, 274f function see left ventricular function
lanthanides 68 mechanical dysfunction  583
LAP see left atrial pressure (LAP) myocardial fibrosis  174
late gadolinium enhancement (LGE)-​CMR outflow tract see left ventricular outflow
cardio-​oncology  616 tract (LVOT)
challenges in  307 pulsed-​wave Doppler transthoracic
constrictive pericarditis  711, 713 echocardiography 20
DCM diagnosis  662 regional systolic function see regional left
HCM  633, 641 ventricle systolic function
infiltrative cardiomyopathy  648, 650f relaxation  509–​10, 510f
LVDD diagnosis  516 remodelling & hypertrophy  173–​4
myocardial fibrosis assessment  386 reverse remodelling  591–​2, 593
myocardial viability  555, 556f, 557 short axis MRI  69, 70f
necrosis/​fibrosis in myocarditis  720–​2, 721f, short-​axis transoesophageal
721t, 722f echocardiography 25
primary amyloidosis  617 short-​axis view, transthoracic
RV function  531–​2 echocardiography  5, 5f, 6f
leaflet aneurysm  275, 276f size  186, 205, 383
Leaman score  440, 469 stress echocardiography  93
left atrial appendage (LAA)  236 systolic function  501–​2, 634–​5, 634f
closure  124, 125f TAVI risk stratification  322–​4, 324f
post-​procedural electrophysiology CT  311 transthoracic echocardiography, long-​axis
thrombus 114 parasternal view  8
transoesophageal echocardiography  33, 34f, transthoracic echocardiography, long axis
310, 311f view  4, 5, 5f, 6f, 7–​8, 7f, 17f
left atrial pressure (LAP) unloading 608
CT 153 untwisting velocity  510
LVDD  510–​11 ventriculography 339
overload in mitral stenosis  341 volume  113–​14, 113f, 114b, 423
left atrial volume indexed to body surface area wall thickness  38t
(LAVi)  512, 513–​14 left ventricle ejection fraction (LVEF)  508
left atrium cancer therapeutics-​related cardiac
3D echocardiography  94 dysfunction 675
diameter  38, 38t cardio-​oncology  614
diastolic function  307, 308f cardiotoxicity definition  616
function  207, 512–​13 CMR 615
longitudinal strain  108, 512 DCM 661
LVDD assessment  513 deterioration 174
reservoir strain  512 echocardiography  510–​11, 511f
size  209, 512 HCM  635, 636
strain measurement  513 mitral regurgitation & aortic
systolic dysfunction  510 stenosis  226, 227f
systolic function  307, 308f nuclear imaging  555
volume 38t, 306, 666 SPECT 47
left-​sided valvular heart disease  227 TAVI risk stratification  324
left ventricle (LV) left ventricle end-​systolic volume (LVESV)  498
3D echocardiography  92–​3, 92f left ventricle filling pressure (LVFP)
afterload in mitral valve regurgitation  201 assessment 511
aortic valve regurgitation  186 left ventricular diastolic dysfunction (LVDD)
AVS and  173–​4 atrial fibrillation  516
contrast echocardiography  113–​14, constrictive pericarditis  516–​17
116, 548 diagnosis  513–​16, 513f, 514f
diastolic compliance  510 HCM 516
diastolic dysfunction see left ventricular LA pressure  510–​11
diastolic dysfunction (LVDD) left atrial function  513
diastolic function see left ventricular diastolic left ventricular diastolic function  507–​18,
function 635–​6, 635f
dimensions & volumes  498 CRT 593
832 I ndex

echocardiography  509–​10 LVEF see left ventricle ejection fraction (LVEF); Medtronic Harmony Transcatheter Pulmonary
invasive evaluation  508–​9 left ventricular ejection fraction (LVEF) Valve  378, 379f
left atrium size  512 LVESV (left ventricular end-​systolic metabolic diseases  638
123
physiology  507–​8 volume) 577 I-​metaiodobenzylguanidine (MIBG) imaging
left ventricular ejection fraction (LVEF)  634 LVNC (left ventricular non-​compaction)  676–​7, CAD 569
3D echocardiography  92 688–​9 cardiac innervation  565–​68, 569, 572
acute coronary syndromes  415 LVOT see left ventricular outflow tract (LVOT) cardio-​oncology  617
CAD 398 LVOTO see left ventricular outflow tract DCM 668
contrast echocardiography  113–​14, 113f, 114b obstruction (LVOTO) infiltrative cardiomyopathy  649
DCM diagnosis  662 SPECT  47, 572, 668
mortality prediction  499 M metoprolol 64
MRI  303–​4 MACE (Major Cardiovascular Adverse MIA (Minimally Invasive Annuloplasty)
SPECT 42 Events) 487 device 372t
standard values  38t MAD (mitral annular disjunction)  238, 239f MIBG imaging see 123I-​
left ventricular end-​diastolic pressure MADIT-​CRT (Multicenter Automatic metaiodobenzylguanidine (MIBG)
(LVEDP)  508–​9, 508f Defibrillator Implantation Trial imaging
DCM 661 With Cardiac Resynchronization microcalcifications  139, 474
increase in  510, 511f Therapy)  592, 593f microvascular disease  481–​93
left ventricular end-​diastolic volume magnetic resonance angiography (MRA)  75 future perspectives  489f, 490
(LVEDV) 498 non-​contrast see non-​contrast-​enhanced historical factors  481
standard values  38t magnetic resonance angiography physiology & dysfunction  482, 484
left ventricular end-​systolic volume (NCE-​MRA) type 1 dysfunction  484–​7
(LVESV) 577 magnetic resonance imaging (MRI)  67–​78 type 2 487–​8, 487f
left ventricular function  186, 205, 395–​6, 396f, aortic disease  757–​9 type 3 488
503–​5, 504t ASD  534, 534f, 536t type 4 488–​90
acute coronary syndromes  415 cardiac function  69, 70f, 71, 71f, 72f microvascular obstruction (MVO)  489
apical  2/​4-​chamber transthoracic cardiac morphology  71, 73–​4 microvascular spasm  484
echocardiography 21–​2 cardio-​oncology  622 mid-​ventricular obstruction, HCM  633
CAD PET  423 contraindications  67–​68 Millipede device  372t
STE 106 contrast agents  68, 73–​4, 74f Minimally Invasive Annuloplasty (MIA)
wall motion  395, 396f haemodynamic assessment  534 device 372t
left ventricular non-​compaction (LVNC)  678–​9, infective endocarditis  279, 280f minimally invasive surgery, mitral valve
688–​689 myocardial perfusion  74, 75f repair 238
left ventricular outflow tract (LVOT) myocardial perfusion imaging with  130 MIP (maximum intensity projections)  75
3D echocardiography  95 myocarditis in DCM  670–​1, 670f, 671f MIRACLE (Multicenter InSunc Randomized
aortic valve area measurement  167f, non-​contrast-​enhanced tissue Clinical Evaluation)  588
169f, 169–​70 characterization  71, 72f, 73, 73f MIRACLE study  592, 593–​4, 593f
AR jet width  184 percutaneous pulmonary valve mirror image artefact  16t
atrioventricular septal defects  788 replacement  383–​4, 384f, 385f, 386, 386f Mistral device  373t
CMR/​MSCT  813, 815 PET and  51, 131, 131f, 13940 MitraClip procedure  125, 125f, 342, 344, 345,
congenitally corrected transposition of the physics of  67 346f, 347–​48t
great arteries and  801 pulse sequences  68–​9 mitral annular disjunction (MAD)  238, 239f
diameter 38t right atrium  521 mitral annular plane systolic excursion
HCM 630 right heart chamber size  520 (MAPSE) 501
obstruction see left ventricular outflow tract RV  520, 524, 526f, 530–​2, 530f, 532f mitral annulus  200, 337
obstruction (LVOTO) RV assessment  540t early diagnostic velocity  509–​10
transposition of the great arteries and  797 RV hypertrophy  524, 526 mitral E/​e’ ratio  511
valvular prostheses  255 scars 583 Mitralign Percutaneous Annuloplasty
left ventricular outflow tract obstruction techniques  69–​9 System 350
(LVOTO)  792–​3 tissue characterization  71, 73–​4 mitral inflow
HCM  632, 632–​3 vascular diseases  622 anterograde velocity  202
intraoperative transoesophageal velocity-​encoded  75, 76f LVDD diagnosis  513
echocardiography 235 see also cardiac magnetic resonance (CMR) mitral paravalvular leak closure  122f
levosimendan 548 Major Cardiovascular Adverse Events mitral regurgitation volume, CMR  666
Libman–​Sachs masses  273 (MACE) 487 mitral stenosis
lidocaine 27 MAPSE (mitral annular plane systolic aetiology 340
lipoma 732t, 735–​6, 736f, 737f excursion) 501 aortic stenosis and  226
liposarcoma  737–​38 maximum intensity projections (MIP)  75 associated valve disease evaluation  340
liver, iron overload  656–​7 MCE see myocardial contrast diagnosis 225t
long axis view, transthoracic echocardiography echocardiography (MCE) haemodynamic consequence assessment  341
see transthoracic echocardiography, long MCQs (multiple choice questions)  80 severity grading  340
axis view MDCT see multidetector computed TAVI risk stratification  324, 325f
low-​attenuation plaques  438–​39, 438f tomography (MDCT) transcatheter treatment see transcatheter
Luminity  111–​12, 112t mean mitral gradient, measurement  193 mitral stenosis treatment
lutetium oxyorthosilicate (LSO)  46 mean pulmonary artery pressure mitral systolic anterior motion  632
lutetium-​yttrium oxyorthosilicate (LYSO)  46 (mPAP)  533–​4 mitral valve
LVDD see left ventricular diastolic Eisenmenger syndrome  804 3D echocardiography  94–​5
dysfunction (LVDD) estimation 363 anatomy & function  199–​200, 200f, 236f
LVEDP see left ventricular end-​diastolic see also pulmonary artery pressure (PAP) annulus 90
pressure (LVEDP) mechanical index (MI), contrast apical 2-​chamber transthoracic
LVEDV see left ventricular end-​diastolic volume echocardiography 113 echocardiography  21, 23f
(LVEDV) mechanical valvular prostheses  251, 252f area see mitral valve area (MVA)

colour-​coded apical long axis view  16, 22f
complex anatomy  337
congenitally corrected transposition of the
great arteries  801
continuous-​wave Doppler transthoracic
echocardiography 20
disease assessment  337–​40
HCM  630–​2
isolated cleft  794, 794f
leaflets  199–​200
long-​axis parasternal view  8
morphology  191, 341
parachute mitral valve  794
pulsed-​wave Doppler transthoracic
echocardiography 20
regurgitation see mitral valve
regurgitation (MR)
repair see mitral valve repair/​replacement
replacement see mitral valve repair/​
replacement
short-​axis views  11, 25
stenosis see mitral valve stenosis
surgery  236, 362
transcatheter replacement see transcatheter
mitral valve replacement (TMVR)
transgastric short-​axis transoesophageal
echocardiography  34, 36f
transoesophageal echocardiography  25
transthoracic echocardiography  8, 11, 16, 22f
mitral valve area (MVA)
3D echocardiography  95
calculation in mitral stenosis  340
measurement  191, 192f
mitral valve clips  97
mitral valve commissure  23, 27f
mitral valve regurgitation (MR)  187, 199–​209
3D echocardiography  94
aetiology 344
aortic stenosis and  225–​6, 226f, 227f
AR and  226–​7
AVS and  175
cardiac magnetic resonance  208, 208f, 209f
colour 4-​chamber view transthoracic
echocardiography 22
consequences of  205, 206f, 207
CRT 593
diagnosis 225t
evaluation of  201–​7, 202f, 203f, 207–​9,
342, 344
exercise echocardiography  207–​8
functional see functional mitral
regurgitation (FMR)
HCM 630
intraoperative evaluation  207, 207f
intraoperative transoesophageal
echocardiography  234–​5, 236
MSCT 209
paravalvular leak and  295–​6
pathophysiology  200–​1, 201f
qualitative assessment  202, 204f
quantitative assessment  204–​5, 205f, 206f
repairability assessment  207
semi-​quantitative assessment  202–​3
severity assessment  202–​5
severity grading  344
TAVI risk stratification  324
transcatheter techniques  342, 343f
mitral valve repair/​replacement
intraoperative transoesophageal
echocardiography  236–​41, 236f, 237f, 238f
post-​pump intraoperative transoesophageal
echocardiography 239f, 241–​3, 242f
pre-​pump intraoperative transoesophageal
echocardiography  238, 240, 240f
mitral valve stenosis  191–​198
3D echocardiography  95
CMR 193
degenerative  196–​7
echocardiography  194–​5, 196
exercise echocardiography  193
imaging in decision-​making  193–​4
MSCT 193
percutaneous mitral commisurotomy  194–​5,
196
quantification of  191–​3
mixed aortic valve disease  227, 229, 230f
mixed mitral valve disease  229
mixed valvular heart disease  227, 229
imaging role  229–​30
M-​mode echocardiography  3, 36, 38
aortic valve regurgitation  186
cardiac tamponade  704
heterograft bioprosthesis  253
subaortic stenosis  792
transthoracic echocardiography, short-​axis
views  11–​12, 18f
modified Duke’s criteria  278
Modified Look-​Locker Inversion Recovery
(MOLLI) 666
modified Simpson’s rule  498
molecular imaging
PET 49
SPECT  47, 48f
MOLLI (Modified Look-​Locker Inversion
Recovery) 666
mortality, valvular prostheses  282
motion artefacts
myocardial perfusion-​CMR  452
PET data correction  46
MPI see myocardial performance index (MPI,
Tei-​index)
MPR (multiplanar reformatting)  75
MPR (myocardial perfusion reserve)  454f
MPRI (myocardial perfusion reserve index)  74
MPS see myocardial perfusion
scintigraphy (MPS)
MR see mitral valve regurgitation (MR)
MRA (magnetic resonance angiography)  75
MRI see magnetic resonance imaging (MRI)
MR-​IMPACT I  456
MR-​IMPACT II  456
MR-​INFORM trial  456–​7
MSCT see multislice computed
tomography (MSCT)
MUGA see multigated radionuclide
angiography (MUGA)
Multicenter Automatic Defibrillator
Implantation Trial With Cardiac
Resynchronization Therapy (MADIT-​
CRT)  592, 593f
Multicenter InSunc Randomized Clinical
Evaluation (MIRACLE)  588
multidetector computed tomography (MDCT)
ARVC 685
CAD see coronary artery disease MDCT
cardiac hybrid imaging  130
electrophysiology  308–​10
myocarditis  717, 718f
pulmonary valve  219
spatial resolution  60, 61f
tricuspid valve  214, 215f
valvular prostheses assessment  259, 260f
multigated radionuclide angiography (MUGA)
cardio-​oncology  623t
I n de x 833
RV/​LV function  505
multimodal imaging
AVS  165–​6t, 170–​1
training and competence  83
multiplanar reformatting (MPR)  75
multiple choice questions (MCQs)  80
multiple gated cardiac blood pool imaging  616
multiple valvular heart disease (MVHD)  225–​7
imaging modalities  225
imaging role  229–​30
MUltisite STimulation In Cardiomyopathy
(MUSTIC) trial  592
multislice computed tomography
(MSCT)  809–​21
anatomical imaging  811
aortic aneurysms  773, 774f
aortic disease  771–​80
aortic dissection  777
aortic stenosis  815
AR 815
atrioventricular septal defects  789
calcific AVS  163–​4
characteristics 810t
coarctation of the aorta  791
congenital heart disease  784, 809, 810f
congenitally corrected transposition of the
great arteries  801
functional imaging  811–​19
image analysis  810
infective endocarditis  279, 279f, 280f
inflammatory aortic disease  774
intramural haematoma  777, 777f
limitations of  779
mitral valve regurgitation  209
mitral valve stenosis  193
patent ductus arteriosus  789–​90
protocol  772–​3
protocols 810
RV outflow tract (RVOT) dysfunction  816
multivessel disease  135, 136f
muscular ventricular septal defects  786
type 4 292, 292t
MUSTIC (MUltisite STimulation In
Cardiomyopathy) trial  592
MVA see mitral valve area (MVA)
MVHD see multiple valvular heart
disease (MVHD)
MVO (microvascular obstruction)  489
myocardial blood flow (MBF)
CAD PET  423
cardiac hybrid imaging  137, 138f
myocardial contrast
echocardiography 116f, 117
PET  47–​48, 49f
vasodilator stress  484
myocardial contrast echocardiography
(MCE)  114, 116–​18
alcohol septal ablation in HCM  640
CAD  117–​18, 117f
cardiac masses  118
cardio-​oncology  623t
coronary flow reserve  117
limitations of  118
myocardial blood flow  116f, 117
myocardial viability  118
physical principles  116, 116f
stress testing  117
myocardial deformation  549–​1
analysis  498–​499
imaging  396–​7, 397f, 499, 503
STE  550–​1
tissue Doppler imaging  550, 550f
834 I ndex

myocardial function diagnosis  722, 724–​6, 725f, 725t HCM 630

HCM  634–​6 echocardiography  715–​16, 716f infiltrative cardiomyopathy  649, 651–​2,
pathological remodelling, STE  106–​7 fulminant vs. non-​fulminant  716 651f, 654
SPECT 47 hybrid imaging  717–​18 LV non-​compaction  677
STE see speckle-​tracking MDCT  717, 718f myocardial viability  554–​5
echocardiography (STE) myocardial scintigraphy  716–​17, 717f procedures  47–​51
myocardial ischaemia  404 necrosis & fibrosis  720–​2, 721f, 722f radiation dose reduction  50–​1
assessment of  636 oedema  719–​20, 720t technical aspects  41–​7
intraoperative transoesophageal tissue characterization  719–​2, 724–​6 see also positron emission tomography
echocardiography 235 viral infections  668–​69 (PET); single-​photon emission computed
quantification by PET  423 myocardium tomography (SPECT)
symptoms detection by CT  154 blood flow see myocardial blood flow (MBF) nuclear ECG-​gated SPECT imaging  504t, 505
myocardial performance index (MPI, cardio-​oncology  614 nuclear radionuclide angiography (RNA)  504t,
Tei-​index)  501 contrast echocardiography see myocardial 505
tricuspid annular plane systolic contrast echocardiography (MCE)
excursion  528–​29, 528f deformation see myocardial deformation O
myocardial perfusion fibro-​fatty replacement  686, 687f obesity 486
abnormalities  130–​1 function see myocardial function oblique  2 chamber transoesophageal
CMR see myocardial perfusion-​CMR functional assessment by echocardiography 31, 33, 33f
idiopathic DCM  667 dobutamine-​CMR  449–​50 obstructive coronary artery disease  137
MRI  74, 75f hibernation 546 occlusive peripheral artery disease  621
SPECT 47 inflammation  48–​49 OCT (optical coherence tomography)  153
myocardial perfusion-​CMR  452–​60, 453t iron loading  656–​87 oedema  719–​20, 720t
CAD protocols  453, 454–​5, 454f metabolic imaging in DCM  668, 669f oesophagitis 311
cost-​effectiveness  459–​60 metabolism  48–​9 optical coherence tomography (OCT)  153
diagnosis 453t, 455–​7 MRI tagging  71, 71f Optison  111–​12, 112t
future developments  460, 461f perfusion see myocardial perfusion oropharyngeal anaesthesia  27
image display  455, 455f, 456f reperfusion and STEMI  488–​9 oxygen-​15(15O)-​labelled water PET  422, 422t
ischaemia 447 scintigraphy see myocardial scintigraphy myocardial blood flow  47–​8
limitations  460, 460b strain see myocardial strain
prognostic value  457, 458–​59t stunting  545, 546 P
reading 455 tissue characterization  303–​4 pacemakers 68
safety of  457 viability see myocardial viability PAD (peripheral artery disease)  621
technique  452, 454f myofibrosarcoma  737–​38 papillary fibroelastoma (PFFs)  733–​4, 735f
myocardial perfusion imaging myxoma  732–​3, 732t, 733f, 734f papillary muscles
CT  150–​1, 150f myxomatous mitral valve disease  238, 239f mitral valve  200
CTA and  135 tricuspid valve  362
DCM  667, 667f N parachute mitral valve  794
hybrid imaging  130 napkin-​ring sign (NRS)  439 paraprosthetic regurgitation  265–​6, 266f
PET 48 National Board of Echocardiography (NBE)  81t parasternal long-​axis (PLAX) view
myocardial perfusion reserve (MPR)  454f National Institute of Health and Clinical AVS 161
myocardial perfusion reserve index (MPRI)  74 Excellence (NICE)  471 RV echocardiography  521
myocardial perfusion scintigraphy (MPS)  405t Navier Stokes equations  151 parasternal short-​axis (PSAX) view
acute coronary syndrome  414 Navigate device  373t AVS 161
CAD  409–​10 NCE-​MRA see non-​contrast-​enhanced magnetic RV echocardiography  521–​2
stable CAD  405–​6 resonance angiography (NCE-​MRA) parasternal view, transthoracic
myocardial scintigraphy near field cluster artefact  16t echocardiography see transthoracic
CAD in cardio-​oncology  619 necrosis, myocarditis  720–​2, 721f, 722f echocardiography, parasternal view
myocarditis  716–​17, 717f NeoChord DS1000 system  350 paravalvular leak (PVL)
myocardial strain neo-​left ventricular outflow tract  353, 355f clinical presentation/​features  295
idiopathic DCM  667 neuromuscular disorders, DCM and  674 closure see paravalvular leak closure
MRI  71, 72f New York Heart Association (NYHA)  196 evaluation 295
myocardial twist  499 nitrogen-​13(13N)-​ammonia PET  47–​48, 422, 422t grading 295
myocardial viability  545–​64 non-​contrast-​enhanced magnetic resonance intervention in5ications  297
clinical setting  551–​3 angiography (NCE-​MRA) mitral regurgitation and  295–​6
CMR  555–​59, 556f aortic disease  759, 759f prevalence 295
definition 545 aortic measures  759f, 760 risk factors  295
diagnostic tools  552t non-​contrast-​enhanced tissue characterization Paravalvular Leak Academic Research
imaging clinical results  557, 558f, 559f, 560f idiopathic DCM  666 Consortium (PLARC)  295, 296f
nuclear imaging  554–​5 MRI  71, 72f, 73, 73f paravalvular leak closure  295–​9
myocardial viability echocardiography  546–​54 non-​ischaemic myocardial disease  74, 74f 3D echocardiography  97–​98
contrast echocardiography  548 non-​sarcomeric hypertrophic device sizing  298
interpretation  547–​49, 547t, 548f cardiomyopathy 638 echocardiography–​fluoroscopy fusion
methodology  546–​7 non-​transmural necrosis  546 imaging  125, 126f
myocardial contrast echocardiography  118 NORRE study  614 procedural guidance  295–​298
myocarditis  715–​29 NRS (napkin-​ring sign)  439 paravalvular mitral regurgitation  348
anatomic & functional abnormalities  719 nuclear cardiology  41–​55 paraventricular mitral leaks (PVML)
biopsy vs. CMR  727 applications  47–​51 closure  345, 348
cardio-​oncology  617–​18 CAD  403–​19 transoesophageal echocardiography  338
clinical recommendations  727–​28, 728b Chagas’ disease  672 PAREPET trial  573
CMR  718–​28, 727f data analysis  41–​7 PARTNER  1 (Placement of Aortic
DCM and  668–​1 DCM  667–​8, 667f Transcatheter Valves) trial 328–​9

parturition, DCM and  676
PASCAL device  344, 345, 345f, 372t
tricuspid valve replacement  366
patent ductus arteriosus (PDA)  789–​90, 789f
patent foramen ovale (PFO)  534
closure  289–​90
fossa ovalis redundancy and  290, 291f
prevalence  289–​90
transcatheter closure by 3D
echocardiography 96
transoesophageal echocardiography short-​
axis view  33, 34f
patient motion/​position, SPECT  42, 42f, 43f
patient selection
3D echocardiography  90
atrial fibrillation ablation  307
CIED 305
CRT device  305, 305f
CT  63–​4, 63t
ICD 305
PAU see penetrating atherosclerotic
ulcer (PAU)
PCAT (pericoronary adipose tissue)  443–​4
PCWP (pulmonary capillary wedge
pressure) 508
PDA (patent ductus arteriosus)  789–​90, 789f
penetrating atherosclerotic ulcer (PAU)  753,
753f, 762, 765–​7, 766f, 775, 777–​8, 778f
blunt injury  777–​78
classification 778f
postoperative imaging  779, 779f
Penn conversion  37
percutaneous aortic valve implantation  96–​7, 97f
percutaneous closure, ventricular septal
defect  293–​4, 293f, 294f
percutaneous left atrial appendage  98
percutaneous mitral balloon
commissurotomy (PMBC)
evaluation for  341, 341b
procedure for  341–​2, 342f, 343t
during transcatheter mitral valve
interventions 339
percutaneous mitral commisurotomy (PMC)
complication detection  195–​6
complications 196f
contraindications 195b
mitral valve stenosis
echocardiography  194–​5
Wilkins’ score  194
percutaneous pulmonary valve replacement
(PPVI)  377–​81
balloon-​expandable pulmonary valve  377–​78,
378f
clinical indications  381–​2, 382t
future perspectives  387
patient assessment  381–​5, 386
results of  379–​81, 381f
self-​expandable pulmonary valve  379–​81,
379f, 380f
periaortic bleeding  752
pericardial cysts  732t
pericardial disease  620–​1
pericardial effusion  697–​706
aortic dissection  752, 752f
cardiac CT  701–​2, 703f, 704f
cardiac MRI  702–​3
chest X-​ray  700
classification  698–​9, 699b
clinical presentation  699
constrictive pericarditis  710, 710f
echocardiography  700–​1, 701f
pathophysiology  697–​8, 698f
pericoronary adipose tissue (PCAT)  443–​4
perimembranous ventricular septal
defects  786, 787f
type 2 292, 292t
peripartum cardiomyopathy (PPCM)  676
peripheral artery disease (PAD)  621
peripheral leak (PPL)  242
peripheral VA-​extracorporeal membrane
oxygenation  606, 607f, 608f
PFFs (papillary fibroelastoma)  733–​4, 735f
PFO see patent foramen ovale (PFO)
PH see pulmonary hypertension (PH)
pharmacological cardiac stress  405t
CAD 398
phase-​array catheters  126
phase-​sensitive inversion recovery (PS-​IR)
magnetic resonance imaging  72f, 73
phosphate radiolabelled derivatives  47
PHT (pressure half-​time)  191, 192–​3
PISA see proximal isovelocity surface area (PISA)
Placement of Aortic Transcatheter Valves
(PARTNER 1) trial  328–​9
planar scintigraphic imaging  566, 567f
PLARC (Paravalvular Leak Academic Research
Consortium)  295, 296f
PLAX see parasternal long-​axis (PLAX) view
PMBC see percutaneous mitral balloon
commissurotomy (PMBC)
PMC see percutaneous mitral
commisurotomy (PMC)
PML (posterior mitral leaflets)  337
porcelain aorta  320, 321f, 622
positron emission tomography (PET)
acute coronary syndromes & myocardial
viability  551, 551f
atherosclerosis  473–​575
CAD see coronary artery disease PET
cardiac innervation  568
cardio-​oncology  617
CMR and  51, 131, 131f, 139–​40, 762
CT and  668, 716
data correction  46–​7
DCM myocardial metabolic imaging  668
infective endocarditis  279–​1
infiltrative cardiomyopathy  651, 654
integrated MRI  51, 131, 131f
LV non-​compaction  677
microvascular disease type 1 486
microvascular disease type 2 487
microvascular disease type 3 488
molecular imaging  49
MRI and  139–​40
MRI and in myocarditis  717–​18
myocardial blood flow  47–​48, 49f
myocardial inflammation  48–​9
myocardial ischaemia  636
myocardial metabolism  48–​9
myocardial perfusion imaging with  130
myocardial viability  554
prosthetic valve infective endocarditis  280–​1
radiation dose reduction  50–​1
radiotracers  474–​5
sarcoidosis  655–​6
scars in CRT imaging viability  585, 586f
signal acquisition  45
SPECT vs. 44
stable CAD  408, 411f
technical aspects  44–​7
positron-​emitting radioisotopes  45
posterior mitral leaflets (PML)  337
posteromedial papillary muscles, mitral
valve 200
I n de x 835
postganglionic presynaptic sympathetic
innervation 568
postoperative imaging
ASD 786
atrial switch procedure  798, 799f
atrioventricular septal defects  788–​9
coarctation of the aorta  791
congenitally corrected transposition of the
great arteries  801
congenital mitral valve anomalies  795
Ebstein’s anomaly  794
echocardiography in aortic disease  754, 754f
LV outflow tract obstruction  793
patent ductus arteriosus  789
penetrating atherosclerotic ulcer  779, 779f
RV outflow tract obstruction  792
tetraology of Fallot  796, 797f
transposition of the great arteries  797–​8
post-​pump intraoperative transoesophageal
echocardiography 232
mitral valve replacement  239f, 241–​3, 242f
systolic anterior motion (SAM)  240–​1,
241f, 241f
PPCM (peripartum cardiomyopathy)  676
PPL (peripheral leak)  242
PPVI see percutaneous pulmonary valve
replacement (PPVI)
PR see pulmonary regurgitation (PR)
precapillary pulmonary hypertension  527
PRECISE clinical trial  152
pregnancy
congenital heart disease and  804–​5
DCM and  676
preoperative assessment
congenitally corrected transposition of the
great arteries  801
tetralogy of Fallot  795–​6, 795f
pre-​pump intraoperative transoesophageal
echocardiography 233
mitral valve repair  238, 240, 240f
pressure half-​time (PHT)  191, 192–​3
primary amyloidosis  617
primary mitral valve regurgitation  201
primary valve disease, DCM vs. 663
primum atrial septal defect  784, 785f
procedural imaging, CT  310–​11, 310f, 311f
procedural planning, transcatheter mitral valve
interventions  344, 349–​50t, 349f
PROMISE (Prospective Multicenter Imaging
Studies for Evaluation of Chest Pain)  436,
470, 487
prospective electrocardiographic
triggering  59–​60, 60f
Prospective Multicenter Imaging Studies for
Evaluation of Chest Pain (PROMISE)
trial  436, 470, 487
prosthetic valve infective endocarditis
(PVIE)  277–​8, 278f, 281f
PET/​SPECT  280–​1
prosthetic valves
3D echocardiography  94–​5
paravalvular leaks  95–​5
TAVI follow-​up  327t, 329–​30
see also bioprosthetic valves
proximal isovelocity surface area (PISA)
aortic valve regurgitation  185, 185f, 188t,
226–​7, 229f
mitral valve area measurement  191
mitral valve regurgitation  204–​5, 205f,
226–​7, 229f
paravalvular leak grading  295
tricuspid valve  213, 213f
836 I ndex
PS see pulmonary stenosis (PS)
PSAX see parasternal short-​axis (PSAX) view
pseudoaneurysms  274, 275f
pseudotumours 732t
PS-​IR (phase-​sensitive inversion recovery)
magnetic resonance imaging  72f, 73
pulmonary arteries, percutaneous pulmonary
valve replacement  384, 385f
pulmonary artery pressure (PAP)
diastolic pressures in Eisenmenger
syndrome 804
Eisenmenger syndrome  804
systolic pressure  533–​4, 533f, 804
transoesophageal echocardiography  348
see also mean pulmonary artery
pressure (mPAP)
pulmonary capillary wedge pressure
(PCWP) 508
pulmonary embolism  536–​7, 537f
cardio-​oncology  621
pulmonary hypertension (PH)
assessment 535
cardio-​oncology  622
mitral stenosis  341
ventricular assist devices  608
pulmonary regurgitation (PR)  217–​18,
219f, 536
transthoracic echocardiography, parasternal
view  13–​14, 21f
pulmonary stenosis (PS)  217f
congenitally corrected transposition of the
great arteries and  801
severity assessment  217
pulmonary valve (PV)  216–​19
3D echocardiography  96
anatomy 216
hypertension  174–​5
imaging 216
pathology  216–​19, 217f, 218f
percutaneous replacement see
percutaneous pulmonary valve
replacement (PPVI)
subcostal Doppler transthoracic
echocardiography  25, 29f
transthoracic echocardiography, parasternal
view  13–​14, 21f
pulmonary valve replacement (PVR)  363
pulmonary vascular resistance (PVR)  533
pulmonary vein A-​wave velocity
anomalies 535
standard values  38t
pulmonary veins
functionally univentricular heart  803
isolation in CT  310, 310f
mitral valve regurgitation  202–​3
oblique  2 chamber transoesophageal
echocardiography 33
pulmonic stenosis  536, 537f
pulmonic valve, transcatheter
replacement  377–​88
pulsed spectral Doppler imaging  38
pulsed-​wave Doppler (PW)
echocardiography 3
CRT optimization  588–​89, 588f
intimal aortic tear  750
left atrial function evaluation  512
mitral valve regurgitation  202
myocardial performance index  528, 528f
patent ductus arteriosus  789
pulse sequences, MRI  68–​9
PVIE see prosthetic valve infective
endocarditis (PVIE)
PVL see paravalvular leak (PVL) Failure Management II implantable
PVML see paravalvular mitral leaks (PVML) cardioverter defibrillator)  590
right atrium
Q anatomy  519–​20
quadricuspid aortic valve regurgitation  182 echocardiography  521, 521f
quality assurance (QA)  82–​3, 83b minor axis diameter  38t
MRI 521
R pressure  532–​3, 532t
radial strain  105 size measurement  521, 521t
radiation right bundle branch block (RBBB)  686, 687f
cardiac hybrid imaging  134–​5 right coronary artery  520
dose reduction  50–​1 right heart
exposure in CT  65, 146–​7 chamber size  520–​32
radiolabelled phosphate derivatives  47 evaluation  539, 540t
radiomics hemodynamics  532–​4
CAD MDCT  442–​3, 443f imaging  519–​44
CT  154–​5 long axis view  8, 11, 17f
radionucleotide ventriculography  675 short-​axis views  11–​12, 18f
radionuclide imaging  616 wall thickness  520–​32
radiopharmaceuticals 422 right pulmonary artery  33, 34f
radiotherapy, damage to tissues  613 right-​sided index of myocardial performance
railroad-​shaped artefacts, 3D (RIMP) 526
echocardiography 92 right upper pulmonary vein  33, 34f
Ramond–​Ramond (RR) cycle  42 right ventricle (RV)  520
random clinical trials (RCTs), CRT  592, 593f 3D echocardiography  93–​4
Rashkind double umbrella  293 anatomy & physiology  519–​20
Rastelli procedure  798 area  522–​3
real-​time mode, 3D echocardiography  88 assessment 540t
reduced leaflet motion (RLM)  332 AVS  174–​5
refraction artefacts  16t base-​to-​apex length  38t
regadenoson 405t cardiomyopathic conditions  538–​9
regional left ventricle systolic diameter  38, 38t
function  499–​500 diastolic function see right ventricle diastolic
wall motion score index  500, 501f function
regional myocardial function echocardiography 520
quantification 500 ejection fraction see right ventricular ejection
STE 108 fraction (RVEF)
regional wall motion assessment focused apical four-​chamber view  522, 523f
contrast echocardiography  114 function see right ventricle function
echocardiography  503–​4 hypertrophy  524, 526
regurgitant flow (RF)  187 hypertrophy in Eisenmenger
regurgitation, valvular prostheses  264–​6 syndrome  804, 804f
replacement myocardial fibrosis  666–​7 inflow tract  25, 35, 35f
repolarization/​depolarization linear dimensions  522, 524t, 525f
abnormalities  686–​7, 687f MRI 520
respiratory motion, MRI  69 myocardium 520
restrictive pericarditis, constrictive pericarditis outflow tract see right ventricle outflow
vs. 713 tract (RVOT)
REsynchronization reVErses Remodelling overload see right ventricle overload
in Systolic left vEntricular dysfunction conditions
(REVERSE) study  592 parasternal long-​axis view  521
Resynchronization for the HemodYnamic pathology  534–​39
Treatment for Heart Failure Management pressure overload  536
II implantable cardioverter defibrillator size  383, 526, 666
(RHYTHM II ICD)  590 size measurement  363, 367f, 368f, 521–​4,
retrospective 526
electrocardiographic-​gating  309–​10 systolic dysfunction  324
CT–​ECG synchronized acquisition systolic function see right ventricle systolic
mode  59, 59f function
reverberation artefact  15t, 92 volume  69, 523–​4, 525f
REVERSE (REsynchronization reVErses wall see right ventricle wall
Remodelling in Systolic left vEntricular right ventricle diastolic function
dysfunction) study  592 echocardiography  529–​30
RF (regurgitant flow)  187 MRI  531, 532f
rhabdomyoma  731–​2, 732t right ventricle-​focused apical four-​chamber
rhabdomyosarcoma  737–​38, 738f, 739f view  522, 523f
rheumatic aortic valve regurgitation  182 right ventricle function  526–​32
rheumatic aortic valve stenosis  162, 162f acute coronary syndromes  415
rheumatic mitral stenosis  226, 228f assessment  503–​5, 504t
rheumatic mitral valve stenosis  191, 192f CRT 593
RHYTHM II ICD (Resynchronization for Eisenmenger syndrome  804
the HemodYnamic Treatment for Heart MRI  530–​2, 530f, 531f, 532f

STE 108
systolic function see right ventricle systolic
function
tissue characterization  531–​2
ventricular assist devices  608
right ventricle outflow tract (RVOT)  522, 525f
ARVC functional evaluation  684
right ventricle overload conditions  534–​38
interatrial shunt  534–​5
right ventricle systolic function
echocardiography  526–​29
MRI 528t, 530–​1, 530f, 531f
right ventricle wall
thickness 38t
transthoracic echocardiography, long-​axis
parasternal view  8
right ventricular ejection fraction (RVEF)  521
3D echocardiography  93, 93f
right ventricular outflow tract (RVOT)  520
diameter 38t
dysfunction  377, 816
percutaneous pulmonary valve replacement
and 382
subcostal transthoracic echocardiography  25
transthoracic echocardiography, parasternal
view  13–​14, 21f
right ventricular outflow tract obstruction
(RVOTO)  791–​2, 792f
right ventricular systolic pressure (RVSP)  533–​4,
533f
RIMP (right-​sided index of myocardial
performance) 526
RLM (reduced leaflet motion)  332
Ross procedure  248
rotational catheters  126
rubidium-​182182Rb)-​labelled compounds  47–​48,
422, 422t
RV see right ventricle (RV)
RVEF see right ventricular ejection
fraction (RVEF)
RVOT see right ventricle outflow tract (RVOT)
RVOTO (right ventricular outflow tract
obstruction)  791–​2, 792f
RVSP (right ventricular systolic pressure)  533–​4,
533f
S stable CAD  406–​8, 407f, 408f, 409f,
SAM (systolic anterior motion)  240–​1,
240f, 241f
SAPIEN XT valve  378
sarcoidosis  655–​6
sarcomas  737–​38
sarcomeric hypertrophic cardiomyopathy  629
SARF (severe acute respiratory failure)  599–​
600, 600f, 602
SAVR (surgical aortic valve replacement)
contraindications  315, 318
SCD (sudden cardiac death)  629
Scottish Computed Tomography of the Heart
(SCOT-​HEART)  436, 470–​1
SE see stress echocardiography (SE)
sECG (stress electrocardiography)  405–​6
secondary mitral valve regurgitation  201,
397–​8
secundum atrial septal defect  784, 785f
segmental left ventricular function  395–​6
segmental strain curves  105
segment involvement score (SIS)  439
segment stenosis score (SSS)  439
self-​expandable pulmonary valve  378–​9,
379f, 380f
septal morphology, HCM  630
severe acute respiratory failure (SARF)  599–​
600, 600f, 602
shadowing, 3D echocardiography  92
short-​axis view
LV  5, 5f, 6f
transoesophageal echocardiography  33, 34f,
36, 36f
transthoracic echocardiography  5, 5f, 6f
short inversion-​time inversion recovery (STIR)
aortitis  767, 767f
ARVC  685, 686f
idiopathic DCM  666
myocarditis 719
side lobe artefact  16t
signal-​to-​noise ratio (SNR), MRI  68–​9
Simpson’s method
global LV motion  396
idiopathic DCM echocardiography  664
simultaneous multiplane mode, 3D
echocardiography 88
single-​beam acquisition, CT  147, 147t
single-​photon emission computed tomography
(SPECT) 47
ARVC  685–​6
attenuation correction  43
CAD  47, 412–​13, 413f
cancer therapeutics-​related cardiac
dysfunction 675
cardio-​oncology  616, 617f, 623t
DCM  668, 671, 672f
dedicated cameras  49–​0
dedicated cardiac-​only scanners  137
ECG gating  42–​3
functional-​gated  42–​3, 44f
HF & cardiac innervation imaging  571
infective endocarditis  279–​1
microvascular disease type 2 487
molecular imaging  47, 48f
myocardial function  47
myocardial perfusion  47, 130
myocardial viability  552, 554
myocarditis  671, 672f, 717
patient position  42, 42f
PET vs. 44
prosthetic valve infective endocarditis  280–​1
scars in CRT imaging viability  583
410f, 411f
systemic data analysis  43–​4
technical aspects  42–​4, 44f
single-​tilted-​disc prostheses  251, 252f
Doppler haemodynamic parameters  261t
studies on  256t
sinus of Valsalva  363
measurements  761, 761f
normal structure  771
sinus venosus atrial septal defect  784, 785f
SIS (segment involvement score)  439
sixteen-​segment model, regional LV systolic
function  499, 500f
skill development  80
SmartDelay Determined AV Optimization: A
Comparison to Other AV Delay Methods
Used in Cardiac Resynchronization
Therapy (SMART-​AVI) Trial  591
SNR (signal-​to-​noise ratio), MRI  68–​9
Society of Cardiac Magnetic Resonance  520
Society of Thoracic Surgeons (STS)  361
Sonovue  111–​12, 112t
sPAP see systolic pulmonary artery
pressure (sPAP)
spatial resolution, CT  58, 60, 61f
I n de x 837
speckle-​tracking echocardiography
(STE)  103–​9
atrial function  108
cancer therapeutics-​related cardiac
dysfunction  614–​15
cardio-​oncology  107, 614–​15, 623t
Chagas’ disease  672
clinical applications  106
HCM 107
idiopathic DCM  664
ischaemic heart disease  107–​8, 107f
left atrial function evaluation  512, 512f
LV assessment  499, 501f, 502f
LV function  106
LV mechanical dysfunction  583, 583f
myocardial deformation  103, 104f, 105,
396–​7, 550–​1
myocardial function & pathological
remodelling  106–​7
primary amyloidosis  617
regional myocardial function  108
RV function  108
strain calculations  105, 105f, 106f
spin-​echo sequences, MRI  68
spotty calcium, coronary heart disease  439
SSFP see steady-​state free precession (SSFP)
SSS (segment stenosis score)  439
stable coronary artery disease  426, 427f, 428,
428f, 429f
stain imaging, tricuspid annular plane systolic
excursion 527f, 529
Starr–​Edwards Ball Cage valves  260
STE see speckle-​tracking
echocardiography (STE)
steady-​state free precession (SSFP)
anatomical imaging  813f
aortic disease  757
aortic measures  760, 761f
aortic valve regurgitation  187
cine imaging  448
idiopathic DCM  666
LVDD diagnosis  516
right atrium  521, 521t
tricuspid valve  214
STEMI (ST-​elevation myocardial infarction),
myocardial reperfusion  488–​9
stented bioprosthetic valves
Doppler haemodynamic parameters  261–​2t
normal regurgitant flow  260
studies on  256–​7t
stentless bioprosthetic valves  257t
STICH study  553, 555
STIR see short inversion-​time inversion
recovery (STIR)
stitching artefacts  90
St Jude bileaflet prosthetics  242
strain
classifications 103
congenital heart disease  805
strain echocardiography
ARVC diagnosis  682, 683f
cardio-​oncology  616
tetraology of Fallot  797
strain rate
congenital heart disease  805
myocardial performance index  501–​2
strength-​training, Athlete’s heart  538
stress echocardiography (SE)
CAD  400, 618–​19
cardio-​oncology  618–​19, 623t
congenital heart disease  805
contrast echocardiography  114, 115f
838 I ndex
stress echocardiography (SE)  (cont.)
dipyridamole  398, 405t, 548
LV assessment  93
myocardial contrast  117
myocardial ischaemia  636
myocardial viability  547, 547t
see also dobutamine stress
echocardiography (DSE)
stress electrocardiography (sECG)  405–​6
stroke risk  621
stroke volume (SV)
calculation  168, 498
MRI 69
ST-​segment depression  409
subaortic stenosis  792, 792f
subcostal transthoracic
echocardiography  24–​5, 28f
RV 522
subvalvular apparatus, mitral valve
stenosis  194, 194f
sudden cardiac death (SCD)  629
supercristal ventricular septal defect (type
1)  291–​2, 292t
superior cavopulmonary anastomosis  801, 803f
superior vena cava (SVC)  519
anatomy and CT  310
super-​responders, CRT  592–​3, 595f
supravalvar stenosis  792
surgery
aortic dissection  763–​4, 764f
myectomy in HCM  640
ventricular septal defect  292–​3
surgical aortic valve replacement (SAVR)
contraindications  315, 318
SV see stroke volume (SV)
SVC see superior vena cava (SVC)
sympathetic nerve imaging  668
SYNTAX III trial  152
systemic amyloidosis  645
systemic data analysis, SPECT  43–​4
systemic hypertension  486
systolic anterior motion (SAM)  240–​1,
240f, 241f
systolic deformations, cardiac wall  103,
104f, 105
systolic dysfunction, cardio-​oncology  614
systolic function, congestive HF  503
systolic left ventricle function  497–​506,
634–​5, 634f
systolic pulmonary artery pressure (sPAP)
estimation 363
mitral valve regurgitation  207
T developments  98–​100
T1 mapping
endomyocarditis 725
infiltrative cardiomyopathy  648, 649f
T1, MRI  67
T1 relaxation studies, HCM  634
T1-​weighted images
ARVC 685
atherosclerosis 761f, 762
cardio-​oncology  616
T2 mapping
cardio-​oncology  616
endomyocarditis 725
infiltrative cardiomyopathy  648, 650f
T2, MRI  67
T2* normal values, myocardial iron
loading  656, 657
TA see tricuspid annulus (TA)
table feed, CT  58
TAC (time-​activity curves)  44
TAD (thoracic aortic dissection)  775
Takayasu’s cardiomyopathy  767–​9
Takotsubo cardiomyopathy  689, 691
TandemLife ProtekDue  605, 605t
TAPSE see tricuspid annular plane systolic
excursion (TAPSE)
TAVI see transcatheter aortic valve
implantation (TAVI)
TAVR see transcatheter aortic valve
replacement (TAVR)
TCFAs (thin cap fibroatheromas)  439
TDI see tissue Doppler imaging (TDI)
technetium-​99m(99mTc)-​3,3-​diphosphono-​1,2-​
propanodicarboxylic acid (DPD)  651
technetium-​99m(99mTc)-​compounds  47
technetium-​99m(99mTc)-​pyrophosphate
infiltrative cardiomyopathy  649, 651f
SPECT 47
TAVI risk stratification  323–​4
technetium-​99m(99mTc)-​sestamibi  47
technetium-​99m(99mTc)-​tetrosformin  47
TEE see transoesophageal echocardiography
(TEE/​TOE)
Teichholz equation
global LV motion  396
M-​mode measurements  36
Tei-​index see myocardial performance index
(MPI, Tei-​index)
temporal resolution, CT  58, 60–​1, 61f
tetralogy of Fallot (TOF)  216, 218, 219f, 795–​7
morphology  795, 795f
TGA (transposition of the great
arteries)  817–​18, 818f
thalassaemia major (TM)  656
thermodilution 339
thin cap fibroatheromas (TCFAs)  439
thoracic aortic dissection (TAD)  775
thoracic aortic injury  767
thoracic artery disease  761–​69
three-​dimensional (3D) colour Doppler  88
three-​dimensional (3D) echocardiography
(3DE)  87–​102
acquisition techniques  88
aortic valve  96
artefacts  91–​2
ASD closure  96
cancer therapeutics-​related cardiac
dysfunction 615
cardio-​oncology  615, 623t
congenital heart disease  805
constrictive pericarditis  710
data set display  89–​1, 89f, 90f
infective endocarditis  278–​9, 279f
left atrium  94
LV  92–​3, 92f
LV mechanical dysfunction  582f, 583
mitral valve  94–​5, 237f
mitral valve clips  97
mitral valve stenosis  191–​3
myocardial viability  549
paravalvular leak  97–​98, 295, 296, 297f,
298, 298f
patient selection  91
percutaneous aortic valve
implantation  96–​7, 97f
percutaneous left atrial appendage
occlusion 98
PFO closure  96
pitfalls 91
pulmonary valve  96, 216f
RV  93–​4, 93f
RV volume  523
transcatheter intervention  96
transeptal puncture  289, 289t
tricuspid valve  95–​6, 96f, 212f, 213, 213f,
363, 366f
two-​dimensional (2D) echocardiography
vs.  92–​98
valvular heart disease  224
three-​dimensional (3D) perfusion CMR  460
three-​dimensional (3D) right ventricular
ejection fraction  529
three-​dimensional (3D) rotational
angiography  387, 388f
three-​dimensional (3D) transoesophageal
echocardiography  751, 751f
three-​dimensional (3D) transthoracic
echocardiography
CRT follow-​up  592
pericardial effusion  701
thrombolysis in myocardial infarction
(TIMI) 551
thrombosis, valvular prostheses  262
thrombus 732t
extracorporal support  609–​10, 610f
TID (transient ischaemic dilatation)  423
time-​activity curves (TAC)  44
time-​of-​flight, PET  46, 46f
time-​resolved MRA  763–​4
tissue Doppler imaging (TDI)
cancer therapeutics-​related cardiac
dysfunction 614
congenital heart disease  805
constrictive pericarditis  713
HCM 634
myocardial deformation  550, 550f
myocardial performance index  529, 529f
systolic/​global myocardial systolic
function 500
201
Tl compounds, SPECT  47
TM (thalassemias major)  656
TMVR see transcatheter mitral valve
replacement (TMVR)
TOE see transoesophageal echocardiography
(TEE/​TOE)
TOF see tetralogy of Fallot (TOF)
TOPAS (True or Pseudo Severe Aortic
Stenosis) 171
TP see transeptal puncture (TP)
TR see tricuspid valve regurgitation (TR)
training  79–​84
elements of  80
future perspectives  83
multimodality imaging  83
need for  79–​80
programme models  82, 82f
sources  80, 81t
transapical access, TAVI procedure  322, 323f
transcatheter aortic valve implantation
(TAVI)  95, 315–​35
aortic valve implantation  325, 326f,
327f, 328f
degenerative mitral valve stenosis  196
echocardiography–​fluoroscopy fusion
imaging 123f
late follow-​up  327–​33
non-​femoral access  321–​2
patient selection  316–​25, 316t
procedural planning imaging  316, 318–​22
risk stratification  322–​5, 324f
transcatheter aortic valve replacement
(TAVR)  95, 171

future perspectives  333
late follow-​up  327, 328t
mitral stenosis and aortic stenosis  226, 228f
transcatheter mitral stenosis treatment  340–​56
preprocedural evaluation  340–​1
transcatheter mitral valve replacement
(TMVR)  337–​59, 338f, 352–​4, 353–​4f,
355f, 356b
annular approaches  350, 351f
artificial chord implantation  350, 352, 352f
imaging as guide  337–​40
imaging in specific interventions  344–​5,
345f, 346f, 347–​48t, 348, 350, 352–​4
pre-​procedure imaging  338–​9
during procedures  339–​40
transcatheter pulmonic valve
replacement  377–​88
transcatheter tricuspid valve repair/​
replacement  361–​76
adjacent anatomy interactions  366
antithrombotic drugs  366–​7
considerations for  363, 365–​7, 370f, 371,
371t, 372–​4t
device anchoring  365–​6
durability  367, 371
future perspectives  371
recurrence  367, 371, 374t
tricuspid valve access  365
transcatheter vein thrombosis
pannus vs. 333
TAVI follow-​up  330, 330–​1t, 331–​2t, 332
transcranial Doppler, PFO  290
transducer holding  4–​5, 4f, 5f
transeptal puncture (TP)  287–​89
echocardiography–​fluoroscopy fusion
imaging  124, 124f
transgastric long-​axis transoesophageal
echocardiography  33, 35f
transgastric short-​axis transoesophageal
echocardiography  33, 34f
transient ischaemic dilatation (TID)  423
transmitral Doppler flow
constrictive pericarditis  710, 710f
LV relaxation  509
transmitral L wave  512f, 511
transmitral necrosis  546
transoesophageal echocardiography (TEE/​TOE)
abscesses in infective endocarditis  274, 275f
acute aortic syndrome diagnosis  750,
750f, 751f
alcohol septal ablation in HCM  640
aorta imaging  749, 749f
aortic annulus size in TAVI  316, 318, 319f
aortic disease  747
aortic dissection  763
aortic valve anatomy  316, 317f
aortic valve area  164
atherosclerosis 762
bicaval view  31, 33, 34f
CIED-​related infective endocarditis  278
congenital heart disease  783–​4
continuous wave Doppler measurements  37
contrast agents and  114
data acquisition  28–​7
deep intubation to gastric fundus  33, 35, 37f
Eisenmenger syndrome  804
extracorporeal support  600
five-​chamber view  29
four-​chamber view  29, 31f
HCM surgery  640
infective endocarditis  271–​2, 280t
intimal aortic tear  750
intra-​operative see intraoperative
transoesophageal echocardiography
(IOTEE/​IOTOE)
intraoperative see intraoperative
transoesophageal echocardiography
(IOTEE/​IOTOE)
left atrial appendage  310, 311f
long-​axis view  29, 31f, 33, 35f
mitral valve anatomy  194, 196f
mitral valve regurgitation  201, 202f, 203f
mitral valve stenosis  197
M-​mode measurements  35, 37
myxoma  733, 733f
oblique  2 chamber view 31, 33, 32f
paravalvular leak  296, 297–​298, 297f,
298, 298f
patient preparation  27
PFO  290, 290f
pre-​pump intraoperative see pre-​pump
intraoperative transoesophageal
echocardiography
pre-​transcatheter mitral valve
interventions  338, 339f
probe insertion  28, 30f, 31f
prosthetic valve infective
endocarditis  277–​78
prosthetic valve obstruction  262, 264,
264f, 265f
pulmonary artery pressure  348
pulsed spectral Doppler measurements  37
right atrium  521, 521f
short-​axis view  25, 33, 33f, 33, 34f, 35
spatial resolution  25–​30
standard values in  37, 38, 38t, 39t
transcatheter mitral valve
interventions  348, 349f
during transcatheter mitral valve
interventions 340
transeptal puncture  288, 288f, 289, 289f
tricuspid valve  213
tricuspid valve imaging  363, 365f
triplane approach  31, 32f
two-​chamber view see two-​chamber
transoesophageal echocardiography
two-​dimensional measurements  37
valvular prostheses assessment  253–​4,
254f, 259
valvular prostheses follow-​up  282
ventricular assist devices  607–​8
ventricular septal defect closure  294–​5
transposition of the great arteries (TGA)  797–​8,
817–​18, 818f
transprosthetic gradients, valvular
prostheses 254t
transseptal puncture (TSP)  299
transsubclavian access, TAVI
procedure  321–​2, 323f
transthoracic Doppler
echocardiography (TTDE)
coronary flow reserve evaluation  399
microvascular disease type 1 486
valvular prostheses assessment  254
transthoracic echocardiography (TTE)  3–​7
abscesses in infective endocarditis  274, 275f
acute aortic syndrome diagnosis  749–​50,
749f, 750f
acute cardiovascular disease  753
alcohol septal ablation in HCM  640
aorta imaging  748
aortic disease  747, 748f
aortic valve anatomy  316
aortic valve area  164
I n de x 839
aortic valve regurgitation  183
apical 2-​chamber view  20–​1, 23f
apical 4-​chamber view  21–​2, 23, 24f, 27f
artefact identification  7, 11f, 12f, 13f, 14f,
15–​16t, 15f
ASD  290, 292f, 536t
cardiac lymphoma  738–​9, 739f
cardio-​oncology  614
CIED-​related infective endocarditis  278
colour 4-​chamber view  22, 24f, 25f
congenital heart disease  783
constrictive pericarditis  709–​10
continuous-​wave Doppler  20, 22, 37
data acquisition  7–​8, 11–​14, 16, 20–​5
Doppler 4-​chamber view  22–​3, 26f
extracorporeal support  599
five-​chamber view  23–​4, 27f
HCM  632, 638
image optimization  7, 8f, 9–​10t, 9f
infective endocarditis  271, 271–​, 272
LVDD diagnosis  516
LVH 638
LV systolic function  322–​4
mitral valve regurgitation  201
mitral valve repair  237–​38, 237f
mitral valve stenosis  194
M-​mode measurements  35, 37
non-​coronary transcatheter interventions  96
percutaneous pulmonary valve
replacement  382–​3, 382f, 383f
pericardial effusion  700
pre-​transcatheter mitral valve
interventions 338
prosthetic valve infective endocarditis  277–​8
pulsed spectral Doppler measurements  37
pulsed-​wave Doppler  20
standard values in  35, 37, 38t, 39t
subcostal scanning  24–​5, 28f
three-​dimensional see three-​dimensional
(3D) transthoracic echocardiography
transducer holding  4–​5, 4f, 5f
tricuspid valve  213
tricuspid valve imaging  363, 364f
two-​dimensional measurements  37
valvular prostheses follow-​up  282
ventricular septal defect closure  294
transthoracic echocardiography, apical long-​axis
view  14, 16, 22f
transthoracic echocardiography, long axis view
colour-​coded apical view  16, 20, 22f
LV  4, 5, 5f, 6f, 7–​8, 7f, 17f
parasternal view  8, 17f
right heart  8, 11, 17f
transthoracic echocardiography, oblique apical
views 14
transthoracic echocardiography,
parasternal view
aortic valve level  12–​13, 20f
midpapillary level  12, 19f
mitral valve level  12, 19f
transthoracic echocardiography, short-​axis view
LV  5, 6f
parasternal view, aortic valve level  12–​13, 20f
parasternal view, midpapillary level  12, 19f
parasternal view, mitral valve level  12, 19f
right heart  11–​12, 18f
transthyretin (ATTR)  646
transvalvular jet velocities/​pressure
gradients  164–​70
measurement 162t, 164, 165–​6t, 166f, 167f
signal confusion  166–​7, 167f
technical errors  164, 166, 166f
840 I ndex
trastuzumab 614
Trialign devices  372t
Tricentro device  373t
TriCinch Coil 4Tech  372t
TriCinch device  365
TriClip device  366
tricuspid annular plane systolic excursion
(TAPSE)  108, 526–​7, 527f, 797
3D RVEF  529
fractional area change  524t, 527f, 528
myocardial performance index  528–​29, 528f
RV systolic function  530–​1, 531f
stain imaging  527f, 529
tricuspid annular velocity  527–​28, 527f
tricuspid annular velocity (S’)  527–​28, 527f
tricuspid annulus (TA)  211–​12, 212f
dilatation 95
tricuspid valve  211–​16
3D echocardiography  95–​6, 96f
anatomy  211–​12, 212f, 362–​7
congenitally corrected transposition of the
great arteries and  801
imaging  213–​14, 216, 363, 364f, 365f, 366f,
367f, 368f, 369f, 370t
in-​valve and valve-​in-​ring  373t
leaflets 362
mitral stenosis  340
pathology  212–​13, 212f
post-​intraoperative transoesophageal
echocardiography  245, 247, 247–​48f
transcatheter replacement see transcatheter
tricuspid valve repair/​replacement
tricuspid valve regurgitation (TR)  211, 535
AVS  174–​5
CMR/​MSCT  817
colour 4-​chamber view transthoracic
echocardiography  22, 25f
Eisenmenger syndrome  804
intraoperative transoesophageal
echocardiography  236, 249, 249f
left-​sided VHD and  227
quantification of  363, 369f
severity of  363, 369t, 526
TAVI risk stratification  324
velocity in LVDD diagnosis  513–​14
Tricuspid Valve Repair System (TVRS)  372t
triplane approach, transoesophageal
echocardiography  31, 32f
Trisol device  373t
tropoelastin 472
True or Pseudo Severe Aortic Stenosis
(TOPAS) 171
Trypanosoma cruzi infection see Chagas’ disease
TSP (transseptal puncture)  299
TTDE see transthoracic Doppler
echocardiography (TTDE)
TTE see transthoracic echocardiography (TTE)
tube current
CT 58
CT–​ECG synchronized acquisition mode  59
tube voltage, CT  58
TVRS (Tricuspid Valve Repair System)  372t
two-​chamber transoesophageal
echocardiography  31, 31f
transgastric short-​axis view  33, 34f
two-​dimensional (2D)-​axial lateral resolution,
transthoracic echocardiography  9t
two-​dimensional (2D) biplane Simpson
approach 592
two-​dimensional (2D)-​brightness, transthoracic
echocardiography 10t
two-​dimensional (2D)-​contrast, transthoracic
echocardiography 9t
two-​dimensional (2D) echocardiography
cardio-​oncology  614, 623t
idiopathic DCM  663–​4, 663f, 664f
mitral valve stenosis  191–​3
patent ductus arteriosus  789
pulmonary valve  216, 216f
three-​dimensional echocardiography
vs.  92–​98
tricuspid valve  213
two-​dimensional (2D) spatial resolution,
transthoracic echocardiography  9t
two-​dimensional (2D) speckle-​tracking
echocardiography 635
two-​dimensional (2D) tomographic slices  90–​1
tyrosine kinase inhibitors  614
U ventricle offloading  610, 611f
ultrasmall superparamagnetic iron oxide
(USPIO) particles  472
undifferentiated pleomorphic sarcoma  737–​8
unicuspid aortic valve regurgitation  182
V scarring 305
Valsalva manoeuvre  511, 511f
valve function
MRI  69, 70f, 71
ventricular assist devices  606f, 608
valves
perforation in infectious
endocarditis  275, 276f
regurgitation assessment  805
regurgitation in extracorporeal support  604f,
605f, 606f, 609
stenosis assessment  805, 806f
valvular heart disease (VHD)  223–​32
cardio-​oncology  619–​20
haemodynamic interactions  224, 224b
imaging modalities  224–​5, 225t
TAVI risk stratification  324, 325f
transthoracic echocardiography  233
valvular prostheses  251–​70
anterograde flow  249f, 256–​7t, 259–​
60, 261–​2t
dehiscence in infectious endocarditis  275–​6
Doppler haemodynamic parameters  261–​2t
embolism risk  282
endocarditis  266–​7, 267f, 268f, 269f
follow-​up  282
function assessment  252–​9
function/​dysfunction  259–​68
haemolysis  268, 269f
mortality 282
normal regurgitant flow  260, 263f
obstruction  260, 262, 264
prognosis 282
regurgitation  264–​6
specifications & parameters  251–​2
structural deterioration  266, 266f, 267f
thrombosis 262
transprosthetic gradients  254t
see also single-​tilted-​disc prostheses
variable shunting, atrioventricular septal
defects  787–​8, 788f
vascular diseases, cardio-​oncology  621–​2,
622f
vascular echo Doppler imaging  621–​2
vascular endothelial growth factor (VEGF)  621
vasodilator stress  484
CMR 634
vegetations, infective endocarditis  272–​3, 273f
VEGF (vascular endothelial growth
factor) 621
velocity-​encoded (VENC) cine-​cardiac
magnetic resonance imaging  758
velocity-​encoded magnetic resonance
imaging  75, 76f
vena cava
width 188t
see also superior vena cava (SVC)
vena contracta (VC)  94
width  184, 184f, 203
venous anatomy imaging  584
Venous P-​valve  378, 380f
venous thromboembolism (VTE)  621
venovenous (VV) delay  589, 590, 590f, 591
venovenous (VV-​)extracorporeal membrane
oxygenation  602, 602f, 603–​4, 603f, 604f
ventricles
assist devices  602t, 607–​8
left see left ventricle (LV)
mass in cardio-​oncology  615–​16
right see right ventricle (RV)
size 798
volumes  384, 384f, 615–​16
ventricular arrhythmias
ARVC  686–​7
cardiac MRI  304f
diagnosis with cardiac MRI  305
MRI  303–​6
ventricular function
assessment in functionally univentricular
heart 803
cardio-​oncology  614, 615–​16
SPECT 47
ventricular recovery  608
ventricular septal defect closure  291–​5
echocardiography  294–​5
percutaneous closure  293–​4
surgery  292–​3
ventricular septal defects (VSDs)  786–​7, 787f
associated anomalies  787
classification  291–​2, 292t
CMR/​MSCT  812–​13
congenitally corrected transposition of the
great arteries and  801
definition 291
percutaneous closure  293f, 294f
post-​surgery imaging  787
transposition of the great arteries and  797
ventricular untwisting  508
vertical long axis (VLA) MRI  69, 70f
VHD see valvular heart disease (VHD)
viral infections, myocarditis  668–​9
VSDs see ventricular septal defects (VSDs)
VTE (venous thromboembolism)  621
vulnerable plaques
CMR  472, 473f
CTCA  469–​70, 470f
W
wall motion score index  501, 501f
Wilkins’ score, percutaneous mitral
commisurotomy results  195, 195t
Working group of Nuclear Cardiology and
Cardiac Computed Tomography  410
X
X-​ray source, CT  57