The Right Ventrice in Health and Disease

Respiratory Medicine
Series Editor: Sharon I.S. Rounds
Norbert F. Voelkel
Dietmar Schranz Editors
The Right
Ventricle
in Health
and Disease
Respiratory Medicine
Series Editor:
Sharon I.S. Rounds
More information about this series at http://www.springer.com/series/7665
https://www.facebook.com/groups/2202763316616203
Norbert F. Voelkel • Dietmar Schranz
Editors
The Right Ventricle

in Health and Disease
Editors
Norbert F. Voelkel, M.D. Dietmar Schranz, M.D.
Department of Medicine Pediatric Heart Center
Virginia Commonwealth University Justus-Liebig University
Richmond, VA, USA Giessen, Germany
Videos to this book can be accessed at http://www.springerimages.com/videos/978-1-4939-1064-9
ISSN 2197-7372 ISSN 2197-7380 (electronic)

ISBN 978-1-4939-1064-9 ISBN 978-1-4939-1065-6 (eBook)
DOI 10.1007/978-1-4939-1065-6
Springer New York Heidelberg Dordrecht London
Library of Congress Control Number: 2014950066
© Springer Science+Business Media New York 2015

This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of
the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation,
broadcasting, reproduction on microfilms or in any other physical way, and transmission or information
storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology
now known or hereafter developed. Exempted from this legal reservation are brief excerpts in connection
with reviews or scholarly analysis or material supplied specifically for the purpose of being entered and
executed on a computer system, for exclusive use by the purchaser of the work. Duplication of this
publication or parts thereof is permitted only under the provisions of the Copyright Law of the Publisher’s
location, in its current version, and permission for use must always be obtained from Springer.
Permissions for use may be obtained through RightsLink at the Copyright Clearance Center. Violations
are liable to prosecution under the respective Copyright Law.
The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication
does not imply, even in the absence of a specific statement, that such names are exempt from the relevant
protective laws and regulations and therefore free for general use.
While the advice and information in this book are believed to be true and accurate at the date of
publication, neither the authors nor the editors nor the publisher can accept any legal responsibility for
any errors or omissions that may be made. The publisher makes no warranty, express or implied, with
respect to the material contained herein.
Printed on acid-free paper
Humana Press is a brand of Springer

Springer is part of Springer Science+Business Media (www.springer.com)
Preface
The consensus of the working group is that the role of the right ventricle in a spec-
trum of cardiovascular diseases has been relatively neglected proportionate to its
central importance. Advancing knowledge through research about the unique
genetic, molecular, cellular, and functional characteristics of the right ventricle and
their vulnerability to disease will lead to progress in the treatment of cardiomyopa-
thy, pulmonary arterial hypertension, right ventricular ischemic syndromes, and
valvular heart disease. The success in such effort requires collaborations between
and among clinical and basic investigators from various disciplines, including those
in respiratory/pulmonary and cardiovascular fields as well from neuroscientists,
immunologists, endocrinologists, and biomedical engineers. Joint meetings of the
American Heart Association and the American Thoracic Society would be appro-
priate venues to promote the importance of understanding the right ventricle and
would help to accelerate the gathering of information leading to better treatment and
preventative means to reduce morbidity and mortality associated with right heart
failure and left heart failure.
Awareness should be promoted in the pulmonary and cardiology research com-
munities about the lack of knowledge of the right ventricle with well-publicized
requests for research proposals. New and established investigators should be encour-
aged to enter this fruitful area of research.
Videos to this book can be accessed at http://www.springerimages.com/
videos/978-1-4939-1064-9
*Report of a National Heart, Lung, and Blood Institute Working Group on
Cellular and Molecular Mechanisms of Right Heart Failure, Circulation, 2006.
As a physicist, I wonder why it is that biology and medicine seem to have so few new
theories—Murray Gell-Mann, Nature 491, 561, 2012.
Richmond, VA, USA Norbert F. Voelkel

Giessen, Germany Dietmar Schranz
Introduction
While Bacon was thinking. Harvey was acting… No longer were men to rest content with
careful observation with accurate description… Here for the first time a great physiological
problem was approached from the experimental side by a man with a modern scientific
mind… To the age of the hearer, in which men had heard, and heard only, had succeeded
the age of the eye, in which men had seen and had been content only to see. But at last came
the age of the hand—the thinking, devising, planning hand; that hand as an instrument of
the mind… from which we may date the beginning of experimental medicine.
—William Osler, Harveian Oration, 1906.
Historically, the right ventricle of the heart has received less attention when compared
to the left ventricle and there are several reasons for this wrong treatment of the right
ventricle. Experiments of cauterization of the RV-free wall muscle showed that the
overall pump function of the heart was not badly compromised—at least in the short
run [1]. Some concluded that the RV was not important. Of course physicians taking
care of patients with severe pulmonary hypertension continue to observe that this is not
so: patients still die from RV failure. However, even in the early days of pulmonary
hypertension research clinicians were puzzled by the fact that there were some long-
term surviving patients; these patients were untreated and had high pulmonary artery
pressures [2]. A recent survey estimates that 8 % of patients with severe pulmonary
hypertension are in NYHA functional class I [3]. This begs the questions: why do some
patients—with essentially the same RV afterload—fail earlier than others? Are there
different RV phenotypes? What, if anything, protects the RV of some patients against
failure?
Some of these questions were put into a sharp focus at the 1997 Aspen Lung
Conference [4], yet the pebble that Michael Bristow threw into this lake did not
draw particularly wide circles. In 2005, the Lung Division of the NIH hosted a
workshop dedicated to the right ventricle in health and disease and the report of the
working group was published in 2006 [5]. This report also highlighted the impor-
tance of RV failure for the outcome of patients with left-sided heart failure [6].
vii
viii Introduction
While working on a review article on RV failure, it became clear that one impor-
tant explanation for our knowledge gaps was the lack of animal models of chronic
RV failure. Such models are necessary to investigate the transition from compen-
sated RV hypertrophy to dysfunction and failure. Imaging studies have advanced
from “looks like” to detailed functional analysis of the RV inflow and outflow tract
and the question: why does the RV fail? is now being approached with the toolkits
of cell and molecular biology and bioinformatics.
From the vantage point of the physician caring for patients with severe PH sooner
or later the pulmonary hypertension syndrome develops into an RV failure syn-
drome. Some clinicians have been overheard teaching: “I don’t care much about the
pulmonary artery pressure—as long as the right ventricle performs well.” The acute
response of the RV to pulmonary vasodilators appears to predict the outcome in
patients with advanced heart failure and pulmonary hypertension [7]. If we follow
that thought a bit further, we arrive at a therapeutic goal that can be stated as fol-
lows: Treatment of patients with severe PH means prevention of RV failure and
effective reversal of established RV failure. Sir William’s “thinking, devising, plan-
ning hand” must touch the right ventricle. Experiments can be designed to predict-
ably push the compensated pressure-overloaded RV into failure. From such
experiments, we can learn about what makes the RV fail and when RV failure can
still be reversed—and how to reverse it.
The goal of this comprehensive examination of the RV in this monography is to
touch the right ventricle, in fact, to get a firm grip on it. One would hope that a firm
grip on the right ventricle will improve patient survival.
In the area of congenital and pediatric heart problems, the right ventricle is the
focus of interest. Right ventricular failure mainly determinates if a congenital heart
malformation becomes a disease. Outcome and therapeutic options are influenced
by the right ventricular morphology, position, and function. Usually the right ven-
tricle is a tripartite structure and in a sub-pulmonary position. However, congenital
heart malformations might be associated with a right ventricle as sub-aortic and
single ventricle or with a bi- and even a unipartite structure. The mechanisms of the
right ventricular pathophysiology with its heart–lung, electro-mechanical, and
right–left heart interactions need to be recognized in congenital and acquired heart
disease. Additionally, the pressure or volume (over-) loaded right ventricle and the
systemic right ventricle in a biventricular or univentricular circulation have to be
analyzed in the context of the structural, biochemical, and physiological differences
of the right and left ventricle. Currently, the exact mechanism of right ventricular
survival even with lifelong systemic pressures remains not fully understood.
Congenital heart defects might inform us about novel therapeutic strategies in heart
failure syndromes with normally positioned ventricles.
Introduction ix
References
1. Starr I, Jeffers WA, Meade RH. The absence of conspicuous increments of venous pressure
after severe damage to the right ventricle of the dog, with discussion of the relation between
clinical congestive heart failure and heart disease. Am Heart J. 1943;26:291–301.
2. Voelkel NF, et al. Primary pulmonary hypertension between inflammation and cancer. Chest.
1998;114(3 Suppl):225S–30S.
3. Badesch DB, et al. Pulmonary arterial hypertension: baseline characteristics from the REVEAL
Registry. Chest. 2010;137(2):376–87.
4. Bristow MR, et al. The pressure-overloaded right ventricle in pulmonary hypertension. Chest.
1998;114(1 Suppl):101S–6S.
5. Voelkel NF, et al. Right ventricular function and failure: report of a National Heart, Lung, and
Blood Institute Working Group on cellular and molecular mechanisms of right heart failure.
Circulation. 2006;114(17):1883–91.
6. Ghio S, et al. Independent and additive prognostic value of right ventricular systolic function
and pulmonary artery pressure in patients with chronic heart failure. J Am Coll Cardiol.
2001;37(1):183–8.
7. Gavazzi A, et al. Response of the right ventricle to acute pulmonary vasodilation predicts the
outcome in patients with advanced heart failure and pulmonary hypertension. Am Heart J.
2003;145(2):310–6.
Contents
Part I The Normal Right Ventricle
1 Normal Development and Morphology

of the Right Ventricle: Clinical Relevance ............................................ 3
Adriana L. Gittenberger-de Groot, Robert E. Poelmann,
Rebecca Vicente-Steijn, Margot M. Bartelings, Harm Jan Bogaard,
and Monique R.M. Jongbloed
2 Physiology of the Right Ventricle........................................................... 19
Robert Naeije, Ryan J. Tedford, and François Haddad
3 The Neonatal Transition of the Right Ventricle ................................... 41
Michael V. Di Maria and Steven H. Abman
4 Advanced Imaging of the Right Ventricle............................................. 57
Titus Küehne
Part II Congenital Abnormalities
5 Subpulmonary Right Ventricle in Congenital Heart Disease ............. 79

Christian Apitz, Heiner Latus, and Dietmar Schranz
6 The Systemic Right Ventricle in Biventricular
and Univentricular Circulation ............................................................. 103
Heiner Latus, Christian Apitz, and Dietmar Schranz
7 Right Ventricle in Structural and Functional Left Heart
Failure in Children .................................................................................. 117
Dietmar Schranz, Heiner Latus, and Christian Apitz
8 Missing a Sub-pulmonary Ventricle: The Fontan Circulation ........... 135
Marc Gewillig and Derize E. Boshoff
xi
xii Contents
Part III Acute Right Heart Failure
9 Acute Right Ventricular Failure ............................................................ 161

Anthony R. Cucci, Jeffrey A. Kline, and Tim Lahm
Part IV Chronic Right Ventricular Failure
10 Echocardiography of Chronic Right Heart Failure ............................. 209

Florence H. Sheehan and Per Lindqvist
11 Hemodynamic Evaluation and Exercise Testing
in Chronic Right Ventricular Failure .................................................... 249
Onno A. Spruijt, Anton Vonk-Noordegraaf, and Harm J. Bogaard
12 Cardiac MRI and PET Scanning in Right Ventricular Failure .......... 265
Mariëlle C. van de Veerdonk, J. Tim Marcus, Harm-Jan Bogaard,
and Anton Vonk Noordegraaf
13 The Pathobiology of Chronic Right Ventricular Failure ..................... 283
Norbert F. Voelkel, Jose Gomez-Arroyo, Antonio Abbate,
and Harm J. Bogaard
14 The Sick Lung Circulation and the Failing Right Ventricle ............... 303
Norbert F. Voelkel
15 Exercise-Induced Right Heart Disease in Athletes .............................. 315
David Prior and Andre La Gerche
16 Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) .......... 337
Luisa Mestroni, Francesca Brun, Anita Spezzacatene,
Gianfranco Sinagra, and Matthew R.G. Taylor
17 The Right Ventricle in Left Heart Failure ............................................ 361
Louis J. Dell’Italia
18 The Right Ventricle in Chronic Lung Diseases .................................... 391
Norbert F. Voelkel and Otto C. Burghuber
19 Treatment of Chronic Right Heart Failure........................................... 401
Jasmijn S.J.A. van Campen and Harm J. Bogaard
20 Atrial Septostomy.................................................................................... 419
Julio Sandoval and Adam Torbicki
21 Right Ventricular Assist Devices............................................................ 439
Lynn R. Punnoose, Marc A. Simon, Daniel Burkhoff,
and Evelyn M. Horn
Contents xiii
22 Animal Models of Chronic Right Ventricular

Stress and Failure .................................................................................... 455
Jose Gomez-Arroyo, Michiel Alexander de Raaf,
Harm Jan Bogaard, and Norbert F. Voelkel
Epilogue ........................................................................................................... 471
Index ................................................................................................................. 473
Contributors
Antonio Abbate, M.D., Ph.D. VCU Pauley Heart Center, Virginia Commonwealth
University, Richmond, VA, USA
Steven H. Abman, M.D. Department of Pediatrics, University of Colorado,
Denver, CO, USA
Christian Apitz, M.D. Department of Pediatric Cardiology, Justus-Liebig-
University, Giessen, Germany
Margot M Bartelings
Harm J. Bogaard, M.D., Ph.D. Department of Pulmonary Medicine, VU University
Medical Center, Amsterdam, The Netherlands
Derize Boshoff, M.D., Ph.D. Department of Paedatric Cardiology, University
Hospital Lenven, Leuven, Belgium
Francesca Brun, M.D. Department of Cardiology, Ospedali Riuniti and University
of Trieste, Trieste, Italy
Otto Chris Burghuber, M.D. Department of Respiratory and Critical Care
Medicine, Otto Wagner Hospital, Vienna, Austria
Daniel Burkhoff, M.D., Ph.D. Department of Medicine, Columbia University,
New York, NY, USA
Jasmijn S.J.A. van Campen, M.D.
Anthony R. Cucci, M.D. Department of Internal Medicine, Division of Pulmonary/
Critical Care, Indian University, Indianapolis, IN, USA
Louis J. Dell’Italia, M.D. Department of Medicine, University of Alabama and
Birmingham Medical Center, Birmingham, AL, USA
André La Gerche, M.B.B.S., Ph.D. Department of Medicine, St Vincent’s
Hospital, University of Melbourne, Fitzroy, VIC, Australia
xv
xvi Contributors
Marc Gewillig, M.D., Ph.D. Department of Pediatric Cardiology, University

Hospital Leuven, Leuven, Belgium
Jose Gomez-Arroyo, M.D., Ph.D. Department of Immunology, University of
Pittsburgh, Pittsburgh, VA, USA
Adriana L. Gittenberger-De Groot, Ph.D. Department of Anatomy and
Embryology, Cardiology, Leiden University Medical Center, Leiden, The
Netherlands
Francois Haddad, M.D. Department of Medicine, Stanford University, Palo Alto,
CA, USA
Evelyn M. Horn, M.D. Department of Medicine/Division of Cardiology, Weill
Cornell Medical College of Cornell University, New York, NY, USA
Monique R.M. Jongbloed, M.D., Ph.D. Department of Anatomy & Embryology,
Cardiology, Leiden University Medical Center, Leiden, The Netherlands
Jeffrey A. Kline, M.D. Emergency Medicine, Indiana University School of
Medicine, Indianapolis, IN, USA
Titus Küehne, M.D., Ph.D. Department of Pediatric Cardiology/Congenital Heart
Disease, Charité—Berlin and German Heart Institute Berlin, Berlin, Germany
Tim Lahm, M.D. Department of Medicine, Division of Pulmonary, Allergy,
Critical Care, Occupational and Sleep Medicine, Indiana University School of
Medicine and Richard L. Roudebush VA Medical Center, Indianapolis, IN, USA
Heiner Latus, M.D. Department of Pediatric Cardiology, Justus-Liebig-University,
Giessen, Germany
Per Lindqvist Departments of Surgical and Peri-operative Sciences/Heart Center,
Clinical Physiology, Umeå University Hospital, Umeå, Sweden
J. Tim Marcus, Ph.D. Department of Physics and Medical Technology, VU
University Medical Center, Amsterdam, The Netherlands
Michael V. Di Maria, M.D. Department of Pediatrics, University of Colorado
School of Medicine, Aurora, CO, USA
Luisa Mestroni, M.D. Cardiovascular Institute, University of Colorado Anschutz
Medical Campus, Auroroa, CO, USA
Robert Naeije, M.D., Ph.D. Laboratoire de physiologie, Université Libre de
Bruxelles, Bruxelles, Belgium
Anton Vonk Noordegraaf, M.D., Ph.D. Department of Pulmonary Diseases,
VU University Medical Centre, Amsterdam, The Netherlands
Robert E. Poelmann, Ph.D. Department of Anatomy and Embryology, Leiden
University Medical Center, Leiden, The Netherlands
Contributors xvii
David L. Prior, M.B.B.S., Ph.D., F.R.A.C.P., D.D.U., F.C.S.A.N.Z. Department

of Cardiology, St. Vincent’s Hospital, University of Melbourne, Fitzroy, VIC,
Australia
Lynn R. Punnoose, M.D. Department of Cardiology, University of Pittsburgh
Medical Center, Pittsburgh, PA, USA
Michiel Alexander de Raaf, M.Sc., B.A.Sc. Department of Pulmonary Medicine,
VU University Medical Center, Amsterdam, The Netherlands
Julio Sandoval, M.D. Division of Research, National Institute of Cardiology of
Mexico, Mexico City, Mexico
Florence H. Sheehan, M.D. Department of Medicine/Cardiology, University of
Washington, Seattle, WA, USA
Marc A. Simon, M.D., M.S. Heart and Vascular Institute, University of Pittsburgh
Medical Center, Pittsburgh, PA, USA
Gianfranco Sinagra, M.D., F.E.S.C. Department of Cardiology, Ospedali Riuniti
and University of Trieste, Trieste, Italy
Anita Spezzacatene, M.D. Department of Cardiology, Ospedali Riuniti and
University of Trieste, Trieste, Italy
Onno A. Spruijt, M.D. Department of Pulmonary Diseases, VU University
Medical Center, Amsterdam, The Netherlands
Matthew R.G. Taylor, M.D., Ph.D. Department of Medicine, University of
Colorado Denver, Aurora, CO, USA
Ryan J. Tedford, M.D. Division of Cardiology, Department of Medicine, The
Johns Hopkins School of Medicine, Baltimore, MD, USA
Adam Torbicki, M.D., Ph.D. Department of Pulmonary Circulation and
Thromboembolic Diseases, Center Postgraduate Medical Education, Otwock, Poland
Marielle C. van de Veerdonck
Rebecca Vicente-Steijn
Part I
The Normal Right Ventricle
Chapter 1
Normal Development and Morphology
of the Right Ventricle: Clinical Relevance
Adriana L. Gittenberger-de Groot, Robert E. Poelmann,

Rebecca Vicente-Steijn, Margot M. Bartelings, Harm Jan Bogaard,
and Monique R.M. Jongbloed
Introduction
In recent years, the relevance of knowledge on right ventricular (RV) characteristics

has become increasingly appreciated, as RV function is an important determinant of
survival in a large number of cardiovascular diseases [1]. While a scale of pharma-
cological therapies is available to support function and morphology of the diseased
left ventricle (LV), therapies aimed at long-term improvement of RV function are
scarce [2]. Thus far, the effect of medical therapies which proved to be beneficial in
left ventricular (LV) disease is generally less marked for the dysfunctional RV [3–5].
The differences in pharmacotherapeutical approaches to RV disease are a reflection
of a spectrum of underlying differences between the RV and LV. In this respect it is
Electronic supplementary material: Supplementary material is available in the online version of this
chapter at 10.1007/978-1-4939-1065-6_1. Videos can also be accessed at http://www.springerimages.
com/videos/978-1-4939-1064-9.
A.L.G.-d. Groot, Ph.D. (*) • M.R.M. Jongbloed, M.D., Ph.D.

Depatment of Anatomy & Embryology, Cardiology, Leiden University Medical Center,
Einthovenweg 20, Leiden 2300 RL, The Netherlands
e-mail: A.L.Gittenberger-de_Groot@lumc.nl; M.R.M.jongbloed@lumc.nl
R.E. Poelmann, Ph.D.
Department of Anatomy & Embryology, Leiden University Medical Center,
Einthovenweg 20, Leiden 2300 RL, The Netherlands
e-mail: R.E.Poelmann@LUMC.nl
R. Vicente-Steijn • M.M. Bartelings
H.J. Bogaard, M.D., Ph.D.
Department of Pulmonary Medicine, VU University Medical Center,
De Boelelaan 1117, Amsterdam 1007 MB, The Netherlands
e-mail: hj.bogaard@vumc.nl
© Springer Science+Business Media New York 2015 3

N.F. Voelkel, D. Schranz (eds.), The Right Ventricle in Health and Disease,
Respiratory Medicine, DOI 10.1007/978-1-4939-1065-6_1
4 A.L.G.-d. Groot et al.
interesting that there is a difference in expression in cytochrome genes, necessary

for metabolic events, between the RV and LV [6].
From a morphological point of view, the RV has a particularly complex architec-
ture. Developmentally, there are clear spatiotemporal differences in development of
both ventricles, as we will discuss in this chapter.
Although not as profound as in the LV, the initially markedly trabeculated and
thin walled RV will develop a compact layer, reflecting the function of a normal RV
which is aimed at volume capacity as opposed to the pressure capacity that is neces-
sary in the LV. Below we will discuss the relevance of different cell types in ven-
tricular development, with a pivotal role for the epicardium and its derived cells.
Morphological and developmental differences between the normal RV and LV
are also indicated by the pathology of both ventricles. A sidedness in ventricular
disease can be recognized for instance in cardiomyopathies like ventricular non-
compaction, occurring typically in the LV, and arrhythmogenic RV cardiomyopa-
thy/dysplasia, that has a propensity to occur in the RV (see Chap. 16). Likewise,
specific congenital heart diseases may involve hypoplasia of isolated segments of
the right ventricle [7–9].
Dedicated cell- or drug-based therapy may become of interest for the treatment
of RV disease [10, 11]. Proper understanding of the differences between the LV and
RV on a morphological and molecular level is important for development of these
therapies. In this chapter developmental aspects of the RV will be discussed and
related to the observed morphological differences between the RV and LV in the
postnatal heart, as well as to clinical entities.
Cardiac Development and Impact on the RV
The heart is derived from the splanchnic mesoderm that fuses in the midline around
approximately 19 days of human development. This fusion results in a primitive
heart tube that is at the outset linear. Embryonic blood entering the venous pole of
the tube is directed, via an initially peristaltic wave of contraction, towards the arte-
rial pole of the heart. After a process of looping and septation, as well formation of
the cardiac valves and a specialized cardiac conduction system, the heart will gain
its mature form (Fig. 1.1).
Although this primitive heart tube was initially considered to be a miniature of
the adult heart, more detailed data on early development of the heart were subse-
quently derived from animal studies including mouse and avian. These data corre-
late remarkably well with the descriptive work on human embryos from the early
and mid-1990s [12–15]. Many descriptions and clarifications used here are based on
animal experiments.
In the beginning of 2000, several studies brought prominently forward that the
early embryonic heart tube was not the sole source of all components of the heart.
This had already been established by Maria Victoria de la Cruz based on Indian ink
injections in the embryonic avian heart tube [16]. The two best known papers to
1 Normal Development and Morphology of the Right Ventricle… 5
Fig. 1.1 Cardiac development: looping and septation. Schematic representation (a, b, d and f ) and
electron microscopy images (c, e, g) of different stages of heart development, from heart fields (a) to
a mature four-chambered septated heart (f ). In early developmental stages, bilateral cardiogenic
heart fields (first and second heart fields) are present in the primitive plate (a). The structures derived
from the second heart field are depicted in yellow whereas the structures derived from the first heart
field are depicted in brown (a, b, d and f ). The primitive heart tube is formed after the fusion of the
bilateral plates of mesoderm (b) from the first heart field (brown). The tube is lined with cardiac jelly
(grey). A scanning electron microscopy (SEM) image of a comparable stage in chick heart develop-
ment is depicted in (c). After looping of the heart has started, the different compartments of the heart
can be recognized, the right portion of the ventricle (V) and the outflow tract (OFT) have started to
form from the second heart field (yellow, d), while the left portion of the ventricle is derived from
the first heart field (brown). A SEM image of a comparable stage in chick heart development is
depicted in (e). Eventually, looping and septation as well as formation of the cardiac valves will be
accomplished and the heart will have its mature adult form (f ). A SEM of a comparable stage
in chick heart development is depicted in (e). A atrium, Ao aorta, AP arterial pole, LA left atrium,
LV left ventricle, PT pulmonary trunk, RA right atrium, RV right ventricle, VP venous pole
promote this concept are from the group of Roger Markwald [17] who describes the
anterior heart field that adds myocardium to the outflow tract (OFT), while Margaret
Kirby’s group describes almost the same population of cells and refers to this as the
secondary heart field [18]. Thereafter, based on tracing studies using the LIM domain
homeobox gene Isl1 as a marker of the late addition of myocardium to the heart tube,
it turned out that the addition was taking place not only at the OFT but also at the
inflow tract [19]. The term allotted to this wider spread mesodermal population, resid-
ing between the gut and the heart tube, was second heart field (SHF) as opposed to
first heart field (FHF) being the source of the cells of the primary heart tube (Fig. 1.2).
Fig. 1.2 Schematic overview of cellular contributions to the developing heart. The left part of the
figure depicts a schematic view of the primitive plate with mesenchyme of the first heart field
(brown), second heart field (SHF, yellow) and (putative) neural crest cells (blue). The cellular con-
tributions to the different compartments of the developing heart are schematically attached to the
primitive plate. The first heart field (brown) gives rise to the primary heart tube (PHT) that contrib-
utes to the left ventricle (LV), atrioventricular canal (AVC) and part of the atria. During further
development, cells are recruited to the heart from the SHF (yellow). The SHF can at the arterial
pole of the heart be divided in the so-called secondary heart field, giving rise to the distal outflow
tract (OFT; DOT) and in the anterior heart field (AHF) contributing to the proximal OFT (POT),
the arterial pro-epicardial organ (aPEO) and the right ventricle (RV). At the venous pole of the
heart, contributions are derived from the so-called posterior heart field (PHF), that supplies among
other elements of the atria including the interatrial septum, cardiac conduction system (CCS), the
myocardium surrounding the putative pulmonary and caval veins (PV & CV), as well as to the
venous pro-epicardial organ (vPEO). An extracardiac contribution from the cardiac neural crest
cells is depicted in blue. The right part of the figure shows cartoons of lateral views of an embryo
during these processes in early (upper panel) and more progressed (lower panel) development.
The PHT is lined on the inside by cardiac jelly (light blue). The mesoderm of the second heart field
is depicted by the yellow area behind the primary heart tube, from which cells will be recruited to
the heart tube at both the arterial and venous poles. As development proceeds (lower panel) seg-
ments of the heart will develop by progressive contribution of cells from the first and second heart
field (yellow areas at the arterial en venous pole of the heart tube). BV brain ventricles, C coelomic
cavity, DAo dorsal aorta, DMP dorsal mesenchymal protrusion, SAN sinoatrial node, G gut, ggL
ganglia, IFT inflow tract, PAA pharyngeal arch arteries, SV sinus venosus. The right panel is pub-
lished in [68] and reproduced with permission
The use of the terms second and secondary heart field has led to some confusion. Our
group designated the contribution of SHF to include both the posterior heart field
providing the inflow tract, and the anterior heart field providing the OFT (Fig. 1.2).
Remarkably, already in the primitive plate the areas of FHF and SHF can be
designated [20] (Fig. 1.1). It should be noted, however, that although a distinction
in nomenclature (i.e. FHF versus SHF) is generally made, both heart fields should
probably be regarded as a spatiotemporal continuum, from which cells are progres-
sively derived during cardiovascular development, with an earliest contribution to the
primary heart tube.
The FHF is the source of the primitive LV, the atrioventricular canal myocardium
and a small part of the atria, together constituting the primary heart tube. A very
time laborious study of LaacZ cell tracing [21] revealed that almost the complete
RV including the RV side of the ventricular septum is SHF derived [22] (indicated
in yellow in Figs. 1.1 and 1.2). The RV OFT compartment shows a molecular dis-
tinction [23]. Together with observations on asymmetric distribution of Nkx2.5
positive SHF derived cells in the mesoderm of the OFT, we provide in this chapter
novel data on the relative repositioning of the ascending aorta and pulmonary trunk.
Posterior heart field derived are the sinus venosus myocardium, encompassing
the entrance of the superior and inferior caval vein and the coronary sinus. Recently,
our concept was proven that the pulmonary veins also belong to this sinus venosus
derived incorporation [24, 25].
Positioning of the OFT: The Pulmonary Push Concept
In the primary embryonic heart tube, the atrioventricular canal with the endocardial
cushions completely connects to the primitive left sided ventricle. The OFT, initially
situated entirely above the primitive RV, connects to the unseptated aortic sac that
still needs to be divided into a pulmonary and aortic orifice leading to the great
arteries. As mentioned above, during development the heart tube shows a dextral
looping leading to a marked almost circular groove which is referred to as the inner
curvature. The inner curvature is reflected internally by the primary fold or ring
positioned between the primitive LV and the RV, which is still expanding due to the
material addition of the SHF (Fig. 1.1). Both the atrioventricular canal myocardium
and the nontrabeculated component of the OFT are lined by endocardial cushions.
During remodelling and septation of the OFT, the aorta becomes connected to the
LV. The long held idea was that rotation of the endocardial cushions was instrumen-
tal together with additional shortening of the subaortic OFT myocardium [26]. The
mechanisms underlying rotation as well as the inferred apoptosis (programmed cell
death) in the OFT have always remained hypothetical. We discovered an asymmet-
ric and late contribution of Nkx2.5 expressing primitive mesenchyme (see Ref.
[27]) on top of addition of smooth muscle cells preferentially to the pulmonary side
of the OFT [28]. Analyzing this in 3D reconstructions we devised a new hypothesis
in which rotational movement must be substituted for an anterior push of the sub-
pulmonary myocardium resulting in lengthening of the RV OFT (Fig. 1.3 and
Supplemental Video 1.1). This mechanism eliminates the requirement of marked
subaortic apoptosis to understand the relative low position of the aortic orifice
wedged between the tricuspid and the mitral orifice.
Fig. 1.3 Outflow tract positioning: the pulmonary push concept. 3D reconstructions of an embry-
onic day (E) 12.5 mouse embryonic heart. An anterior (a), right lateral (b) and posterior (c) view
are depicted to elucidate the asymmetric contribution of Nkx2.5 positive mesenchyme (yellow)
mainly to the left (putative pulmonary) side of the heart. Colour coding in the 3D reconstructions:
red: aorta and left ventricle (LV) lumen; blue: pulmonary trunk (Pu), ductus arteriousus (DA) and
right ventricle (RV) lumen; grey: transparent myocardium. OFT outflow tract. Modified after [28]
Tricuspid Orifice Formation
The dextral looping process and the relocation of the pulmonary orifice includes a
marked relocation of the atrioventricular (AV) canal allowing the future tricuspid
orifice to channel into the RV inflow tract compartment. Several concepts for this
remodelling process have been proposed. Initially, the right side of the AV canal with
the putative tricuspid orifice is positioned to the left of the primary fold (Fig. 1.1).
The originally very small RV inflow tract enlarges and becomes positioned to the
right of this fold. The exact mechanism in which this is achieved still remains elusive
but concepts will be described in the section on ventricular septation.
Role of the Epicardium in Development of the Compact

Myocardial Layer and Coronary Vascular Formation
The primary heart tube consists of an endocardial inner surface, a thick basement
membrane, referred to as cardiac jelly, and an outer myocardial layer. During loop-
ing and SHF addition, the cardiac jelly persists in two endocardial cushion areas
situated in the AV canal and in the OFT. Both cushion areas play a role in cardiac
valve formation as well as in septation.
The remaining cardiac tube forming the future LV and RV is a two layered thin
structure that borders on the outside to the coelomic cavity. Subsequently, two
essential processes take place. First, the future outer compact myocardial layer and
an inner trabecular layer become distinct, and second, progressive myocardial
compaction needs to occur. The mechanism underlying trabecular formation,
linked to AV valve development, has recently been described [29]. The system of
trabeculations has an important mechanical function in the heart tube [30] main-
taining ventricular wall strength. The trabecular sinuses also serve as a reservoir for
blood. Before the complete development of the RV there is little difference in the
trabecular architecture of the RV and LV [31] (Fig. 1.4). The compact layer of the
myocardium still has to increase in thickness and interaction with the epicardium
is an essential component of this process.
Most of the epicardium is derived from the so-called pro-epicardial organ (vPEO)
positioned at the venous pole of the heart [32]. Recently we have shown that a second
epicardial organ (aPEO) can be distinguished at the OFT (Fig. 1.2). Epicardial cells
migrate from both sources over the heart (vPEO derived) and great arteries (aPEO
derived). The anterior surface of the RV is the last to be covered in this process [33].
The epicardium becomes relatively dormant in adult life. However, the role of the
epicardium in cardiac development has received the attention of many research
groups because myocardial injury is associated with adult reactivation, which may
play a role in repair after myocardial infarction, Several recent reviews cover this
area [32, 34–36] containing the information on the underlying primary research.
The data that reflect specifically on the development and morphology of the RV
will be presented here. The epicardium derived from the vPEO is referred to as car-
diac epicardium (cEP) as it covers only the myocardium up to the ventriculo-arterial
junction. After this covering a process of epithelial-mesenchymal-transition (EMT)
leads to a population of epicardium derived cells (EPDCs) that move into the sub-
epicardial space and subsequently migrate into the myocardium. Many genes and
molecular pathways are involved in this process [37]. Having entered the myocar-
dium, EPDCs will differentiate into the smooth muscle cells of the coronary arteries
and into intracardiac fibroblasts. It cannot be excluded that these populations are
already programmed to their fate while still being on the surface [38] which might,
therefore, harbour a heterogeneous epicardial population. When epicardial out-
growth [39], the process of EMT or migration are disturbed [32], normal compac-
tion of the ventricular myocardium will not take place leading in the most severe
cases to a very thin compact myocardium or embryonic death. This has been
described in many animal models based on mutated genes influencing the epicar-
dium or the ensuing cross-talk between epicardium and myocardium (an example is
shown in Fig. 1.4 for a TGFβ mutant mouse). This important population for myocar-
dial differentiation shows a temporo-spatial difference in the contribution to the RV
and LV wall (unpublished data). In summary (1) the EPDC migration into the RV
precedes slightly the migration into the LV wall, (2) eventually the LV receives more
EPDCs and (3) there is a difference in anterior to posterior deposition of EPDCs in
the RV wall. The RV receives relatively more EPDCs than the LV, and in both ven-
tricles the posterior wall holds more EPDCs than the anterior wall. Whether this
observation is relevant for adult RV and LV function is not known but it is tempting
Fig. 1.4 Development of the compact myocardial layer. (a–d) Myocardial thickening and com-
paction of the right ventricular (RV) wall throughout mouse heart development: from embryonic
day (E) 11.5 up to E14.5. A compact myocardial layer can be observed starting only at E14.5 in
the RV. (e–h) Myocardial thickening and compaction of the left ventricular (LV) wall during the
same stages of mouse heart development (E11.5–E14.5). Development of a compact myocardial
layer can be observed starting from E12.5 and increasing in subsequent stages. (i and j) Overview
sections of the heart at stage E13.5 in wild type (WT, i) and TGFβ2 knockout (−/−, j) embryos.
In TGFβ2 knockout embryos thin myocardium is observed in both the LV and RV. The interven-
tricular septum (IVS) has a spongeous appearance. Bars: 100 μm
to relate it to non-compaction cardiomyopathies and the difference between RV and

LV types. In several forms of congenital heart disease, the posteriorly situated inflow
compartment is mostly affected, as is described for pulmonary atresia with intact
ventricular septum resulting in a bi- or unipartite ventricle.
The EPDCs that differentiate into smooth muscle cells start to cover the main
arterial stems that have grown into the aorta at specific sites of the aortic wall [40,
41]. These initial observations in avian embryos are now confirmed in mouse
studies [42]. The reason that normally the coronary vessels do not penetrate
the pulmonary wall is postulated to relate to the specific myocardial origin of
the subpulmonary OFT.
Disturbed epicardial contribution can lead to diminished coronary vasculariza-
tion of the myocardium as well as absent or pin-point coronary arterial orifices [41,
43]. The relevance for specific RV pathology might relate to the incompletely
understood preference of ventriculo-coronary-arterial communications (VCACs) or
fistulae in case of pulmonary atresia without ventricular septal defect (VSD) in the
hypoplastic RV [7, 8]. A similar coronary arterial pathology is not seen in the hypo-
plastic left heart [44]. It is unclear whether myocardial architecture dictates distribu-
tion of the microvascular coronary capillaries or vice versa. It is obvious that the
normal LV has a more regular patterning of capillaries compared to the RV [45].
Morphology Right Versus Left Ventricle (Fig. 1.5)
The RV morphology is clearly different from the LV based on a number of structural

characteristics of the RV cavity. The entrance into the RV from the right atrium is
via the tricuspid orifice which is encircled by a fibrous annulus composed of fine
collagen. The tricuspid valve consists of three valve leaflets: the posterior, the ante-
rior and the septal leaflet. These leaflets are attached by chordae tendineae to the
papillary muscles including the septal and moderator band. In general the RV is
divided into three parts: the tripartite division [46]. Following the flow, these consist
of (1) a posteriorly located inlet segment. Subsequently, crossing the septal to mod-
erator band continuity (Fig. 1.5) (2) the trabecular component reaching up to the
apex. The latter apical compartment is lined by relatively coarse trabeculations that
distinguish the RV from the finely trabeculated LV. The last compartment is (3) the
relatively smooth walled OFT leading to the pulmonary orifice and pulmonary
trunk. The pulmonary orifice harbours three semilunar valve leaflets. The anchorage
of this orifice into the OFT myocardium differs from the way into which the aortic
orifice is embedded into the LV [47–49].
At birth, the difference in thickness of the compact layer of the myocardium
between the RV and LV is less marked, but after birth, when the low pressure pul-
monary circulation and the high pressure systemic circulation become functional,
the compact myocardium of the RV will remain evidently thinner as compared to
the increasingly thickened LV. This is most obvious in the trabecular component
and the anterior and lateral wall.
Fig. 1.5 Ventricular morphology. (a–d) Pictures of a neonatal heart of 36 weeks gestation
(a) Frontal and (b) superior view, showing the normal left anterior position of the pulmonary trunk
(PT) as related to the aorta (Ao). (c) View into the right ventricle (RV). The tricuspid valve (TV) is
separated from the orifice of the pulmonary trunk (PT) by muscle tissue of the supraventricular
crest, consisting of the ventriculoinfundibular fold (VIF) and the septal band (SB). The septal band
(SB) is continuous with the moderator band (MB) that has been cut in this view. In the normal
heart, the outflow tract septum cannot be recognized as a separate entity. (d) View into the left
ventricle (LV). The mitral valve (MV) is in fibrous continuity with the aortic valve (Ao). The wall
of ventricular septum (IVS) is smooth. (e) Drawing of the anatomical structures of the RV, showing
the different compartments. The inlet septum (IS) is separated from the trabeculated apical part by
the septal band (SB). The part above this continuity towards the PT is the outflow part of the RV.
(f) Adult heart, in which the RV has been fenestrated to demonstrate the moderator band (MB), that
crosses the RV lumen from the IVS towards the lateral wall. (g) Close up of the MB. (h) Neonatal
heart with two ventricular septal defects (VSD): the upper defect (indicated by one probe) is a
perimembranous VSD, characterized by a fibrous continuity in the lower rim of the defect.
The lower defect (indicated by two probes) is a central muscular VSD. A case of transposition of
the great arteries with a malalignment VSD (probe) where the outlet septum (asterisk) is malaligned
with the remainder of the IVS and thus can be recognized as structure separated from the ventricu-
loinfundibular fold (VIF) and the septal band. The pulmonary orifice (PT) overrides the septum
and is partly above the RV
Myocardial Architecture
Studying cross sections of the heart or using the more advanced imaging modalities
in the clinic clearly show the banana shaped cavity of the RV enclosing in part the
more globular LV. The myocardial layering and architecture demonstrates that the
various sheets of myocardium differ between the RV and LV. Meticulous dissection
techniques have supported a wrapping of myocardial layers allowing the complete
ventricular myocardium to be exposed as a single sheet after enzymatic degradation
of the collagen [50]. It is extremely difficult to decide whether the myocardial archi-
tecture as such is the result of a developmental Anlage, or is caused by a functional
adjustment of the intermingling of fibrous and myocardial layers.
Recent studies of our group on ventricular septation and the RV and LV myocar-
dial layers support an inherent different development of the architecture of the RV
and LV. This is most obvious in the anterior part of the ventricular septum in which
during ballooning of the RV and LV cavities the RV myocardium is in a more verti-
cal position as compared to the more circular expansion of the LV [51]. Finally, the
RV myocardial fibre direction is oriented in two layers, whereas the LV wall shows
a three layered structure [45].
Ventricular Septation
The RV and the LV aspect of the ventricular septum pose completely different
morphologies.
While the RV surface is dominated by the septal band and the specific attach-
ments of the tricuspid leaflets to this structure, the LV surface is smooth and shows
no attachments of chordae tendineae to the mitral leaflets. Furthermore, the RV has
a marked muscular band between the tricuspid and pulmonary valve, the so-called
supraventricular crest, while in the LV the aortic and mitral valves are in fibrous
continuity. These differences originate in the development of the interventricular
septum. The literature agrees on the development of the muscular subpulmonary
myocardium which is seen in the RV as the supraventricular crest. The supraven-
tricular crest consists in fact of three structures, the ventriculoinfundibular fold, the
septal band (that carries the right bundle branch, and is continuous with the modera-
tor band) and the outlet septum (Fig. 1.5). These three structures are well aligned in
a normal heart, thus forming an anatomical continuum, in which the outlet septum
cannot be recognized as a separate structure. The outlet septum is a myocardial struc-
ture derived from the fusion of the proximal part of the OFT and endocardial ridges
which myocardialize secondarily, under the influence of migrating neural crest cells
[52–54]. In a normal heart this structure is only for a very small part a real OFT
septum due to the relative repositioning of the aortic and pulmonary orifice (see
pulmonary push concept). The OFT ridges, are, however, fused to the AV endocar-
dial cushions that close off the embryonic interventricular foramen, hereby com-
pletely separating the RV from the LV. Abnormal positioning or development of the
outlet septum results in incorrect fusion with the main body of the ventricular septum
and the formation of a VSD and only then the OFT septum is recognizable as a sepa-
rate structure. Malalignment and hypoplasia of the OFT septum are the cause of
most types of VSDs seen in congenital heart disease. Most genetic causes for OFT
malformations in the human heart relate to genes expressed in the SHF including the
Tbx1 mutation in the 22q11 deletion syndrome. As the SHF population and neural
crest cells have a specific interaction, a primary neural crest cell problem may also
play a role. An important function for the subpopulation of neural crest cells is in the
separation of the aortic and pulmonary trunk. In animal experiments neural crest cell
deficiency leads to common arterial trunk (persistent truncus arteriosus) [55, 56].
Several theories have dominated the field to explain the origin of the main part of
the ventricular septum. Several authors [12, 13] agreed on a three component origin,
consisting of (1) the already mentioned OFT myocardium, (2) the inlet septum sepa-
rating the posterior part of the ventricles between the tricuspid and the mitral orifice
and (3) a primary or anterior trabeculated part. In this concept, the primary ring or
fold was the basis for the primary septum with its natural borderline as the septal
band, the inlet septum being a separate structure. These two parts had to merge and
abnormal fusion or merging could explain the central muscular VSD [57]. This
hypothesis was replaced [58, 59] by the postulate that the primary fold was the
source of both the anterior trabeculated component and the inlet septum. As a con-
sequence the tricuspid orifice had to cross over the inlet component of the primary
fold. A combination of both hypotheses was proposed [56] in which the tricuspid
orifice and its underlying developing inlet component of the RV developed as part of
the posterior part of the primary fold. Recent unpublished observations from our
group, based on extensive comparative developmental research (evo-devo studies)
comparing various vertebrates including snakes, lizards and crocodiles, revert the
balance towards a three part ventricular septum which also provides a better expla-
nation for the specific morphology of the RV as well as the variation in characteris-
tics of the VSDs. The most simple membranous VSD is the result of non-fusion of
the endocardial cushions at their meeting site in the interventricular foramen
(Fig. 1.5). The fibrous tissue of the membranous septum at this site is endocardial
cushion derived. There is no separate status for an atrioventricular septal component,
with an interventricular and an atrioventricular part (between the LV OFT and the
right atrium). This is just a consequence of asymmetric RV and LV OFT septation.
Clinical Considerations
The developmental components and underlying cell types that are essential for RV
formation have already been related to a number of congenital heart defects.
RV dysfunction is a recognized problem in adult patients with congenital or
acquired heart disease, especially when the RV has to endure high pressures, e.g.
when it functions as a systemic ventricle or in patients with pulmonary hypertension
regardless of the cause [2, 60]. Most medical therapies have no or limited effect on
RV function in situations of RV overload. In patients with transposition of the great
arteries and a systemic RV, a reversed P450 gene (involved in the metabolic pathway
of a.o. ACE inhibitors and beta-blockers) expression profile in the ventricles was
observed [6], supporting that the RV adjusts itself to the high systemic pressures.
Indeed, animal studies suggest that the use of certain beta-blockers may be benefi-
cial [61], although adverse effects have also been reported in patients with portopul-
monary hypertension and an overloaded RV [4]. Furthermore, in the clinical setting
treatment with angiotensin receptor blockers did not result in improved RV func-
tion, this effect is beyond dispute in patients with LV disease [3, 5, 62]. This indi-
cates a different sensitivity of the LV versus RV for specific drugs, which might
relate to the different developmental background (FHF versus SHF) of both ventri-
cles. It was recently suggested that the multipotent EPDCs may have potential for
cell-based therapies [35, 63–65]. More important, the paracrine function of EPDCs
during cardiac development may be preserved in adult life, which can be relevant for
the development of novel treatment strategies in cardiovascular disease [32, 66, 67].
The interaction between myocardium and epicardium may follow different patterns
in the RV and LV.
The differences in the developmental background of the RV and LV might
explain sidedness in the occurrence of certain cardiomyopathies the ventricular
non-compaction or dysplasia. In addition, insight in the tripartite morphology pres-
ent in the RV after a normal sequence of developmental processes also sheds light
on the bi-or unipartite ventricles that can be observed in patients with congenital
heart disease. Also the preferential occurrence of VCACs in the RV suggests a
unique RV programme that is different from LV events. Future studies are needed to
elucidate the mechanisms that guide EPDC-myocardium interaction separately in
the RV and LV, and may take us a step further towards the development of therapies
aimed at improving RV function.
Acknowledgements The authors gratefully thank Ron Slagter, Bert Wisse en Judith den Boeft for
their help in preparing the figures.
References
1. Bleasdale RA, Frenneaux MP. Prognostic importance of right ventricular dysfunction. Heart.
2002;88:323–4.
2. Haddad F, Doyle R, Murphy DJ, Hunt SA. Right ventricular function in cardiovascular dis-
ease, part II: pathophysiology, clinical importance, and management of right ventricular fail-
ure. Circulation. 2008;117:1717–31.
3. Dore A, Houde C, Chan KL, et al. Angiotensin receptor blockade and exercise capacity in
adults with systemic right ventricles: a multicenter, randomized, placebo-controlled clinical
trial. Circulation. 2005;112:2411–6.
4. Provencher S, Herve P, Jais X, et al. Deleterious effects of beta-blockers on exercise capacity
and hemodynamics in patients with portopulmonary hypertension. Gastroenterology. 2006;
130:120–6.
5. van der Bom T, Winter MM, Bouma BJ, et al. Effect of valsartan on systemic right ventricular
function: a double-blind, randomized, placebo-controlled pilot trial. Circulation. 2013;127:
322–30.
6. Thum T, Borlak J. Gene expression in distinct regions of the heart. Lancet. 2000;355:979–83.
7. Gittenberger-de Groot AC, Sauer U, Bindl L, Babic R, Essed CE, Buhlmeyer K. Competition
of coronary arteries and ventriculo-coronary arterial communications in pulmonary atresia
with intact ventricular septum. Int J Cardiol. 1988;18:243–58.
8. Gittenberger-de Groot AC, Tennstedt C, Chaoui R, Lie-Venema H, Sauer U, Poelmann
RE. Ventriculo coronary arterial communications (VCAC) and myocardial sinusoids in hearts
with pulmonary artresia with intact ventricular septum: two different diseases. Prog Pediatr
Cardiol. 2001;13:157–64.
9. Daubeney PE, Delany DJ, Anderson RH, et al. Pulmonary atresia with intact ventricular septum:
range of morphology in a population-based study. J Am Coll Cardiol. 2002;39:1670–9.
10. Umar S, de Visser YP, Steendijk P, et al. Allogenic stem cell therapy improves right ventricular
function by improving lung pathology in rats with pulmonary hypertension. Am J Physiol
Heart Circ Physiol. 2009;297:H1606–16.
11. Castellani C, Padalino M, China P, et al. Bone-marrow-derived CXCR4-positive tissue-
committed stem cell recruitment in human right ventricular remodeling. Hum Pathol. 2010;41:
1566–76.
12. van Mierop LH, Kutsche LM. Development of the ventricular septum of the heart. Heart
Vessels. 1985;1:114–9.
13. Wenink ACG. Embryology of the ventricular septum. Separate origin of its components.
Virchows Arch. 1981;390:71–9.
14. Pexieder T. Development of the outflow tract of the embryonic heart. Birth Defects.
1978;14:29–68.
15. Viragh S, Challice CE. Origin and differentiation of cardiac muscle cells in the mouse.
J Ultrastruct Res. 1973;42:1–24.
16. De la Cruz MV, Gomez CS, Arteaga MM, Argüello C. Experimental study of the development
of the truncus and the conus in the chick embryo. J Anat. 1977;123:661–86.
17. Mjaatvedt CH, Nakaoka T, Moreno-Rodriguez R, et al. The outflow tract of the heart is
recruited from a novel heart-forming field. Dev Biol. 2001;238:97–109.
18. Waldo KL, Hutson MR, Ward CC, et al. Secondary heart field contributes myocardium and
smooth muscle to the arterial pole of the developing heart. Dev Biol. 2005;281:78–90.
19. Cai CL, Liang X, Shi Y, et al. Isl1 identifies a cardiac progenitor population that proliferates
prior to differentiation and contributes a majority of cells to the heart. Dev Cell. 2003;5:
877–89.
20. Abu-Issa R, Waldo K, Kirby ML. Heart fields: one, two or more? Dev Biol. 2004;272:281–5.
21. Meilhac SM, Esner M, Kelly RG, Nicolas JF, Buckingham ME. The clonal origin of myocar-
dial cells in different regions of the embryonic mouse heart. Dev Cell. 2004;6:685–98.
22. Kelly RG. Building the right ventricle. Circ Res. 2007;100:943–5.
23. Bajolle F, Zaffran S, Kelly RG, et al. Rotation of the myocardial wall of the outflow tract is
implicated in the normal positioning of the great arteries. Circ Res. 2006;98:421–8.
24. Douglas YL, Jongbloed MR, DeRuiter MC, Gittenberger-de Groot AC. Normal and abnormal
development of pulmonary veins: state of the art and correlation with clinical entities. Int J
Cardiol. 2010;147:13–24.
25. Lescroart F, Mohun T, Meilhac SM, Bennett M, Buckingham M. Lineage tree for the venous
pole of the heart: clonal analysis clarifies controversial genealogy based on genetic tracing.
Circ Res. 2012;111:1313–22.
26. Pexieder T. Cell death in the morphogenesis and teratogenesis of the heart. Adv Anat Embryol
Cell Biol. 1975;51:1–99.
27. Bajolle F, Zaffran S, Meilhac SM, et al. Myocardium at the base of the aorta and pulmonary
trunk is prefigured in the outflow tract of the heart and in subdomains of the second heart field.
Dev Biol. 2008;313:25–34.
28. Scherptong RW, Jongbloed MR, Wisse LJ, et al. Morphogenesis of outflow tract rotation dur-
ing cardiac development: the pulmonary push concept. Dev Dyn. 2012;241:1413–22.
29. Kruithof BP, Kruithof-de Julio M, Poelmann RE, Gittenberger-de-Groot AC, Gaussin V,
Goumans MJ. Early myocardial trabeculation and differential remodeling of the left and right
atrioventricular myocardium; implications for cardiac valve formation and a role for TGFbeta2.
Int J Dev Biol. 2013; in press.
30. Sedmera D, Pexieder T, Rychterova V, Hu N, Clark EB. Remodeling of chick embryonic

ventricular myoarchitecture under experimentally changed loading conditions. Anat Rec.
1999;254:238–52.
31. Wenink ACG, Gittenberger-de Groot AC. Left and right ventricular trabecular patterns.
Consequence of ventricular septation and valve development. Br Heart J. 1982;48:462–8.
32. Gittenberger-de Groot AC, Winter EM, Bartelings MM, Goumans MJ, DeRuiter MC,
Poelmann RE. The arterial and cardiac epicardium in development, disease and repair.
Differentiation. 2012;84:41–53.
33. Vrancken Peeters M-PFM, Mentink MMT, Poelmann RE, Gittenberger-de Groot
AC. Cytokeratins as a marker for epicardial formation in the quail embryo. Anat Embryol.
1995;191:503–8.
34. Perez-Pomares JM, Pompa JL. Signaling during epicardium and coronary vessel development.
Circ Res. 2011;109:1429–42.
35. Limana F, Capogrossi MC, Germani A. The epicardium in cardiac repair: from the stem cell
view. Pharmacol Ther. 2011;129:82–96.
36. Smart N, Dube KN, Riley PR. Epicardial progenitor cells in cardiac regeneration and
neovascularisation. Vascul Pharmacol. 2013;58:164–73.
37. Bax NA, Van Oorschot AA, Maas S, et al. In vitro epithelial-to-mesenchymal transformation
in human adult epicardial cells is regulated by TGFbeta-signaling and WT1. Basic Res Cardiol.
2011;106:829–47.
38. Acharya A, Baek ST, Huang G, et al. The bHLH transcription factor Tcf21 is required for
lineage-specific EMT of cardiac fibroblast progenitors. Development. 2012;139:2139–49.
39. Gittenberger-de Groot AC, Vrancken Peeters MP, Bergwerff M, Mentink MM, Poelmann
RE. Epicardial outgrowth inhibition leads to compensatory mesothelial outflow tract collar and
abnormal cardiac septation and coronary formation. Circ Res. 2000;87:969–71.
40. Bogers AJJC, Gittenberger-de Groot AC, Poelmann RE, Péault BM, Huysmans
HA. Development of the origin of the coronary arteries, a matter of ingrowth or outgrowth?
Anat Embryol. 1989;180:437–41.
41. Eralp I, Lie-Venema H, DeRuiter MC, et al. Coronary artery and orifice development is associ-
ated with proper timing of epicardial outgrowth and correlated Fas ligand associated apoptosis
patterns. Circ Res. 2005;96:526–34.
42. Tian X, Hu T, He L, et al. Peritruncal coronary endothelial cells contribute to proximal coro-
nary artery stems and their aortic orifices in the mouse heart. PLoS One. 2013;8:e80857.
43. Lie-Venema H, Gittenberger-de Groot AC, van Empel LJP, et al. Ets-1 and Ets-2 transcription
factors are essential for normal coronary and myocardial development in chicken embryos.
Circ Res. 2003;92:749–56.
44. Sauer U, Gittenberger-de Groot AC, Geishauser M, Babic R, Buhlmeyer K. Coronary arteries
in the hypoplastic left heart syndrome. Circulation. 1989;80:168–76.
45. Oosthoek PW, Moorman AFM, Sauer U, Gittenberger-de Groot AC. Capillary distribution in
the ventricles of hearts with pulmonary atresia and intact ventricular septum. Circulation.
1995;91:1790–7.
46. Sauer U, Bindl L, Pilossoff V, et al. Pulmonary atresia with intact ventricular septum and right
ventricle coronary artery fistulae: selection of patients for surgery. In: Doyle EF, Engler ME,
Gersony WM, Rashlund WJ, Talmer NS, editors. Pediatric cardiology. New York: Springer;
1986. p. 566–78.
47. Hokken RB, Bartelings MM, Bogers AJJC, Gittenberger-de Groot AC. Morphology of the
pulmonary and aortic roots with regard to the pulmonary autograft procedure. J Thorac
Cardiovasc Surg. 1997;113:453–61.
48. Bartelings MM, Gittenberger-de Groot AC. The arterial orifice level in the early human
embryo. Anat Embryol. 1988;177:537–42.
49. Lalezari S, Hazekamp MG, Bartelings MM, Schoof PH, Gittenberger-de Groot AC. Pulmonary
artery remodeling in transposition of the great arteries: relevance for neoaortic root dilatation.
J Thorac Cardiovasc Surg. 2003;126:1053–60.
50. Torrent-Guasp F, Kocica MJ, Corno AF, et al. Towards new understanding of the heart structure
and function. Eur J Cardiothorac Surg. 2005;27:191–201.
51. Meilhac SM, Esner M, Kerszberg M, Moss JE, Buckingham ME. Oriented clonal cell growth
in the developing mouse myocardium underlies cardiac morphogenesis. J Cell Biol. 2004;164:
97–109.
52. Poelmann RE, Mikawa T, Gittenberger-de Groot AC. Neural crest cells in outflow tract septation
of the embryonic chicken heart: differentiation and apoptosis. Dev Dyn. 1998;212:373–84.
53. van den Hoff MJ, Moorman AF, Ruijter JM, et al. Myocardialization of the cardiac outflow
tract. Dev Biol. 1999;212:477–90.
54. Waldo K, Miyagawa-Tomita S, Kumiski D, Kirby ML. Cardiac neural crest cells provide new
insight into septation of the cardiac outflow tract: aortic sac to ventricular septal closure. Dev
Biol. 1998;196:129–44.
55. Kirby ML, Gale TF, Stewart DE. Neural crest cells contribute to normal aorticopulmonary
septation. Science. 1983;220:1059–61.
56. Gittenberger-de Groot AC, Bartelings MM, DeRuiter MC, Poelmann RE. Basics of cardiac
development for the understanding of congenital heart malformations. Pediatr Res. 2005;57:
169–76.
57. Wenink ACG, Oppenheimer-Dekker A, Moulaert AJ. Muscular ventricular septal defects:
a reappraisal of the anatomy. Am J Cardiol. 1979;43:259–64.
58. Lamers WH, Wessels A, Verbeek FJ, et al. New findings concerning ventricular septation in the
human heart. Implications for maldevelopment. Circulation. 1992;86:1194–205.
59. Moorman AFM, Christoffels VM. Cardiac chamber formation: development, genes and evolution.
Physiol Rev. 2003;83:1223–67.
60. Voelkel NF, Natarajan R, Drake JI, Bogaard HJ. Right ventricle in pulmonary hypertension.
Compr Physiol. 2011;1:525–40.
61. Bogaard HJ, Natarajan R, Mizuno S, et al. Adrenergic receptor blockade reverses right heart
remodeling and dysfunction in pulmonary hypertensive rats. Am J Respir Crit Care Med.
2010;182:652–60.
62. Borgdorff MA, Bartelds B, Dickinson MG, Steendijk P, Berger RM. A cornerstone of heart
failure treatment is not effective in experimental right ventricular failure. Int J Cardiol.
2013;169:183–9.
63. Winter EM, Grauss RW, Hogers B, et al. Preservation of left ventricular function and attenua-
tion of remodeling after transplantation of human epicardium-derived cells into the infarcted
mouse heart. Circulation. 2007;116:917–27.
64. Winter EM, Van Oorschot AA, Hogers B, et al. A new direction for cardiac regeneration therapy:
application of synergistically acting epicardium-derived cells and cardiomyocyte progenitor
cells. Circ Heart Fail. 2009;2:643–53.
65. Zhou B, Pu WT. Epicardial epithelial-to-mesenchymal transition in injured heart. J Cell Mol
Med. 2011;15:2781–3.
66. Gittenberger-de-Groot AC, Winter EM, Poelmann RE. Epicardium-derived cells (EPDCs) in
development, cardiac disease and repair of ischemia. J Cell Mol Med. 2010;14:1056–60.
67. Smart N, Riley PR. The epicardium as a candidate for heart regeneration. Future Cardiol.
2012;8:53–69.
68. Jongbloed MR, Vicente SR, Hahurij ND, et al. Normal and abnormal development of the
cardiac conduction system; implications for conduction and rhythm disorders in the child
and adult. Differentiation. 2012;84:131–48.
Chapter 2
Physiology of the Right Ventricle
Robert Naeije, Ryan J. Tedford, and François Haddad
One must inquire how increasing pulmonary vascular

resistance results in impaired right ventricular function
(JT Reeves, 1988)
Introduction with Evolutionary and Historical Perspectives
The right ventricle (RV) is functionally coupled to the pulmonary circulation.

Evolution from ancestors of fishes to amphibians, reptiles, and finally birds and
mammals has led to progressively greater oxygen consumption requiring a thinner
pulmonary blood gas barrier built into a separated low-pressure/high-flow vascular
system [1]. This has resulted in a progressive unloading and reshaping of the RV as
a thin-walled flow generator. When pulmonary vascular resistance (PVR) is low and
the peripheral requirements for flow minimal, RV pumping does not significantly
contribute to the transit blood through the lungs and to the left heart. In 1943, Starr
and his colleagues showed that ablation of the RV free wall in dogs is compatible
with life without a substantial increase in systemic venous pressures [2]. Without a
functional RV, the preloading of the left ventricle (LV) becomes exclusively
dependent on systemic venous return, which is driven by a mean systemic filling
pressure (Pms) of normally less than 10 mmHg [3]. However, Pms can be increased
R. Naeije, M.D., Ph.D. (*)

Laboratoire de physiologie, Université Libre de Bruxelles,
Route de Lennik 808, Bruxelles 1070, Belgium
e-mail: rnaeije@ulb.ac.be
R.J. Tedford, M.D.
Department of Medicine, The Johns Hopkins School of Medicine,
568 Carnegie; 600 North Wolfe Street, Baltimore, MD 21287, USA
e-mail: Ryan.Tedford@jhmi.edu
F. Haddad, M.D.
Department of Medicine, Standford University, 205 Swain Way, Palo Alto, CA 94304, USA
e-mail: fhaddad@stanford.edu

20 R. Naeije et al.
to 15–20 mmHg by an increase in effective blood volume and systemic nervous

system activation without clinically identifiable edema. The limit of this adapta-
tion is determined by the flow-resistive properties of the pulmonary circulation.
Normal mean pulmonary artery pressure (Ppa)-flow (Q) relationships vary from
0.5 to 3 mmHg/L/min [4]. Thus in the absence of a RV but presence of steep
Ppa-Q relationships, moderate levels of exercise with a cardiac output of 10 L/min
would require a Pms of at least 35–40 mmHg, which would be unlikely to remain
clinically silent.
With this already established knowledge at their time, Fontan and Baudet intro-
duced in 1971 the first cavo-pulmonary anastomosis bypassing the RV as a palliative
intervention for cardiac malformations [5] (see also Chap. 8). It has since been
shown that patients with the so-called “Fontan circulation” may indeed enjoy a near-
normal sedentary life for several decades, but rapidly deteriorate when Ppa increases
due to pulmonary vascular remodeling (e.g., with altitude exposure) or increased LV
filling pressures [6]. The RV becomes essential to the preservation of the quality of
life, enabling exercise and survival as soon as the PVR reaches high-normal values,
and definitely so in patients with all forms of pulmonary hypertension [7, 8].
Do the Laws of the Heart Apply to the RV?
The RV differs from the LV not only in structure, but also because of its embryo-
logical development (see Chap. 1). The RV, including its outflow tract is derived
from the anterior heart field, whereas the LV and the atria are derived from the pri-
mary heart field [7]. Accordingly, it is often assumed that the RV and the LV are
functionally very different. As a matter of fact, a brisk increase in PVR produced by
pulmonary arterial constriction to mimic massive pulmonary embolism, induces an
acute dilatation and pump failure of the RV [9], and there is no clinical counterpart
of this observation for the LV. However, a gradual increase in PVR allows for RV
adaptation and remodeling, basically similar to the LV facing a progressive increase
in systemic vascular resistance [10]. Beat-to-beat changes in preload or afterload
are accompanied by a heterometric dimension adaptation described by Starling’s
law of the heart. Sustained changes in load are associated with a homeometric
contractility adaptation, often referred to as “Anrep’s law of the heart”.
In 1912, Gleb Vassilevitch von Anrep who had been trained by Ivan Petrovich
Pavlov in St. Petersburg, reported on the rapid increase in LV contractility in
response to an aortic constriction [11]. He explained this observation by a reflex
adrenergic reaction because similar effects could be induced by the administration
of adrenaline. Pavlov himself was actually more interested in gastrointestinal physi-
ology and sent von Anrep to London to work under the supervision of Starling and
Bayliss on the humoral control of digestion. Once in London, von Anrep confirmed
his observation of an increased contractility induced by an increase loading in
Starling’s heart–lung preparation. Further work in Starling’s laboratory definitely
established that after an acute increase in either venous return or in systemic vascular
2 Physiology of the Right Ventricle 21
resistance, the heart initially dilates allowing for increased or maintained stroke
volume (SV) respectively, but after a few minutes cardiac dimensions return to
baseline in spite of persistently increased loading, indicating increased contractility.
Starling thought that much of this “homeometric” adaptation exclusively observed
in the LV was related to an increased metabolism which accompanies an increase in
coronary blood flow when blood pressure was raised. Von Anrep rather hypothe-
sized a release of myocardial stores of catecholamines by mechanical stretch,
because the homeometric adaptation was observed in isolated hearts. Later studies
have repeatedly confirmed the predominant role of homeometric, or systolic func-
tion adaptation to changes in loading conditions, leaving Starling’s heterometric
adaptation for beat-to-beat adaptations in venous return, for example after changing
body position, or for situations of failing systolic function adaptation, for example
in advanced heart failure [12]. This homeometric adaptation to afterload has been
demonstrated in the RV exposed to pulmonary arterial constriction and in condi-
tions of constant coronary perfusion [13, 14].
It is therefore possible to define RV failure as a dyspnea-fatigue syndrome with
eventual systemic congestion, caused by the inability of the RV to maintain flow
output in response to metabolic demand without heterometric adaptation [9, 10].
This definition encompasses a spectrum of clinical situations, from preserved
maximum cardiac output and aerobic exercise capacity at the price of increased RV
end-diastolic volumes (EDVs) to low-output states with small RV volumes at rest.
This being said, many questions remain unanswered. Whether the time-course of
chronic systolic function adaptation to afterload is the same for the RV and the LV
remains unclear. Comparisons between studies are difficult because of differences
in ventricular structure and relative changes in arterial pressure. Contractility
responses to increased afterload may be affected by extrinsic factors such as volume
status, ventricular interaction, coronary perfusion, and yet unknown circulating
mediators related to the presence of systemic or pulmonary vascular diseases.
Ventricular hypertrophy may contribute to contractile force and decrease wall
tension, but the mechanisms of adaptation remain incompletely understood.
Systolic Function
The gold standard measurement of contractility in vivo is the maximal elastance

(Emax), or the maximum value of the ratio between ventricular pressure and volume
measured continuously during the cardiac cycle (i.e., the “pressure–volume loop”)
[10]. Left ventricular Emax coincides with end-systole, and is thus equal to the ratio
between end-systolic pressure (ESP) and end-systolic volume (ESV). End-systolic
elastance (Ees) is measured at the upper left corner of a square-shape pressure–
volume loop [15]. Because of low pulmonary vascular impedance, the normal RV
pressure–volume loop has a triangular shape and Emax occurs before the end of ejec-
tion, or end-systole. However, a satisfactory definition of Emax can be obtained by the
generation of a family of pressure–volume loops at decreasing venous return [16].
22 R. Naeije et al.
Fig. 2.1 Single beat method to measure right ventriculo-arterial coupling. Left: a maximum pres-
sure (Pmax) is calculated from nonlinear extrapolation of early and late isovolumic portions of the
right ventricular pressure (PRV) curve. A straight line is drawn from Pmax and the end-diastolic
volume (EDV) tangent to the end-systolic pressure (Pes)–volume (ESV) point. In the case of this
theoretical illustration, RV maximum elastance (Emax) coincides with end-systole, thus
Emax = (Pmax − Pes)/SV, where SV is the stroke volume. The arterial elastance Ea is defined by the
ratio Pes/SV
With increasing impedance in pulmonary hypertension, the shape of the RV

pressure–volume loop changes. RV pressure rises throughout ejection and peaks at
or near end-systole. Emax then typically occurs at ESP, similar to the LV loop.
Instantaneous measurements of RV volumes are difficult to obtain at the bedside,
and so are manipulations of venous return. This is why single beat methods have
been developed, initially for the LV [17], then transposed to the RV [18]. The single
beat method relies on a maximum pressure Pmax calculation from a nonlinear extrap-
olation of the early and late portions of a RV pressure curve, an integration of
pulmonary flow and synchronization of the signals. Emax is estimated from the slope
of a tangent from Pmax to the pressure–volume curve (Fig. 2.1).
The single beat method can be applied with relative changes in volume measured
by integration of the ejected flow rather than with measurements of absolute
volumes. This is due to the fact that Emax is not dependent on preload, or EDV [10].
An excellent agreement between directly measured Pmax (by clamping the main
pulmonary artery for one beat) and calculated Pmax has been demonstrated in a large
animal experimental preparation without pulmonary hypertension [18]. In states of
increased impedance, lower vascular compliance, and increased pulsatile loading, a
late systolic rise in RV pressure occurs. Therefore, it remains unknown if fitting a
sine wave to the isovolumetric portions of the RV pressure tracing will accurately
determine Pmax. Thus the single beat method to estimate RV-arterial coupling will
require further validation in patients with severe pulmonary hypertension (Table 2.3).
Measurements of RV Emax by conductance catheter technology and inferior vena
cava balloon obstruction have been reported in normal volunteers [19, 20]. More
recently, a limited number of Emax determinations have been reported in patients

with pulmonary arterial hypertension (PAH) either using the single beat approach,
fluid-filled catheters, and magnetic resonance imaging (MRI) [21] or a multiple beat
approach with venous return decreased by a Valsalva maneuver and conductance
catheters [22]. The single beat approach with a high-fidelity Millar catheter and
integration of a transonic measurement of pulmonary flow were reported in a patient
with a systemic RV corrected and congenitally transposition of the great arteries [23].
These limited reports confirm the importance of systolic function adaptation to
afterload previously demonstrated in various animal species [24], or experimental
models of acute [24–26] or chronic [27–31] pulmonary hypertension.
Coupling of Systolic Function to Afterload
Measurements of systolic function are ideally load-independent, which means con-

stancy over a wide range of immediate changes in preload or afterload. The require-
ment is met with an acceptable approximation by Emax in intact hearts. This is because
Emax is the only point of the pressure–volume curve that is common in systole to
ejecting and non-ejecting beats, and thus the optimal translation to a pressure–
volume relationship of an isolated muscle active tension length relationship.
However, as already discussed, Emax adapts to afterload after a few beats. It is therefore
important to correct Emax for afterload.
There are three possible measurements of afterload [32, 33]. The first is maxi-
mum ventricular wall stress, which is approximated by the maximum value of the
product of volume and pressure, divided by the wall thickness. This is a transposi-
tion of Laplace’s law for spherical structures, and thus problematic for the RV
because of considerable regional variations of the internal radius. The second is
based on measurements of the forces that oppose flow ejection, or the hydraulic
load. This calculation optimally requires a spectral analysis arterial pressure and
flow waves, with derived impedance calculations [33]. A more straightforward
approach is to derive arterial elastance (Ea) as it is “seen” by the ventricle and thus
graphically determined using a pressure volume loop and by dividing maximal
elastance pressure by SV (Fig. 2.1) [10].
Thus contractility coupled to afterload is defined by a ratio of Emax to Ea. The
optimal mechanical coupling of Emax to Ea is equal to 1. The optimal energy transfer
from the ventricle to the arterial system occurs at Emax/Ea ratios of 1.5–2 [10].
RV-Arterial Coupling in Experimental Pulmonary Hypertension
RV-arterial coupling measured with the Emax/Ea ratio has been investigated in
various models of pulmonary hypertension. The results are summarized in Table 2.1.
Acute hypoxia-induced increase in PVR was associated with a preserved RV-arterial
coupling because of increased RV contractility [18, 24, 34–36]. Preserved RV-arterial
coupling was also reported in pulmonary hypertension due to either microembolism
24 R. Naeije et al.
Table 2.1 RV-arterial coupling in experimental models of pulmonary hypertension

Model Animal Emax Emax/Ea References
Acute hypoxia Dog, goat, pig ↑ – [18, 24, 34–36]
Monocrotaline Rat ↑ ↓ [31]
Sepsis, early Pig ↑ – [26]
Sepsis, late Pig – ↓ [26]
Acute embolism Dog, goat, pig ↑ – [24]
Acute PA banding Dog, goat, pig ↑ – [24]
AP shunting 3 mo Pig ↑ – [29]
AP shunting 6 mo Pig ↓ ↓ [29]
Acute RVF Dog, pig ↓ ↓ [38–41]
Chronic heart failure Dog – ↓ [42]
Emax maximum right ventricular elastance, Ea pulmonary arterial elastance, PA pulmonary artery,
AP aorta-pulmonary, mo month, RVF right ventricular failure
Fig. 2.2 Families of right ventricular pressure–volume loops at decreasing venous return in rats.
Emax is defined by a straight line tangent to the upper border of the pressure–volume loop families.
Measurements are obtained in a control animal, after induction of pulmonary hypertension (PH)
by the administration of monocrotaline and after induction of monocrotaline-PH under bisoprolol
therapy. PH was associated with a marked adaptative increase in Emax, which was further improved
by bisoprolol therapy. From source data of Ref. [31]
or pulmonary arterial banding (PAB) [24]. Endotoxin shock was associated with
a deterioration of RV-arterial coupling because of impaired contractility [26].
A chronic aorta-pulmonary shunt as a model of a persistent ductus arteriosus in
growing piglets was associated with preserved RV-arterial coupling after 3 months
[29, 37] but uncoupling occurred after 6 months because of decreased RV contrac-
tility resulting in a decreased cardiac output and increased right atrial pressure [30].
Persistent RV failure after tight transient PAB was characterized by a profound
RV-arterial uncoupling because of a persistent decrease in contractility and reactive
increase in PVR [38–41]. Monocrotaline-induced pulmonary hypertension was
associated with RV-arterial uncoupling because of an insufficient increase in con-
tractility to match increased afterload (Fig. 2.2) [31]. Mild pulmonary hypertension
in pacing-induced heart failure was associated with RV-uncoupling due to the

absence of an adaptive increase in RV contractility [42].
Taken together, these studies support the notion of a predominant RV systolic
function adaptation to increased afterload in various models of pulmonary hyperten-
sion, but with RV-arterial uncoupling in the context of inflammation (endotoxemia,
monocrotaline), long-term increase in PVR, or left sided heart failure.
Pharmacology of RV-Arterial Coupling
In patients with severe pulmonary hypertension right ventricular function is a major

determinant of quality of life, exercise capacity, and overall outcome [8]. Treatment
strategies for these patients logically aim at the decrease in RV afterload often assessed
by a measurement of PVR—or improvement in maximum cardiac output obtained by
unloading the RV assessed by exercise capacity. However, it has been proposed that
some of the vasodilators used for the treatment of PAH might also have intrinsic posi-
tive inotropic effects. There are data suggesting that this could be a mechanism of
action of prostacyclins [43] or phosphodiesterase-5 inhibitors [44]. In addition to
these perhaps “hidden” vasodilator drug actions, treatments specifically targeting the
RV are now under consideration. The most obvious would be interventions aimed at
the excessive neuro-humoral activation, which have been shown to improve survival
in LV failure [45, 46]. Finally, patients with pulmonary hypertension may be exposed
to the cardiovascular effects of general anesthesia or require treatments with inotropic
drugs in case of severe RV failure [47, 48]. In all these circumstances, improved
knowledge of the effects of the interventions on the components of RV-arterial
coupling is desirable. Recent experimental animal studies reporting on the effects of
pharmacological interventions on RV-arterial coupling are listed in Table 2.2.
Table 2.2 Effects of pharmacological intervention in experimental pulmonary hypertension

(see Table 2.1)
Model Drug Emax Ea Emax/Ea References
Acute hypoxia Dobutamine ↑ – ↑ [18]
Acute RHF Dobutamine ↑ ↓ or – ↑ [38, 39]
Acute RHF Levosimendan ↑ ↓ ↑ [39, 41]
Acute RHF Norepinephrine ↑ – [38]
Chronic heart failure Milrinone ↑ – ↑ [42]
Chronic heart failure Nitroprusside – – – [42]
Chronic heart failure Nitric oxide – – – [42]
Acute hypoxia Propranolol ↓ ↑ ↓ [18]
Monocrotaline Bisoprolol ↑ – ↑ [31]
AP shunting 3 mo Epoprostenol – ↓ ↑ [37]
Acute RHF Epoprostenol – ↓ ↑ [40]
Acute hypoxia Sildenafil – ↓ ↑ [35]
Monocrotaline Sildenafil ↑ ↓ ↑ [49]
Hypoxia Isoflurane ↓ ↑ ↓ [29]
26 R. Naeije et al.
Table 2.3 RV-arterial coupling in patients with pulmonary arterial hypertension

Diagnosis Emax Ea Emax/Ea References
IPAH (n = 11) ↑ ↑ ↓ or – [21, 22]
CCTGA (n = 1) ↑ ↑ ↓ [23]
SSc-PAH (n = 7) ↑ ↑ ↓ [22]
IPAH idiopathic pulmonary arterial hypertension, SSc-PAH systemic sclerosis associated PAH,
CCTGA congenitally corrected transposition of the great arteries (systemic right ventricle)
Catecholamines may cause pulmonary vasoconstriction and tachycardia [47].

Moreover, treatment with catecholamine has been associated with increased mortality
in patients with acute or chronic RV failure [48] and these data cause concern.
Low-dose dobutamine increased RV-arterial coupling by an inotropic effect without
[18, 39] or with [38] a decreased afterload. Low-dose norepinephrine improved
RV-arterial coupling through an exclusive positive inotropic effect, which was how-
ever less pronounced than that achieved with low-dose dobutamine [38].
Experimentally acute administration of propranolol caused deterioration of RV-arterial
coupling through combined negative inotrope effect and pulmonary vasoconstriction
during acute hypoxia [18]. In the context of chronic administration of bisoprolol
improved RV-arterial coupling by an improved contractility in monocrotaline-induced
pulmonary hypertension (Fig. 2.2) [31].
Acute administration of epoprostenol or inhaled nitric oxide improved RV-arterial
coupling exclusively via pulmonary vasodilation effects in a model of high-flow-
induced pulmonary hypertension [37]. Acute epoprostenol partially restored RV-arterial
coupling through an exclusive pulmonary vascular effect in PAB-induced persistent
RV failure [40] or was associated with maintained RV-arterial coupling because of
decreased contractility in proportion to a decreased PVR during acute hypoxia [36].
Levosimendan improved RV-arterial coupling through combined positive inotropy and
vasodilation in PAB-induced persistent RV failure [39, 41]. Sildenafil improved
RV-arterial coupling in hypoxia because of exclusive pulmonary vasodilation [35], but
improved coupling by a positive inotropic effect in monocrotaline-induced pulmonary
hypertension [49]. Bosentan had no intrinsic effect on contractility in pulmonary
hypertension after 3 months of aorta-pulmonary shunting [29]. Milrinone improved
RV-arterial coupling by an improved contractility in pacing-induced congestive heart
failure with mild pulmonary hypertension, while nitroprusside or inhaled nitric oxide
had no effect [42]. Isoflurane and enflurane caused deterioration of RV-arterial
coupling because of a combined decrease in contractility and increase in PVR [34].
It is important to point out that acute and chronic effects of interventions on
RV-arterial coupling in acute and chronic experimental pulmonary hypertension
models may be quite different, as shown for β-blockers or sildenafil. This is a chal-
lenge to test of drugs in multiple experimental models and, makes the extrapolation
to the clinical situation of patients with pulmonary hypertension difficult.
RV-Arterial Coupling Measurements in Patients

with Pulmonary Hypertension
Measurements of both Emax and Ea have been reported in a small number of patients
with pulmonary hypertension. In a first study of six patients with idiopathic PAH but
no clinical RV failure, compared to six controls, Kuehne measured RV volumes by
MRI and RV pressures using fluid-filled catheters, synchronized the signals and cal-
culated Emax and Ea using the single beat method [21]. Emax was increased threefold,
from 1.1 ± 0.1 to 2.8 ± 0.5 mmHg/mL, but Ea was increased from 0.6 ± 0.5 to 2.7 ± 0.2,
so that the Emax/Ea ratio decreased from 1.9 ± 0.2 to 1.1 ± 0.1. Yet RV volumes were
not increased, indicating “sufficient” coupling, at least under resting conditions.
Tedford reported on RV-arterial coupling in five patients with idiopathic PAH
and seven with systemic sclerosis (SSc)-associated PAH [22]. In this study, RV
volumes and pressures were measured with conductance catheters and Emax defined
by a family of pressure–volume loops as venous return decreased by a Valsalva
maneuver (validated against inferior vena cava obstruction). Typical tracings are
shown in Fig. 2.3. In IPAH patients, Emax was 2.3 ± 1.1, Ea 1.2 ± 0.5, and Emax/Ea
preserved at 2.1 ± 1.0. In SSc-PAH patients, Emax was decreased to 0.8 ± 0.3 in the
presence of an Ea at 0.9 ± 0.4, so that Emax/Ea was decreased to 1.0 ± 0.5. The authors
also showed that there was no disproportionate decrease in pulmonary arterial com-
pliance in SSc-PAH patients, suggesting that the depressed Emax in SSc-PAH was
not caused by a relatively higher pulsatile hydraulic load. Additionally, seven
Fig. 2.3 Right ventricular pressure–volume loops at decreasing venous return in a patient with
systemic sclerosis (SSc)-associated pulmonary arterial hypertension (PAH), left, and in a patient
with idiopathic PAH (IPAH), right. The slope of linearized maximum elastance pressure–volume
relationship is higher at similar mean pulmonary artery pressure in IPAH. Source data from
Ref. [22]
28 R. Naeije et al.
patients with SSc but without pulmonary hypertension maintained preserved

coupling (Emax/Ea 2.3 ± 1.2).
Finally, there is a case report of RV-arterial uncoupling in an asymptomatic young
man with a congenitally corrected transposition of the great arteries [23]. In this
patient, the systemic RV Emax/Ea ratio was of 1.2, in the range of the ratio reported
in IPAH patients by Kuehne [21], while the pulmonary LV Emax/Ea was perfectly
preserved at a value of 1.7. A decreased systemic RV Emax/Ea probably heralds
failure, which is known to occur in these patients after several decades of life.
Together, these results confirm the dominant role of a homeometric adaptation of
the RV to increased afterload, and document uncoupling when the hydraulic load
remains too high for too long, or when systemic disease is present. From a method-
ological point of view, Emax and Ea show variability with a trend towards higher
control values when measurements are based on families of pressure–volume loops
rather than on single beat analysis. Targeted therapies in PAH patients might also
have affected the results.
Thus it appears that in general RV-arterial coupling is maintained by an adaptive
increase of the Emax in PAH models of chronic hypoxia or aorta-pulmonary shunting
when associated with only a moderate increase in pulmonary artery pressures.
However, prolonged mechanical stress such as induced by 6 months of overcircula-
tion in piglets, or due to altered LV function following several weeks of pacing in
dogs, may cause uncoupling of the RV from the pulmonary circulation, increased
filling pressures, and congestion. Monocrotaline has extra-pulmonary toxic effects
and causes an inflammatory pulmonary vascular disease [50]. This is associated
with decreased RV systolic function adaptation and leads to increased RV volumes.
A general trend of reported studies is that pulmonary arterial obstruction such as
pulmonary stenosis or PAB allows for a better and more prolonged preservation of
RV-arterial coupling than the increased PVR of various forms of pulmonary vascu-
lar diseases [46, 51]. A heterometric adaptation may contribute to RV systolic func-
tion adaptation in any model depending on the volume status and the impact of an
increased preload to afterload-induced changes, with volume overload as a cause of
enhanced RV hypertrophy [52].
The determinants of long-term preservation of RV-arterial coupling in patients
with severe pulmonary hypertension or with a systemic RV are not known. The
molecular events leading to RV-arterial uncoupling and increased RV volumes
remain to be identified. Knowledge of the signaling pathways responsible for main-
tained RV function in the presence of severely increased afterload may guide the
development of new therapies [46].
The current understanding of the pathophysiology of RV failure include neuro-
humoral activation, expression of inflammatory mediators, apoptosis, capillary loss,
oxidative stress, and metabolic shifts, with variable fibrosis and hypertrophy [45,
46] (see Chap. 13). The exact sequence of events and interactions are being explored
and has to be referenced to measurements of RV function, as illustrated in recent
studies which showed inflammation and apoptosis correlated with decreased Emax/Ea
in acute [53] as well as chronic [30, 54] models of RV failure.
Simplified Methods for the Measurement

of RV-Arterial Coupling
Volume Measurements
A ratio of elastances can be simplified to a ratio of volumes, provided ESV is mea-

sured at the point of maximal elastance, not at the end of ejection. This is dependent
on loading conditions. Pressure–volume relationships of the RV chronically exposed
to increased pulmonary artery pressure tend to resemble LV pressure–volume loops,
with a decreased difference between Emax and Ees. LV pressure–volume loops after
a Mustard procedure, which connects the LV to the pulmonary circulation are indis-
tinguishable from the triangularly shaped normal RV, while the overall shape of the
pressure–volume loop of the systemic RV resembles that of the normal LV [55].
Sanz measured ESV and SV by MRI and showed that the SV/ESV ratio is ini-
tially preserved in patients with mild pulmonary hypertension, but decreases with
increasing disease severity [56]. One problem regarding the SV/ESV ratio is the
inherent assumption that the ESP–ESV relationship is linear and that the line crosses
the origin. This is incorrect, because ventricular volume at a zero filling pressure is
positive. Therefore the ESP/ESV ratio under-estimates Emax. There could be com-
pensation by ESV being lower than the ventricular volume at the point of Emax, but
probably insufficiently so in pulmonary hypertension. Thus the SV/ESV as a simple
volume measurement of RV-arterial coupling requires further evaluation and also of
its functional and prognostic relevance. It can be reasoned that the SV/ESV ratio
includes the information of RV ejection fraction (EF), or SV/EDV [32] in a less
preload-dependent manner, but the validity of this remains to be established.
A recent study reported on the negative impact on outcome of a decreased RVEF
in spite of a targeted therapy-associated decrease in the PVR in patients with PAH
[57]. Systemic vasodilating effects of targeted therapies in PAH may increase sys-
temic venous return and increase EDV, which decreases EF if the SV remains
unchanged, while an increased cardiac output may decrease PVR without any
change in pulmonary artery pressure [58].
Current progress in the field of echocardiography allows assessment of the pul-
monary circulation and RV function [59, 60] even though the accuracy may be
problematic for individual decision-making based on strict cut-off values [61].
Advances in three-dimensional echocardiography offer now the perspective of eas-
ier bedside measurements of RV volumes [62], and thus of EF or SV/ESV for the
evaluation of RV-arterial coupling (see Chap. 10).
Pressure Measurements
Another simplified approach for the measurement of RV-arterial coupling intro-

duced by Trip relies on a Pmax calculated from a RV pressure curve, which is easily
obtained during a right heart catheterization, mean Ppa (mPpa) taken as a surrogate
30 R. Naeije et al.
of ESP, and RV volume measurements by MRI [63]. The authors calculated Emax as
(Pmax − mPpa)/(EDV − ESV) and Emax assuming V0 = 0 as mPpa/ESV. V0 is the extrap-
olated volume intercept of the linear best fit of a multipoint maximum elastance
pressure–volume relationship. The results showed that mPpa/ESV was lower than
(Pmax − mPpa)/SV, on average about half the value, while V0 ranged from −8 to
171 mL and was correlated to EDV and ESV. From this the authors concluded that
V0 is dependent on RV dilatation, and thus the estimated Emax more preload-
dependent than previously assumed. This is possible, although an alternative expla-
nation is in the uncertainties of extrapolations from linear fits of relationships that
have been demonstrated to be curvilinear [64]. End-systolic elastance or Emax is best
determined by interpolation of pressure–volume coordinates [64], with tightening
by a correction for EDV [10, 22]. Further uncertainty is related to the use of an
mPpa/SV ratio or slope of (Pmax − mPpa)/SV as a surrogate of Emax determination
from single or (better) multiple beat pressure–volume relationships.
Alternative Methods to Evaluate RV-Arterial Coupling
The Pump Function Graph
The coupling of RV function to the pulmonary circulation can also be described by

pump function curves relating mean the RV pressure to SV [65]. A pump function
graph is built from measurements of the mean RV pressure and SV, a calculated Pmax
at zero SV and a parabolic extrapolation to a zero pressure SV (Fig. 2.4). In this
representation, an increase in preload shifts the curve to greater SV with no change
in shape, while an increased contractility leads to a higher Pmax with no change in
maximum SV.
The pump function graph helps to understand that at a high PVR, a fall in
pressure markedly increases SV while at a low PVR, the pressure is more affected
than SV [32].
The pump function graph has been used to demonstrate a greater degree of RV
failure at any given level of mPpa in SSc-PAH as compared to idiopathic PAH [66],
this has subsequently been confirmed by Emax/Ea determinations [22]. The limita-
tions of the pump function graph are its sensitivity to changes in preload and, as
already mentioned, to the use of the mean RV or mean pulmonary artery pressure
as surrogates for the maximum elastance RV pressure.
The Contractile Reserve
Systolic function adaptation to afterload can also be tested dynamically to

determine a contractile reserve, or the capacity to increase contractility at a given
level of loading. Contractile or ventricular reserve is determined using exercise or
Fig. 2.4 Pump function curve defined by mean right ventricular pressure (mRVP) as a function of
stroke volume (SV). The maximum mRVP (mRVOmax) at SV = 0 is calculated from a maximum
RVP determination (see Fig. 2.1). The zero pressure point results from a parabolic extrapolation,
from measured and zero SV points. Increased preload shifts the curve in parallel to higher
SV. Increased contractility increases pressure generated at any given value of SV, but in proportion
to decreased SV
pharmacological stress tests (typically an infusion of dobutamine); the contractile

reserve has been shown to be a strong predictor of outcome in heart failure [67]. The
evaluation of the RV contractile reserve has not yet been reported in patients with
pulmonary hypertension. In rats after PAB, Emax was increased to the same extent in
response to 2.5 μg/kg/min of dobutamine in controls, suggesting that systolic func-
tion is preserved in this pulmonary hypertension model [28].
A simple noninvasive approach was recently introduced by Grünig [68]. In that
study, Doppler echocardiography was used to measure RV systolic pressure from
the maximum velocity of tricuspid regurgitation at rest and at exercise in 124
patients with either PAH or chronic thrombo-embolic pulmonary hypertension
(CTEPH). An exercise-induced increase of the RVSP by >30 mmHg was a strong
predictor of exercise capacity and survival. Further studies will explore improved
indices with incorporation of volume measurements and ESP determinations, as
this is now becoming possible using noninvasive bedside methodology.
Surrogate Measurements of RV-Arterial Coupling
Right ventricular systolic function can be estimated by a series of invasive and

noninvasive measurements, which are available in daily clinical practice.
32 R. Naeije et al.
Right heart catheterization allows for measurements of Ppa, right atrial pressure
and cardiac output (Fick or thermodilution) and thus calculations of RV function
curves such as cardiac output, SV or stroke work (SW, mean Ppa × SV) as a function
of right atrial pressure. Stroke work calculated as mPpa × SV ignores the pulsatile
component of work. It has been recently estimated that the pulsatile component of
SW amounts to 23 % of total work independently of type and severity of pulmonary
hypertension, so that total SW = 1.3mPpa × SV [69]. This fixed relationship is
explained by the fact that PVR × pulmonary arterial compliance (Ca), or RC-time of
the pulmonary circulation, remains approximately at the same value in normal sub-
jects and in patients with pulmonary hypertension [70]. The RC-time is actually
decreased in left heart failure [71] and in patients with proximal operable CTEPH
[72], but increased in purely distal pulmonary micro-vascular obstruction [73].
However, the deviations are relatively mild. The pulsatile component of RVSW var-
ies on average from 20 to 26 %, with extremes of from 15 to 30 %. Therefore, total
work is estimated to vary between 1.2 and 1.4 times steady-flow work. The near-
constancy of the RC-time thus implies a relatively stable prediction of total RVSW. It
remains that right atrial pressure is an imperfect surrogate of preload, which is mea-
sured in the intact heart by the EDV.
Right ventricular contractility can be measured by preload recruitable SW
(PRSW) defined by SW–EDV relationships at variable venous return [74]. The
slope of PRSW has been shown to be reproducible and sensitive to changes in con-
tractile state. However, whether PRSW is useful to evaluate RV-arterial coupling
has not been clearly shown. The measurement requires invasive volume and high-
fidelity pressure measurements with a manipulation of venous return, and is thus
difficult to implement at the bedside.
Measurements of RV volumes, ejection fraction, and SV/ESV ratios are possible
by imaging techniques such as MRI or three-dimensional echocardiography. The
limitation of imaging is the absence of direct pressure measurements. It has recently
been proposed to use noninvasive Doppler echocardiographic measurements of a
tricuspid annular plane excursion (TAPSE) as a measure of RV systolic function and
of the maximum velocity of tricuspid regurgitation-derived systolic Ppa (SPpa) as a
measure of afterload, and derive a TAPSE/SPpa ratio as an estimation of RV-arterial
coupling [75]. This indirect index of RV-arterial coupling may be useful as it has
been shown to predict survival in patients with left heart failure and decreased or
preserved ejection fraction.
A series of imaging-derived indices of RV systolic function, such as MRI-
determined EF or Doppler echocardiographic measurements of fractional area
change measured in the four-chamber view (a surrogate of EF), TAPSE, tissue
Doppler imaging (TDI) of the tricuspid annulus systolic velocity S wave and iso-
volumic acceleration (IVA) or maximum velocity (IVV), strain or strain rate have
been shown to be related to functional state and prognosis in severe pulmonary
hypertension [59, 60]. Isovolumic phase indices such as the IVA or IVV are proba-
bly less preload-dependent, and as such the closest estimates of Emax measurements
[76, 77].
Diastolic Function
So far we have focused on RV systolic function and RV-arterial coupling as the

essential biomechanical mechanism of ventricular function adaptation to increased
afterload. However, a Starling heterometric adaptation may occur at any stages the
disease progresses to, depending on the rate of progression, degree of inflammatory
component of the pulmonary hypertension, and systemic conditions which affect
cardiac function. There is thus interest in taking into account diastolic function in
the RV adaptation to pulmonary hypertension.
Diastolic function is described by a diastolic elastance curve determined by a
family of pressure–volume loops at variable loading. It is curvilinear thus impossi-
ble to express as a single number. Several formulas have been proposed [32]. Most
recently Rain reported on 21 patients with PAH in whom RV diastolic stiffness was
estimated by fitting a nonlinear exponential curve through the diastolic pressure–
volume relationships, with the formula P = α(eVβ − 1), where α is a curve fitting
constant and β a diastolic stiffness constant [78]. In that study, the diastolic stiffness
constant β was closely associated with disease severity.
A series of surrogate measurements of diastolic function are provided by Doppler
echocardiography: isovolumic relaxation time and a decreased ratio of transmittal E
and A waves or mitral annulus TDI E′/A′ waves, increased right atrial or RV surface
areas on apical four-chamber views, altered eccentricity index on a parasternal short
axis view, estimates of right atrial pressure from RV diastolic function indices or
inferior vena cava dimensions, pericardial effusion, and the so-called Tei index,
which is the ratio of isovolumetric time intervals to ventricular ejection time [59, 60].
Ventricular Interaction
Right ventricular function must be put into the context of its direct and indirect
interactions with LV function. Direct interaction, or ventricular interdependence, is
defined by the forces that are transmitted from one ventricle to the other ventricle
through the myocardium and pericardium, independent of neural, humoral, or circu-
latory effects [79]. Diastolic ventricular interaction refers to the competition for space
within the indistensible pericardium when RV dilates, which alters LV filling and
may be a cause of inadequate cardiac output response to metabolic demand. Right
heart catheterization and imaging studies have shown that in patients with severe
pulmonary hypertension, pulmonary artery wedge pressure and LV peak filling rate
are increased in proportion to a decreased RV ejection fraction [80]. Systolic interac-
tion refers to positive interaction between RV and LV contractions. It can be shown
experimentally that aortic constriction, and enhanced LV contraction, markedly
improves RV function in animals with PAB [81]. Similarly, in electrically isolated
ventricular preparations in the otherwise intact dog heart, LV contraction contributes
a significant amount (~30 %) to both RV contraction and pulmonary flow [82]. This
is explained by a mechanical entrainment effect, but also by LV systolic function
34 R. Naeije et al.
determining systemic blood pressure which is an essential determinant of RV

coronary perfusion. Increased RV filling pressures and excessive decrease in blood
pressure may be a cause of RV ischemia and decreased contractility. An additional
cause of negative ventricular interaction disclosed by imaging studies is asynchrony,
which has been shown to develop in parallel to increased pulmonary artery pressures
and contributes to altered RV systolic function and LV under-filling [83].
A Global View on RV Failure
An integrated view of the pathophysiology of RV failure is depicted in Fig. 2.5.

Pulmonary hypertension increases RV afterload requiring a homeometric adap-
tation. When this adaptation fails, the RV enlarges, decreasing LV filling because of
competition for space within the pericardium. This decreases stroke volume and
Fig. 2.5 Pathophysiology of right ventricular (RV) failure. The magnetic resonance images show
the evolution from homeometric to heterometric adaptation of RV function in advanced pulmonary
hypertension. The echocardiographic images show an improved ventricular diastolic interaction
with reversal of the transmittal flow E and A waves, indicating improved left ventricular diastolic
function with diuretic therapy. Numbers indicate the targets of therapeutic interventions: (1) pul-
monary vascular resistance, (2) contractility, (3) diastolic interaction. and (4) systolic interaction.
EDV end-diastolic volume
blood pressure with a negative systolic interaction as a cause of further RV-arterial

uncoupling. This may be aggravated by RV ischemia due to a decreased coronary
perfusion pressure (gradient between diastolic blood pressure and right atrial pres-
sure). Understanding these interactions may allow one to identify specific targets of
therapeutic interventions.
Perspective
In 1989 John (Jack) Reeves called a greater investment in research to explore the
pathophysiology and pathobiology of RV failure in pulmonary hypertension. It was
already known at his time that pulmonary hypertension is a common complication
of cardiac and pulmonary diseases, and that symptoms, exercise capacity and
outcome in the patients are considerably influenced by RV function. Yet, he deplored
that the RV was getting insufficient attention in clinical and basic research pulmo-
nary circulation programs [84]. Since then we have made progress, but not quite
enough. There is much more work to do and more to be learned [46, 85].
What Are the Priorities?
The first is to improve the translation to the intact heart of newly discovered molecu-
lar signaling pathways related to maintained or failing RV function in various models
of pulmonary hypertension. This will require more measurements of systolic and
diastolic function using pressure–volume relationships. As reviewed in the present
chapter, the knowledge is available and should be more extensively applied.
The next priority is to improve RV function phenotyping in clinical research.
Invasiveness of measurements is an obstacle to much needed faster progress. Experts
in imaging and clinical physiologists are therefore urged to collaborate in the devel-
opment of validated noninvasive methods of evaluation. This will be indispensable
to improved definition of the biological determinants of RV adaptation to various
pulmonary hypertensive states, and targeted therapeutic innovation.
Acknowledgment Figure 2.2 was redrawn by Louis Handoko from source data reported in Ref. [31].
References
1. West JB. Role of the fragility of the pulmonary blood-gas barrier in the evolution of the
pulmonary circulation. Am J Physiol Regul Integr Comp Physiol. 2013;304:R171–6.
after severe damage to the RV of the dog, with discussion of the relation between clinical
congestive heart failure and heart disease. Am Heart J. 1943;26:291–301.
36 R. Naeije et al.
3. Guyton AC. Determination of cardiac output by equating venous return curves with cardiac
response curves. Physiol Rev. 1954;35:123–9.
4. Naeije R, Vanderpool R, Dhakal BP, Saggar R, Saggar R, Vachiery JL, Lewis GD. Exercise
induced pulmonary hypertension physiological basis and methodological concerns. Am J
Respir Crit Care Med. 2013;187:576–83.
5. Fontan F, Baudet F. Surgical repair of tricuspid atresia. Thorax. 1971;26:240–8.
6. Gewillig M. The Fontan circulation. Heart. 2005;91:839–46.
7. Haddad F, Hunt SA, Rosenthal DN, Murphy DJ. Right ventricular function in cardiovascular
disease, part I. Anatomy, physiology, aging and functional assessment of the right ventricle.
Circulation. 2008;117:1436–48.
8. Haddad F, Doyle R, Murphy DJ, Hunt SA. Right ventricular function in cardiovascular disease,
part II. Pathophysiology, clinical importance, and management of right ventricular failure.
Circulation. 2008;117:1717–31.
9. Guyton AC, Lindsey AW, Gilluly JJ. The limits of right ventricular compensation following
acute increase in pulmonary circulatory resistance. Circ Res. 1954;2:326–32.
10. Sagawa K, Maughan L, Suga H, Sunagawa K. Cardiac contraction and the pressure-volume
relationship. New York: Oxford University; 1988.
11. von Anrep G. On the part played by the suprarenals in the normal vascular reactions of the
body. J Physiol. 1912;45:307–17.
12. Sarnoff SJ, Mitchell JH, Gilmore JP, Remensnyder JP. Homeometric autoregulation of the
heart. Circ Res. 1960;8:1077–91.
13. Rosenblueth A, Alanis J, Lopez E, Rubio R. The adaptation of ventricular muscle to different
circulatory conditions. Arch Int Physiol Biochim. 1959;67:358–73.
14. Taquini AC, Fermoso JD, Aramendia P. Behaviour of the right ventricle following acute
constriction of the pulmonary artery. Circ Res. 1960;8:315–8.
15. Suga H, Sagawa K, Shoukas AA. Load independence of the instantaneous pressure-volume
ratio of the canine left ventricle and effects of epinephrine and heart rate on the ratio. Circ Res.
1973;32:314–22.
16. Maughan WL, Shoukas AA, Sagawa K, Weisfeldt ML. Instantaneous pressure-volume
relationship of the canine right ventricle. Circ Res. 1979;44:309–15.
17. Sunagawa K, Yamada A, Senda Y, Kikuchi Y, Nakamura M, Shibahara T. Estimation of the
hydromotive source pressure from ejecting beats of the left ventricle. IEEE Trans Biomed Eng.
1980;57:299–305.
18. Brimioulle S, Wauthy P, Ewalenko P, Rondelet B, Vermeulen F, Kerbaul F, Naeije R. Single-beat
estimation of right ventricular end-systolic pressure-volume relationship. Am J Physiol Heart
Circ Physiol. 2003;284:H1625–30.
19. Brown KA, Ditchey RF. Human right ventricular end-systolic pressure-volume relation
defined by maximal elastance. Circulation. 1988;78:81–91.
20. Dell’Italia LJ, Walsh RA. Application of a time-varying elastance model to right ventricular
performance in man. Cardiovasc Res. 1988;22:864–74.
21. Kuehne T, Yilmaz S, Steendijk P, Moore P, Groenink M, Saaed M, Weber O, Higgins CB,
Ewert P, Fleck E, Nagel E, Schulze-Neick I, Lange P. Magnetic resonance imaging analysis of
right ventricular pressure-volume loops: in vivo validation and clinical application in patients
with pulmonary hypertension. Circulation. 2004;110:2010–6.
22. Tedford RJ, Mudd JO, Girgis RE, Mathai SC, Zaiman AL, Housten-Harris T, Boyce D,
Kelemen BW, Bacher AC, Shah AA, Hummers LK, Wigley FM, Russell SD, Saggar R, Saggar
R, Maughan WL, Hassoun PM, Kass DA. Right ventricular dysfunction in systemic sclerosis
associated pulmonary arterial hypertension. Circ Heart Fail. 2013;6(5):953–63.
23. Wauthy P, Naeije R, Brimioulle S. Left and right ventriculo-arterial coupling in a patient with
congenitally corrected transposition. Cardiol Young. 2005;15:647–9.
24. Wauthy P, Pagnamenta A, Vassali F, Brimioulle S, Naeije R. Right ventricular adaptation to
pulmonary hypertension. An interspecies comparison. Am J Physiol Heart Circ Physiol.
2004;286:H1441–7.
25. de Vroomen M, Cardozo RH, Steendijk P, van Bel F, Baan J. Improved contractile perfor-
mance of right ventricle in response to increased RV afterload in newborn lamb. Am J Physiol
26. Lambermont B, Ghuysen A, Kolh P, Tchana-Sato V, Segers P, Gérard P, Morimont P, Magis D,
Dogné JM, Masereel B, D’Orio V. Effects of endotoxic shock on right ventricular systolic
function and mechanical efficiency. Cardiovasc Res. 2003;59:412–8.
27. Leeuwenburgh BP, Helbing WA, Steendijk P, Schoof PH, Baan J. Biventricular systolic func-
tion in young lambs subject to chronic systemic right ventricular pressure overload. Am J
Physiol Heart Circ Physiol. 2001;281:H2697–704.
28. Faber MJ, Dalinghaus M, Lankhuizen IM, Steendijk P, Hop WC, Schoemaker RG, Duncker
DJ, Lamers JM, Helbing WA. Right and left ventricular function after chronic pulmonary
artery banding in rats assessed with biventricular pressure-volume loops. Am J Physiol Heart
Circ Physiol. 2006;291:H1580–6.
29. Rondelet B, Kerbaul F, Motte S, Van Beneden R, Remmelink M, Brimioulle S, Mc Entee K,
Wauthy P, Salmon I, Ketelslegers JM, Naeije R. Bosentan for the prevention of overcirculation-
induced pulmonary hypertension. Circulation. 2003;107:1329–35.
30. Rondelet B, Dewachter C, Kerbaul F, Kang X, Fesler P, Brimioulle S, Naeije R, Dewachter
L. Prolonged overcirculation-induced pulmonary arterial hypertension as a cause of right ven-
tricular failure. Eur Heart J. 2012;33:1017–26.
31. de Man FS, Handoko ML, van Ballegoij JJ, Schalij I, Bogaards SJ, Postmus PE, der Velden J,
Westerhof N, Paulus WJ, Vonk-Noordegraaf A. Bisoprolol delays progression towards right
heart failure in experimental pulmonary hypertension. Circ Heart Fail. 2012;5:97–105.
32. Vonk-Noordegraaf A, Westerhof N. Describing right ventricular function. Eur Respir J. 2013;41:
1419–23.
33. Chesler NC, Roldan A, Vanderpool RR, Naeije R. How to measure pulmonary vascular and
right ventricular function. Conf Proc IEEE Eng Med Biol Soc. 2009;1:177–80.
34. Kerbaul F, Rondelet B, Motte S, Fesler P, Hubloue I, Ewalenko P, Naeije R, Brimioulle
S. Isoflurane and desflurane impair right ventricular-pulmonary arterial coupling in dogs.
Anesthesiology. 2004;101:1357–61.
35. Fesler P, Pagnamenta A, Rondelet B, Kerbaul F, Naeije R. Effects of sildenafil on hypoxic
pulmonary vascular function in dogs. J Appl Physiol. 2006;101:1085–90.
36. Rex S, Missant C, Segers P, Rossaint R, Wouters PF. Epoprostenol treatment of acute pulmo-
nary hypertension is associated with a paradoxical decrease in right ventricular contractility.
Intensive Care Med. 2008;34:179–89.
37. Wauthy P, Kafi AS, Mooi W, Naeije R, Brimioulle S. Effects of nitric oxide and prostacyclin
in an over-circulation model of pulmonary hypertension. J Thorac Cardiovasc Surg.
2003;125:1430–7.
38. Kerbaul F, Rondelet B, Motte S, Fesler P, Hubloue I, Ewalenko P, Naeijer R, Brimioulle
S. Effects of norepinephrine and dobutamine on pressure load-induced right ventricular failure.
Crit Care Med. 2004;32:1035–40.
39. Kerbaul F, Rondelet B, Demester JP, Fesler P, Huez S, Naeije R, Brimioulle S. Effects of
levosimendan versus dobutamine on pressure load-induced right ventricular failure. Crit Care
Med. 2006;34:2814–9.
40. Kerbaul F, Brimioulle S, Rondelet B, Dewachter C, Hubloue I, Naeije R. How prostacyclin
improves cardiac output in right heart failure in conjunction with pulmonary hypertension.
Am J Respir Crit Care Med. 2007;175:846–50.
41. Missant C, Rex S, Segers P, Wouters PF. Levosimendan improves right ventriculovascular
coupling in a porcine model of right ventricular dysfunction. Crit Care Med. 2007;35:
707–15.
42. Pagnamenta A, Dewachter C, McEntee K, Fesler P, Brimioulle S, Naeije R. Early right
ventriculo-arterial uncoupling in borderline pulmonary hypertension on experimental heart
failure. J Appl Physiol. 2010;109:1080–5.
43. Rich S, McLaughlin VV. The effects of chronic prostacyclin therapy on cardiac output and
symptoms in primary pulmonary hypertension. J Am Coll Cardiol. 1999;34:1184–7.
38 R. Naeije et al.
44. Nagendran J, Archer SL, Soliman D, Gurtu V, Moudgil R, Haromy A, St Aubin C, Webster L,
Rebeyka IM, Ross DB, Light PE, Dyck JR, Michelakis ED. Phosphodiesterase type 5 is highly
expressed in the hypertrophied human right ventricle, and acute inhibition of phosphodiester-
ase type 5 improves contractility. Circulation. 2007;116:238–48.
45. Bogaard HJ, Abe K, Vonk Noordegraaf A, Voelkel NF. The right ventricle under pressure.
Cellular and molecular mechanisms of right heart failure in pulmonary hypertension. Chest.
2009;135:794–804.
46. Voelkel NF, Gomez-Arroyo J, Abbate A, Bogaard HJ. Mechanisms of right heart failure—a
work in progress and plea for further prevention. Pulm Circ. 2013;3:137–43.
47. Hoeper MM, Granton J. Intensive care unit management of patients with severe pulmonary
hypertension and right heart failure. Am J Respir Crit Care Med. 2011;184:1114–24.
48. Sztrymf B, Günther S, Artaud-Macari E, Savale L, Jaïs X, Sitbon O, Simonneau G, Humbert
M, Chemla D. Left ventricular ejection time in acute heart failure complicating pre-capillary
pulmonary hypertension. Chest. 2013;144(5):1512–20.
49. Borgdorff MA, Bartelds B, Dickinson MG, Boersma B, Weij M, Zandvoort A, Silié HH,
Steendijk P, de Vroomen M, Berger RM. Sildenafil enhances systolic adaptation, but does not
prevent diastolic dysfunction, in the pressure-loaded right ventricle. Eur J Heart Fail.
2012;14:1067–74.
50. Gomez-Arroyo JG, Farkas L, Alhussaini AA, Farkas D, Kraskauskas D, Voelkel N, Bogaard
HJ. The monocrotaline model of pulmonary hypertension in perspective. Am J Physiol Lung
Cell Mol Physiol. 2012;302:L363–9.
51. Bogaard HJ, Natarayan R, Henderson SC, Long CS, Kraskauskas D, Smithson L, Ockaili R,
McCord JM, Voelkel NF. Chronic pulmonary artery pressure elevation is insufficient to explain
right heart failure. Circulation. 2009;120:1951–60.
52. Borgdorff MA, Bartels B, Dickinson MG, SteeDdijk P, de Vroomen M, Berger RM. Distinct
loading conditions reveal various patterns of right ventricular adaptation. Am J Physiol Heart
Circ Physiol. 2013;305:H354–364.
53. Dewachter C, Dewachter L, Rondelet B, Fesler P, Brimioulle S, Kerbaul F, Naeije R. Activation
of apoptotic pathways in experimental acute afterload-induced right ventricular failure. Crit
Care Med. 2010;38:1405–13.
54. Belhaj A, Dewachter L, Kerbaul F, Brimioulle S, Dewachter C, Naeije R, Rondelet B. Heme
oxygenase-1 and inflammation in experimental right ventricular failure on prolonged
overcirculation-induced pulmonary hypertension. PlosOne. 2013;8(7):e69470.
55. Redington AN, Rigby RL, Shinebourne EA, Oldershaw PJ. Changes in pressure-volume
relation of the right ventricle when its loading conditions are modified. Br Heart J. 1990;
63:45–9.
56. Sanz J, García-Alvarez A, Fernández-Friera L, Nair A, Mirelis JG, Sawit ST, Pinney S, Fuster
V. Right ventriculo-arterial coupling in pulmonary hypertension: a magnetic resonance study.
Heart. 2012;98:238–43.
57. van de Veerdonk MC, Kind T, Marcus JT, Mauritz GJ, Heymans MW, Bogaard HJ, Boonstra
A, Marques KM, Westerhof N, Vonk-Noordegraaf A. Progressive right ventricular dysfunction
in patients with pulmonary arterial hypertension responding to therapy. J Am Coll Cardiol.
2011;58:2511–9.
58. Sniderman AD, Fitchett DH. Vasodilators and pulmonary arterial hypertension: the paradox of
therapeutic success and clinical failure. Int J Cardiol. 1988;20:173–81.
59. Roberts JD, Forfia PR. Diagnosis and assessment of pulmonary vascular disease by Doppler
echocardiography. Pulm Circ. 2011;1:161–81.
60. Bossone E, D’Andrea A, D’Alto M, Citro R, Argiento P, Ferrara F, Cittadini A, Rubenfire M,
Naeije R. Echocardiography in pulmonary arterial hypertension. J Am Soc Echocardiogr.
2013;26:1–14.
61. D’Alto M, Romeo E, Argiento P, D’Andrea A, Vanderpool R, Correra A, Bossone E, Sarubbi
B, Calabrò R, Russo MG, Naeije R. Accuracy and precision of echocardiography versus right
heart catheterization for the assessment of pulmonary hypertension. Int J Cardiol.

2013;168(4):4058–62.
62. Zhang QB, Sun JP, Gao RF, Lee APW, Feng YL, Liu XR, Sheng W, Liu F, Yu CM. Feasibility
of single-beat full volume capture real-time three-dimensional echocardiography for quantifi-
cation of right ventricular volume: validation by cardiac magnetic resonance imaging. Int J
Cardiol. 2013;168(4):3991–5.
63. Trip P, Kind T, van de Veerdonk MC, Marcus JT, de Man FS, Westerhof N, Vonk-Noordegraaf
A. Accurate assessment of load-independent right ventricular systolic function in patients with
pulmonary hypertension. J Heart Lung Transplant. 2013;32:50–5.
64. Kass DA, Beyar R, Lankford E, Heard M, Maughan WL, Sagawa K. Influence of contractile
state on the curvilinearity of in situ end-systolic pressure-volume relationships. Circulation.
1989;79:167–78.
65. Elzinga G, Westerhof N. The effect of an increase in inotropic state and end-diastolic volume
on the pumping ability of the feline left heart. Circ Res. 1978;42:620–8.
66. Overbeek MJ, Lankhaar JW, Westerhof N, Voskuyl AE, Boonstra A, Bronzwaer JG, Marques
KM, Smit EF, Dijkmans BA, Vonk-Noordegraaf A. Right ventricular contractility in systemic
sclerosis-associated and idiopathic pulmonary arterial hypertension. Eur Respir J. 2008;31:
1160–6.
67. Haddad F, Vrtovec B, Ashley EA, Deschamps A, Haddad H, Denault AY. The concept of ven-
tricular reserve in heart failure and pulmonary hypertension: an old metric that brings us one
step closer in our quest for prediction. Curr Opin Cardiol. 2011;26:123–31.
68. Grünig E, Tiede H, Enyimayew EO, Ehlken N, Seyfarth HJ, Bossone E, D’Andrea A, Naeije
R, Olschewski H, Ulrich S, Nagel C, Halank M, Fischer C. Assessment and prognostic
relevance of right ventricular contractile reserve in patients with pulmonary arterial hyperten-
sion. Circulation. 2013;128(18):2005–15.
69. Saouti N, Westerhof N, Helderman F, Marcus JT, Boonstra A, Postmus PE, Vonk-Noordegraaf
A. Right ventricular oscillatory power is a constant fraction of total power irrespective of pul-
monary artery pressure. Am J Respir Crit Care Med. 2010;182:1315–20.
70. Lankhaar JW, Westerhof N, Faes TJ, Gan CT, Marques KM, Boonstra A, van den Berg FG,
Postmus PE, Vonk-Noordegraaf A. Pulmonary vascular resistance and compliance stay
inversely related during treatment of pulmonary hypertension. Eur Heart J. 2008;29:1688–95.
71. Tedford RJ, Hassoun PM, Mathai SC, Girgis RE, Russell SD, Thiemann DR, Cingolani OH,
Mudd JO, Borlaug BA, Redfield MM, Lederer DJ, Kass DA. Pulmonary capillary wedge
pressure augments right ventricular pulsatile loading. Circulation. 2012;125:289–97.
72. Mackenzie Ross RV, Toshner MR, Soon E, Naeije R, Pepke-Zaba J. Decreased time constant
of the pulmonary circulation in chronic thromboembolic pulmonary hypertension. Am J
Physiol Heart Circ Physiol. 2013;305:H259–64.
73. Pagnamenta A, Vanderpool RR, Brimioulle S, Naeije R. Proximal pulmonary arterial obstruc-
tion decreases the time constant of the pulmonary circulation and increases right ventricular
afterload. J Appl Physiol. 2013;114:1586–92.
74. Karunanithi MK, Michniewicz J, Copeland SE, Feneley MP. Right ventricular preload recruit-
able stroke work, end-systolic pressure-volume, and dP/dtmax-end-diastolic volume relations
compared as indexes of right ventricular contractile performance in conscious dogs. Circ Res.
1992;70:1169–79.
75. Guazzi M, Bandera F, Pelissero G. Tricuspid annular systolic excursion and pulmonary sys-
tolic pressure relationship in heart failure: an index of right ventricular contractility and prog-
nosis. Am J Physiol Heart Circ Physiol. 2013;305(9):H1373–81.
76. Vogel M, Schmidt MR, Christiansen SB, Cheung M, White PA, Sorensen K, Redington
AN. Validation of myocardial acceleration during isovolumic contraction as a novel non-
invasive index of right ventricular contractility. Circulation. 2002;105:1693–9.
77. Ernande L, Cottin V, Leroux PY, Girerd N, Huez S, Mulliez A, Bergerot C, Ovize M, Mornex
JF, Cordier JF, Naeije R, Derumeaux G. Right isovolumic contraction velocity predicts sur-
vival in pulmonary hypertension. J Am Soc Echocardiogr. 2013;26:297–306.
40 R. Naeije et al.
78. Rain S, Handoko ML, Trip P, Gan TJ, Westerhof N, Stienen G, Paulus WJ, Ottenheijm C,
Marcus JT, Dorfmuller P, Guignabert C, Humbert M, Macdonald P, Dos Remedios C, Postmus
PE, Saripalli C, Hidalgo CG, Granzier HL, Vonk-Noordegraaf A, van der Velden J, de Man
FS. Right ventricular diastolic impairment in patients with pulmonary arterial hypertension.
Circulation. 2013;128(18):2016–25.
79. Santamore WP, Dell’Italia LJ. Ventricular interdependence: significant left ventricular contri-
butions to right ventricular systolic function. Progr Cardiovasc Dis. 1998;40:289–308.
80. Lazar JM, Flores AR, Grandis DJ, Orie JE, Schulman DS. Effects of chronic right ventricular
pressure overload on left ventricular diastolic function. Am J Cardiol. 1993;72:1179–82.
81. Belenkie I, Horne SG, Dani R, Smith ER, Tyberg JV. Effects of aortic constriction during
experimental acute right ventricular pressure loading. Further insights into diastolic and
systolic ventricular interaction. Circulation. 1995;92:546–54.
82. Damiano Jr RJ, La Follette P, Cox Jr JL, Lowe JE, Santamore WP. Significant left ventricular
contribution to right ventricular systolic function. Am J Physiol. 1991;261:H1514–24.
83. Marcus JT, Gan CT, Zwanenburg JJ, Boonstra A, Allaart CP, Götte MJ, Vonk-Noordegraaf
A. Interventricular mechanical asynchrony in pulmonary arterial hypertension: left-to-right
delay in peak shortening is related to right ventricular overload and left ventricular underfill-
ing. J Am Coll Cardiol. 2008;51:750–7.
84. Reeves JT, Groves BM, Turkevich D, Morrisson DA, Trapp JA. Right ventricular function in
pulmonary hypertension. In: Weir EK, Reeves JT, editors. Pulmonary vascular physiology and
physiopathology. New York: Marcel Dekker; 1989. p. 325–51. Chap 10.
85. Voelkel NF, Quaife RA, Leinwand LA, Barst RJ, McGoon MD, Meldrum DR, Dupuis J, Long
CS, Rubin LJ, Smart FW, Suzuki YJ, Gladwin M, Denholm EM, Gail DB. Right ventricular
function and failure: report of a National Heart, Lung, and Blood Institute working group on
cellular and molecular mechanisms of right heart failure. Circulation. 2006;114:1883–189.
Chapter 3
The Neonatal Transition of the Right Ventricle
Michael V. Di Maria and Steven H. Abman
Introduction and Overview
Neonatal survival is dependent on successful adaptation of the fetal cardiopulmo-

nary system at birth, which is required for the lung to assume its essential postnatal
role for gas exchange [1–3]. The most dramatic event at birth involves the pulmo-
nary circulation, which should rapidly undergo a marked fall in pulmonary vascular
resistance (PVR) to accommodate an eight- to tenfold increase in pulmonary blood
flow in the immediate postnatal period. This fall in PVR at birth is due to increased
oxygen tension, loss of fetal lung liquid, establishment of the air–liquid interface,
ventilation, and shear stress, which cause vasodilation through enhanced release of
vasodilators, such as nitric oxide (NO) and prostacyclin, and decreased production
of vasoconstrictors, such as endothelin-1 (ET-1) (Fig. 3.1) [2]. Failure to achieve or
sustain this normal drop in PVR leads to the syndrome of persistent pulmonary
hypertension of the newborn (PPHN), which is characterized by profound hypox-
emia due to extra-pulmonary shunt, poor cardiac output, and significant morbidity
and mortality [4–6].
In addition to changes in the pulmonary circulation, the fetal myocardium also
adapts rapidly during the transition, and the right ventricle (RV) undergoes striking
functional and structural changes after birth, summarized in Table 3.1. Due to the
presence of “fetal shunts,” communications between the systemic and pulmonary
circulations through the patent foramen ovale (FO) and ductus arteriosus (DA)
M.V. Di Maria, M.D. (*)

Department of Pediatrics, University of Colorado School of Medicine,
13123 East 16th Avenue, Box 100, Aurora, CO 80045, USA
e-mail: michael.dimaria@childrenscolorado.org
S.H. Abman, M.D.
Department of Pediatrics, University of Colorado,
1717 East Arizona Avenue, Denver, CO 80210, USA
e-mail: steven.abman@ucdenver.edu

42 M.V. Di Maria and S.H. Abman
Fig. 3.1 Physiologic changes in the right ventricle during the transition from fetal to neonatal life
Table 3.1 Maturational change in the right ventricle in the fetus, newborn, and infant
Fetus Neonate Infant/adult
Myocardial Larger non-contractile Persistence of increased Increased RV chamber
structure mass, randomly oriented RV mass size, decreased wall
myofibers thickness
Preload High resting myocardial Persistence of relatively Increased compliance,
tension, with decreased poor compliance decreased filling
compliance pressures
Afterload Systemic RV afterload, Decreasing afterload Continued decrease in
ejecting into the aorta via following ductal closure afterload over the first
the ductus arteriosus and gaseous inflation 6 weeks of life
of the lungs
Contractility Decreased contractility due High contractility due to Decreased adrenergic
to structural immaturity increased adrenergic tone tone, with greater
and calcium metabolism contractile reserve
Cardiac RVCO 1.2–1.5× greater 30 % decrease in RVCO RVCO = LVCOa
output than LVCO with closure of the PDA
and PFO
Substrate RV free wall perfusion Decreased RV blood flow Transition to fatty
utilization exceeds that of the LV and oxygen consumption acids as the primary
Primary fuel source: fuel source
carbohydrate
a
Absence of any shunt lesions. RV right ventricle, PVR pulmonary vascular resistance, RVCO right
ventricular cardiac output, LV left ventricle, PDA patent ductus arteriosus, PFO patent foramen ovale
in utero, the left and right ventricles are functionally coupled prior to birth (Fig. 3.2).
The RV serves as the “systemic ventricle” in utero, as most of the RV output crosses
the widely patent DA and provides 2/3 of combined ventricular output (CVO) in the
normal fetus. In fact, RV wall thickness exceeds that of the LV in fetal life, reflecting
3 The Neonatal Transition of the Right Ventricle 43
Fig. 3.2 Prenatal echocardiogram from a normal fetus, illustrating right ventricular ejection of
blood into the descending aorta via the ductus arterioles
its dominant functional role in utero. Pulmonary blood flow accounts for only
8–10 % of CVO due to the high PVR and low systemic vascular resistance provided
by the placental circulation [1–3]. Left and right atrial pressures and pressures in the
great arteries are equivalent due to the widely patent FO and DA, respectively.
Whereas pulmonary vasodilation is the central hemodynamic event during the
immediate transition, resistance of the systemic circulation rapidly increases due to
loss of the low resistance placental circulation and increased systemic vascular tone
after clamping of the umbilical cord. Thus, increased systemic vascular resistance,
the marked fall in PVR, and functional closure of the “fetal channels” account for the
progressive decrease in RV wall thickness and increase in LV mass after birth [7, 8].
Unlike changes in the RV during the normal transition, RV hypertrophy (RVH)
persists in the setting of sustained elevations of PVR due to birth at altitude, PPHN,
congenital heart disease, and other cardiopulmonary disorders.
In addition to these dramatic physiologic changes, the neonatal transition of the
RV is further characterized by remarkable cellular, molecular and metabolic adapta-
tions [9]. The fetal heart grows and develops during normal intrauterine life at low
oxygen tensions (20–30 Torr) that would induce severe hypoxic stress responses in
postnatal life, yet the fetus thrives and is well-prepared for the normal transition at
birth. Insights into mechanisms underlying the normal metabolic and functional
transition from fetal to neonatal life are not only important for better understanding
of neonatal cardiopulmonary diseases, but will also provide insights into adaptive
and maladaptive responses in the adult RV. Finally, there is growing support for
the concept that perinatal events from fetal life may impact susceptibility for adult
disease (“fetal programming”) and the effects of epigenetic signaling on stress
responses throughout the “life course” [10, 11].
In this chapter, we discuss mechanisms underlying transition of the RV at birth,
including changes in RV metabolism, structure and function in the normal fetus;
early changes in the RV during transition at birth and postnatal adaptations; and
pathophysiologic features associated with failure of the normal transition associated
with PPHN.
Fetal Right Ventricular Metabolism, Structure, and Function
Oxygen Tension, Metabolism, and Substrate Utilization
The normal fetus thrives in its low oxygen environment in utero (PaO2 roughly
18–25 Torr) and this low oxygen tension is essential for normal myocardial growth,
development, and functional maturation in utero. The predominant use of carbohy-
drates for energy substrates, including glucose, lactate, and pyruvate, is a unique
feature of fetal myocardial metabolism [12, 13]. ATP generation via these relative
oxygen-sparing glycolytic pathways rather than fatty acid oxidation (FAO) repre-
sents a key strategy of the fetal heart to tolerate and thrive despite low oxygen levels
in normal fetal life [14]. This adaptive feature allows the fetal heart to be more
resistant to hypoxia-induced cell injury than the adult heart [15]. Expression of
hypoxia-induced genes, such as hypoxia inducible factor (HIF-1) and vascular
endothelial growth factor (VEGF) play central roles in modulating myocyte devel-
opment, myocardial angiogenesis, and fetal heart remodeling [16, 17].
Immediately after birth, however, patterns of substrate utilization switch to
FAO. This switch to fatty acid utilization over carbohydrates enhances the efficiency
of myocardial ATP production, a pattern that is largely sustained throughout adult
life [18]. However, myocardial metabolism remains capable of late adaptations that
allow switches in substrate utilization. Mechanisms generally involve the “Randle
Cycle,” in which FAO attenuates glucose oxidation via feedback inhibition to adapt
myocardial metabolism to different forms of nutrient supply with injury or stress
[19–21].
This normal metabolic switch at birth accompanies the expression of “adult”
isoforms of metabolic enzymes and other proteins. However, in diverse conditions,
such as hypoxia, ischemia, hypertrophy, atrophy, diabetes, and hypothyroidism, the
postnatal heart may revert to the “fetal” gene program [14, 21]. These adaptive
mechanisms are also a feature of failing heart muscle, where at a certain point, this
fetal-like reprogramming no longer suffices to support cardiac structure and func-
tion. Metabolic regulation in the postnatal heart likely plays a critical role mediating
gene expression in response to stress, which potentially protects the stressed myo-
cardium from severe functional impairment and apoptosis. That is, with stress due to
ischemia, pressure or volume overload, the RV adjusts metabolic function to switch
its preferential substrate from fatty acids to carbohydrates. As glucose metabolism

requires less oxygen consumption for an equivalent amount of ATP generation, this
is likely a successful adaptive strategy. However, long-term dependence on glucose
utilization for ATP generation is not efficient and can lead to energy starvation and
cardiac failure [22]. These events may be mediated by long-term changes in regula-
tion of critical “fetal genes,” such as protein kinase C epsilon, heat shock protein 70,
and endothelial nitric oxide synthase (eNOS), which can predispose the developing
heart to increased susceptibility to injury and induce myocardial dysfunction [21].
With aging, physiologic suppression of glucose oxidation by fatty acids is altered,
with greater dependence on glucose metabolism and relatively less FA use [23].
Importantly, decreased RV fatty acid uptake and oxidation has been demonstrated
by PET studies in humans with pulmonary hypertension [24].
The partial pressure of oxygen in the blood entering the RV is significantly lower
than the blood entering the LV, by virtue of the fact the oxygen-rich blood returning
from the placenta is directed through the widely patent FO by the Eustachian valve.
This distribution of fetal blood flow maximizes oxygen delivery to the brain and
coronary circulations in utero and protects against hypoxic injury [25]. Myocardial
oxygen consumption studies showed no difference between fetal and adult sheep
[13], suggesting that the fetal RV has relatively higher myocardial blood flow. Other
experiments in which myocardial blood flow was measured in fetal lambs showed
greater oxygen delivery to the RV free wall, as compared to the LV free wall [26].
The right side of the ventricular septum receives more coronary flow than the left
side in utero, which is reversed in the adult [26]. This pattern reflects the RV’s role
as the dominant functional ventricle in utero, with higher oxygen utilization.
Although physiologically normal, the low oxygen tensions in the healthy fetus
are necessary for normal cardiac development, yet a further drop in oxygen tension
due to intrauterine stress readily becomes pathologic and mediates harmful effects
that cause myocardial injury and severe dysfunction during the neonatal transition
as in PPHN. Perinatal hypoxia causes marked LV and RV dysfunction with sus-
tained pulmonary hypertension after birth, which can masquerade as “primary” pul-
monary vascular disease [5].
In addition, prenatal events can alter gene expression patterns in fetal hearts and
related signaling patterns that may increase susceptibility for adult disease, known as
“Barker’s Hypothesis.” [27]. For example, myocardial growth, function, and gene
regulation may be persistently altered by prolonged intrauterine hypoxia, hemody-
namic stress, inflammation or nutritional deficits. This concept of persistent disease
after disruptions of normal fetal programming, largely through epigenetic mecha-
nisms, has recently been supported in a study of young adults who were prematurely
born [28]. In this study, RV structure and function were quantified by magnetic reso-
nance imaging in preterm-born young adults and compared with term controls. RV
ventricular end diastolic volume was significantly smaller and RV mass increased in
former preterm adults [28]. In addition to changes in myocardial structure, RV ejec-
tion fraction (RVEF) and systolic function remained lower in the preterm population,
demonstrating a persistent impact on the RV, long after the perinatal events related to
premature birth. These findings were more striking than was previously observed in
assessments of LV structure and performance in these patient groups [29].
Fetal RV Structure
The fetal myocardium differs from that of the postnatal heart in several important
ways, shown in Table 3.1. Electron micrographs (Fig. 3.3) of the fetal myocardium
show smaller myocytes and a greater proportion of “non-contractile mass,” consist-
ing of nuclei, mitochondria, and cell membranes [12]. In fact, only 30 % of the fetal
myocardium contains contractile mass in contrast to 60 % in the adult [12]. The
diameter of fetal cardiomyocytes is only 5–7 μm, whereas adult myocytes are much
larger, roughly 15–25 μm [30]. The increase in muscle mass during gestation is
almost exclusively the result of an increase in cell numbers [30]. Fetal myocardial
nuclei are large and polyploidy is unusual. In the early gestation fetus, the longitu-
dinal orientation of the sarcomeres is more random, but the fibers become more
parallel as the fetus nears term [1–3, 12]. Evidence from studies of human fetuses
suggests that the LV and RV grow at the same rate [2, 31]. The fetal heart grows by
rapid cardiomyocyte proliferation early on in gestation, but then loses the ability to
Fig. 3.3 Electron

micrographs illustrating
change in myocardial
structure illustrating smaller
myocytes with larger
non-contractile mass of the
fetus (upper panel) in
comparison with the postnatal
myocardium (lower panel).
(From Smolich et al. [46])
propagate with further myocyte differentiation during late gestation. The fetal heart
responds to stress with hypertrophy of existing cardiac cells, unlike the adult cardio-
myocyte, which is in a more differentiated state and has less ability to divide.
Fetal RV Function
Preload
With regard to preload, the fetal heart operates at the upper limit of the Starling
curve (Fig. 3.4). Studies in fetal lambs have shown that a 10 % decrease in blood
volume decreases CO, whereas a 10 % increase in volume elevates atrial pressures
without changing the CO [4–6, 32, 33]. Data from animal studies have clearly dem-
onstrated that the fetal RV has a higher resting tension than the adult RV, indicating
lower ventricular compliance in utero [1–3, 12, 34]. This inability to tolerate addi-
tional preload, where even small increases in intravascular volume may dramatically
increase central venous pressure, may lead to congestive heart failure and hydrops
fetalis; this is characterized by pleural effusions, anasarca, and high perinatal mor-
tality. Interventricular interactions between the fetal RV and LV are also particularly
striking, as even small changes in LV pressure reduce RV preload [7, 8, 12].
Afterload
In utero, the RV ejects blood into the pulmonary trunk, which trifurcates into the left and
right pulmonary arteries and the ductus arteriosus (DA) (Fig. 3.5). Most of the RV output
crosses the ductus arteriosus due to high PVR, and the RV serves both the pulmonary
Fig. 3.4 Differences in the relationship between filling pressure and stroke volume in the fetal and
adult right ventricles. As shown, stroke volume is markedly increased for a given right atrial pres-
sure in the adult when compared with the fetal RV. (Adapted from Rychik J et al., [35])
Normal
PH
PVR
Fetus Birth Neonate Infant

Qp
Fetus Birth Neonate Infant
Fig. 3.5 Schematic illustrating perinatal changes in pulmonary vascular resistance and blood flow
in normal and PPHN infants. (Adapted from Rudolph AM, 2004)
and systemic circulations. The aortic isthmus, the section of the aorta between the left
subclavian artery and the insertion of the DA, is narrower than the descending aorta,
which functionally separates the two circulations to a small extent [8, 9]. RV and LV
wall thickness are approximately equivalent in utero, resulting in a greater wall thickness
to radius ratio for the RV. According to La Place’s law, this results in greater RV wall
stress [10, 11, 35], and causes greater sensitivity to changes in afterload [12, 13, 36].
Due to the widely patent DA, the fetal RV is more affected by increased systemic
vascular resistance than high PVR. Acute elevations of fetal systemic blood pres-
sure reduce RV stroke volume [16, 17, 37]. Sustained elevation of systemic arterial
pressure causes striking RVH, pulmonary hypertensive vascular disease, and RV
failure in severe cases. Thus, increased fetal PVR increases the risk for PPHN at
birth, but is not sufficient in itself to cause RVH or RV failure in utero, without
associated hemodynamic stress (e.g., closure of the DA or systemic hypertension
[18, 38, 39]. Banding of the pulmonary artery (see also Chaps. 5 and 22) in fetal
sheep to simulate pulmonary stenosis causes striking RVH. Over time, some fetuses
develop a large, dilated tricuspid valve and RV, whereas others develop a hypoplastic
right AV valve and ventricle [19–21, 30]. Factors determining which pathway (RVH
or dilation with an underdeveloped RV) is followed remain uncertain.
Contractility and Cardiac Output
Contractility of the fetal heart is less than that of the adult myocardium at similar
muscle lengths [12, 14, 21]. Isometric force development, including the extent and
velocity of shortening at any load, are reduced in the fetus when compared to the
adult [12, 22]. This is partly due to structural immaturity of the myocardium, from
fewer sarcomeres and the lack of parallel orientation of myofibrils. Calcium man-
agement is impaired in fetal cardiomyocytes due to maturational differences in the
t-tubule system of the sarcoplasmic reticulum (SR) [21, 40]. Isolated fetal vesicles
with SR have a 60 % decrease in active accumulation of calcium, lower calcium
pump protein expression, and activity [23, 40]. Decreased sympathetic innervation
of the fetal heart and variability in adrenergic receptors also reduce fetal myocardial
contractility [8, 24]. Human RV output in utero is 1.2–1.5 times that of the LV, rep-
resenting 60–70 % of CVO [25, 35]. At 20 weeks gestation, ovine pulmonary blood
flow is around 13 % of the CVO, which increases to 20 % by 30 weeks [13, 41].
Cardiac MRI has recently been used to quantify pulmonary blood flow and oxygen
saturation in human fetuses, and these results have been consistent with past studies
[26, 42]. Flow patterns in the branch pulmonary arteries are very characteristic in
the fetus, consisting of a short period of forward flow (first third of systole), fol-
lowed by backflow, which extends throughout the remainder of systole into diastole
[8, 26]. This deflection, known as the peak early diastolic reversed flow, is due to
reflection of the pressure wave generated by the RV when it encounters high resis-
tance in the pulmonary vascular bed [5, 43] (see also Chap. 4).
RV Transition and Postnatal Adaptation at Birth
Within minutes after delivery, pulmonary artery pressure falls and blood flow
increases in response to birth-related stimuli. Mechanisms contributing to the fall in
PVR at birth include establishment of an air–liquid interface, rhythmic lung disten-
sion, increased oxygen tension, and altered production of vasoactive substances.
Physical stimuli, such as increased shear stress, ventilation and increased oxygen,
cause pulmonary vasodilation in part by increasing production of vasodilators, NO
and prostacyclin (PgI2). Pretreatment with the arginine analogue, nitro-L-arginine,
blocks NOS activity, and attenuates the decline in PVR after delivery of near term
fetal lambs [27, 44]. These findings suggested that about 50 % of the rise in pulmo-
nary blood flow at birth might be directly related to the acute release of NO. Specific
mechanisms that cause NO release at birth include the marked rise in shear stress,
increased oxygen, and ventilation. Increased PaO2 triggers NO release, which aug-
ments vasodilation through cGMP kinase-mediated stimulation of K+-channels [1,
28]. Other vasodilator products, including PgI2, also modulate changes in pulmo-
nary vascular tone at birth. Rhythmic lung distension and shear stress stimulate both
PgI2 and NO production in the late gestation fetus, but increased O2 tension triggers
NO activity and overcomes the effects of prostaglandin inhibition at birth.
Changes in tone of the ductus arteriosus (DA) also play a major role in the transi-
tion at birth. Since most of RV output crosses the DA in utero, patency of the DA is
absolutely vital for fetal survival and well-being. Premature DA closure in utero
causes severe pulmonary hypertension, congestive heart failure, hydrops fetalis,
or severe hypoxemia. In contrast, an inability of the DA to close after birth may
complicate lung disease in the premature newborn with respiratory distress
syndrome or cause high-flow pulmonary vascular injury during postnatal life.

In addition, maintaining DA patency can be critical for survival in newborns and
infants with ductus—dependent cyanotic congenital heart disease. Finally, insights
into the unique nature of regulation of the DA, especially with regard to smooth
muscle cell tone, proliferation, and synthetic functions, may provide important les-
sons in vascular biology. For example, changes in oxygen tension have striking
effects on DA smooth muscle that are unique and differ from its neighboring smooth
muscle cells in systemic (aortic) and pulmonary circulations. Low PO2 constricts
pulmonary vessels but dilates the DA. The increase in PO2 contributes to the fall in
PVR at birth but paradoxically constricts the DA.
In addition to this fall in PVR, one of the most important hemodynamic changes
influencing the RV results from removal of the placenta from the systemic circula-
tion due to clamping the umbilical cord. The DA remains open early, which aug-
ments pulmonary blood flow due to predominant left-to-right shunting into the lung,
due to elevated systemic arterial pressure along with the fall in PVR. As the DA
closes, the RV ejects solely into the pulmonary arterial tree.
Neonatal RV Structure
After the normal transition, progressive reduction of RV mass follows the progres-
sive and sustained reduction of PVR with closure of “fetal channels,” especially the
DA, summarized in Table 3.1. With the fall in PVR, RV work decreases and RV
mass progressively decreases [45]. Conversely, the left ventricle becomes larger and
thicker-walled as a result of increased systemic vascular resistance [46]. Interestingly,
there is a disproportionate rate of change of chamber size and wall thickness post-
natally between the two ventricles. The LV becomes larger and thicker-walled faster
than the RV wall thickness falls [12, 45]. In a rat model, there is a 61 % greater
proliferation of myocytes in the LV than RV during the first 5 days of life [12, 47].
As opposed to the fetal myocardium, in which myocyte numbers increase without
changes in size, neonatal myocyte diameter increases markedly in the week after
birth [12, 46]. The capability of the RV to perform work is dependent on its blood
supply which more rapidly increases in the LV than the RV [30, 48].
Neonatal RV Function
Preload
Reflecting structural changes in the RV after the transition, RV compliance increases as

its wall thins in response to reduced afterload. In the early newborn period, the RV has
similar compliance characteristics as the fetal RV [12, 30], which are relatively higher
than adult RV compliance. At all ages, the RV is more compliant than the LV [12].
Over the ensuing weeks, both RV wall thickness and compliance continue to morph
into the adult pattern. As a result of progressive increase in RV compliance, the new-
born heart is better equipped to tolerate additional volume with an increase in CO when
compared to the fetus, and the volume-induced increase continues with age. Infusion
of isotonic fluid in newborn sheep caused a marked increase in CO at 6-week-old
lambs in contrast with minimal changes at 1 week [49].
Afterload
After DA closure, the neonatal RV ejects solely into the pulmonary vascular bed;
thus, RV afterload is dictated solely by PVR as in the adult circulation. PA pressures
were measured in neonatal dogs and goats, confirming that RV pressures approxi-
mate LV pressure on the first day of life, but rapidly decrease to nearly half-systemic
levels over the first day of life [7]. Subsequently, there was a slower decrease over
the following 5–6 weeks, eventually reaching adult pressures. Even modest chronic
hypoxia or high flow due to anatomic shunt lesions with congenital heart disease
significantly slows this maturational decline in PVR and RV remodeling [7].
Along with abrupt pulmonary vasodilation at birth, the pulmonary arteries
undergo an immediate reorganization of the vessel wall, with endothelial flattening
and stretching of the smooth muscle layer [50]. During the early postnatal period,
the ratio of medial wall thickness to the external diameter progressively falls [25].
A concurrent increase in lung arterial and microvascular proliferation occurs in par-
allel with the growth of new lung units, markedly increasing the perfused surface
area and further reducing PVR [25, 51].
Ventriculo-arterial coupling of the RV to the pulmonary arterial tree differs in
important ways from coupling of the LV and aorta. Coupling refers to end-sys-
tolic RV elastance (Ees) divided by the pulmonary arterial elastance (Ea); this
ratio is obtained by constructing pressure–volume loops and varying the preload
and contractility of the myocardium (see Chap. 2). The Windkessel properties of
the aorta, the ability of the walls to expand and recoil, results in very efficient
energy transfer. Conversely, the short, proximal large vessels of the pulmonary
arterial tree are responsible for the finding that a significant (30–40 %) amount of
the energy is not converted into flow [52]. Current data on the maturational
changes of RV-PA coupling during development and in childhood pulmonary
vascular diseases are limited.
Contractility and Cardiac Output
As discussed above, fetal and newborn RV compliance are similar in the initial
hours to days after birth, which means that additional preload will not significantly
augment CO, and that newborn infants are primarily reliant on heart rate in order
to increase CO, especially with acute stress. When adjusted for afterload, LV
contractility is highest in neonatal humans and sheep, but undergoes a progressive

decrease over the first several years of life [53]. Similar studies in the neonatal RV
have not been performed. In the immediate postnatal period, there is a small decrease
in RV output (30 %) and a small increase in LV output (25 %), resulting in no net
change in CO [8]. This increase in LV output may be related to the increased meta-
bolic requirement of maintaining body temperature [8]. During the first postnatal
week, LV output doubles but then declines over the next 6 weeks [49]. This increase
in CO is partly related to an increase in beta-adrenergic stimulation [54].
Neonatal RV Metabolism
Oxygen consumption per unit weight of myocardium is similar in fetal and adult
hearts, but slightly higher in neonates. Myocardial oxygen consumption is propor-
tional to stroke work, which is equal the area bounded by the pressure volume loop.
RV stroke work drops rapidly due to the decrease in output and PVR at birth [26].
Notably, coronary venous blood, which can be readily used to measure LV oxygen
consumption as the LV drains to the coronary sinus, cannot be measured from the
RV, as it drains directly into the cardiac chambers via the thebesian veins. It is not
clear how quickly after birth the predominant fuel source shifts from carbohydrate
to fatty acids as the primary energetic substrate occurs [8]. In comparing fetal and
early neonatal sheep, gestational age-related differences were not found in the
efficiency of myocardial ATP production or mitochondrial function [12].
RV Function in PPHN and Failure of Transition After Birth
PPHN is a clinical syndrome that is characterized by the failure to achieve or sustain

the normal decline in PVR at birth leading to right-to-left extra-pulmonary shunting
of blood across the patent DA or FO and profound hypoxemia. PPHN may be asso-
ciated with diverse cardiopulmonary disorders such as meconium aspiration, sepsis,
pneumonia, asphyxia, congenital diaphragmatic hernia, respiratory distress syn-
drome, and others. Echocardiographic signs such as increased RV dilation, RVH,
and septal flattening are suggestive of PPHN, but evident of predominantly right-to-
left extra-pulmonary shunt is pathognomonic of PPHN. When severe LV dysfunc-
tion accompanies pulmonary hypertension, pulmonary vasodilation alone may be
ineffective in improving oxygenation, and must be accompanied by targeted thera-
pies to increase cardiac performance and decrease LV afterload. Systemic hemody-
namic variables should be optimized with volume and “cardiotonic” therapy
(dobutamine, dopamine, and milrinone), in order to enhance CO and systemic O2
transport. Systemic hypotension may worsen right-to-left shunting, impair oxygen
delivery, and worsen gas exchange in patients with parenchymal lung disease.
Significant RV dysfunction may occur in PPHN when the RV is forced to eject

solely into the high resistance pulmonary vascular bed [55]. As the RV of the fetus
and young neonate exhibits a high degree of sensitivity to afterload [36], this
approach should be used with caution, and accompanied by careful longitudinal
assessment of biventricular function. Clinically, the assessment of neonatal RV wall
thickness, chamber size, and systolic function remains largely qualitative. Several
attempts have been made at characterizing RV performance in the setting of PPHN,
and estimates of RVEF in preterm neonates with PPHN have shown significantly
decreased RVEF [56]. In Infants who fail to respond to medical management, as
evidenced by failure to sustain improvement in oxygenation with good hemody-
namic function, may require treatment with extracorporeal membrane oxygenation.
Inhaled nitric oxide (iNO) therapy (5–20 ppm) improves oxygenation and decreases
the need for ECMO therapy in patients with diverse causes of PPHN [57, 58]. In the
setting of severe RV failure with poor responsiveness to pulmonary vasodilator
therapy and low CO, the initiation of prostaglandin E1 (PgE1) infusion to maintain
patency of the DA has been used to sustain CO while tolerating hypoxemia.
Conclusions
Rapid changes during the fetal-neonataltransition, including the striking rise in

oxygen tension, drop in PVR, removal of the placenta from the systemic circulation
with elevation of SVR, closure of “fetal channels” dramatically alter metabolic and
functional demands on the RV at birth. Successful adaptation to postnatal life is
further associated with progressive changes in RV structure, function and metabo-
lism that evolve into the adult phenotype, which includes thinning of the RV free
wall, thickening of the LV, and functional changes in RV compliance and responses
to loading conditions. Disruption of the normal transition due to adverse perinatal
events can alter the RV transition at birth, as in diseases associated with
PPHN. Finally, greater insight about birth-related changes and mechanisms under-
lying fetal programming may enhance our understanding of adaptive and maladap-
tive responses of the RV in adult onset pulmonary hypertension.
References
1. Rudolph AM. Fetal and neonatal pulmonary circulation. Annu Rev Physiol. 1979;41(1):
383–95.
2. Gao Y, Raj JU. Regulation of the pulmonary circulation in the fetus and newborn. Physiol Rev.
2010;90(4):1291–335.
3. Heymann MA, Soifer SJ. Control of fetal and neonatal pulmonary circulation. In: Weir EK,
Reeves JT, editors. Pulmonary vascular physiology and pathophysiology. New York: Dekker;
1989. p. 33–50.
4. Levin DL, Heymann MA, Kitterman JA, Gregory GA, Phibbs RH, Rudolph AM. Persistent
pulmonary hypertension of the newborn infant. J Pediatr. 1976;89(4):626–30.
5. Abman SH, Kinsella JP. Inhaled nitric oxide for persistent pulmonary hypertension of the
newborn: the physiology matters! Pediatrics. 1995;96(6):1153–5.
6. Geggel RL, Reid LM. The structural basis of PPHN. Clin Perinatol. 1984;11(3):525–49.
7. Rudolph AM. The changes in the circulation after birth. Their importance in congenital heart
disease. Circulation. 1970;41(2):343–59.
8. Rudolph A. Congenital diseases of the heart. 3rd ed. San Francisco, CA: Wiley; 2011.
9. Patterson AJ, Zhang L. Hypoxia and fetal heart development. Curr Mol Med. 2010;10(7):653.
10. Cavasin MA, Demos-Davies K, Horn TR, Walker LA, Lemon DD, Birdsey N, et al. Selective
class I histone deacetylase inhibition suppresses hypoxia-induced cardiopulmonary remodel-
ing through an antiproliferative mechanism. Circ Res. 2012;110(5):739–48.
11. Archer SL, Marsboom G, Kim GH, Zhang HJ, Toth PT, Svensson EC, et al. Epigenetic attenu-
ation of mitochondrial superoxide dismutase 2 in pulmonary arterial hypertension: a basis for
excessive cell proliferation and a new therapeutic target. Circulation. 2010;121(24):2661–71.
12. Friedman WF. The intrinsic physiologic properties of the developing heart. Prog Cardiovasc
Dis. 1972;15(1):87–111.
13. Fisher DJ, Heymann MA, Rudolph AM. Myocardial oxygen and carbohydrate consumption in
fetal lambs in utero and in adult sheep. Am J Physiol. 1980;238(3):H399–405.
14. Taegtmeyer H, Sen S, Vela D. Return to the fetal gene program. Ann N Y Acad Sci.
2010;1188(1):191–8.
15. Ascuitto RJ, Ross-Ascuitto NT. Substrate metabolism in the developing heart. Semin Perinatol.
1996;20(6):542–63.
16. Compernolle V, Brusselmans K, Franco D, Moorman A, Dewerchin M, Collen D, et al. Cardia
bifida, defective heart development and abnormal neural crest migration in embryos lacking
hypoxia-inducible factor-1alpha. Cardiovasc Res. 2003;60(3):569–79.
17. Sugishita Y, Leifer DW, Agani F, Watanabe M, Fisher SA. Hypoxia-responsive signaling regu-
lates the apoptosis-dependent remodeling of the embryonic avian cardiac outflow tract. Dev
Biol. 2004;273(2):285–96.
18. Fisher SA, Burggren WW. Role of hypoxia in the evolution and development of the cardiovas-
cular system. Antioxid Redox Signal. 2007;9(9):1339–52.
19. Hue L, Taegtmeyer H. The Randle cycle revisited: a new head for an old hat. Am J Physiol
Endocrinol Metab. 2009;297(3):E578–91.
20. Randle PJ, Garland PB, Hales CN, Newsholme EA. The glucose fatty-acid cycle. Its role in
insulin sensitivity and the metabolic disturbances of diabetes mellitus. Lancet. 1963;1(7285):
785–9.
21. Altin SE, Schulze PC. Metabolism of the right ventricle and the response to hypertrophy and
failure. Prog Cardiovasc Dis. 2012;55(2):229–33.
22. Razeghi P, Young ME, Alcorn JL, Moravec CS, Frazier OH, Taegtmeyer H. Metabolic gene
expression in fetal and failing human heart. Circulation. 2001;104(24):2923–31.
23. Kates AM, Herrero P, Dence C, Soto P, Srinivasan M, Delano DG, et al. Impact of aging on
substrate metabolism by the human heart. J Am Coll Cardiol. 2003;41(2):293–9.
24. Can MM, Kaymaz C, Tanboga IH, Tokgoz HC, Canpolat N, Turkyilmaz E, et al. Increased
right ventricular glucose metabolism in patients with pulmonary arterial hypertension. Clin
Nucl Med. 2011;36(9):743–8.
25. Rudolph AM. High pulmonary vascular resistance after birth: I. Pathophysiologic consider-
ations and etiologic classification. Clin Pediatr. 1980;19(9):585–90.
26. Fisher DJ, Heymann MA, Rudolph AM. Regional myocardial blood flow and oxygen delivery
in fetal, newborn, and adult sheep. Am J Physiol. 1982;243(5):H729–31.
27. Barker DJ, Osmond C. Infant mortality, childhood nutrition, and ischaemic heart disease in
England and Wales. Lancet. 1986;1(8489):1077–81.
28. Lewandowski AJ, Bradlow WM, Augustine D, Davis EF, Francis J, Singhal A, et al. Right
ventricular systolic dysfunction in young adults born preterm. Circulation. 2013;128(7):713–20.
29. Lewandowski AJ, Augustine D, Lamata P, Davis EF, Lazdam M, Francis J, et al. Preterm heart
in adult life: cardiovascular magnetic resonance reveals distinct differences in left ventricular
mass, geometry, and function. Circulation. 2013;127(2):197–206.
30. Rudolph AM. Myocardial growth before and after birth: clinical implications. Acta Paediatr.
2007;89(2):129–33.
31. St John Sutton MG, Raichlen JS, Reichek N, Huff DS. Quantitative assessment of right and
left ventricular growth in the human fetal heart: a pathoanatomic study. Circulation. 1984;
70(6):935–41.
32. Thornburg KL, Morton MJ. Filling and arterial pressures as determinants of left ventricular
stroke volume in fetal lambs. Am J Physiol. 1986;251(5 Pt 2):H961–8.
33. Gilbert RD. Control of fetal cardiac output during changes in blood volume. Am J Physiol.
1980;238(1):H80–6.
34. Romero T, Covell J, Friedman WF. A comparison of pressure-volume relations of the fetal,
newborn, and adult heart. Am J Physiol. 1972;222(5):1285–90.
35. Rychik J. Fetal cardiovascular physiology. Pediatr Cardiol. 2004;25(3):201–9.
36. Reller MD, Morton MJ, Reid DL, Thornburg KL. Fetal lamb ventricles respond differently to
filling and arterial pressures and to in utero ventilation. Pediatr Res. 1987;22(6):621–6.
37. Thornburg KL, Morton MJ. Filling and arterial pressures as determinants of RV stroke volume
in the sheep fetus. Am J Physiol. 1983;244(5):H656–63.
38. Levin DL, Hyman AI, Heymann MA, Rudolph AM. Fetal hypertension and the development
of increased pulmonary vascular smooth muscle: a possible mechanism for persistent pulmo-
nary hypertension of the newborn infant. J Pediatr. 1978;92(2):265–9.
39. Abman SH, Shanley PF, Accurso FJ. Failure of postnatal adaptation of the pulmonary circula-
tion after chronic intrauterine pulmonary hypertension in fetal lambs. J Clin Invest. 1989;
83(6):1849–58.
40. Mahony L, Jones LR. Developmental changes in cardiac sarcoplasmic reticulum in sheep.
J Biol Chem. 1986;261(32):15257–65.
41. Rasanen J, Wood DC, Debbs RH, Cohen J, Weiner S, Huhta JC. Reactivity of the human fetal
pulmonary circulation to maternal hyperoxygenation increases during the second half of preg-
nancy: a randomized study. Circulation. 1998;97(3):257–62.
42. Seed M, van Amerom JFP, Yoo S-J, Nafisi Al B, Grosse-Wortmann L, Jaeggi E, et al. Feasibility
of quantification of the distribution of blood flow in the normal human fetal circulation using
CMR: a cross-sectional study. J Cardiovasc Magn Reson. 2012;14:79.
43. Grant DA, Hollander E, Skuza EM, Fauchère JC. Interactions between the right ventricle and
pulmonary vasculature in the fetus. J Appl Physiol. 1999;87(5):1637–43.
44. Abman SH, Chatfield BA, Hall SL, McMurtry IF. Role of endothelium-derived relaxing factor
during transition of pulmonary circulation at birth. Am J Physiol. 1990;259(6 Pt 2):H1921–7.
45. Joyce JJ, Dickson PI, Qi N, Noble JE, Raj JU, Baylen BG. Normal right and left ventricular
mass development during early infancy. Am J Cardiol. 2004;93(6):797–801.
46. Smolich JJ, Walker AM, Campbell GR, Adamson TM. Left and right ventricular myocardial
morphometry in fetal, neonatal, and adult sheep. Am J Physiol. 1989;257(1 Pt 2):H1–9.
47. Anversa P, Olivetti G, Loud AV. Morphometric study of early postnatal development in the left
and right ventricular myocardium of the rat. I. Hypertrophy, hyperplasia, and binucleation of
myocytes. Circ Res. 1980;46(4):495–502.
48. Olivetti G, Anversa P, Loud AV. Morphometric study of early postnatal development in the left
and right ventricular myocardium of the rat. II. Tissue composition, capillary growth, and sar-
coplasmic alterations. Circ Res. 1980;46(4):503–12.
49. Klopfenstein HS, Rudolph AM. Postnatal changes in the circulation and responses to volume
loading in sheep. Circ Res. 1978;42(6):839–45.
50. Haworth SG, Hislop AA. Effect of hypoxia on adaptation of the pulmonary circulation to
extra-uterine life in the pig. Cardiovasc Res. 1982;16(6):293–303.
51. Hislop A, Reid L. Intra-pulmonary arterial development during fetal life-branching pattern and
structure. J Anat. 1972;113(Pt 1):35.
52. Chin KM, Coghlan G. Characterizing the right ventricle: advancing our knowledge. Am J
Cardiol. 2012;110(6 Suppl):3S–8S.
53. Kimball TR, Daniels SR, Khoury P, Meyer RA. Age-related variation in contractility estimate
in patients less than or equal to 20 years of age. Am J Cardiol. 1991;68(13):1383–7.
54. Teitel DF, Sidi D, Chin T, Brett C, Heymann MA, Rudolph AM. Developmental changes in
myocardial contractile reserve in the lamb. Pediatr Res. 1985;19(9):948–55.
55. Danhaive O, Margossian R, Geva T, Kourembanas S. Pulmonary hypertension and right
ventricular dysfunction in growth-restricted, extremely low birth weight neonates. J Perinatol.
2005;25(7):495–9.
56. Koestenberger M, Nagel B, Ravekes W, Urlesberger B, Raith W, Avian A, et al. Systolic
right ventricular function in preterm and term neonates: reference values of the tricuspid
annular plane systolic excursion (TAPSE) in 258 patients and calculation of Z-score values.
Neonatology. 2011;100(1):85–92.
57. Kinsella JP, Neish SR, Shaffer E, Abman SH. Low dose inhalational nitric oxide therapy in
PPHN. Lancet. 1992;340:819–20.
58. Roberts JD, Polaner DM, Lang P, Zapol WM. Inhaled NO in PPHN. Lancet. 1992;340:818–9.
Chapter 4
Advanced Imaging of the Right Ventricle
Titus Küehne
Overview of CMR Methods for the Study

of RV Form and Function
CMR offers several imaging methods that are used in clinical routine and research
for the assessment of the RV. State-of-the-art clinical methods and emerging tools
that form part of current research are briefly described in this section.
Cine CMR for Analysis of RV Pump Function and Beyond
Cine CMR is one of the most frequently used methods for the quantitative assess-
ment of phasic RV volumes and muscle mass. In addition, cine MRI provides the
data that can be used in more sophisticated postprocessing methods: similar to tis-
sue Doppler echocardiography, feature tracking allows to measure myocardial
deformation. In addition cine MRI data can be used for computing pressure–volume
relations or they form the anatomical boarders for intraventricular flow analysis or
electro-biomechanical modeling.
Cine MRI of RV anatomy and function is acquired in a relatively well-
standardized multiphase multisclice approach with typically 25 phases per cardiac
cycle and slice thickness of 8 mm in adults and 6 mm in the young [1, 2]. Current
research focuses on the acquisition of ventricular volumes and mass using fast 3D
techniques that can acquire all information within one single breathold [3, 4].
T. Küehne, M.D., Ph.D. (*)

Department of Pediatric Cardiology/Congenital Heart Disease, Charité—Berlin
and German Heart Institute Berlin, Augustenburger Platz 1, Berlin 13353, Germany
e-mail: Kuehne@dhzb.de

58 T. Küehne
The current technical standard for cine CMR is steady state free precession pulse
sequences that can be applied using 1.5 and modern 3.0 T scanners [5–7]. At 3.0 T,
care must be taken to avoid artifacts, because increased susceptibility and B0-field
inhomogeneity at higher field strengths such as 7.0 T broaden the sensibility to
off-resonance [5]. On the other hand, high field strengths yield the promises to
noninvasively study myocardial anatomy at a microscopic scale.
Phase Contrast CMR for Arterial and Intraventricular

Blood Flow Analysis
Blood flow analysis conventionally focused on the blood flow within arterial or
venous vasculature. Novel methods that will be detailed below allow to study blood
flow within the heart chambers (Fig. 4.1). MRI assessment of blood flow is based on
phase-contrast or “velocity encoding” techniques (VEC CMR).
Fig. 4.1 Representative intraventricular blood flow profiles of the right (RV) and left ventricle
(LV) at diastole and systole in a healthy control. The main trajectories of blood flow are indicated
4 Advanced Imaging of the Right Ventricle 59
In RV disease, one of the most frequent clinical applications of VEC MRI is the
assessment of RV volume or pressure overload due to valve dysfunction (regurgitant
fraction), pressure gradients, or shunt volumes. The current gold standard is to
measure blood flow through one single 2D plane; this can be measured using 1.5
and 3.0 T scanners [8, 9]. 2D VEC CMR was shown in various studies to be a
robust tool to quantify blood flow velocity profiles and derived volumes yielding
low inter- and intraobserver as well as low inter-study variability [2, 8, 10]. Flow
measurements can be performed during a breathold or even in real time [11, 12].
However, the accuracy of VEC MRI has several technical limitations. These
include, amongst others, spin dephasing in chaotic turbulent flow [13, 14]. The
method’s reliability can be impacted in vessel segments with local chaotic flow, for
example, due to vessel narrowing [15, 16]. A limited spatial resolution can restrict
its use in small moving vessels like the coronary arteries. In addition, the assess-
ment of pressure gradients using the simplified Bernoulli equation can induce
errors, because this equation can only be applied, like in Doppler echocardiography,
to nonviscous fluids. Only the convective and transient effects can be considered but
not the viscous loss and turbulent ones. Because the pressure drop in stenotic vessel
segments is mainly affected by the momentum loss due to vortex formation behind
a stenosis, it is well resolved by the Pressure-Poisson equation.
Recently, four-dimensional flow applications (4D VEC CMRI) that measure
flow velocities in a three-dimensional volume were introduced and validated [17,
18]. The validity of 4D compared to 2D VEC CMR for measuring quantitative flow
was shown [19, 20]. The theoretical advantages of 4D versus 2D VEC CMR are
manifold because flow analysis in the areas of interest is done during postprocess-
ing. Therefore, time consuming and sometimes error prone selection of 2D image
planes is omitted [19, 21]. In addition, velocity profiles are measured in all three
dimensions which enables us to derive a multitude of new parameters like relative
pressure-maps or wall-shear stress {Markl, 2010 #3} [22–24].
In addition, the analysis of 4D blood flow opens new doors for the noninvasive
assessment of pressure fields (maps) [17, 25]. This method provides time-resolved
blood flow velocities in a three-dimensional volume that can cover the entire heart
and great arteries. From these velocity fields, dynamic pressure differences can be
computed by solving the Pressure-Poisson equation [25].
Fig. 4.1 (continued) by the arrows and there are important differences between the RV and
LV. The filling of the LV resembles the filling of a wine glass, where during RV filling the majority
of blood is directed towards the outflow tract. Filling patterns and associated loss of kinetic energy
are substantial in disease (see other figures)
60 T. Küehne
Lt-Gd-Enhancement, T1-Mapping, and T1/T2 for the Study

of Fibrotic Tissue, Inflammation, or Fat Infiltrates
The late gadolinium enhancement (LGE) approach is based on impaired washout of

extracellular contrast agents from areas with focal myocardial fibrosis. This method
has been originally developed for visualization of scars in ischemic heart diseases;
however, it has been extended to many other applications. In the pressure over-
loaded RV, LGE is observed in ventricular insertion points, particularly in advanced
cases of pulmonary hypertension [26]. The extent of hyperenhancement is related to
the right ventricular systolic dysfunction [27, 28]. In PHT, the extent of delayed
enhancement of myocardial mass is related to right ventricular dysfunction corre-
lated with worse right ventricular function and hemodynamics. Other studies also
found hyperenhancement in patients with Tetralogy of Fallot, however, without
clear clinical correlation [29, 30]. However, LGE does not allow quantitative assess-
ment and misses diffuse fibrotic processes. Therefore, alternative methods like
T1-mapping were developed that use parametric strategies to also detect and quan-
tify diffuse fibrosis [31–34] (Fig. 4.2). The assessment of RV fibrosis may provide
prognostic information, however this remains to be studied in great detail.
T2 or combined T2/T1 weighted imaging (STIR) are sensitive to water and
therefore allow the identification of increased water content, of myocardial edema,
for example, in the setting of myocarditis [35]. The extent of edema can correlate
with the clinical state and can be of prognostic value [36]. In addition, these tech-
niques are of value for the study of cardiomyopathies [37]. T1 or T2 weighted
images in combination with fat-suppression techniques are also part of the CMR
criteria which characterize RV dysplasia [38].
Fig. 4.2 Diffuse fibrosis of the myocardium as visualized and quantified by T1-mapping
techniques
CMR Feature Tracking, Tissue Maps, and Tagging

for Measuring Tissue Deformation and Regional Wall Motion
In analogy to tissues Doppler echocardiography, CMR techniques allow us to

measure the amount and/or velocities of myocardial tissue deformation (strain and
strain rate, respectively). Their derivate are considered parameters of myocardial
performance and diastolic relaxation. Compared to tissue Doppler, all CMR meth-
ods are limited by low temporal resolution but have the large advantage of operator
independency and comprehensive 3D assessment. By CMR, tissue deformation and
regional wall motion can be measured by the following techniques: Feature tracking
is a postprocessing method, comparable to Doppler spackle tracking, that can be
performed using conventional cine MR images as they are acquired during most
CMR routine studies [39–41]. This method is appealing because it does not require
additional scanning. Other methods, require extra dedicated scanning, are CMR
Tagging or phase-contrast based tissue maps [42–45]. 3D Tagging techniques are
independent of morphology and operator [46]. Newer techniques have been devel-
oped to allow single heartbeat assessment of RV strain [47].
MR Spectroscopy: A Research Tool for Imaging Cell Metabolism
Impaired high-energy phosphate metabolism may play a critical role in the patho-
genesis of RV failure due to PAH. However, due to technical and sensitivity reasons,
the use of 31P-MR spectroscopy to characterize the energy metabolism of the right
ventricle in the human heart does not yet play a significant role [48]. Higher field
strength and improved techniques may in the future allow MR spectroscopy to play
a role in the assessment of patients and their response to therapies. With the latest
advancements in 3 T and even 7 T MR technology, multi-voxel spectroscopic
(chemical shift) imaging of phosphorous metabolites for the right ventricle comes
into reach. This would allow us to investigate cellular energy metabolism and clarify
some of the pathophysiologic mechanisms which underlie the different phenotypes
of right ventricular dysfunction and failure. The evaluation of metabolic pathways is
also the subject of the nuclear medicine techniques described in Chap. 13.
Angiography, 3DWH, and Diffusion-Tensor Imaging

for the Assessment of Anatomy at a Macro-
and Microscopic Scale
MR angiography and 3D whole heart (3DWH) imaging are widely used in the clini-
cal routine to define the anatomy of the RV and the thoracic vessels. The latter tech-
nique does not require contrast media. This is of interest because in patients with
renal failure gadolinium based contrast media can induce nephrogenic systemic
62 T. Küehne
Fig. 4.3 Three-

dimensional reconstruction
of intraventricular anatomy
based on 3DWH MR
imaging method. Shown is a
Swiss-cheese VSD seen
from the left ventricle
fibrosis, which appears to occur with a lower incidence in children [49]. MR angiog-
raphy is a fast and precise method for visualizing the pulmonary vasculature. 3DWH
is more time consuming but provides also information about the intracardiac anat-
omy, including the proximal coronary artery; this is particularly important when
planning percutaneous pulmonary valve replacement. 3DWH also offers the oppor-
tunity to visualize a complex anatomy in the form of virtual or printed cast models
that can be of value for the planning of surgical treatment (Fig. 4.3) [50].
Diffusion-tensor imaging allows us to visualize and quantify the 3D architecture
of myocyte chains (fibers) (Fig. 4.4). This non-destructive method offers unique
opportunities to study the biomechanical properties of the ventricles [51]. Recent
studies showed that the RV lacks the extensive zone of circular myocytes seen in the
mid-portion of the left ventricular walls. Without such structural support, the right
ventricle is ill equipped to sustain a permanent increase in afterload [52]. Because
of its long image acquisition time, DTI cannot be applied in the beating heart. Still,
this method is valuable for studying the pathophysiology of the RV.
Image Based Modeling
Image based modeling methods have an enormous potential. Pushed to their present
limits they can be useful when it comes to testing patient-specific treatment strategies,
simulating the evolution of the disease and predicting the outcome of catheter
Fig. 4.4 Diffuse tensor MR images (DTI) of an ex vivo murine heart (top-down view). The aggre-
gated myocytes (“fibers”) are visualized for the left and right ventricle. The right panels show the
course of a bundle of selected aggregates through the myocardium (seen from top-down). DTI is
not suited for in vivo imaging but it provides valuable information that are essential to understand
the biomechanical adaptation of the RV to overload conditions. This information can be then used
and integrated into electro-biomechanical models of the heart allowing simulation of pathophysi-
ologically important conditions (right panel; Courtesy Gernot Planck, University of Graz, Austria)
intervention, surgery, or the response to personalized pharmacological treatment [53].

For these reasons, modeling methods have been developed in the past for multi-bio-
logical scales. Biomedical models focus on the simulation of processes at the omics
level, the level of cell physiology or tissue metabolism. All these models are still
subject to basic research. In contrast, Imaging based models have already reached a
level of maturity and advanced them from a purely experimental stage of research to
first clinical applications.
In this context, CMR provides the high quality quantitative information of anat-
omy and function that are required for accurate and robust modeling. These models
allow to simulate myocardial deformation (using electro-biomechanical principles,
Fig. 4.4) [54, 55], blood flow (by applying computational fluid dynamics, Figs. 4.5
and 4.6) [56–58], or ventricular pressures and volumes (by applying lumped-
parameter models) [59, 60]. One of the current important innovations is the applica-
tion of computational fluid dynamics in congenital heart disease. First human
studies showed their great potential to simulate and predict energy loss of blood
flow in the Fontan circulation (see Chap. 8) or the pressure drop across the stenosis
in aortic coarctation before and after intervention (Fig. 4.5) [60–62]. The same prin-
ciples of simulation before treatment planning are applied in current research to the
pulmonary artery system (Fig. 4.6). Thus, image based modeling opens new ave-
nues where imaging transcends a purely diagnostic method and becomes a tool to
simulate disease pathways, plan patient-specific treatment strategies and predict
their hemodynamic outcome. Future research will have to validate these methods,
and prove that the use of these methods and tools improves outcome.
64 T. Küehne
Fig. 4.5 The figure shows the principles of blood flow simulations in a patient with aortic coarc-
tation. Large panels: computational fluid dynamic based simulation of blood profiles before, at
virtual stent placement, and after real treatment. Small panels: anatomy and the position of virtual
stents (red color). Such simulation allows to test the best type of treatment that results in optimum
flow profiles
Differential Analysis of RV Form and Function by CMR
RV Systolic Pump Function at Rest and During Stress
Despite enormous progress in quantitative echocardiography CMR is still consid-

ered the gold standard for the assessment of RV systolic pump function. Low inter-
study variability makes CMR reliable for follow-up studies [1, 2, 63–65]; however,
CMR is not the preferred tool for serial assessment in short intervals due to limita-
tions in costs and availability.
Cine CMR and VEC CMR based pediatric normative percentile values of biven-
tricular and biatrial pump function became recently available [66–68]. Several stud-
ies have defined thresholds for RV dilation due to valve insufficiency in Tetralogy
of Fallot. New research highlights gender differences in the response of the RV to
pressure and volume overload in children and adolescents [69, 70]. In addition,
there is growing evidence that the RV should not be assessed in isolation but a func-
tional assessment should include its subcompartments (inflow, trabecular-apical,
and outflow tract). This is of great clinical importance because the different compo-
nents contribute differently to RV remodeling and dysfunction [30, 51].
Fig. 4.6 Image and flow based modeling of pulmonary blood flow and wall shear stress of virtual
stenting and pulmonary valve replacement. The simulation indicated that the existing pressure gradient
could be slightly decreased, however, due to the geometric constellation without improving blood flow
volumes through the right pulmonary artery. The predicted values were confirmed after treatment
Systolic pump function analysis of the RV and LV is conventionally performed

based on short-axis cine CMR views. More recent reports propose a strict transverse
(axial) imaging plane, particularly when the study is focused on the RV [2, 71, 72].
If standardized protocols are used for image acquisition, the inter-study variability
was reported to be low, no matter whether images were acquired in short-axis or
transverse planes [2, 51, 64, 65, 73–75]. In contrast, intraobserver and interobserver
variability are an important source of error that must be considered for the compari-
son with follow-up studies [1, 2, 73].
Systolic pump function and their reference values are based on measurements at
rest. Recent reports, however, point out that the functional reserve (ability to increase
stroke volumes under stress) can be a marker of disease progression [76]. In CMR,
assessment of the functional reserve can be done by including a pharmacological
stress with dobutamine [77, 78].
66 T. Küehne
RV Diastolic Function
The role of LV diastolic dysfunction in heart failure has been investigated and is
now appreciated. However, there is about a paucity of data regarding the contribu-
tion of RV diastolic dysfunction to failure. Several studies have observed RV stiff-
ening in the pressure overloaded RV [79–81], but in contrast to the straight forward
analysis of systolic pump function, the assessment of diastolic function requires a
much more sophisticated approach. Time–volume relations of the cardiac chambers
that can be obtained from cine MRI or blood flow measurements are suitable to
study the interplay between atrial, ventricular, and pulmonary function during ven-
tricular filling [79, 80]. In addition, after surgery, pericardial scars seem to impor-
tantly impact RV filling [82].
The analysis of time–volume curves is cumbersome and not recommended for
clinical use. Intrinsic parameters of myocardial relaxation can be determined by
end-diastolic pressure–volume relations using the same CMR approaches as
described in the section below. In addition, the assessment of diastolic strain-rates
by CMR feature tracking, tissue phase mapping, or tagging is feasible. However,
when it comes to diastolic function analysis these methods are limited due to the
relatively low temporal resolution of CMR compared to tissue Doppler techniques.
A surrogate of diastolic dysfunction may be the extent of myocardial fibrosis.
Novel T1-mapping techniques can quantify the degree of diffuse fibrosis. This
method is also described in more detail below.
RV Performance Beyond Pump Function
Tissue deformation: Myocardial strain and strain rates can be measured by cine
CMR based feature tracking, myocardial Tagging, or tissue phase maps [39–46]. In
experimental models and in patients with RV pressure overload due to PAH, global
and regional RV strain is reduced already during the early adaptive period, presum-
ably due to hypertrophy of the RV wall [44, 47].
Pressure–volume relations: The gold standard measurements which describe ven-
tricular function and myocardial performance are the end-systolic and end-diastolic
pressure–volume relations. For research purposes such relations can be determined
by conductance or impedance catheters which measure ventricular volumes and
pressures simultaneously {Baan, 1992 #38} [83]. However, the accuracy of the RV
studies with these catheters is limited because they require a symmetrically shaped
ventricular cavity studies for volume measurements. As an alternative, CMR guided
catheterization makes use of invasive pressure measurements and combined with
cine CMR derived ventricular volumes [84, 85]. From such data end-systolic pres-
sure–volume relationships can be computed and myocardial contractility as well as
diastolic compliance can be obtained. Different CMR methods have been introduced
and validated; they either alter ventricular loading or are based on estimations from
a single steady-state beat [12, 84–87]. Other concepts, that may facilitate clinical
use, are fully noninvasive approximations [88, 89] or combined pressure–volume
measurements by real-time 3D echocardiography [90].
Kinetic energy: As stated above, pressure–volume relations are well established and
assess RV work load and the efficiency of the mechanical work. However, this
approach neglects important energy losses when the ventricle pumps blood into the
arterial system. During diastolic filling blood enters the ventricular chambers with a
given amount of kinetic energy. In the healthy heart, the intraventricular blood pro-
files show characteristic patterns that allow the blood to keep its momentum during
systolic ejection (Fig. 4.7). In this case, the energy loss due to uncontrolled vortex
formation is minimal. However, in the presence of valve disease local turbulence
occurs which changes the characteristic intraventricular blood flow patterns.
Moreover, in the dilated ventricle, vortex formations cause a significant loss of the
kinetic energy which makes up an important part of the total energy consumed by
the blood pumping heart (Fig. 4.7) [91–93]. The energetic efficiency is therefore
directly determined by pressure load, chamber size, and blood flow kinetics.
This should be kept in mind when designing a treatment plan in order to prevent
the transition from compensated RV dysfunction to frank failure.
Fig. 4.7 The graphs show representative RV time–volume curve (time normalized), blood flow
kinetic energy (KE) curves (in mJ) of a healthy control, and a patient with Tetralogy of Fallot. The
patient had dilated RV due to pulmonary regurgitation (PR). There is substantial increase of energy
loss in the diseased RV. The left panels show color coded 4D flow velocities during mid-diastole
and early systole measured by velocity-encoded MRI. High velocities (red color) represent high
kinetic energy of the flowing blood. The images illustrate nicely that in the patient there are high
kinetic energies due to pulmonary insufficiency. In addition, the mobilized kinetic energy at sys-
tole is much higher than in the control
68 T. Küehne
RV Tissue Characterization (Including Focal and Diffuse

Fibrosis) and Perfusion
CMR is regarded as the reference method for noninvasive evaluation of myocardial

tissue properties. Given the current MR technology, in-plane resolution ranges from
1.0 × 1.0 to 2.0 × 2.0 mm2. Reliable tissue analysis requires a structure width of at
least three pixels, translating into a minimal wall thickness of 3–6 mm depending on
the MR technique to be used. While these conditions are not always met in normal
right ventricles or dilated right ventricular disease, such as ARVD (see Chap. 16),
right ventricular hypertrophy caused by pressure overload leads to wall diameters
that are in the majority of patients sufficient for tissue analysis.
One of the most intriguing aspects of CMR tissue analysis in the context of the
pressure overload (pulmonary stenosis or PAH) is its ability to detect myocardial
fibrosis. The late gadolinium enhancement (LGE) approach allows qualitative
visualization of scars but is missing diffuse myocardial fibrosis. Extensive animal
and human research is ongoing to develop and apply T1-mapping methods to study
the presence and functional impact of diffuse fibrosis on the ventricular function
[32–34].
Adenosine stress perfusion MRI has been successfully used to quantify myocar-
dial perfusion reserve (MPR) which is a significantly reduced in sclerodermia
patients with PAH as compared to scleroderma patients without PAH [94].
Pulmonary Vascular Function
Improved knowledge of pulmonary vascular function is an essential part of the

work-up of RV function. Quantitative blood flow volumes can be obtained using 2D
or 4D VEC MRI (see above). These flow volume data provide quantitative informa-
tion about pulmonary perfusion, left–right lung perfusion mismatch, intracardiac
shunt volumes or collateral flow through aorto-pulmonary or veno-venous collater-
als [21, 95–98]. Perfusion and shunt volumes can be determined for baseline condi-
tions. In addition, their response to pharmacologically induced changes, such as
selective pulmonary vascular dilators, can be determined [99, 100].
The pulmonary arteries in PAH are characterized by typical morphological
changes and the size and growth of the pulmonary arteries can be determined by cine
CMR or MR angiography. In patients with Fontan circulation, impaired growth of
the pulmonary arteries despite normal somatic growth has been demonstrated [101].
The combination of pulmonary flow volumes combined with invasive pressure
data permits us to calculate the pulmonary vascular resistance. While thermodilution
based measurements are known to have limited reproducibility in the presence of RV
dysfunction, oxymetry is time consuming and invasive as repeated catheter manipu-
lations are required. In addition, the presence of shunt and collateral flow provide
only estimate data. As an alternative, MRI guided catheterization was introduced
and validated for simultaneous assessment of VEC MRI flow and invasive pressures
[99, 100]. Current directions go to combine MRI flow with sequentially obtained
pressures from right heart catheterization [102]. The time window should be small
and physiologic condition (e.g. volume loading) similar between the two studies. An
estimate of pulmonary resistance may also be noninvasively derived from MRI flow
measurements [103].
The distensibility of given pulmonary vascular segments is the difference in the
vessel cross-sectional area during diastole and systole and can be measured by
Echocardiography or cine MRI. Combining distensibility with flow derived param-
eters allows the calculation of vascular compliance or stiffness, a parameter that has
been shown to predict mortality in PAH [104]. This approach uses pulse wave
velocities that are either based on the transit time of flow or the flow area [105]. The
assessment of total pulmonary vascular compliance is a valuable and more global
index of pulmonary vascular function that requires assessment of high fidelity inva-
sive pulse pressures [106].
References
1. Luijnenburg SE, Robbers-Visser D, Moelker A, Vliegen HW, Mulder BJ, Helbing WA.
Intra-observer and interobserver variability of biventricular function, volumes and mass in
patients with congenital heart disease measured by CMR imaging. Int J Cardiovasc Imaging.
2010;26:57–64.
2. Beerbaum P, Barth P, Kropf S, Sarikouch S, Kelter-Kloepping A, Franke D, Gutberlet M,
Kuehne T. Cardiac function by MRI in congenital heart disease: impact of consensus training
on interinstitutional variance. J Magn Reson Imaging. 2009;30:956–66.
3. Jahnke C, Nagel E, Gebker R, Bornstedt A, Schnackenburg B, Kozerke S, Fleck E, Paetsch
I. Four-dimensional single breathhold magnetic resonance imaging using kt-BLAST enables
reliable assessment of left- and right-ventricular volumes and mass. J Magn Reson Imaging.
2007;25:737–42.
4. Parish V, Hussain T, Beerbaum P, Greil G, Nagel E, Razavi R, Schaeffter T, Uribe S. Single
breath-hold assessment of ventricular volumes using 32-channel coil technology and an
extracellular contrast agent. J Magn Reson Imaging. 2010;31:838–44.
5. Lee HL, Shankaranarayanan A, Pohost GM, Nayak KS. Improved 3-tesla cardiac cine
imaging using wideband. Magn Reson Med. 2010;63:1716–22.
6. Moon JC, Lorenz CH, Francis JM, Smith GC, Pennell DJ. Breath-hold flash and fisp cardio-
vascular MR imaging: left ventricular volume differences and reproducibility. Radiology.
2002;223:789–97.
7. Schar M, Kozerke S, Fischer SE, Boesiger P. Cardiac SSFP imaging at 3 tesla. Magn Reson
Med. 2004;51:799–806.
8. Kilner PJ, Gatehouse PD, Firmin DN. Flow measurement by magnetic resonance: a unique
asset worth optimising. J Cardiovasc Magn Reson. 2007;9:723–8.
9. Lotz J, Doker R, Noeske R, Schuttert M, Felix R, Galanski M, Gutberlet M, Meyer GP. In
vitro validation of phase-contrast flow measurements at 3 t in comparison to 1.5 t: precision,
accuracy, and signal-to-noise ratios. J Magn Reson Imaging. 2005;21:604–10.
10. Powell AJ, Maier SE, Chung T, Geva T. Phase-velocity cine magnetic resonance imaging
measurement of pulsatile blood flow in children and young adults: in vitro and in vivo
validation. Pediatr Cardiol. 2000;21:104–10.
70 T. Küehne
11. Korperich H, Gieseke J, Barth P, Hoogeveen R, Esdorn H, Peterschroder A, Meyer H,

Beerbaum P. Flow volume and shunt quantification in pediatric congenital heart disease by
real-time magnetic resonance velocity mapping: a validation study. Circulation. 2004;109:
1987–93.
12. Schmitt B, Steendijk P, Ovroutski S, Lunze K, Rahmanzadeh P, Maarouf N, Ewert P, Berger
F, Kuehne T. Pulmonary vascular resistance, collateral flow, and ventricular function in
patients with a Fontan circulation at rest and during dobutamine stress. Circ Cardiovasc
Imaging. 2010;3:623–31.
13. Gatehouse PD, Rolf MP, Graves MJ, Hofman MB, Totman J, Werner B, Quest RA, Liu Y, von
Spiczak J, Dieringer M, Firmin DN, van Rossum A, Lombardi M, Schwitter J, Schulz-
Menger J, Kilner PJ. Flow measurement by cardiovascular magnetic resonance: a multi-
centre multi-vendor study of background phase offset errors that can compromise the
accuracy of derived regurgitant or shunt flow measurements. J Cardiovasc Magn Reson.
2010;12:5.
14. Markl M, Bammer R, Alley MT, Elkins CJ, Draney MT, Barnett A, Moseley ME, Glover GH,
Pelc NJ. Generalized reconstruction of phase contrast MRI: analysis and correction of the
effect of gradient field distortions. Magn Reson Med. 2003;50:791–801.
15. Stahlberg F, Sondergaard L, Thomsen C, Henriksen O. Quantification of complex flow using
MR phase imaging—a study of parameters influencing the phase/velocity relation. Magn
Reson Imaging. 1992;10:13–23.
16. O’Brien KR, Cowan BR, Jain M, Stewart RA, Kerr AJ, Young AA. MRI phase contrast veloc-
ity and flow errors in turbulent stenotic jets. J Magn Reson Imaging. 2008;28:210–8.
17. Markl M, Draney MT, Hope MD, Levin JM, Chan FP, Alley MT, Pelc NJ, Herfkens RJ. Time-
resolved 3-dimensional velocity mapping in the thoracic aorta: visualization of 3-directional
blood flow patterns in healthy volunteers and patients. J Comput Assist Tomogr. 2004;28:
459–68.
18. Markl M, Harloff A, Bley TA, Zaitsev M, Jung B, Weigang E, Langer M, Hennig J,
Frydrychowicz A. Time-resolved 3d MR velocity mapping at 3t: improved navigator-gated
assessment of vascular anatomy and blood flow. J Magn Reson Imaging. 2007;25:824–31.
19. Nordmeyer S, Riesenkampff E, Crelier G, Khasheei A, Schnackenburg B, Berger F, Kuehne
T. Flow-sensitive four-dimensional cine magnetic resonance imaging for offline blood flow
quantification in multiple vessels: a validation study. J Magn Reson Imaging. 2010;32:
677–83.
20. Stalder AF, Russe MF, Frydrychowicz A, Bock J, Hennig J, Markl M. Quantitative 2d and 3d
phase contrast MRI: optimized analysis of blood flow and vessel wall parameters. Magn
Reson Med. 2008;60:1218–31.
21. Valverde I, Rachel C, Kuehne T, Beerbaum P. Comprehensive four-dimensional phase-
contrast flow assessment in hemi-Fontan circulation: systemic-to-pulmonary collateral flow
quantification. Cardiol Young. 2011;21:116–9.
22. Ebbers T, Farneback G. Improving computation of cardiovascular relative pressure fields
from velocity MRI. J Magn Reson Imaging. 2009;30:54–61.
23. Frydrychowicz A, Stalder AF, Russe MF, Bock J, Bauer S, Harloff A, Berger A, Langer M,
Hennig J, Markl M. Three-dimensional analysis of segmental wall shear stress in the aorta by
flow-sensitive four-dimensional-MRI. J Magn Reson Imaging. 2009;30:77–84.
24. Harloff A, Nussbaumer A, Bauer S, Stalder AF, Frydrychowicz A, Weiller C, Hennig J, Markl
M. In vivo assessment of wall shear stress in the atherosclerotic aorta using flow-sensitive 4d
MRI. Magn Reson Med. 2010;63:1529–36.
25. Krittian SB, Lamata P, Michler C, Nordsletten DA, Bock J, Bradley CP, Pitcher A, Kilner PJ,
Markl M, Smith NP. A finite-element approach to the direct computation of relative cardiovas-
cular pressure from time-resolved MR velocity data. Med Image Anal. 2012;16:1029–37.
26. Shehata ML, Lossnitzer D, Skrok J, Boyce D, Lechtzin N, Mathai SC, Girgis RE, Osman N,
Lima JA, Bluemke DA, Hassoun PM, Vogel-Claussen J. Myocardial delayed enhancement in
pulmonary hypertension: pulmonary hemodynamics, right ventricular function, and remodel-
ing. AJR Am J Roentgenol. 2011;196:87–94.
27. Blyth KG, Groenning BA, Martin TN, Foster JE, Mark PB, Dargie HJ, Peacock AJ. Contrast
enhanced-cardiovascular magnetic resonance imaging in patients with pulmonary hyperten-
sion. Eur Heart J. 2005;26:1993–9.
28. McCann GP, Gan CT, Beek AM, Niessen HW, Vonk Noordegraaf A, van Rossum AC. Extent
of MRI delayed enhancement of myocardial mass is related to right ventricular dysfunction
in pulmonary artery hypertension. AJR Am J Roentgenol. 2007;188:349–55.
29. Park SJ, On YK, Kim JS, Park SW, Yang JH, Jun TG, Kang IS, Lee HJ, Choe YH, Huh
J. Relation of fragmented QRS complex to right ventricular fibrosis detected by late gado-
linium enhancement cardiac magnetic resonance in adults with repaired tetralogy of fallot.
Am J Cardiol. 2012;109:110–5.
30. Wald RM, Haber I, Wald R, Valente AM, Powell AJ, Geva T. Effects of regional dysfunction
and late gadolinium enhancement on global right ventricular function and exercise capacity
in patients with repaired tetralogy of fallot. Circulation. 2009;119:1370–7.
31. Broberg CS, Chugh SS, Conklin C, Sahn DJ, Jerosch-Herold M. Quantification of diffuse
myocardial fibrosis and its association with myocardial dysfunction in congenital heart dis-
ease. Circ Cardiovasc Imaging. 2010;3:727–34.
32. Messroghli D, Nordmeyer S, Dietrich T, Dirsch O, Kaschina E, Savvatis K, D OHI, Klein C,
Berger F, Kuehne T. Assessment of diffuse myocardial fibrosis in rats using small animal look-
locker inversion recovery (salli) t1 mapping. Circ Cardiovasc Imaging. 2011;4(6):636–40.
33. Messroghli DR, Radjenovic A, Kozerke S, Higgins DM, Sivananthan MU, Ridgway
JP. Modified look-locker inversion recovery (molli) for high-resolution t1 mapping of the
heart. Magn Reson Med. 2004;52:141–6.
34. Flett AS, Hayward MP, Ashworth MT, Hansen MS, Taylor AM, Elliott PM, McGregor C,
Moon JC. Equilibrium contrast cardiovascular magnetic resonance for the measurement of
diffuse myocardial fibrosis: preliminary validation in humans. Circulation. 2010;122:138–44.
35. D Oh-I, Ridgway JP, Kuehne T, Berger F, Plein S, Sivananthan M, Messroghli
DR. Cardiovascular magnetic resonance of myocardial edema using a short inversion time
inversion recovery (stir) black-blood technique: Diagnostic accuracy of visual and semi-
quantitative assessment. J Cardiovasc Magn Reson. 2012;14:22
36. Davis KL, Mehlhorn U, Laine GA, Allen SJ. Myocardial edema, left ventricular function,
and pulmonary hypertension. J Appl Physiol (1985). 1995;78:132–7.
37. Masci PG, Schuurman R, Andrea B, Ripoli A, Coceani M, Chiappino S, Todiere G, Srebot V,
Passino C, Aquaro GD, Emdin M, Lombardi M. Myocardial fibrosis as a key determinant of
left ventricular remodeling in idiopathic dilated cardiomyopathy: a contrast-enhanced cardio-
vascular magnetic study. Circ Cardiovasc Imaging. 2013;6:790–9.
38. Quarta G, Husain SI, Flett AS, Sado DM, Chao CY, Tome Esteban MT, McKenna WJ,
Pantazis A, Moon JC. Arrhythmogenic right ventricular cardiomyopathy mimics: role of car-
diovascular magnetic resonance. J Cardiovasc Magn Reson. 2013;15:16.
39. Morton G, Schuster A, Jogiya R, Kutty S, Beerbaum P, Nagel E. Inter-study reproducibility
of cardiovascular magnetic resonance myocardial feature tracking. J Cardiovasc Magn
Reson. 2012;14:43.
40. Schuster A, Kutty S, Padiyath A, Parish V, Gribben P, Danford DA, Makowski MR, Bigalke
B, Beerbaum P, Nagel E. Cardiovascular magnetic resonance myocardial feature tracking
detects quantitative wall motion during dobutamine stress. J Cardiovasc Magn Reson.
2011;13:58.
41. Harrild DM, Han Y, Geva T, Zhou J, Marcus E, Powell AJ. Comparison of cardiac MRI tissue
tracking and myocardial tagging for assessment of regional ventricular strain. Int J Cardiovasc
Imaging. 2012;28:2009–18.
42. Kvitting JP, Ebbers T, Engvall J, Sutherland GR, Wranne B, Wigstrom L. Three-directional
myocardial motion assessed using 3d phase contrast MRI. J Cardiovasc Magn Reson.
2004;6:627–36.
43. Codreanu I, Robson MD, Golding SJ, Jung BA, Clarke K, Holloway CJ. Longitudinally and
circumferentially directed movements of the left ventricle studied by cardiovascular mag-
netic resonance phase contrast velocity mapping. J Cardiovasc Magn Reson. 2010;12:48.
72 T. Küehne
44. Voeller RK, Aziz A, Maniar HS, Ufere NN. Taggar AK. Bernabe NJ: Jr., Cupps BP, Moon
MR. Altered right ventricular strain and right atrial function in mild versus severe right
ventricular pressure overload. Am J Physiol Heart Circ Physiol; 2011.
45. Shehata ML, Cheng S, Osman NF, Bluemke DA, Lima JA. Myocardial tissue tagging with
cardiovascular magnetic resonance. J Cardiovasc Magn Reson. 2009;11:55.
46. Rutz AK, Ryf S, Plein S, Boesiger P, Kozerke S. Accelerated whole-heart 3d CSPAMM for
myocardial motion quantification. Magn Reson Med. 2008;59:755–63.
47. Shehata ML, Basha TA, Tantawy WH, Lima JA, Vogel-Claussen J, Bluemke DA, Hassoun
PM, Osman NF. Real-time single-heartbeat fast strain-encoded imaging of right ventricular
regional function: normal versus chronic pulmonary hypertension. Magn Reson Med.
2010;64:98–106.
48. Spindler M, Schmidt M, Geier O, Sandstede J, Hahn D, Ertl G, Beer M. Functional and meta-
bolic recovery of the right ventricle during bosentan therapy in idiopathic pulmonary arterial
hypertension. J Cardiovasc Magn Reson. 2005;7:853–4.
49. Nardone B, Saddleton E, Laumann AE, Edwards BJ, Raisch DW, McKoy JM, Belknap SM,
Bull C, Haryani A, Cowper SE, Abu-Alfa AK, Miller FH, Godinez-Puig V, Dharnidharka
VR, West DP. Pediatric nephrogenic systemic fibrosis is rarely reported: a radar report.
Pediatr Radiol. 2014;44(2):173–80.
50. Riesenkampff E, Rietdorf U, Wolf I, Schnackenburg B, Ewert P, Huebler M, Alexi-
Meskishvili V, Anderson RH, Engel N, Meinzer HP, Hetzer R, Berger F, Kuehne T. The
practical clinical value of three-dimensional models of complex congenitally malformed
hearts. J Thorac Cardiovasc Surg. 2009;138:571–80.
51. Bodhey NK, Beerbaum P, Sarikouch S, Kropf S, Lange P, Berger F, Anderson RH, Kuehne
T. Functional analysis of the components of the right ventricle in the setting of tetralogy of
fallot. Circ Cardiovasc Imaging. 2008;1:141–7.
52. Nielsen E, Smerup M, Agger P, Frandsen J, Ringgard S, Pedersen M, Vestergaard P,
Nyengaard JR, Andersen JB, Lunkenheimer PP, Anderson RH, Hjortdal V. Normal right ven-
tricular three-dimensional architecture, as assessed with diffusion tensor magnetic resonance
imaging, is preserved during experimentally induced right ventricular hypertrophy. Anat Rec
(Hoboken). 2009;292:640–51.
53. Smith N, de Vecchi A, McCormick M, Nordsletten D, Camara O, Frangi AF, Delingette H,
Sermesant M, Relan J, Ayache N, Krueger MW, Schulze WH, Hose R, Valverde I, Beerbaum
P, Staicu C, Siebes M, Spaan J, Hunter P, Weese J, Lehmann H, Chapelle D, Rezavi
R. Euheart: personalized and integrated cardiac care using patient-specific cardiovascular
modelling. Interface Focus. 2011;1:349–64.
54. Niederer SA, Lamata P, Plank G, Chinchapatnam P, Ginks M, Rhode K, Rinaldi CA, Razavi
R, Smith NP. Analyses of the redistribution of work following cardiac resynchronisation
therapy in a patient specific model. PLoS One. 2012;7:e43504.
55. Weese J, Groth A, Nickisch H, Barschdorf H, Weber FM, Velut J, Castro M, Toumoulin C,
Coatrieux JL, De Craene M, Piella G, Tobon-Gomez C. Frangi AF. Valverde I, Shi Y, Staicu
C, Brown A, Beerbaum P, Hose DR. Generating anatomical models of the heart and the aorta
from medical images for personalized physiological simulations. Med Biol Eng Comput:
Barber DC; 2013.
56. Goubergrits L, Mevert R, Yevtushenko P, Schaller J, Kertzscher U, Meier S, Schubert S,
Riesenkampff E. Kuehne T. Ann Biomed Eng: The impact of MRI-based inflow for the
hemodynamic evaluation of aortic coarctation; 2013.
57. Wendell DC, Samyn MM, Cava JR, Ellwein LM, Krolikowski MM, Gandy KL, Pelech AN,
Shadden SC, LaDisa Jr JF. Including aortic valve morphology in computational fluid dynam-
ics simulations: initial findings and application to aortic coarctation. Med Eng Phys.
2013;35:723–35.
58. LaDisa Jr JF, Dholakia RJ, Figueroa CA, Vignon-Clementel IE, Chan FP, Samyn MM, Cava
JR, Taylor CA, Feinstein JA. Computational simulations demonstrate altered wall shear
stress in aortic coarctation patients treated by resection with end-to-end anastomosis.
Congenit Heart Dis. 2011;6:432–43.
59. Bhattacharya-Ghosh B, Schievano S, Diaz-Zuccarini V. A multi-physics and multi-scale

lumped parameter model of cardiac contraction of the left ventricle: a conceptual model from
the protein to the organ scale. Comput Biol Med. 2012;42:982–92.
60. Coogan JS, Chan FP, Taylor CA, Feinstein JA. Computational fluid dynamic simulations of
aortic coarctation comparing the effects of surgical- and stent-based treatments on aortic
compliance and ventricular workload. Catheter Cardiovasc Interv. 2011;77:680–91.
61. LaDisa Jr JF, Alberto Figueroa C, Vignon-Clementel IE, Kim HJ, Xiao N, Ellwein LM, Chan
FP, Feinstein JA, Taylor CA. Computational simulations for aortic coarctation: representative
results from a sampling of patients. J Biomech Eng. 2011;133:091008.
62. Haggerty CM, de Zelicourt DA, Restrepo M, Rossignac J, Spray TL, Kanter KR, Fogel MA,
Yoganathan AP. Comparing pre- and post-operative Fontan hemodynamic simulations:
implications for the reliability of surgical planning. Ann Biomed Eng. 2012;40:2639–51.
63. Winter MM, Bernink FJ, Groenink M, Bouma BJ, van Dijk AP, Helbing WA, Tijssen JG,
Mulder BJ. Evaluating the systemic right ventricle by CMR: the importance of consistent and
reproducible delineation of the cavity. J Cardiovasc Magn Reson. 2008;10:40.
64. Catalano O, Antonaci S, Opasich C, Moro G, Mussida M, Perotti M, Calsamiglia G, Frascaroli
M, Baldi M, Cobelli F. Intra-observer and interobserver reproducibility of right ventricle
volumes, function and mass by cardiac magnetic resonance. J Cardiovasc Med (Hagerstown).
2007;8:807–14.
65. Grothues F, Moon JC, Bellenger NG, Smith GS, Klein HU, Pennell DJ. Interstudy reproduc-
ibility of right ventricular volumes, function, and mass with cardiovascular magnetic reso-
nance. Am Heart J. 2004;147:218–23.
66. Sarikouch S, Koerperich H, Boethig D, Peters B, Lotz J, Gutberlet M, Beerbaum P, Kuehne
T. Reference values for atrial size and function in children and young adults by cardiac MR:
a study of the German competence network congenital heart defects. J Magn Reson Imaging.
2011;33:1028–39.
67. Sarikouch S, Peters B, Gutberlet M, Leismann B, Kelter-Kloepping A, Koerperich H, Kuehne
T, Beerbaum P. Sex-specific pediatric percentiles for ventricular size and mass as reference
values for cardiac MRI: assessment by steady-state free-precession and phase-contrast MRI
flow. Circ Cardiovasc Imaging. 2010;3:65–76.
68. Robbers-Visser D, Boersma E, Helbing WA. Normal biventricular function, volumes, and
mass in children aged 8 to 17 years. J Magn Reson Imaging. 2009;29:552–9.
69. Sarikouch S, Boethig D, Peters B, Kropf S, Dubowy KO, Lange P, Kuehne T, Haverich A,
Beerbaum P. Poorer right ventricular systolic function and exercise capacity in females after
repair of tetralogy of fallot: A gender comparison of standard deviation scores based on sex-
specific reference values in healthy controls. Imaging: Circ Cardiovasc; 2013.
70. Sarikouch S, Koerperich H, Dubowy KO, Boethig D, Boettler P, Mir TS, Peters B, Kuehne T,
Beerbaum P. Impact of gender and age on cardiovascular function late after repair of tetralogy of
fallot: percentiles based on cardiac magnetic resonance. Circ Cardiovasc Imaging. 2011;4:703–11.
71. Alfakih K, Plein S, Bloomer T, Jones T, Ridgway J, Sivananthan M. Comparison of right
ventricular volume measurements between axial and short axis orientation using steady-state
free precession magnetic resonance imaging. J Magn Reson Imaging. 2003;18:25–32.
72. Fratz S, Schuhbaeck A, Buchner C, Busch R, Meierhofer C, Martinoff S, Hess J, Stern
H. Comparison of accuracy of axial slices versus short-axis slices for measuring ventricular
volumes by cardiac magnetic resonance in patients with corrected tetralogy of fallot. Am J
Cardiol. 2009;103:1764–9.
73. Danilouchkine MG, Westenberg JJ, de Roos A, Reiber JH, Lelieveldt BP. Operator induced
variability in cardiovascular MR: left ventricular measurements and their reproducibility.
J Cardiovasc Magn Reson. 2005;7:447–57.
74. Karamitsos TD, Hudsmith LE, Selvanayagam JB, Neubauer S, Francis JM. Operator induced
variability in left ventricular measurements with cardiovascular magnetic resonance is
improved after training. J Cardiovasc Magn Reson. 2007;9:777–83.
75. Mooij CF, de Wit CJ, Graham DA, Powell AJ, Geva T. Reproducibility of MRI measurements
of right ventricular size and function in patients with normal and dilated ventricles. J Magn
Reson Imaging. 2008;28:67–73.
74 T. Küehne
76. Luijnenburg SE, Mekic S, van den Berg J, van der Geest RJ, Moelker A, Roos-Hesselink JW,
Bogers AJ, de Rijke YB, Strengers JL, Mulder BJ, Vliegen HW, Helbing WA. Ventricular
response to dobutamine stress relates to the change in peak oxygen uptake during the 5-year
follow-up in young patients with repaired tetralogy of fallot. Imaging: Eur Heart J Cardiovasc;
2013.
77. Parish V, Valverde I, Kutty S, Head C, Qureshi SA, Sarikouch S, Greil G, Schaeffter T, Razavi
R, Beerbaum P. Dobutamine stress MRI in repaired tetralogy of fallot with chronic pulmo-
nary regurgitation: a comparison with healthy volunteers. Int J Cardiol. 2013; 166:96–105.
78. Valverde I, Parish V, Tzifa A, Head C, Sarikouch S, Greil G, Schaeffter T, Razavi R, Beerbaum
P. Cardiovascular MR dobutamine stress in adult tetralogy of fallot: disparity between CMR
volumetry and flow for cardiovascular function. J Magn Reson Imaging. 2011;33:1341–50.
79. Riesenkampff E, Mengelkamp L, Mueller M, Kropf S, Abdul-Khaliq H, Sarikouch S,
Beerbaum P, Hetzer R, Steendijk P, Berger F, Kuehne T. Integrated analysis of atrio-
ventricular interaction in tetralogy of fallot. Am J Physiol Heart Circ Physiol.
2010;299(2):H364–71.
80. van den Berg J, Wielopolski PA, Meijboom FJ, Witsenburg M, Bogers AJ, Pattynama PM,
Helbing WA. Diastolic function in repaired tetralogy of fallot at rest and during stress: assess-
ment with MR imaging. Radiology. 2007;243:212–9.
81. Luijnenburg SE, Peters RE, van der Geest RJ, Moelker A, Roos-Hesselink JW, de Rijke YB,
Mulder BJ, Vliegen HW, Helbing WA. Abnormal right atrial and right ventricular diastolic
function relate to impaired clinical condition in patients operated for tetralogy of fallot. Int J
Cardiol. 2013;167:833–9.
82. Riesenkampff E, Al-Wakeel N, Kropf S, Stamm C, Alexi-Meskishvili V, Berger F, Kuehne
T. Surgery impacts right atrial function in tetralogy of fallot. J Thorac Cardiovasc Surg.
2014;147(4):1306–11.
83. Kutty S, Kottam AT, Padiyath A, Bidasee KR, Li L, Gao S, Wu J, Lof J, Danford DA, Kuehne
T. Validation of admittance computed left ventricular volumes against real-time three-
dimensional echocardiography in the porcine heart. Exp Physiol. 2013;98:1092–101.
84. Kuehne T, Yilmaz S, Steendijk P, Moore P, Groenink M, Saaed M, Weber O, Higgins CB,
Ewert P, Fleck E, Nagel E, Schulze-Neick I, Lange P. Magnetic resonance imaging analysis
of right ventricular pressure-volume loops: in vivo validation and clinical application in
patients with pulmonary hypertension. Circulation. 2004;110:2010–6.
85. Schmitt B, Steendijk P, Lunze K, Ovroutski S, Falkenberg J, Rahmanzadeh P, Maarouf N,
Ewert P, Berger F, Kuehne T. Integrated assessment of diastolic and systolic ventricular func-
tion using diagnostic cardiac magnetic resonance catheterization: validation in pigs and
application in a clinical pilot study. JACC Cardiovasc Imaging. 2009;2:1271–81.
86. Klotz S, Hay I, Dickstein ML, Yi GH, Wang J, Maurer MS, Kass DA, Burkhoff D. Single-
beat estimation of end-diastolic pressure-volume relationship: a novel method with potential
for noninvasive application. Am J Physiol Heart Circ Physiol. 2006;291:H403–12.
87. Brimioulle S, Wauthy P, Ewalenko P, Rondelet B, Vermeulen F, Kerbaul F, Naeije R. Single-
beat estimation of right ventricular end-systolic pressure-volume relationship. Am J Physiol
88. Klotz S, Dickstein ML, Burkhoff D. A computational method of prediction of the end-
diastolic pressure-volume relationship by single beat. Nat Protoc. 2007;2:2152–8.
89. Ten Brinke EA, Burkhoff D, Klautz RJ, Tschope C, Schalij MJ, Bax JJ, van der Wall EE,
Dion RA, Steendijk P. Single-beat estimation of the left ventricular end-diastolic pressure-
volume relationship in patients with heart failure. Heart. 2011;96:213–9.
90. Kutty S, Li L, Padiyath A, Gribben P, Gao S, Lof J. Bidasee KR. Danford DA: Kuehne
T. Combination of real time three-dimensional echocardiography with diagnostic catheteriza-
tion to derive left ventricular pressure-volume relations. Echocardiography; 2013.
91. Arvidsson PM, Toger J, Heiberg E, Carlsson M, Arheden H. Quantification of left and right
atrial kinetic energy using four-dimensional intracardiac magnetic resonance imaging flow
measurements. J Appl Physiol (1985). 2013;114:1472–81.
92. Carlsson M, Toger J, Kanski M, Bloch KM, Stahlberg F, Heiberg E, Arheden H. Quantification
and visualization of cardiovascular 4d velocity mapping accelerated with parallel imaging or
k-t BLAST: head to head comparison and validation at 1.5 t and 3 t. J Cardiovasc Magn
Reson. 2011;13:55.
93. Fogel MA, Sundareswaran KS, de Zelicourt D, Dasi LP, Pawlowski T, Rome J, Yoganathan
AP. Power loss and right ventricular efficiency in patients after tetralogy of fallot repair with
pulmonary insufficiency: clinical implications. J Thorac Cardiovasc Surg. 2012;143:
1279–85.
94. Vogel-Claussen J, Skrok J, Shehata ML, Singh S, Sibley CT, Boyce DM, Lechtzin N, Girgis
RE, Mathai SC, Goldstein TA, Zheng J, Lima JA, Bluemke DA, Hassoun PM. Right and left
ventricular myocardial perfusion reserves correlate with right ventricular function and pul-
monary hemodynamics in patients with pulmonary arterial hypertension. Radiology.
2011;258:119–27.
95. Beerbaum P, Korperich H, Gieseke J, Barth P, Peuster M, Meyer H. Rapid left-to-right shunt
quantification in children by phase-contrast magnetic resonance imaging combined with sen-
sitivity encoding (sense). Circulation. 2003;108:1355–61.
96. Beerbaum P, Korperich H, Barth P, Esdorn H, Gieseke J, Meyer H. Noninvasive quantifica-
tion of left-to-right shunt in pediatric patients: phase-contrast cine magnetic resonance imag-
ing compared with invasive oximetry. Circulation. 2001;103:2476–82.
97. Grosse-Wortmann L, Al-Otay A, Yoo SJ. Aortopulmonary collaterals after bidirectional
cavopulmonary connection or Fontan completion: quantification with MRI. Circ Cardiovasc
Imaging. 2009;2:219–25.
98. Fratz S, Hess J, Schwaiger M, Martinoff S, Stern HC. More accurate quantification of pulmo-
nary blood flow by magnetic resonance imaging than by lung perfusion scintigraphy in
patients with Fontan circulation. Circulation. 2002;106:1510–3.
99. Muthurangu V, Taylor A, Andriantsimiavona R, Hegde S, Miquel ME, Tulloh R, Baker E,
Hill DL, Razavi RS. Novel method of quantifying pulmonary vascular resistance by use of
simultaneous invasive pressure monitoring and phase-contrast magnetic resonance flow.
Circulation. 2004;110:826–34.
100. Kuehne T, Yilmaz S, Schulze-Neick I, Wellnhofer E, Ewert P, Nagel E, Lange P. Magnetic
resonance imaging guided catheterisation for assessment of pulmonary vascular resistance:
in vivo validation and clinical application in patients with pulmonary hypertension. Heart.
2005;91:1064–9.
101. Ovroutski S, Ewert P, Alexi-Meskishvili V, Holscher K, Miera O, Peters B, Hetzer R, Berger
F. Absence of pulmonary artery growth after Fontan operation and its possible impact on late
outcome. Ann Thorac Surg. 2009;87:826–31.
102. Sanz J, Kariisa M, Dellegrottaglie S, Prat-Gonzalez S, Garcia MJ, Fuster V, Rajagopalan
S. Evaluation of pulmonary artery stiffness in pulmonary hypertension with cardiac magnetic
resonance. JACC Cardiovasc Imaging. 2009;2:286–95.
103. Garcia-Alvarez A, Fernandez-Friera L, Mirelis JG, Sawit S, Nair A, Kallman J, Fuster V,
Sanz J. Non-invasive estimation of pulmonary vascular resistance with cardiac magnetic
resonance. Eur Heart J. 2011;32:2438–45.
104. Gan CT, Lankhaar JW, Westerhof N, Marcus JT, Becker A, Twisk JW, Boonstra A, Postmus
PE, Vonk-Noordegraaf A. Noninvasively assessed pulmonary artery stiffness predicts mortal-
ity in pulmonary arterial hypertension. Chest. 2007;132:1906–12.
105. el Ibrahim SH, Shaffer JM, White RD. Assessment of pulmonary artery stiffness using
velocity-encoding magnetic resonance imaging: evaluation of techniques. Magn Reson
Imaging. 2011;29:966–74.
106. Muthurangu V, Atkinson D, Sermesant M, Miquel ME, Hegde S, Johnson R, Andriantsimiavona
R, Taylor AM, Baker E, Tulloh R, Hill D, Razavi RS. Measurement of total pulmonary arte-
rial compliance using invasive pressure monitoring and MR flow quantification during
MR-guided cardiac catheterization. Am J Physiol Heart Circ Physiol. 2005;289:H1301–6.
Part II
Congenital Abnormalities
Chapter 5
Subpulmonary Right Ventricle in Congenital
Heart Disease
Christian Apitz, Heiner Latus, and Dietmar Schranz
In congenital heart diseases (CHDs) right ventricular function and subsequent

dysfunction have been much more appreciated than in structurally normal hearts
[1]. However, much less is known about the right ventricle (RV) compared to left
ventricular morphology and function. Before we discuss questions concerning right
ventricular (dys-) function in the context of CHD, its interaction with the pulmonary
circulation and its electro-mechanical and left-to-right as well as right-to-left heart
interactions, we ask whether the morphology of the correctly positioned RV shows
a normal development. In CHD, morphological distinctive features can be already
detected during fetal life and it is well known that cardiac structural changes in the
fetus can develop within days, exquisitely dependent on physiological or nonphysi-
ological blood flow. Not enough blood flow might lead to hypoplastic structures,
and high or re-directed blood flow may influence the choice of the surgical strategy
[2–6]. Figures 5.1a, b show prenatal ultrasound images, performed in a fetus of 30
and 32 gestational weeks, respectively. A small but tripartite RV associated with a
severe pulmonary valve stenosis, regressed to a bipartite and malfunctioning RV
within only 2 weeks. This adverse development prompted elective delivery of the
baby. Considering the option to generate a biventricular circulation instead of a
univentricular Fontan circulation (Chap. 8), the premature newborn with a birth
weight of less than 2,000 g was catheterized; the minimally perforated pulmonary
valve was crossed by a floppy-guide wire and gradually balloon dilated; and the
prostaglandin treated patent ductus arteriosus was stented by a coronary stent
com/videos/978-1-4939-1064-9.
C. Apitz, M.D. • H. Latus, M.D. • D. Schranz (*)
Department of Pediatric Cardiology, Justus-Liebig-University,
Feulgenstrasse 12, Giessen 35392, Germany
e-mail: christian.apitz@paediat.med.uni-giessen.de; heiner.latus@googlemail.com;
dietmar.schranz@paediat.med.uni-giessen.de

80 C. Apitz et al.
Fig. 5.1 (a) Prenatal ultrasound performed in a fetus of 30 gestational weeks depicts a four-
chamber view with a tripartite right ventricle. (b) Two weeks later in the 32 gestational week, the
dysfunctional right ventricle was bipartite
(Fig. 5.2a–f, Video 5.1). As a consequence of the balloon dilated pulmonary valve,
the right ventricular pressure fell from above systemic to about 60 % of the
systemic level, a gradient across the pulmonary valve of 15 mmHg resulted with a
regurgitation of 1–2° and the extremely compromised right ventricular function
recovered (Videos 5.2a and 5.2b). Moreover, the pulmonary blood flow was sup-
ported by the slightly collapsed but hyper-contractile RV and by a left-to-right shunt
through the stented ductus arteriosus. The hypothesis underlying this procedure is
that the right ventricle has the potential for re-development of its tripartite shape
and should be able to maintain the cardiac output at least under resting conditions.
If indeed such a restoration of the RV morphology and function can be achieved,
atrial septum defects (ASD) as well as a malfunctioning pulmonic valve may be
treated in the future by percutaneous device closure of the ASD as well as by valve
replacement (Fig. 5.3). However, in the case of insufficient right ventricular growth,
one-and-a-half circulation by combining direct superior caval vein right pulmo-
nary artery connection (Glenn-shunt) with a preserved right ventricular left
pulmonary artery connection might be an additional option [7], instead of a Fontan
circulation via a total cavo-pulmonary connection (Fig. 5.3).
We wish to summarize as follows:
5 Subpulmonary Right Ventricle in Congenital Heart Disease 81
Fig. 5.2 (a) Shows the right ventricular angiography in the lateral 90° plane; the ventricle is still
bipartite (see Video 5.1), the pulmonary valve nearly completely closed. After crossing the valved
membrane the right ventricular pressure decreased from supra- to sub-systemic pressure values by
gradual balloon dilatation using a 5 mm (b), followed by a 7 × 20 mm balloon. The coronary sup-
port wire placed via the ductus in the descending aorta (DAO) was then used for duct stenting (c).
Right ventricular pulmonary unit and the duct were delineated by angiography performed with
hand-injected contrast medium (d). Based on the calculated length and width of the duct, a
4 × 20 mm Liberte premounted coronary stent was uneventfully implanted (e, f)
The well-developed right ventricle has a triangular shape with tripartite mor-
phology (inlet, trabecular, and outlet part). In addition to a genetic disposition,
blood flow is a major determinant of RV growth. During fetal life and immedi-
ately postnatally the right ventricle can change from tri- to bi- and perhaps a uni-
partite morphology, and the latter may be associated with right ventricular
dependent coronary blood flow disturbances, including coronary obstructions
(Fig. 5.4, Video 5.3). In such circumstances the only therapeutic option is heart
transplantation.
However, the postnatally fully adapted and fully developed adult tripartite right
ventricle has a three times greater compliance when compared to the left ventricle
because of its three times thinner right ventricular wall diameter. The morphology
of the RV is further characterized by a “moderator-band” (Latin “moderare” = con-
tain) containing right ventricular dilatation, by the tricuspid valve, which has a
82 C. Apitz et al.
Fig. 5.3 Shown is a one-and-half (1.5) circulation with superior caval vein connection to the right
pulmonary artery and antegrade flow through an obstructed right ventricular outflow tract, in
which a melody-valve was implanted percutaneously. The passive laminar flow within the right
lung was protected against the pulsatile flow of the right pulmonary circulation by a surgical pul-
monary banding. PAP pulmonary artery pressure, PPVI percutaneous pulmonary valve implanta-
tion, RVP right ventricular pressure
Fig. 5.4 Shown is a cartoon in which different morphologies of the right ventricle associated with
pulmonary atresia (PAT) and intact ventricular septum are summarized. (a, b) Shows a tripartite
right ventricle with an option of biventricular repair, (c) demonstrates a bipartite right ventricle
with and (d) a unipartite ventricle, respectively. Reprinted with permission from Myung K. Park.
In: Pediatric Cardiology for Practitioners. Mosby Elsevier; 5th edition 2008
Fig. 5.5 Depicted is a four-chamber view (MRI) in an adult patient with restrictive cardio-
myopathy in whom a small atrial communication was performed by transcatheter technique to
reduce left atrial pressure and the increased pulmonary artery pressure; the left atrium is still domi-
nant, the PA-pressure decreased to normal values; In addition, the relationship of the mitral to tri-
cuspid valve becomes demonstrable; the insertion of tricuspid valve at the ventricular septum is
more apically positioned
papillary muscle fixed at the interventricular septum, and by a more apically

positioned tricuspid valve annulus when compared to the mitral valve, which helps
to identify the right from the left ventricle (Fig. 5.5). From a functional point of
view, the right ventricle has, in comparison to the ellipsoid and coaxially contract-
ing left ventricle, a time-delayed contraction pattern with movement from the inlet
to outlet part; its coronary perfusion does not only occur during diastole, but prefer-
entially during systole. The postnatal fully adapted RV is afterload sensitive and
more preload dependent the younger the child. In general, the differences between
the neonatal myocardium and the adult heart are summarized in Fig. 5.6.
The principle of “form follows function” very much applies to the RV and its
ability to adapt to different loading conditions. The volume loaded RV leads to
ventricular dilatation, pressure loading of the RV to a myocardial hypertrophy, and
the combination of obstruction and regurgitation to ventricular dilatation despite
wall hypertrophy. Ischemia of the right ventricle leads to an acute right ventricular
dilatation [8] and impairment of function. Figure 5.7 summarizes the major right
ventricular stress factors: right ventricular ischemia, and right ventricular volume
and pressure overload.
84 C. Apitz et al.
Fig. 5.6 Characteristics of structure and function of the newborn heart. The newborn heart has the
capability for hyperplasia and angiogenesis, and self-renewal
Fig. 5.7 Right ventricular (RV) failure might be caused by myocardial disease as ischemia, vol-
ume overload, high afterload, or all of these components together. CHD congenital heart disease,
PH pulmonary hypertension, PR pulmonary valve regurgitation, TR tricuspid regurgitation
Congenital Heart Disease with a Volume Overloaded

Right Ventricle
Three of the most common lesions associated with RV volume overload are: atrial
septum defects, significant pulmonary and tricuspid valve regurgitation.
Atrial Septum Defect
Communications at the atrial level are described by their anatomical location.

The ostium secundum defect, caused by an insufficiently developed septum primum,
is with about 70 % the most prevalent ASD. An ASD-II exists as an isolated and also
as an associated congenital defect. The ostium primum (ASD-I) defect is often asso-
ciated with a cleft within the mitral valve. Sinus venosus defects are positioned at
the connection of the superior or inferior caval vein respectively. A coronary sinus
defect is rare [9]. In general, the pathophysiology of an ASD is described as follows:
“a large (2 cm in adults) ASD results in hemodynamically significant left-to-right
shunting, right ventricular volume overload and subsequently to right ventricular
dilation [10].” Several questions remain unanswered in the context of an ASD asso-
ciated with a shunt (Fig. 5.8a, b, Video 5.4): what causes left-to-right, right-to-left,
or no shunting in a restrictive, nonrestrictive, or even missing interatrial septum
(common atrium)? Considering normal anatomy, shunt-direction in an unrestricted
atrial defect depends on the ratio of the right and left ventricular compliance; in a
restrictive defect by the difference of the atrial pressures. Based on the above-
mentioned normal right ventricular wall thickness the compliance of the right
ventricle is three times that of the left, and therefore the Qp (pulmonary blood flow)
to Qs (systemic blood flow) ratio is 3:1. Any higher Qp raises the question of an
additional anatomical or functional cause, for example, an anomalous pulmonary
venous connection or increased left ventricular end-diastolic pressure (LVEDP).
An increased LVEDP combined with an unrestricted ASD might also be associated
with severe pulmonary arterial hypertension (PAH) already during infancy. The
mechanism remains currently unclear, but the assessment of PAH associated with
an ASD has to include the measurement of the LVEDP and also a test occlusion of
the ASD during LVEDP measurement, to find out whether the LVEDP increases
during occlusion. Alternatively, incomplete closure by perforated patch or fenes-
trated occluder technique might be a sufficient therapeutic option; Fig. 5.8 the
residual defect within the patch might be closed by a transcatheter device technique
whenever the left ventricle is adapted to the acutely changed loading condition after
ASD closure. Precapillary PH co-existing with ASD might be a hazard in children;
in such cases, PAH might not be caused by the ASD, but based on currently unknown
genetic disposition, in this case the ASD seemed to be associated.
An atrial right-to-left shunt, with well-tolerated cyanosis is observed in situa-
tions where the RV is poor developed or non-compliant, as it occurs in RV-hypoplasia,
86 C. Apitz et al.
Fig. 5.8 (a) Magnetic

resonance imaging (MRI)
four-chamber view of the
heart of an 18-year-old young
woman: right atrium and
right ventricle are
enormously dilated
associated with a huge atrial
septum defect (ASD) and
“pseudo” small (34 mL/m2),
but relatively unloaded left
ventricle. (b) Intraoperative
transesophageal
echocardiogram shows the
surgical patch by which the
ASD was closed; in
3D-technique (top) the 3.7
mm perforated patch is nicely
seen, which allows closure by
a transcatheter device
technique whenever the left
ventricle is adapted to the
acutely changed loading
condition after ASD closure
in patients with tricuspid and pulmonary valve atresia, stenosis, or severe insuffi-
ciency, as in the Ebstein anomaly.
An RV with normal anatomy tolerates volume overload due to an ASD well for
many years. Symptoms caused by a significant atrial shunt are related to its patho-
physiology, i.e., in young children a left-to-right shunt leads to active pulmonary
hyperemia, which is responsible for pulmonary infections during infancy and early
childhood and for the exercise intolerance of the adolescent. However, the exercise
intolerance is in the beginning due to the limitation to increase the systemic blood
flow—as during heavy exercise. The flow through the lungs is likely limited by a
ratio of Qp/Qs ratio in a range of 3:1 at rest, and the regulating variable Qs of about
3.5 L/m2 × min. If there is no intrinsic LV diastolic dysfunction, acquired diastolic
LV dysfunction occurs infrequently before the second decade of life. The same is
true for the ASD associated with PAH. However, decades of volume overload can
be detrimental and results in increased morbidity and mortality [11]. An interventional

or surgical closure of an isolated ASD reverses the RV volume overload, best when
performed during the first decade of life. ASD closure in an older patient can lead
to an incomplete remodeling of an already structurally affected RV as well LV.
Additionally, morbidity is further enhanced by atrial arrhythmias and left ventricu-
lar diastolic dysfunction [12–15]. Interventional ASD occlusion is the treatment of
choice for most ASDs of the secundum type, while primum type and sinus venosus
defects have to be closed surgically. A superior sinus venosus ASD is very fre-
quently associated with a partial anomalous pulmonary venous return (PAPVR) of
the right upper pulmonary vein, which aberrantly drains into the right atrium instead
of the left atrium. PAPVR results in additional volume overload of the RV and
should be corrected during the same operation if technically feasible.
Significant Pulmonary Valve Regurgitation
The absent pulmonary valve syndrome is a rare congenital variant of pulmonary

valve regurgitation (Fig. 5.9). Already during fetal life the pulmonary vessel-
bronchial unit might be affected by extreme pulmonary regurgitation; postnatally
the pulmonary arterial branches are enormously dilated and may lead to airway
obstructions, which might be life threatening despite immediate cardiovascular
correction. However, acquired forms of pulmonary valve regurgitation are observed
more frequently. The most frequent cause of significant pulmonary valve regurgita-
tion is a repaired Tetralogy of Fallot (TOF), especially, when during corrective
surgery a “transannular patch” has been used, which results in a loss of integrity of
the pulmonary valve annulus and a certain degree of pulmonary valve sufficiency.
Fig. 5.9 MRI in a patient

with absent pulmonary valve
syndrome. Characteristic is a
pseudo-valve with extremely
dilated central pulmonary
arteries (+ dilated bronchial
system) caused by systolic-
diastolic shunt volume shift
88 C. Apitz et al.
Pulmonary regurgitation leads to RV dilation and can result in RV dysfunction [16].

There is a linear relationship between pulmonary regurgitation and RV size.
Geometric remodeling after TOF repair can be associated with electrical remodel-
ing characterized by a progressive right bundle brunch block and predisposition to
atrial but in particular ventricular dysrhythmias [17]. The duration of the QRS
complex correlates with RV volume load and serves as a primary predictor of
life-threatening arrhythmias and sudden death. Adverse ventricular–ventricular
interactions in patients with repaired TOF appear to be relevant but are still not well
understood. There is a close relationship between RV and LV ejection fractions in
patients with TOF [18, 19]. In addition, MRI studies show fibrosis of the LV
myocardium in TOF patients [20], which illustrate that this disease, which was
previously considered as an exclusive right ventricular disease, appears to be a
biventricular disease. Timely pulmonary valve replacement can result in reverse
remodeling of the RV dilation and may protect patients from adverse effects of
pulmonary regurgitation. Especially, if serial imaging of the RV demonstrates pro-
gression of RV dilation, prompt referral for pulmonary valve replacement is usually
recommended before RV dysfunction ensues. Serial follow-up measurements of RV
volumes, ideally by MRI are recommended [21, 22]. Following pulmonary valve
replacement, RV stress and volume overload usually decrease and RV function
improves [23, 24].
Significant Tricuspid Regurgitation
Tricuspid valve dysplasia or Ebstein’s anomaly are malformations with a high

incidence of tricuspid regurgitation. Ebstein’s anomaly is a complex heart malfor-
mation characterized by an apical displacement of the posterior and septal tricuspid
leaflets (Video 5.5). As a consequence, the tricuspid valve shows significant regur-
gitation and the right heart chambers in particular the right atrium, can be signifi-
cantly dilated. There are also forms of tricuspid valve dysplasia and Ebstein’s-like
anomalies in patients with congenitally corrected transposition of the great arteries,
where the tricuspid valve represents the systemic atrio-ventricular valve (see Chap. 8).
Ebstein’s malformation is a rare defect, but from a pathophysiological point of view
highly interesting. The malformation per se can present with a lifelong compen-
sated hemodynamic situation but on the other end of the spectrum be associated
with fetal hydrops and death before birth. As a rule of thumb, any congenital heart
defect remains compensated as long as the tricuspid, mitral or common atrio-
ventricular valve is not incompetent. A fetus with tricuspid dysplasia or Ebstein’s
anomaly might develop heart failure because of ineffective forward flow across the
pulmonary valve due to a combination of tricuspid regurgitation and functional- or
morphological pulmonary atresia (PAT). The presence of pre- and persistent postna-
tal parallel circulations of the systemic and pulmonary vasculature is important for
survival. However, if the fetal blood pressure rises after umbilical cut, the degree of
tricuspid regurgitation increases, and the annulus of the tricuspid valve dilates. The
pulmonary valve is held in a closed position by still high pulmonary vascular resis-
tance and a pulmonary-aortic communication established by the ductus arterio-
sus; an open duct might be lifesaving, but the closed pulmonary valvular leaflets can
develop to a morphological pulmonic stenosis or even atresia. The right atrium
dilates in response to tricuspid regurgitation and becomes thin, and right-to-left
shunting increases through the foramen ovale. Lymphatic flow is high due to the
presence of high venous pressure, and the intravascular oncotic pressure (due to low
fetal albumin) combine to produce a fetal hydrops. As a consequence of the
described sequence of events, neonates who survive fetal heart failure, often present
with profound cyanosis, and may require prostaglandins to maintain adequate flow
of blood to the lungs during the early neonatal period when pulmonary resistance is
high. In this situation, it is necessary to distinguish a functional from an anatomic
PAT. Children with functional atresia can possibly be weaned off prostaglandins
while maintaining adequate oxygen saturation as the pulmonary resistance falls.
In neonates that cannot be weaned from prostaglandins, or in those with anatomic
PAT, it is necessary to construct a systemic-to-pulmonary shunt to maintain ade-
quate pulmonary blood flow by generating a surgical shunt or, as in our institution,
by duct stenting [25, 26].
In addition to the described scenarios, severe tricuspid valve regurgitation is even
rarely associated with a significant pulmonary valve regurgitation, which leads to
pulmonary run off from the aorta through the duct, pulmonary artery, low pressure
right ventricle and atrium; low cardiac output lastly leads to death, if the pulmonary
valve is not immediately closed by surgical ligation or by transcatheter device
placement.
Figure 5.10a, b shows chest film images from a newborn with Ebstein’s anomaly
and respiratory failure. Right atrial plication in order to reduce the volume of the
atrialized right ventricle might improve the lung volume.
In the older patients with Ebstein’s anomaly depending on the progressiveness of
symptoms, a variety of surgical options exist to repair the malformed tricuspid valve
Fig. 5.10 Shown is a chest X-ray (anterior-posterior view) of a newborn with Ebstein’s anomaly
before and after right atrial reduction plasty with impressive improvement of the lung volume
(Video by Dr. Grohmann, Department of Pediatric Cardiology, Freiburg)
90 C. Apitz et al.
Fig. 5.11 MRI pictures of an enormously dilated RV in Diastole and Systole as well as a bidirec-
tional Glenn-anastomosis to unload the volume overloaded right ventricle due to a high degree of
Ebstein tricuspid valve regurgitation
depending on the progressiveness of symptoms. Most surgical strategies are based

on techniques to mobilize the leading edge of the antero-superior leaflet, aiming to
create a competent mono cusp valve with or without plication of the atrialized
portion of the RV. Da Silva’s “Cone” operation is an additional surgical option,
which generates impressive results [27]. Tricuspid valve replacement should only
be the final option. Combining tricuspid repair with volume unloading Glenn shunt
is an additional option, if the pulmonary vascular resistance allows cava superior
right pulmonary artery connection (Fig. 5.11a–c).
The question of early elective repair to preserve and possibly improve ventricular
function, and reduce the risk of late arrhythmias in relatively asymptomatic chil-
dren, continues to be debated [28, 29]. Ebstein’s anomaly carries one of the highest
risks for arrhythmias because of associated pathological pathways such as WPW,
which might contribute to the development of heart failure.
Other forms of tricuspid regurgitation are secondary, due to severe RV dilation
causing tricuspid annular dilation, as it is seen in patients with RV dysplasia, in
patients with RV dilation after a repair of TOF, or as a consequence of direct valvu-
lar trauma during reparative surgery [30].
Congenital Heart Disease Associated with a Pressure

Overloaded Right Ventricle
Considering the anatomy, geometry, physiology, and normal right ventricular

pressure-volume relations, the RV is several-fold more sensitive to changes in after-
load compared to the left ventricle [31]. A small rise in afterload in an unprepared
RV causes a rapid and linear decline in cardiac output. Such a scenario is often
observed after heart transplantation in a recipient with pre-transplant increased
pulmonary vascular resistance. Massive pulmonary thrombo- and air-embolism or

any other acute obstructions of the pulmonary valve are situations in which the RV
fails immediately. Its thin free wall is disposed to ventricular dilatation and acute
impairment of the coronary artery perfusion (see also Chap. 9) the impact on the
filling of the LV is often deleterious [32, 33].
Chronic pressure load is usually well tolerated by an adapted RV (see Chaps. 13
and 32), which may enable the right ventricle to generate systemic pressures (Chap. 8).
Mild or moderate pressure load leads to a hypertrophic adaption of the RV myocar-
dium, as well as an improvement of systolic RV function [34]. The well-adapted,
hypertrophied RV can maintain its function for years. However, a normal sinus
rhythm is needed and volume overload has to be avoided. The chronic pressure
overloaded RV of patients with CHD is usually able to maintain its function well
into the fourth or fifth decade of life. On the other hand, excessive RV pressure load
triggers structural and functional maladaptation of the myocardium, which, if left
untreated, ultimately results in RV dysfunction and failure. The transition from a
compensated status to one of RV contractile dysfunction with decreased cardiac
output, and elevated central venous pressures results from multifactorial, as yet
poorly understood, causes. The type and degree of afterload, function of the tricus-
pid valve, responses of the LV and RV myocardium, and effects of associated
abnormalities all modify the clinical course. Molecular mechanisms are being
investigated; once identified to play an important role they will become therapeutic
targets [35].
There are two major models exemplifying the chronic pressure overload of the
RV in CHD:
RV outflow tract obstruction/pulmonary stenosis
Pulmonary valve stenosis represents the most frequent CHD, which generate a
pressure (over-) loaded right ventricle. The pulmonary valve is mostly dome-shaped
and in 10–20 % of patients dysplastic. However, obstruction may also occur at the
sub- or supra-valvular level (Fig. 5.12). Dysplastic valve and pulmonary artery
obstructions are frequently associated with Noonan, Williams-Beuren, and Alagille
syndromes [36]. The severity of a pulmonary valve stenosis is defined by its pres-
sure gradient across the subpulmonary outflow tract. However, the definition of a
critical pulmonary valve stenosis is not determined by its gradient, but by its ability
to permit a sufficient cardiac output at rest. A critical pulmonary valve stenosis or
any other critical pulmonary obstruction is a life-threatening situation, which needs
to be emergently treated. Pulmonary stenosis, when significant, results in compen-
satory RV hypertrophy, especially at the infundibular level [37]. When prominent,
RVOT hypertrophy can lead to secondary dynamic sub-valvular stenosis. Pulmonary
stenosis can also result in post-stenotic dilation of the pulmonary trunk, which is
common in the dome form of pulmonary stenosis, which often extends to the proxi-
mal left pulmonary artery. This is thought to be the result of the high-velocity jet
through the narrow valve orifice, which is anatomically aimed more toward the left
pulmonary artery (natural continuation of the main pulmonary artery), and can
produce unequal distribution of blood flow in favor of the left lung. However,
92 C. Apitz et al.
Fig. 5.12 Shown is the

lateral projection of a right
ventricular angiography by
which the hypertrophied right
ventricle, the narrowed
infundibulum, a dysplastic
pulmonary valve and, in
particular a left pulmonary
artery branch stenosis, are
visualized
intrinsic abnormalities of the pulmonary arterial wall also contribute to the pulmonary
artery dilatation. Interestingly, post-stenotic dilatation of the pulmonary artery is
rare in patients with dysplastic pulmonary valves. RV failure is rare and most
patients with pulmonary stenosis remain asymptomatic for many years, even when
the stenosis progresses from moderate to severe. Ever since percutaneous balloon
valvuloplasty was introduced in 1982, it has become the treatment of choice for
patients with valvular pulmonary stenosis. Balloon dilation is recommended for
patients with a peak instantaneous Doppler pressure gradient >50 mmHg or a mean
Doppler pressure gradient >35 mmHg [38]. Long-term outcome after balloon
valvuloplasty is excellent, with a low rate of restenosis, whereas significant pulmo-
nary regurgitation is rare [39]. Surgical treatment is warranted in patients with
dysplastic valves in which balloon valvuloplasty is not successful or in patients with
sub- as well as supra-valvular obstructions.
Associated heart or vessel malformations are mostly protective in regard to a
critical cardiocirculatory collapse. The outlet of the subpulmonary morphologically
right or left ventricle might be obstructed in association with various other heart
defects. Well known is the combination of infundibular stenosis, right ventricle
hypertrophy combined with a subaortic, malalignement ventricular septum defect
(VSD) and ante-positioned dilated aorta. More than 125 years ago, Étienne-Louis
Arthur Fallot described in detail the four anatomical characteristics in “blue babies,”
which are well known as “Tetralogy of Fallot.” In this context the intra-cardiac
Fig. 5.13 Shown are differently developed central pulmonary arteries, which are found in associa-
tion with pulmonary atresia and ventricular septal defect (PAT+VSD). (I) PAT+VSD associated
with well-developed central pulmonary arteries have a similar chance for corrective cardiac sur-
gery as a classical Fallot-Tetralogy constellation with severe infundibular as well as pulmonary
valve obstruction. (II) Demonstrates slightly underdeveloped native pulmonary arteries, which can
be postnatally resuscitated by a Blalock-Taussig (BT) shunt or by duct stenting. (III) A severe
hypoplastic native pulmonary artery system associated with major aorto-pulmonary collaterals
(MAPCAs), which supply some pulmonary segments as single or as dual source. (IV) 15–20 % of
PAT+VSD is associated with missing native central arteries, in which the lung segments are exclu-
sively perused by MAPCAs. This morphology demonstrates that central and distal pulmonary
arteries of the lung segments are embryologically different programmed. Surgical unifocalization
of all MAPCAs with connection to the right ventricle by a conduit might be one therapeutic option.
Modified from Aldo R. Castaneda, Richard A. Jonas, John E. Mayer, Frank L Hanley. In: Cardiac
surgery of the neonate & infant. Saunders; 1st edition 1994
malformation of a Fallot Tetralogy associated with a pulmonary atresia is known as

pulmonary atresia (PAT) with VSD. PAT+VSD might have a variably developed
central pulmonary vascular system; PAT can be accompanied by an almost normal
or only slightly diminished central pulmonary artery system, where the pulmonary
circulation is postnatally only ductus arteriosus dependent as shown in Fig. 5.13
(cartoon I, II). In case of diminished or absent central pulmonary arteries, the
peripheral pulmonary vasculature is connected with major aortic pulmonary collat-
erals (MAPCAs), which might be partially or fully taking over the role of the
pulmonary circulation and might be responsible for oxygenation (cartoon III, IV,
Fig. 5.13). These clinical findings suggest a genetically different development of the
central and peripheral pulmonary artery system, and that such MAPCAs could be
responsible for the development of various forms of pulmonary artery hypertension,
if the MAPCAs are surgically used for corrective repair or left intact.
Following corrective surgery, patients with a “repaired Tetralogy of Fallot” can
have both, a pressure and volume overloaded RV. A paradigm change of the current
surgical policy in TOF patients is to relieve a mild residual RV outflow obstruction
in order to avoid excessive pulmonary regurgitation, especially when a transannular
patch is used. Previous studies have demonstrated the deleterious effects of a large
pulmonary regurgitation on RV function during a long-term follow-up [40, 41].
However, the underlying mechanisms and the functional benefits of this approach
remain unclear. Recent studies show that the beneficial effect of mild RVOTO on
94 C. Apitz et al.
RV size and function might be mediated by a relatively preserved RVOT geometry,

reduced pulmonary regurgitation severity, and/or compensatory RV hypertrophy.
The molecular mechanisms of this positive effect of mild pressure overload should
be evaluated.
Pulmonary Hypertension in the Context

of Congenital Heart Disease
Pulmonary Arterial Hypertension (PAH) associated with CHD continues to be an

important cause of morbidity and mortality. Observing the natural course of primary
or idiopathic pulmonary arterial hypertension (iPAH) as well as pulmonary hyper-
tension associated with CHDs adds to our understanding of the pathophysiology
and pathobiology. PAH does not only induce a unique right heart disease, but has
important biventricular impairment (Fig. 5.14a, b).
Redington et al. [42] described the preclinical stage of PAH as follows: “there is
a modified pressure-volume relationship, increased right ventricular power, and
normal cardiac output, despite substantial increases in pulmonary vascular resis-
tance.” The question raises: when does the right ventricle fail? Does right ventricular
failure become obvious at that point when the pulmonary vascular resistance (Rp)
substantially exceeds the systemic vascular resistance (Rs), or are there other, simi-
larly important factors? PAH associated mechanical factors might be regurgitation
of the tricuspid and pulmonary valve or the above-mentioned RV-dependent impair-
ment of the left ventricular diastolic inflow (Fig. 5.15). However, intrinsic mecha-
nisms acting as myocardial depressant factors are also responsible for failure of the
right or subpulmonary positioned ventricle ([43], see also Chaps. 13 and 32). In
addition, the subpulmonary, right or left ventricle are metabolically active, which
may have substantial implications for pharmacotherapy. Genes encoding drug-
metabolizing enzymes, like cytochrome P450 mono-oxygenases, are predominantly
expressed in the right side of the subpulmonary heart chamber, which might explain
the lack of efficacy of certain drugs, for example, angiotensin converting enzyme
inhibitors and angiotensin receptor blockers, on RV function. An atrial switch of the
venous connection to the right and left atria reverses the messenger RNA expression
profiles. The anatomical left, subpulmonary ventricle shows the expression of cyto-
chrome P450 genes normally found in the RV. This emphasizes the importance of the
subpulmonary ventricle and pulmonary circulation for detoxication of drugs and
for the diminished expression of cytochrome P450 genes in the systemic ventricle
[44]. Many questions remain unanswered regarding the enormous variability of the
natural history of CHDs [45]. In general, the prevalence of PAH-CHD has decreased
in developed countries and the number of patients surviving into adulthood has
increased markedly. Today, many of the patients with PAH-CHD have a complex
disease or they received a late diagnosis of their defect. Most of them have pulmonary
hypertension combined with a pre- and post-capillary component. In the past, the vast
majority of PAH-CHD patients did present with congenital cardiac shunts [45, 46].
Fig. 5.14 (a) The schematic depicts the pulmonary and systemic circulation as it can be found in
a patient with severe idiopathic pulmonary arterial hypertension (iPAH). The normal relationship
between the right atrial (RA), right ventricle (RV), left atrial (LA), and left ventricle (LV) based on
a balanced Qp (pulmonary blood flow) to Qs (systemic blood flow) is severely compromised by
high precapillary pulmonary hypertension (Rp > Rs). Right-sided hypertrophy and dilation with
congested systemic veins (C) are associated with an interatrial, and in particular interventricular
septum shift to the left, which might compromise the left ventricular inflow and left ventricular
cardiac output even at rest. (b) Shows the four-chamber view of the heart of an 18-year-old man,
who is treated since 15 years with continuous epoprostenol infusion. The right ventricle is adapted
after years of supra-systemic pulmonary pressures. The interatrial and interventricular septum is
shifted to the left (LVEI, left ventricular eccentricity index of 0.6) in both systole and diastole. In
case of deterioration a right-to-left shunt at the arterial level (Potts-like, see Chap. 7) is planned,
should the functional status become worse
Patients with uncorrected cardiac defects which result in left-to-right shunting are
at risk of developing PAH, owing to the increased shear stress and circumferential
wall stretch induced by increased pulmonary blood flow and pressure, which lead to
endothelial barrier dysfunction and progressive vascular remodeling [47]. One
question always rises: is the increased vascular resistance based on a loss of the
Fig. 5.15 Treatment of acute right heart (RV) failure in children can be in principle adapted to
therapeutic strategies in adults, but with some specifies as younger the patient’s age. The first step
of treatment is always focused on the age-dependent coronary perfusion pressure (difference of the
diastolic systemic blood pressure (SAP) and sinus coronarius, right atrial pressure, CPP). As long
as a sufficient CPP is not established or any other reason for right ventricular ischemia is excluded,
so far all other treatments cannot be successful. However, in most situations of acute right heart
failure an orchestra of therapeutic goals has immediately to be established. To establish a sufficient
CPP by norepinephrine combined with blocking of an induced tachycardia by a β-blocker or
alpha-2 receptor stimulator is not a paradox, but a highly sufficient strategy. In case of a too short
diastolic time a sufficient inotropic response of the right ventricle might be missing as well as
achievement of an adequate SAP by a sufficient time for the left ventricular preload. Therefore,
PDE-3-inhibitor (milrinone), and in particular in children the use of a calcium-sensitizer (levosi-
mendan), and even the application of calcium in newborns and infants are inotropic drugs of the
first choice, instead or in addition to a catecholamine therapy. Norepinephrine is used as a vasocon-
strictor for CPP; this drug seems to be ten times more effective than dopamine [51] by looking at
its effects on the relation of SAP to PAP (pulmonary artery pressure). In addition, the systolic and
in particular diastolic dysfunctional right ventricle is preload dependent because of its reduced
compliance, which is in a healthy newborn even physiologically present. Volume challenge by
Ringer’s solution or blood transfusion in case of anemia is even a “first step” of resuscitation.
However, the immediate effect on the systemic arterial blood pressure has to be observed. Blood
pressure increase might be a positive clinical sign, and decrease a clinical sign of the need for
(additional) inotropic support. In this context echocardiographic guidance of all, and in particular
acute therapeutic manipulations have to be recommended (continuous bedside ECHO). Afterload
influencing drugs are indicated in nearly all-acute causes of RV failure based on a precapillary
mechanism, including thrombo-embolism. Intubation and high FiO2, pH buffering are indicated as
well as precapillary dilative drugs (Prostanoids, PDE-5-inhibitors, NO). However, mechanical
strategies should be considered early and not too late. In anecdotal cases atrioseptostomy, mechan-
ical thrombolysis by balloon dilatation, thrombolysis and thrombus removal by different catheter
techniques, as well as local thrombolysis were successful; the same is true for immediate establish-
ing of ECMO (extra-corporal membrane oxygenation) and RVAD or BIVAD (assist device) were
able to save life even in kids. To transfer the patient from an acute life-saving therapy to a chronic
patient but with the chance for surviving ventriculo–ventricular interactions might be an important
point for success. RV function and in particular dysfunction depends on the relationship of sys-
temic to pulmonary circulation but even a support for an improvement of the intra-cardiac relation-
ship, which includes the atrial and ventricular septum (Fig. 5.13a, b)
cross-sectional vasculature of the pulmonary artery system or is it based on vessel

obstruction (by constriction or micro-thrombosis)? If there is indeed a loss of
vessels, the future neo-angiogenesis strategies might be more promising than the
current vasodilator treatments.
Specific PAH therapies have been directed at reducing the pulmonary vascular
resistance and pressure by alleviating microvascular obstructions. Prostacyclin,
endothelin receptor antagonists, phospho-diesterase (PDE) type 5-inhibitors, and
calcium-channel blockers are all treatments which target the increased RV afterload
[10]. Relieving hypercapnia can also contribute to an improvement of RV function
in some situations. If drug therapy does not lead to an improvement, lung trans-
plantation may be an option. As soon as RV afterload is reduced, the right ventricle
proceeds through a dramatic de-remodeling process, which leads to a near-
normalization of volume indices and function.
For the treatment of acute RV failure a number of synergistically acting drugs are
available (Fig. 5.15 (see also Chap. 22)).
If we consider shunt-dependent PAH, Eisenmenger’s syndrome is the most
advanced form of PAH-CHD, which is characterized by a reversal of a left-to-right
to a right-to-left shunt. The anatomical, pathological, and structural abnormalities
occurring in the pulmonary circulation of these patients are similar to those observed
in other forms of PAH. However, the right-to-left shunts at the ventricular and at the
arterial level are important mechanisms for survival (see also Chap. 21) [48].
A French group created a reverse Potts shunt connecting the left pulmonary artery
to the descending aorta in order to prevent right ventricular failure and to re-
compensate the impaired left ventricular inflow in severe IPAH with supra-systemic
pulmonary hypertension [49]. Whether creation of a reverse Potts shunt [50] could
be of greater benefit when compared to atrial septostomy is unclear. Atrial septos-
tomy might be ineffective in patients with a severely impaired left ventricular inflow.
In this context the question arises, whether an Eisenmenger-reaction caused by
ventricular right-to-left shunt should be surgically converted to an Eisenmenger-
physiology at the arterial level? Normalizing the oxygen saturation in the upper
body by a patch closing the VSD combined with a (valved) conduit between the
pulmonary artery and descending aorta (in order to avoid right ventricular dysfunc-
tion) might have theoretically some advantages.
Summary for the Practitioner
1. CHDs, and their modification by surgery, provide natural models of abnormal

right ventricular physiology and heart-lung and ventricular–ventricular interac-
tions. With increasing understanding of the relevance of these interactions,
more effective therapeutic interventions will be developed.
2. The principle “form follows function” applies to the RV and its ability to adapt
to different loading conditions. The volume overloaded RV leads to dilatation
of the heart chamber, the pressure overloaded RV to a myocardial hypertrophic
response.
98 C. Apitz et al.
3. Three of the most common lesions associated with RV volume overload are:
ASD, significant pulmonary valve regurgitation, and significant tricuspid
regurgitation.
4. Two major models exemplifying pressure overloading of the RV are: RV out-
flow tract obstruction and pulmonary hypertension.
5. There is growing evidence that RV dysfunction develops in many of the CHD
patients and accounts for the considerable morbidity and mortality. RV function
in many forms of CHD needs close surveillance and timely and appropriate
intervention to optimize outcome.
6. Due to its shape the assessment of RV function remains challenging, often
requiring a multi-imaging approach and expert investigation of special studies
(echocardiography, magnetic resonance imaging, invasive assessment with
angiography or pressure-volume loop-catheters).
7. In addition to the systolic RV function, diastolic function has a similar rele-
vance. For example, in patients after a repair of Tetralogy of Fallot, the so-
called “restrictive physiology” may lead to diastolic dysfunction and may affect
long-term outcome. Furthermore, right ventricular pulmonary arterial coupling
of the volume overloaded RV may affect systolic and diastolic function.
8. Atrial and ventricular arrhythmias can be a consequence of chronic pressure
or volume overload or can be due to surgical interventions and may lead to
sudden death.
9. Pediatric pulmonary hypertension is very different from PH in adults. The most
frequent reason for the development of pulmonary hypertension in children is
CHD; however its prevalence has decreased during the last decade due to the
recent advances in congenital heart surgery and interventional catheterization
procedures.
10. Eisenmenger syndrome represents the most advanced form of PAH associated
with CHD. Survival of Eisenmenger patients is much longer than of patients with
idiopathic PAH, which appears to be due to a better adapted, hypertrophied RV,
and acting of the ventricles partially in parallel fashion.
References
1. Redington AN, Van Arsdell GS, Anderson RH, editors. Congenital diseases in the right heart.
London: Springer; 2009.
2. Kohl T. Chronic intermittent materno-fetal hyperoxygenation in late gestation may improve on
hypoplastic cardiovascular structures associated with cardiac malformations in human fetuses.
Pediatr Cardiol. 2010;31:250–63.
3. Friehs I, Illigens B, Melnychenko I, Zhong-Hu T, Zeisberg E, Del Nido PJ. An animal model
of endocardial fibroelastosis. J Surg Res. 2013;182(1):94–100.
4. Stressig R, Fimmers R, Axt-Fliedner R, Gembruch U, Kohl T. Association of intrathoracic
herniation of the liver with left heart hypoplasia in fetuses with a left diaphragmatic hernia but
not in fetuses with a right diaphragmatic hernia. Ultraschall Med. 2011;32 Suppl 2:E151–6.
5. deAlmeida A, McQuinn T, Sedmera D. Increased ventricular preload is compensated by myo-
cyte proliferation in normal and hypoplastic fetal chick left ventricle. Circ Res. 2007;100:
1363–70.
6. Marshall AC, van der Velde ME, Tworetzky W, Gomez CA, Wilkins-Haug L, Benson CB,
Jennings RW, Lock JE. Creation of an atrial septal defect in utero for fetuses with hypoplastic
left heart syndrome and intact or highly restrictive atrial septum. Circulation. 2004;110:253–8.
7. Mavroudis C, Backer CL, Kohr LM, Deal BJ, Stinios J, Muster AJ, et al. Bidirectional Glenn
shunt in association with congenital heart repairs: the 1 ½ ventricular repair. Ann Thorac Surg.
1999;68:976–81.
8. Brookes C, Ravn H, White P, Moeldrup U, Oldershaw P, Redington A. Acute right ventricular
dilatation in response to ischemia significantly impairs left ventricular systolic performance.
Circulation. 1999;100:761–7.
9. English RF, Anderson RH, Ettedgui JA. Interatrial communication. In: Anderson RH, Baker
EJ, Penny DJ, Redington AN, Rigby ML, Wernovsky G, editors. Paediatric cardiology. 3rd ed.
Philadelphia: Elsevier; 2009. p. 523–46.
10. Galiè N, Hoeper MM, Humbert M, et al. Guidelines for the diagnosis and treatment of pulmo-
nary hypertension. Eur Respir J. 2009;34:1219–63.
11. Murphy JG, Gersh BJ, McGoon MD, Mair DD, Porter CJ, Ilstrup DM, McGoon DC, Puga FJ,
Kirklin JW, Danielson GK. Long-term outcome after surgical repair of isolated atrial septal
defect—follow-up at 27 to 32 years. N Engl J Med. 1990;323:1645–50.
12. Gatzoulis MA, Freeman MA, Siu SC, et al. Atrial arrhythmia after surgical closure of atrial
septal defects in adults. N Engl J Med. 1999;340:839–46.
13. Kort HW, Balzer DT, Johnson MC. Resolution of right heart enlargement after closure of
secundum atrial septal defect with transcatheter technique. J Am Coll Cardiol. 2001;38:
1528–32.
14. Schussler JM, Anwar A, Phillips SD, et al. Effect on right ventricular volume of percutaneous
Amplatzer closure of atrial septal defect in adults. Am J Cardiol. 2005;95:993–5.
15. Santoro G, Pascotto M, Sarubbi B, et al. Early electrical and geometric changes after percuta-
neous closure of large atrial septal defect. Am J Cardiol. 2004;93:876–80.
16. Apitz C, Webb GD, Redington AN. Tetralogy of Fallot. Lancet. 2009;374(9699):1462–71.
17. Gatzoulis MA, Balaji S, Webber SA, et al. Risk factors for arrhythmia and sudden cardiac
death late after repair of tetralogy of Fallot: a multicentre study. Lancet. 2000;356:975–81.
18. Davlouros PA, Kilner PJ, Hornung TS, et al. Right ventricular function in adults with repaired
tetralogy of Fallot assessed with cardiovascular magnetic resonance imaging: detrimental role of
right ventricular outflow aneurysms or akinesia and adverse right-to-left ventricular interaction.
J Am Coll Cardiol. 2002;40:2044–52.
19. Tzemos N, Harris L, Carasso S, et al. Adverse left ventricular mechanics in adults with repaired
tetralogy of Fallot. Am J Cardiol. 2009;103:420–5.
20. Babu-Narayan SV, Goketekin O, Moon JC, et al. Late gadolinium enhancement cardiovascular
magnetic resonance of the systemic right ventricle in adults with previous atrial redirection
surgery for transposition of the great arteries. Circulation. 2005;111:2091–8.
21. Therrien J, Siu SC, Harris L, et al. Impact of pulmonary valve replacement on arrhythmia
propensity late after repair of tetralogy of Fallot. Circulation. 2001;103:2489–94.
22. van Straten A, Vliegen HW, Hazekamp MG, et al. Right ventricular function after pulmonary
valve replacement in patients with tetralogy of Fallot. Radiology. 2004;233:824–9.
23. Hagel KJ, Michel-Behnke I, Bauer J, Akintürk H, Schranz D. Percutaneous pulmonary valve
implantation for treatment of a severe bovine pulmonary stenosis in a child with isolated
dextrocardia, ccTGA after double switch repair. Clin Res Cardiol. 2009;98(3):199–200.
24. Jux C, Akintuerk H, Schranz D. Two melodies in concert: transcatheter double-valve replacement.
Catheter Cardiovasc Interv. 2012;80(6):997–1001.
25. Celermajer DS, Bull C, Till JA, et al. Ebstein’s anomaly: presentation and outcome from fetus
to adult. J Am Coll Cardiol. 1994;23:170–6.
26. Schranz D, Michel-Behnke I, Heyer R, Vogel M, Bauer J, Valeske K, Akintürk H, Jux C. Stent
implantation of the arterial duct in newborns with a truly duct-dependent pulmonary circula-
tion: a single-center experience with emphasis on aspects of the interventional technique.
J Interv Cardiol. 2010;23(6):581–8.
100 C. Apitz et al.
27. da Silva JP, da Silva LF. Ebstein’s anomaly of the tricuspid valve: the cone repair. Semin
Thorac Cardiovasc Surg Pediatr Card Surg Annu. 2012;15(1):38–45.
28. Chauvaud S, Berrebi A, d’Attellis N, et al. Ebstein’s anomaly: repair based on functional anal-
ysis. Eur J Cardiothorac Surg. 2003;23:525–31.
29. Di Russo GB, Gaynor JW. Ebstein’s anomaly: indications for repair and surgical technique.
Semin Thorac Cardiovasc Surg Pediatr Card Surg Annu. 1999;2:35–50.
30. Ammash NM, Warnes CA, Connolly HM, et al. Mimics of Ebstein’s anomaly. Am Heart
J. 1997;134:508–13.
31. Suga H, Sagawa K, Shoukas AA. Load independence of the instantaneous pressure-volume
ratio of the canine left ventricle and effects of epinephrine and heart rate on the ratio. Circ Res.
1973;32(3):314–22.
disease, part I: anatomy, physiology, aging, and functional assessment of the right ventricle.
Circulation. 2008;117(11):1436–48.
33. Apitz C, Honjo O, Friedberg MK, Assad RS, Van Arsdell G, Humpl T, Redington AN. Beneficial
effects of vasopressors on right ventricular function in experimental acute right ventricular
failure in a rabbit model. Thorac Cardiovasc Surg. 2012;60(1):17–23.
34. Apitz C, Honjo O, Humpl T, Li J, Assad RS, Cho MY, Hong J, Friedberg MK, Redington
AN. Biventricular structural and functional responses to aortic constriction in a rabbit model
of chronic right ventricular pressure overload. J Thorac Cardiovasc Surg. 2012;144(6):
1494–501.
35. Friedberg MK, Cho MY, Li J, Assad RS, Sun M, Rohailla S, Honjo O, Apitz C, Redington
AN. Adverse biventricular remodeling in isolated right ventricular hypertension is mediated
by increased TGFβ1 signaling and is abrogated by angiotensin receptor blockade. Am J Respir
Cell Mol Biol. 2013;49:19–28.
36. Derrick G, Bonhoeffer P, Anderson RH. Pulmonary stenosis. In: Anderson RH, Baker EJ,
Penny DJ, Redington AN, Rigby ML, Wernovsky G, editors. Paediatric cardiology. 3rd ed.
37. Graham Jr TP. Ventricular performance in congenital heart disease. Circulation. 1991;84:
2259–74.
38. Warnes CA, Williams RG, Bashore TM, Child JS, Connolly HM, Dearani JA, et al. ACC/AHA
2008 Guidelines for the Management of Adults with Congenital Heart Disease: a report of the
American College of Cardiology/American Heart Association Task Force on Practice
Guidelines (writing committee to develop guidelines on the management of adults with con-
genital heart disease). Circulation. 2008;118:e714–833.
39. Jarrar M, Betbout F, Farhat MB, Maatouk F, Gamra H, Addad F, et al. Long-term invasive and
noninvasive results of percutaneous balloon pulmonary valvuloplasty in children, adolescents,
and adults. Am Heart J. 1999;138:950–4.
40. Spiewak M, Biernacka EK, Malek LA, et al. Right ventricular outflow tract obstruction as a
confounding factor in the assessment of the impact of pulmonary regurgitation on the right
ventricular size and function in patients after repair of tetralogy of Fallot. J Magn Reson
Imaging. 2011;33(5):1040–6.
41. Latus H, Gummel K, Rupp S, et al. Beneficial effects of residual right ventricular outflow tract
obstruction on right ventricular volume and function in patients after repair of tetralogy of
Fallot. Pediatr Cardiol. 2013;34(2):424–30.
42. Redington AN, Rigby ML, Shinebourne EA, Oldershaw PJ. Changes in the pressure-volume
relation of the right ventricle when its loading conditions are modified. Br Heart J. 1990;
63:45–9.
43. Bogaard HJ, et al. Chronic pulmonary artery pressure elevation is insufficient to explain right
heart failure. Circulation. 2009;120(20):1951–60.
44. Thum T, Borlak J. Gene expression in distinct regions of the heart. Lancet. 2000;355(9208):
979–83.
45. del Cerro MJ, Abman S, Diaz G, et al. A consensus approach to the classification of pediatric
pulmonary hypertensive vascular disease: report from the PVRI Pediatric Taskforce, Panama
2011. Pulm Circ. 2011;1:286–98.
46. Berger RM, Beghetti M, Humpl T, Raskob GE, Ivy DD, Jing ZC, Bonnet D, Schulze-Neick I,
Barst RJ. Clinical features of paediatric pulmonary hypertension: a registry study. Lancet.
2012;379(9815):537–46.
47. Humpl T, Schulze-Neick I. Pulmonary vascular disease. In: Anderson RH, Baker EJ, Penny
DJ, Redington AN, Rigby ML, Wernovsky G, editors. Paediatric cardiology. 3rd ed.
48. Hopkins WE, Ochoa LL, Richardson GW, Trulock EP. Comparison of the hemodynamics and
survival of adults with severe primary pulmonary hypertension or Eisenmenger syndrome.
J Heart Lung Transpl. 1996;15:100–5.
49. Blanc J, Vouhe P, Bonnet D. Potts shunt in patients with pulmonary hypertension. N Engl J
Med. 2004;350:623.
50. Esch JJ, Shah PB, Cockrill BA, Farber HW, Landzberg MJ, Mehra MR, Mullen MP, Opotowsky
AR, Waxman AB, Lock JE, Marshall AC. Transcatheter Potts shunt creation in patients with
severe pulmonary arterial hypertension: initial clinical experience. J Heart Lung Transplant.
2013;32(4):381–7.
51. Schindler MB, Hislop AA, Haworth SG. Postnatal changes in response to norepinephrine in the
normal and pulmonary hypertensive lung. Am J Respir Crit Care Med. 2004;170(6):641–6.
Chapter 6
The Systemic Right Ventricle in Biventricular
and Univentricular Circulation
Heiner Latus, Christian Apitz, and Dietmar Schranz
The Systemic Right Ventricle in Biventricular Circulation
The right ventricle (RV) in congenital heart disease [1] can be responsible for the
support of pulmonary (subpulmonary RV), the systemic (systemic RV) or for both
circulations (univentricular RV). The subaortic positioned right ventricle (systemic
RV) belongs to congenital heart diseases with transposition abnormalities (Fig. 6.1).
Atrial-ventricular concordance combined with ventriculo-arterial discordance
defines d-loop transposition of the great arteries (d-TGA, [2]); double discordance
is characterized by a congenitally corrected l-loop transposition of the great arteries
(ccTGA, [3, 4]). The origin of both great arteries from the right ventricle is described
as a “double outlet right ventricle, DORV,” which can be associated with or without
malpositioned great arteries and thus with a subpulmonary or subaortic ventricular
septal defect (VSD) (Video 6.1). Considering the anatomic and physiologic princi-
ples of a RV in an unaffected normal circulation, it remains problematic to translate
these to a subaortic RV, which has to provide and to guarantee systemic blood flow.
The main problem relates to the systemic position of the right ventricle and
com/videos/978-1-4939-1064-9.
H. Latus, M.D. • C. Apitz, M.D. • D. Schranz (*)
Department of Pediatric Cardiology, Justus-Liebig-University,
Feulgenstrasse. 10-12, Giessen 35385, Germany
e-mail: heiner.latus@paediat.med.uni-giessen.de; christian.apitz@paediat.med.uni-giessen.de;
dietmar.schranz@paediat.med.uni-giessen.de

104 H. Latus et al.
Fig. 6.1 Congenital corrected Transposition of the Great Arteries (ccTGA) (a) Shows the cartoon
of atrial–ventricular discordance + ventricular–arterial discordance = double discordance. (b)
Depicted is four-chamber view of a ccTGA (atrioventricular discordance) with Ebstein-like valve
(arrows) of the systemic right ventricle, which is connected to the left atrium
tricuspid valve because these structures are not “designed” for long-term function in
a high-pressure circuit. Additionally, the morphological and physiological right–left
ventricular interactions are different when compared to normal anatomy. Under nor-
mal conditions the tripartite right ventricle with its inlet–outlet time-delayed con-
traction pattern produces in a low-pressure pulmonary circulation the same cardiac
output as the left, but by one fifth of the energy cost of the left ventricle. In addition,
the left ventricle seems to be responsible for almost 60 % of the right ventricles
function [5]. In the ccTGA morphology, the ellipsoid contraction of a systemic left
ventricle with a convex right-sided septum is changed to an underutilized subpul-
monary left ventricle where the concave left-shifted septum impacts both the ventricu-
lar and the tricuspid valve function (Chap. 5). Tricuspid valve regurgitation due to its
leaflet insertion at the ventricular septum and the pressure-driven ventricular septum
shift to the left (leftward bulging); this becomes even more pronounced in a stressed
or diseased systemic RV. Tricuspid valve regurgitation in the setting of a systemic
right ventricle is detrimental [6]. Recently published data of adults with a sys-
temic right ventricle have shown that a right ventricular end-diastolic volume above
150 mL/m2 combined with a peak systolic blood pressure during exercise identifies
patients at risk of complications within 1 year in 19 % [7]. Additionally, a major
difference persists between a systemic right ventricle adapted since neonatal life
and a ventricle which is pressure loaded later in life. Among other factors, the coro-
nary perfusion pattern has to be considered. Usually the coronary artery of the RV
in a low-pressure pulmonary circulation is perfused during systole and diastole, but
preferentially during systole. A subaortic positioned RV is exclusively perfused dur-
ing diastole. Coronary blood flow measurements in patients with ccTGA indicate
6 The Systemic Right Ventricle in Biventricular and Univentricular Circulation 105
that the coronary flow reserve is decreased in the absence of ischemic symptoms.
The global impairment of stress flow dynamics may indicate an altered global vaso-
reactivity and quantitative changes in microcirculation, suggesting a role for both in
the pathogenesis of systemic right ventricular dysfunction [8].
In addition to the well-known detrimental effects of pressure, volume overload,
and ischemia the systemic RV has the additional problems of “After-loading—
Metabolizing—Ventricular interaction—Residual lesions.”
Congenitally Corrected Transposition of the Great Arteries
By definition, ccTGA, with its subaortic RV and its particular tricuspid valve (TV)
placement, supports the systemic circulation during neonatal life. Most newborns,
infants, and young children with isolated ccTGA remain asymptomatic. The diag-
nosis may be made in adult life in asymptomatic patients, usually by identifying a
systemic ventricle with RV morphology and its left-sided position; ventricular tra-
beculations, moderator band (trabecula septomarginalis, Leonardo band positioned
between interventricular septum and musculus papillaris anterior), and by TV leaf-
let insertion at the ventricular septum as well as by the slightly more apical insertion
of the septal leaflet of a morphologically tricuspid valve in comparison of the right
side positioned mitral valve (Fig. 6.1a, b, Video 6.2a). Somerville et al. [9] reported
a “natural and unnatural” history of ccTGA with two adequate ventricles managed
over a 20-year period in survivors aged from 1 to 58 years (median 20); all but 10 %
of these had additional anatomic abnormalities. Tricuspid valve abnormalities were
more prevalent in patients with symptomatic heart failure (>50 % of patients) than
those whose main problem was cyanosis (20 % patients); all dysplastic or Ebstein
valves were at least moderately incompetent. Intra-cardiac repair of the lesion leav-
ing the RV in a subaortic position was performed in the past with an early high
mortality rate of more than 20 %; the risk factors for early death or a bad early
outcome or poor result 6 months later related to a poor preoperative symptomatic
status (especially from heart failure), impaired right ventricular function, heart
block and younger age at surgery [10]. Patients with more than mild preoperative
tricuspid regurgitation (TR), whose valves were not replaced, did very poorly [6,
10]. In addition, TR is the most significant independent predictor of outcome.
However, TR strongly relates to RV dysfunction, raising the question whether
TR leads to RV dysfunction or the other way around. By contrast, the course of
patients, who were predominantly cyanotic, was more stable in early childhood and
their surgical outcome was less compromised by a poor preoperative symptomatic
status [9]. Considering the long-term outcome, RV systolic dysfunction might be
the consequence of regurgitation in those with a malformed tricuspid valve as in
Ebstein’s anomaly. It appears that the ventricular geometry and the design and func-
tion of the tricuspid valve are most important [6, 11]. However, the factors respon-
sible for intrinsic failure of the systemic RV are not understood. It is possible that
biventricular interactions are the fundamental basis for this pathophysiology [5].
106 H. Latus et al.
Therefore, some associated lesions might have protective properties others promoting
right ventricular failure. Obstructions at any part of the pulmonary outflow tract are
in a wide range protective by decreasing the rate of early or the rate of late right
ventricular failure due to an unloaded subpulmonary left ventricle. Our improved
understanding of the pathophysiology of interventricular interaction (see also
Chap. 7), has led to the abandonment of complete, gradient-free surgical resection
of any pulmonary obstruction and alternative strategies for the patients with ccTGA
are being developed. Pulmonary artery banding (PAB) is used to retrain the subpul-
monary left ventricle in order to enable a double switch operation consisting of an
atrial switch (Senning, Mustard operation) together with an arterial switch (Jatene—
operation), or by creation of an interventricular tunnel (Rastelli-like operation), but
also as a destination therapy to reverse the septal shift back to the subaortic RV with
a restoration of the tricuspid valve competency and right ventricular function [11,
12]. The question still needs to be answered whether the strategy of PAB is limited
to children or adolescents [12]. In agreement with Redington, the currently unsatis-
factory results in adults after PAB are due to imperfect banding procedures rather
than an intrinsic inability of “retraining” the more aged left ventricle [4]. Assuming
the availability of a banding device that generates a graded outflow obstruction
(adjustable banding) one can hypothesize, that the LV, weaned off systemic pres-
sures even over decades, has the chance for retraining and recovery. New percutane-
ous or Hybrid surgical- (interventional) procedures are now feasible to delay heart
or heart–lung transplantation (Video 6.2b, c). Regarding pathophysiological obser-
vations, reversible PAB is already considered as a prophylactic tool in newborns and
infants with ccTGA [13]. Postnatal adaption of the subpulmonary left ventricle
from fetal or immediate postnatal hypertension to a low-pressure circulation should
be avoided or readapted, if the subpulmonary left ventricle is already unloaded.
The risk of the procedure is low as younger the patient’s age (Fig. 6.2a, b).
Fig. 6.2 (a, b) Congenital corrected Transposition of the Great Arteries (ccTGA) in an infant who
received a prophylactic pulmonary artery banding (PAB) to prevent dilatation of the systemic right
ventricle. By the French [5] technique the PAB is balloon dilatable with the option of “growing”
and therefore hypothetical life-long effectiveness
Recently, Thomas Karl [14] summarized nicely the role of surgical strategies
including the Fontan circulation in the treatment of ccTGA (see also Chap. 8). He
states that the unfavorable outcome for physiologic repairs (including VSD closure,
conduit insertion, TV repair replacement, etc.) are well documented. The physio-
logic repair creates a situation similar to that of the ccTGA with intact ventricular
septum without left ventricular outflow tract obstruction (LVOTO), but with the
added potential burden of myocardial or conduction tissue injury and prosthetic
material. However, the major factor of the unfavorable postoperative evolution is the
structure of the tricuspid valve. The congenital or acquired abnormality of the TV
tends to limit the long-term functional support of in the systemic circulation. In this
context, Roger Mee at al. in Melbourne in the late 1980s was the first employed
PAB for left ventricular retraining in both concordant and discordant TGA [15].
It was noted at the time that patients who had undergone PA banding alone often had
a favorable septal shift, which in itself could reduce tricuspid insufficiency without
additional surgical procedures. Mee et al. extended the developed concept of ana-
tomic repair of TGA patients with failing Mustard or Senning operation to the pri-
mary repair of ccTGA. Additionally, Karl [14, 15] mentioned the strategy proposed
by Mavrouidis et al. [16] for cases of ccTGA with a VSD and LVOTO, which is
known as 1.5 ventricular repair. This approach may be an option that is somewhere
in between the extremes of an anatomic and physiologic repair. In this regard, the
1.5 ventricle repair appears to be an effective solution for selected cases. The LV
volume load is reduced by the use of the bidirectional cavopulmonary shunt (Glenn-
shunt) limiting the LV to PA pressure gradient, which technically constitutes a phys-
iologic repair, with a low mortality [16]. The general concept of the Fontan
circulation in potentially septable biventricular hearts is also part of Chap. 8.
In summary, ccTGA is a highly problematic malformation. The right ventricle in
ccTGA might be considered as a pure form of a systemic right ventricle [4].
Electrical disturbances, as congenital AV-block are already frequently observed in
fetal life as well as life threatening supraventricular tachycardia. In addition to
described coronary functional abnormalities [7], morphological coronary anomalies
are found in 45 % of the heart specimens [17]. Any additional volume or pressure
stress has to be considered as highly dangerous for the systemic RV. However, the
reasons for the intrinsic myocardial right ventricular failure still need to be investi-
gated. Unproportional stress forces are an increased afterload due to any aortic
valve or arch obstructions or volume overload of the systemic RV. Important seems
to be to differentiate between a volume workload caused by tricuspid valve regurgi-
tation, aortic valve insufficiency, or a right ventricle dependent left-to-right shunt.
Considering the data by Prieto et al. [6], those patients with trivial or only mild tri-
cuspid incompetence might have virtually normal symptom-free survival. Improved
knowledge of the mechanisms of systemic RV failure might also have a direct
impact on the assessment of right ventricular dysfunction in an anatomically normal
positioned RV (Chap. 5). Therefore, in the context of an unexplained or idiopathic
precapillary pulmonary hypertension, it is hypothesized that a patient with a subpul-
monary left ventricular might have a better long-term outcome, than a patient with
a morphological normal subpulmonary RV. The left ventricular structure of the
108 H. Latus et al.
subpulmonary ventricle prevents early failure even in the case of suprasystemic

pulmonary hypertension. Theoretically many of therapeutic options exist, but both
ventricles have to be analyzed in concert and not as separate entities.
Atrial Switch Operations (Mustard and Senning Procedure)
d-Transposition of the great arteries (d-TGA) accounts for 2.6–7.8 % of all cases of
CHD [18] and is characterized by ventriculo-arterial discordance resulting in a par-
allel pulmonary to systemic circulation. During fetal life the parallel-connected cir-
culations and the postulated higher right ventricular output of 55 % versus 45 % of
the left ventricle seems to compensate for the relative lower oxygen saturation of the
vital organs. Discussions are still ongoing whether the d-TGA dependent relative
lower oxygen content of the fetal perfused coronary and in particular cerebral circu-
lation has negative consequences. Postnatally uncorrected d-TGA is incompatible
with life unless any communication at the venous, atrial, ventricular, or arterial level
exists, followed by a surgical switch of the circulation either at the atrial or great
artery, known as either physiologic or anatomic repair. The Mustard and Senning
operations [19, 20] have first been performed over 50 years ago and have fundamen-
tally changed the long-term perspective for these patients until Adib Jatene [21] in
Brazil was the first to perform an anatomic repair of d-TGA in 1975. The arterial
switch operation now represents the standard surgical procedure that restores
ventriculo-arterial concordance [22]. However, the atrial switch operation was the
first successful intervention allowing long-term survival of children with d-TGA. By
creating atrioventricular discordance, this procedure turned the systemic and pul-
monary circulation to work in series although the right ventricle remained in a sys-
temic position (Fig. 6.3). The majority of adult d-TGA patients are at a higher risk
of late RV dysfunction, arrhythmias, and tricuspid valve insufficiency. Moons et al.
reported actuarial survival rates at 10, 20, and 30 years of 91.7 %, 88.6 %, and
79.3 %, respectively [18]. The main concern regarding the long-term prognosis for
patients after an atrial switch operation relates to the function of the systemic
RV. The systemic RV in atrial switch patients is characterized by impaired ventricu-
lar filling, a variable pattern of interventricular interaction, ventriculo-vascular
uncoupling, and myocardial perfusion abnormalities resulting in progressive sys-
tolic as well as diastolic dysfunction [23–26]. Defining an RV ejection fraction of
≥50 % as normal, mild ventricular dysfunction can be detected in the majority of
the patients after atrial switch operations, however, in up to 10–20 % of the total
patient population RV dysfunction becomes severe [23]. Reversible and fixed myo-
cardial perfusion defects with concordant regional wall motion abnormalities occur
in the systemic RV 10–20 years after the Mustard repair for d-TGA. These may play
an important role in the development of late right ventricular dysfunction in this
patient group [24]. Derrick et al. [25] found a reduced stroke volume response to
exercise and dobutamine stress in patients after the Mustard operation, despite
appropriate responses in load-independent indexes of contraction and relaxation.
Fig. 6.3 MRI four-chamber view shows the intra-atrial baffle redirecting the pulmonary veins to
the anterior positioned subpulmonary right ventricle; the systemic veins are tunneled and directed
to the subpulmonary posterior positioned left ventricle
The failure to augment stroke volume was caused by impaired right ventricular
filling rates during tachycardia, presumably as a result of impaired atrioventricular
transport, intimately related to the abnormal intra-atrial pathway morphology
(baffle). As a consequence of these findings it has to be considered that atrial switch
patients have chronotropic incompetence because stroke volume decreases propor-
tionally with increasing heart rate, and this despite the use of an inotropic drug, like
dobutamine. In this context, it is mandatory to discriminate between heart failure
caused by systolic and/or diastolic myocardial dysfunction and the incompetence to
adequately increase cardiac output because of filling limitations as by an atrial baf-
fle or due to decreased diastolic compliance as observed in the Fontan circulation
(Chap. 8). Inability to increase systemic flow in the absence of ventricular dysfunc-
tion is also noted in large shunt defects and in patients with a reduced pulmonary
capillary bed (Chap. 5). However, such fundamental pathophysiological differences
as the inability to increase cardiac output despite near normal cardiac function have
to be considered with regards to pharmacological studies. Otherwise well-designed
and methodologically sound, placebo-controlled, double-blind, randomized trials
can lead to misinterpretation. In the study by Dore et al. [26] the effect of angioten-
sin receptor blockade on exercise capacity in adults with systemic right ventricles
was investigated and the authors found that losartan did not improve exercise capac-
ity or reduce NT-proBNP levels. Subsequently, the author’s general conclusion was
that the systemic RV seems to be resistant to the effect of angiotensin-converting
110 H. Latus et al.
enzyme inhibition or angiotensin receptor blockade. Regarding the inclusion criteria

of this study, patients had been selected that did not have a great chance to benefit
from losartan therapy. The study results rather support the pathophysiology of
Mustard patients with a functional class of < NYHA III; in these patients altering the
afterload (because of the mentioned impaired atrioventricular inflow characteris-
tics) cannot adequately increase the cardiac output. Therefore, it remains unknown
whether a severely compromised systemic RV might benefit from angiotensin
receptor blockade. Comparable studies were undertaken in patients with a single
ventricle circulation (Chap. 8), where pathophysiologically non-phenotyped
patients were randomized; again, ACE-inhibitors were found to be not effective
[27]. However, beneficial effects of ACE-inhibitors were reported in the treatment
of children affected by ventricular volume overload due to valvular regurgitation
resulting in the regression of LV volume overload and reduction of LV hypertrophy
[28]. In evaluating the impact of ACE-inhibitors in patients with inflow limitations,
important differences in the pathophysiology of heart failure in congenital versus
acquired heart disease can be defined. However, if drugs such as ACE-inhibitors
reduce ventricular hypertrophy, improve systolic and diastolic function, then should
ventricular size, mass and function, as well as AV-valve regurgitation should become
important study endpoints. Considering the gene expression profile of the systemic
right ventricle, pharmacological therapy with ACE-inhibitors and angiotensin
receptor blockers should be effective as reported in the treatment of the systemic left
ventricle, but less effective in the subpulmonary ventricle, regardless whether
theirs is a left or right morphology (see Chap. 5). The atrial switch of the venous
connection to the right and left atria might reverse the metabolic profile of the
mal-connected ventricles. The anatomical left, subpulmonary ventricle shows the
expression of cytochrome P450 genes normally found in the RV [29]. Emphasizing
the importance of the subpulmonary ventricle and pulmonary circulation for detoxi-
cation of drugs and for the diminished expression of cytochrome P450 genes in the
systemic ventricle [29]. Based on the available published data, whether the right
ventricle is the wrong target, in congenital heart diseases [30] remains presently
unclear. This is particularly true, if pharmacological studies are analyzed with a
direct myocardial focus on mind and neglecting the influence of preload and
afterload [31]. Patients with systemic right ventricle treated with eplerenone
showed an improvement of an altered baseline collagen turnover biomarker profile,
suggesting that reduction of myocardial fibrosis might be a therapeutic target in
these patients. In addition to the pharmacological strategies to support the systemic
right ventricle, mechanical intervention as described above in the context of the
patients with ccTGA is an additional option. Ventriculo-ventricular interaction may
improve the function of the subaortic RV and this may allow left ventricular retrain-
ing in order to prepare the subpulmonary left ventricle for a double switch opera-
tion. The option “to retrain” the subpulmonary left ventricle in adolescents and
young adults in comparison to newborns and infants is probably limited [11], but
retraining may be feasible in adult patients by using novel adjustable pulmonary
banding technique [4].
The Right Ventricle in the Univentricular Circulation
The patient born with a right ventricle as the only functional ventricle responsible
for both, the pulmonary and the systemic circulation is stressed by volume and pres-
sure load. The most common form of a functionally single ventricle is the hypoplas-
tic left heart syndrome (HLHS) [32, 33]. HLHS describes the spectrum of left heart
under-development (Video 6.3), rendering the left side of the heart unable to support
the systemic circulation. Untreated HLHS is fatal. The majority of patients die
within the newborn period [32]. Current management consists of a staged palliation.
The Norwood procedure is usually performed at a few days of age, combining the
aorta and pulmonary artery and creating a systemic to pulmonary artery shunt, and
in the form of the Sano variant, aortic arch reconstruction with a right ventricular to
pulmonary artery shunt [33]. An alternative to such advanced surgical procedures is
the “Giessen Hybrid” approach consisting of surgical bilateral pulmonary banding
and duct stenting and, if necessary, manipulation of the atrial septum without the
need for cardiopulmonary bypass and cardiac arrest [34]. Later surgical stages
involve the connection of the superior vena cava with the pulmonary arteries (Glenn
anastomosis) followed by routing of the inferior vena caval flow to the pulmonary
circulation to complete the total cavopulmonary connection (TCPC), and leaving
the patient with a systemic right ventricle (see Chap. 8). During fetal life the right
ventricle takes over the function of the “missing” left ventricle. The fetal right ven-
tricle in HLHS becomes more spherical because of an increased RV diameter. This
RV is relatively reduced longitudinally, shows a circumferential deformation and an
increased reliance on atrial contraction for ventricular filling [35, 36]. Postnatally, a
double flow volume, consisting of the systemic as well as pulmonary veins, has to
cross the tricuspid valve, which makes the valve vulnerable for insufficiency. In the
context of a dilated tricuspid annulus as well as a right ventricle cavity containing
double the blood volume, the pulmonary valve annulus and pulmonary trunk are
extended. A postnatal patent ductus arteriosus is a conditio sine qua non to support
the systemic circulation via the right ventricle. The postnatal adaption with the ten-
dency of a decreasing pulmonary vascular resistance and spontaneous duct closure
due to a loss of maternal prostaglandins and due to higher blood oxygen saturation
is a risk factor for the acute deterioration and retrograde coronary perfusion. The
combined volume and pressure load persists after a stage I approach, and not before
a stage II approach. With the direct connection of the superior caval vein to the
pulmonary artery to serial circulation the systemic RV adapts with volume reduc-
tion, a preserved stroke volume and an increased ejection fraction [37]. Considering
the published data from the “Pediatric Heart Network Investigators” the presence of
a single systemic right ventricle did appear to predict worse exercise performance
and abnormalities of systolic and diastolic function [38, 39]. In addition, tricuspid
valve repair becomes relatively frequently necessary and may improve significantly
the tricuspid valve coaptation length and reduced right ventricle volume in children
with HLHS [40]. However, it remains unclear whether such a surgical approach
leads to temporary RV improvement related to reduced right ventricle preload,
112 H. Latus et al.
permanent right ventricle dysfunction from a too late repair of the tricuspid valve,
or unavoidable sequel of a right ventricle exposed to a systemic vascular resistance.
Mechanical or electromechanical interventions are currently the most promising
therapeutic strategies to improve support to the failing systemic right ventricle.
However, the results of pharmacological may be better understood in the context of
the intrinsic mechanisms of (right) ventricular dysfunction, and the context of the
different pathophysiology of operated and unoperated congenital heart disease.
Summary for the practitioner
1. The systemic right ventricle in a functionally biventricular or univentricular

circulation, and its modification by surgery, needs to be analyzed, as mentioned
in Chap. 5, in terms of “function and form,” but even more in context of pre-
load, afterload, and rhythm and synchrony.
2. Three of the most common lesions associated with a systemic RV are: congeni-
tal corrected transposition (ccTGA), atrial switch in patients with d-TGA, and
the dominant systemic right ventricle in patients born with HLHS.
3. Systemic pressure load of the subaortic RV is the consequence of the congenital
abnormal morphology. However, the pressure adapted, postnatal never unloaded
RV should have per se long-term survival chance.
4. The systemic RV embedded often in abnormal inflow and/or outflow condi-
tions, and bad-featured with an abnormal ventriculo-ventricular interaction is
disposed for early or mid-term dysfunction with a considerable morbidity and
mortality.
5. Tricuspid valve regurgitation with backward failure of the systemic RV is the
main reason for low cardiac output during exercise or at rest.
6. Therapeutic interventions cannot be transferred from the anatomical normal
biventricular circulation with a failing subaortic left ventricle. Several pharma-
cological studies performed in congenital heart disease with systemic right ven-
tricle remained unsuccessful probably by neglecting limitations to increase the
flow to the heart (preload incompetence), if the afterload deceases.
7. However, pharmacological interventions making positive results to improve
backward failure by chronic tricuspid valve regurgitation or to achieve anti-
fibrotic goals in chronic diastolic dysfunctional right ventricle.
8. Mechanical interventions by retraining an unloaded subpulmonary left ventri-
cle are most promising strategies to improve a failing right ventricle but even to
give the basis for further surgical options.
9. The right ventricle as an univentricular heart remains postnatally adapted to
systemic pressure levels, but life-long highly sensitive to volume overload.
10. A three-stage procedure finishing in a Fontan circulation allows switching a
parallel-connected circulation to serial, volume-reduced circulation.
References
1. Davlouros PA, Niwa K, Webb G, Gatzoulis MA. The right ventricle in congenital heart disease.
Heart. 2006;92 Suppl 1:i27–38.
2. Schiebler GL, Edwards JE, Burchell HB, Dushane JW, Ongley PA, Wood EH. Congenital cor-
rected transposition of the great vessels: a study of 33 cases. Pediatrics. 1961;27(Suppl):
849–88.
3. De la Cruz MV, Amoedo M, Rivera F, Attie F. Arterioventricular relations and their classifica-
tion. Two specimens of arterioventricular discordance and review of published reports. Br Heart
J. 1974;36(6):539–53.
4. Anderson RH, Shinebourne EA, Gerlis LM. Criss-cross atrioventricular relationships producing
paradoxical atrioventricular concordance or discordance. Their significance to nomenclature of
congenital heart disease. Circulation. 1974;50(1):176–80.
5. Altamira LA, Redington AN. Right ventricular failure in congenital heart disease. In: Shaddy
RE, editor. Heart failure in congenital heart disease. London: Springer; 2011.
6. Prieto LR, Hordof AJ, Secic M, Rosenbaum MS, Gersony WM. Progressive tricuspid valve
disease in patients with congenitally corrected transposition of the great arteries. Circulation.
1998;98(10):997–1005.
7. van der Bom T, Winter MM, Groenink M, Vliegen HW, Pieper PG, van Dijk AP, Sieswerda
GT, Roos-Hesselink JW, Zwinderman AH, Mulder BJ, Bouma BJ. Right ventricular end-
diastolic volume combined with peak systolic blood pressure during exercise identifies patients
at risk of complications in adults with a systemic right ventricle. J Am Coll Cardiol.
2013;62:926–36. pii: S0735-109.
8. Hauser M, Bengel FM, Hager A, Kuehn A, Nekolla SG, Kaemmerer H, Schwaiger M, Hess
J. Impaired myocardial blood flow and coronary flow reserve of the anatomical right systemic
ventricle in patients with congenitally corrected transposition of the great arteries. Heart.
2003;89(10):1231–5.
9. Lundstrom U, Bull C, Wyse RK, Somerville J. The natural and “unnatural” history of congeni-
tally corrected transposition. Am J Cardiol. 1990;65(18):1222–9.
10. van Son JA, Danielson GK, Huhta JC, Warnes CA, Edwards WD, Schaff HV, Puga FJ, Ilstrup
DM. Late results of systemic atrioventricular valve replacement in corrected transposition.
J Thorac Cardiovasc Surg. 1995;109(4):642–5.
11. Murtuza B, Barron DJ, Stumper O, Stickley J, Eaton D, Jones TJ, Brawn WJ. Anatomic repair
for congenitally corrected transposition of the great arteries: a single-institution 19-year expe-
rience. Thorac Cardiovasc Surg. 2011;142(6):1348–57.
12. Myers PO, Del Nido PJ, Geva T, Bautista-Hernandez V, Chen P, Mayer JE Jr, Emani
SM. Impact of age and duration of banding on left ventricular preparation before anatomic
repair for congenitally corrected transposition of the great arteries. Ann Thorac Surg.
2013;96:603–10. pii: S0003-4975(13)00833-3.
13. Metton O, Gaudin R, Ou P, Geelli S, Mussa S, Sidi D, Vouhe P, Raisky O. Early prophylactic
pulmonary artery banding in isolated congenitally corrected transposition of the great arteries.
Eur J Cardiothorac Surg. 2010;38:728–34.
14. Karl TR. The role of the Fontan operation in the treatment of congenitally corrected transposition
of the great arteries. Ann Pediatr Card. 2011;4:103–10.
15. Karl TR, Weintraub RG, Brizard CP, Cochrane AD, Mee RB. Senning plus arterial switch
operation for discordant (congenitally corrected) transposition. Ann Thorac Surg. 1997;64:
495–502.
16. Mavroudis C, Backer CL, Kohr LM, Deal BJ, Stinios J, Muster AJ, et al. Bidirectional Glenn
shunt in association with congenital heart repairs: the 1 ½ ventricular repair. Ann Thorac Surg.
1999;68:976–81.
17. Ismat FA, Baldwin HS, Karl TR, Weinberg PM. Coronary anatomy in congenitally corrected
transposition of the great arteries. Int J Cardiol. 2002;86:207–16.
114 H. Latus et al.
18. Moons P, Gewillig M, Sluysmans T, Verhaaren H, Viart P, Massin M, Suys B, Budts W, Pasquet
A, De Wolf D, Vliers A. Long-term outcome up to 30 years after the Mustard or Senning
operation: a nationwide multicentre study in Belgium. Heart. 2004;90(3):307–13.
19. Senning A. Surgical correction of transposition of the great vessels. Surgery. 1959;45:
966–80.
20. Mustard WT. Successful two-stage correction of the transposition of the great vessels. Surgery.
1964;55:469–72.
21. Jatene AD, Fontes VF, Paulista PP, de Souza LC, Neger F, Galantier M, Souza JE. Successful
anatomic correction of transposition of the great vessels. A preliminary report. Arq Bras
Cardiol. 1975;28(4):461–4.
22. Castaneda AR, Trusler GA, Paul MH, et al. The early results of the treatment of simple trans-
position in the current era. J Thorac Cardiovasc Surg. 1988;95:14–27.
23. Hurwitz RA, Caldwell RL, Girod DA, Brown J. Right ventricular systolic function in adoles-
cents and young adults after Mustard operation for transposition of the great arteries. Am J
Cardiol. 1996;77:294–7.
24. Millane T, Bernard EJ, Jaeggi E, Howman-Giles RB, Uren RF, Cartmill TB, Hawker RE,
Celermajer DS. Role of ischemia and infarction in late right ventricular dysfunction after atrial
repair of transposition of the great arteries. J Am Coll Cardiol. 2000;35(6):1661–8.
25. Derrick GP, Narang I, White PA, Kelleher A, Bush A, Penny DJ, Redington AN. Failure of
stroke volume augmentation during exercise and dobutamine stress is unrelated to load-
independent indexes of right ventricular performance after the Mustard operation. Circulation.
2000;102(19 Suppl 3):III154–9.
26. Dore A, Houde C, Chan KL, Ducharme A, Khairy P, Juneau M, Marcotte F, Mercier
LA. Angiotensin receptor blockade and exercise capacity in adults with systemic right ventri-
cles: a multicenter, randomized, placebo-controlled clinical trial. Circulation. 2005;112(16):
2411–6.
27. Hsu DT, Zak V, Mahony L, Sleeper LA, Atz AM, Levine JC, Barker PC, Ravishankar C,
McCrindle BW, Williams RV, Altmann K, Ghanayem NS, Margossian R, Chung WK, Border
WL, Pearson GD, Stylianou MP, Mital S, Pediatric Heart Network Investigators. Enalapril in
infants with single ventricle: results of a multicenter randomized trial. Circulation.
2010;122:333–40.
28. Mori Y, Nakazawa M, Tomimatsu H, Momma K. Long-term effect of angiotensin-converting
enzyme inhibitor in volume overloaded heart during growth: a controlled pilot study. J Am
Coll Cardiol. 2000;36:270–5.
29. Thum T, Borlak J. Gene expression in distinct regions of the heart. Lancet. 2000;355(9208):
979–83.
30. Roche SL, Redington AN. Right ventricle: wrong targets? Another blow for pharmacotherapy
in congenital heart diseases. Circulation. 2013;127(3):314.
31. Dos L, Pujadas S, Estruch M, Mas A, Ferreira-González I, Pijuan A, Serra R, Ordóñez-Llanos
J, Subirana M, Pons-Lladó G, Marsal JR, García-Dorado D, Casaldàliga J. Eplerenone in sys-
temic right ventricle: double blind randomized clinical trial. The evedes study. Int J Cardiol.
2013;168:5167–73. pii: S0167-5273(13)01388.
32. Morris CD, Outcalt J, Menashe VD. Hypoplastic left heart syndrome: natural history in a geo-
graphically defined population. Pediatrics. 1990;85:977–98.
33. Barron DJ, Kilby MD, Davies B, Wright JGC, Jones TJ, Brawn WJ. Hypoplastic left heart
syndrome. Lancet. 2009;374:551–64.
34. Michel-Behnke I, Akintuerk H, Marquardt I, Mueller M, Thul J, Bauer J, Hagel KJ, Kreuder J,
Vogt P, Schranz D. Stenting of the ductus arteriosus and banding of the pulmonary arteries:
basis for various surgical strategies in newborns with multiple left heart obstructive lesions.
Heart. 2003;89(6):645–50.
35. Brooks PA, Khoo NS, Mackie AS, Hornberger LK. Right ventricular function in fetal hypo-
plastic left heart syndrome. J Am Soc Echocardiogr. 2012;25(10):1068–74.
36. Miller TA, Puchalski MD, Weng C, Menon SC. Regional and global myocardial deformation
of the fetal right ventricle in hypoplastic left heart syndrome. Prenat Diagn. 2012;32(10):
949–53.
37. Bellsham-Revell HR, Tibby SM, Bell AJ, Witter T, Simpson J, Beerbaum P, Anderson D,
Austin CB, Greil GF, Razavi R. Serial magnetic resonance imaging in hypoplastic left heart
syndrome gives valuable insight into ventricular and vascular adaptation. J Am Coll Cardiol.
2013;61(5):561–70.
38. Paridon SM, Mitchell PD, Colan SD, Williams RV, Blaufox A, Li JS, Margossian R, Mital S,
Russell J, Rhodes J. A cross-sectional study of exercise performance during the first 2 decades
of life after the Fontan operation. Pediatric Heart Network Investigators. J Am Coll Cardiol.
2008;52(2):99–107.
39. Anderson PA, Sleeper LA, Mahony L, Colan SD, Atz AM, Breitbart RE, Gersony WM,
Gallagher D, Geva T, Margossian R, McCrindle BW, Paridon S, Schwartz M, Stylianou M,
Williams RV, Clark III BJ, Pediatric Heart Network Investigators. Contemporary outcomes
after the Fontan procedure: a Pediatric Heart Network multicenter study. J Am Coll Cardiol.
2008;52(2):85–98.
40. Ugaki S, Khoo NS, Ross DB, Rebeyka IM, Adatia I. Tricuspid valve repair improves early
right ventricular and tricuspid valve remodeling in patients with hypoplastic left heart
syndrome. J Thorac Cardiovasc Surg. 2013;145(2):446–50.
Chapter 7
Right Ventricle in Structural and Functional
Left Heart Failure in Children
Dietmar Schranz, Heiner Latus, and Christian Apitz
The rationale for investigating the role of the right ventricle in children with structural
and/or functional left ventricular heart failure is based on the important interaction
of the sub-pulmonary and sub-aortic ventricle in healthy, and in particular in a failing
systemic ventricle [1, 2]. It is well known that superficial myocardial fibers are
shared and continuous between the right (RV) and the left ventricle (LV), providing
an anatomic basis for normal and abnormal ventriculo-ventricular interactions [3].
Damiano and coworkers showed in an elegant study of normal hearts, where the
ventricles were electrically isolated but mechanically intact, that under basal conditions
the LV contraction contributed more than 65 % of the work of the normal RV [4].
Therefore, under physiological conditions, the mechanical work formed on the right
side of the circulation, is a direct consequence of left ventricular contraction [4].
During the last decades a paradigm shift has occurred from a left or right-sided
“single” ventricle failure to a concept of biventricular disease regardless whether the
left or right ventricle is primarily altered [5, 6].
The first shift occurred when investigators recognized that pulmonary vascular
tone and lung vessel constriction is not only a passive phenomenon of left heart
disease, but might be associated to an “out-of-proportion” precapillary pulmonary
vascular reaction [7, 8]. However, the definition of “out-of-proportion” PH was
based on a transpulmonary gradient (TPG) calculated as the difference of mean
com/videos/978-1-4939-1064-9.
D. Schranz (*)
Department of Pediatric Cardiology, Justus Liebig University,
Feulgenstrasse 10-12, Giessen, Hessen, Germany
e-mail: dietmar.schranz@paediat.med.uni-giessen.de
H. Latus, M.D. • C. Apitz, M.D.
Pediatric Heart Center, Justus-Liebig-University, Feulgenstr 10-12, Giessen, Germany
e-mail: heiner.latus@googlemail.com; christian.apitz@paediat.med.uni-giessen.de

118 D. Schranz et al.
pulmonary artery pressure (PAP) and left atrial pressure, as if the TPG was not the
consequence of a pulsatile biventricular circulation but a rather non-pulsatile
“Fontan-like” circulation (see Chap. 8). Guazzi and Borlaug [7] reviewed that “in
the lung, downstream pressure (LAP) is a much more important contributor to mean
PAP, and this proportion (50 %) can become even greater in heart failure. PAP
elevation may be associated with a purely passive increase in LAP, with a normal
TPG. This hemodynamic situation seems to reflect an early development of precap-
illary vascular changes as during the transition from passive to reactive PH. The
chronicity of the transition from passive to reactive PH is highly variable between
patients and does not appear to be consistently related to the severity of the LAP
elevation. Chronically, the RV may adapt to elevated afterload with hypertrophy.
The RV and LV are connected in series, and the reduction in RV output in advanced
heart failure may lead to under filling of the left ventricle. In addition to series
effects, the right and left heart shares a common space in the pericardium, so that
changes in right heart pressure and volume may affect the left heart in parallel.” This
cross talk or coupling between the right and left sides is referred to as “diastolic
ventricular interaction.” Therefore, the definition of “out-of-proportion” pulmonary
hypertension in children needs to be clarified. In the literature, “out-of-proportion
pulmonary hypertension” (OpPH) is defined by a transpulmonary pressure gradient
(TPG = mean pulmonary artery pressure - left atrial pressure) above 12 (15) mmHg,
if there is no pulmonary venous disease]. However, this definition is in our opinion
misleading and a cause of making wrong decisions. Investigators [9] have shown
that in many circumstances the difference between diastolic PAP and left atrial pres-
sure might be low despite a TPG above 15 mmHg if the mean PAP is utilized for the
TPG calculation. This suggests that the pulmonary vascular remodeling-dependent
increase of the pulmonary vascular resistance is likely not the major cause of the
pulmonary hypertension. Therefore the TPG defined, as the difference of diastolic
PAP and LAP should be added to the definition of “out-of-proportion” PH, which is
even called as PH with precapillary component. However, it has to be noticed, that
the term “out-of-proportion” PH is also encountered in different other conditions, in
particular in children with congenital heart disease ([10]; see Chap. 5).
In addition to the passive and reactive PH in left-heart diseases, more recently
investigators have begun to consider the RV as a participant in the pathophysiology
of left-sided left heart failure [2, 9], and thus as a treatment target. Every symptom-
atic patient with primary left heart disease, for example dilated cardiomyopathy
(DCM), experiences a diastolic right heart inflow impairment before systolic right
heart failure develops as a terminal consequence of increased afterload and isch-
emic coronary perfusion. These observations and conceptual developments justify
the search for additional reversal treatment strategies in order to halt progressive left
ventricular dilation and dysfunction and in an almost paradoxical of prevention of
subsequent right ventricular failure. Accepting these new concept shifts we began to
develop new therapeutic concepts starting with small children with left ventricular
dilated cardiomyopathy (LV-DCM) as well as with restrictive and borderline left
ventricular physiology in newborns and young adults by including the right ventri-
cle in the therapeutic strategy [11–14].
7 Right Ventricle in Structural and Functional Left Heart Failure in Children 119
The Right Ventricle in Context of Left Heart Failure

with Decreased Ejection Fraction
Heart failure of the systemic ventricle whether associated with the morphology of
left (LV), right (RV), or single ventricle (SV) is the main reason and cause of death
in children and in high-income countries, the main indication for heart transplantation
(HTX) [15].
Intrinsic mechanisms initially are compensating at rest, as long, as the right
or sub-pulmonary ventricle is not compromised by an extreme diastolic inflow
problem or by systolic dysfunction caused by an “out-of-proportion” afterload and/
or additional subendocardial ischemia.
In LV-DCM, initially the dilatation of the left ventricle preserves the stroke
volume at rest at the cost of a high end-systolic volume; in the “borderline left
ventricle” (BLV) or restrictive cardiomyopathy (RCM) proportional precapillary
pulmonary hypertension initially prevents pulmonary edema, but this is followed in
a high percentage with an “early out-of-proportion precapillary pulmonary vascular-
reactivity” which is followed by vascular remodeling.
LV-DCM and the Role of the Right Ventricle in Children
Dilated cardiomyopathy of the left ventricle (LV-DCM) is a myocardial disease

with systolic cardiac dysfunction accompanied by progressive left ventricular
dilatation [15–17].
DCM is the most common form of cardiomyopathy in children [18–19]. DCM is
primarily an echocardiographic (ECHO) diagnosis that characterizes a phenotype
associated with a dilated, poorly functioning left ventricle [20, 21]. Right ventri-
cular systolic myocardial function (Video 7.1) is often not or less impaired than the
dysfunctional LV [22]. However, the RV might be compressed by the LV, which
changes its shape through interactions between the RV and the markedly enlarged
LV. Therefore, right ventricular (dys-) function seems to be under-recognized in
children presenting with idiopathic DCM [6, 23, 24]. The severity of LV dilation,
LV dysfunction, and mitral regurgitation has been associated with worse outcomes
in pediatric DCM [20]. Groner et al. [6] found that the need for circulatory support
and a left ventricular ejection fraction z-score less than −8 were primary determi-
nants of outcome, independent of the degree of derangement of the right ventricular
function. Anti-congestive heart failure therapies in pediatric DCM vary among
practitioners, with no large efficacy studies demonstrating a benefit of current regi-
mens [25, 26]. The prognosis varies depending on the underlying etiology [19].
Singh et al. [27] reported that the severity of LV dilation at the time of listing for
heart transplant correlated with the outcome of infants and young children with
DCM. Children who were listed for heart transplantation had a median LVEDD
z-score of +5.7 and only +4.3 if they were not. About one third of children with
DCM die or receive a heart transplant in the first 5 years after diagnosis [20].
Reported freedom from death and transplantation at 1 year are 72 and 69 % and at
5 years 63 and 54 % [27, 28]. Survival rates from the time of DCM diagnosis have
been unchanged over several decades [25, 27, 28]. Thus, there is a need to pursue
additional strategies to avoid or to delay HTX in the pediatric DCM population. The
limited availability of donor organs, the medical side effects, and the reduced func-
tion of the transplanted organ with the passage of time, limit the long-term outcome
of patients after heart transplantation [20]. Alternative therapeutic options for chil-
dren with LV-DCM and advanced heart failure might be electrical re-synchronization
[29], perhaps on a compassionate basis autologous stem cell therapy [30] as well as
reversible pulmonary artery banding (rPAB), in particular in the younger patients,
as long as right ventricular function is still preserved [11, 12].
Observing the natural history of patients with a sub-aortic right ventricle (see
Chap. 6) or single right ventricle the following questions arise:
Can in a newborn, infant, or young child with LV-DCM and preserved right
ventricular function the right ventricle be surgically transformed to have an option
for a single ventricle physiology?
Does a positive myocardial stress, as pulmonary artery banding (PAB) (see
Chap. 13), exerted on the sub-pulmonary ventricle influencing the weak sub-aortic
(left) ventricle for improvement?
What are the mechanical and possibly anti-remodeling right–left heart interac-
tions beyond the mechanical aspects?
Reversible Pulmonary Artery Banding in LV-DCM
Observations of the natural life-span of neonates born with a sub-aortic right ven-
tricle, as in corrected congenital transposition of the great arteries (ccTGA, l-TGA)
or d-transposition of the great arteries (d-TGA) have clearly demonstrated the
importance of a balanced interaction between the ventricles ([31], see also Chap. 6).
A systemic RV might support a sufficient systemic circulation until adulthood, as
long as the sub-pulmonary left ventricle is postnatally prevented to adapt to a low-
pressure pulmonary circulation. Significant left ventricular outflow tract obstruc-
tions, or even pulmonary hypertension forestall systemic right ventricular dilatation
by the persistence of a high pressure LV. Misunderstanding of the pathophysiology
in the past has prompted surgeons to resect such anatomical obstructions. Currently,
PAB is used, if such an obstruction is absent. The surgical technique of PAB was
initially described more than 60 years ago [32]. Still today PAB is used to restrict
pulmonary artery blood flow to balance the systemic and pulmonary circulations in
cases of complex ventricular shunts, and in patients with a morphological right
ventricle of the systemic circulation which are candidates for an anatomic biven-
tricular repair (see Chap. 8). rPAB in corrected transposition of the great arteries
(ccTGA) is not only used for re-training the sub-pulmonary left ventricle [33, 34],
but also as an early preventative approach in newborns, to avoid severe tricuspid
Fig. 7.1 Acute effect of pulmonary artery banding (PAB) in an infant with LV-DCM. (a) TEE
(intraoperative transesophageal ECHO) shown is the four-chamber view in an infant with an
extreme dilated left ventricle (LVEDd left ventricular enddiastolic diameter) and its compression
of right ventricle (RV) before surgical PAB; (b) TTE (transthoracic ECHO) short axis view shows
the PAB and the pulmonary valve (PV); (c) TEE (intraoperative) depicts the acute repositioning of
interventricular septum (IVS) immediate after banding based on the RV pressure increase, LV
volume, and preload reduction as well as improved filling of the pressure loaded RV. Not shown is
the pressure gradient reduction across the PFO caused by the PAB-induced left ventricular preload
reduction
regurgitation that can be associated with the morphological right ventricle in a

systemic position [35].
Based on the convincing results of PAB in conditions with a systemic right
ventricle, we applied PAB for the treatment of DCM [11, 12] to preserve right ven-
tricular systolic and diastolic function as a strategy to delay, or even avoid heart
transplantation in infants and young children with terminal heart failure (Fig. 7.1a–c).
Best summarized is the novel PAB strategy by an editorial comment of LL Bailey
[36]; “done with care, in properly selected candidates, rPAB appears to shift the
ventricular septum leftward, thereby reducing left ventricular (LV) end-diastolic
volume and causing the LV to fall within the Frank-Starling curve, where LV reverse
remodeling may occur and LV ejection fraction increases; this might reduce LV fill-
ing dynamics and end-diastolic pressure and restore ventricular electromechanical
synchrony.” In addition, the use of rPAB seems to be especially attractive in very
young infants, whose potential for myocyte recovery and repopulation seems
greatest [37–39]. The neonatal myocardium is known to contain three times the
number of progenitor (proliferating) cells as found in the hearts of 2-year-olds and
those who are older. Based on our own research, pressure overload is an additional
factor, which leads to an increase of resident cardiac stem cells. Kuehn and coworkers
[40] showed that the percentage of cardiomyocytes undergoing mitosis and cytoki-
nesis was highest in infants, decreasing to low levels by 20 years, and that, between
the first year and year 20 of life, the number of cardiomyocytes in the left ventricle
increased 3.4-fold. They concluded, “that children and adolescents may be able to
regenerate myocardium, and that abnormal cardiomyocyte proliferation may be
involved in myocardial diseases that affect this cell population. These diseases
might be treatable through stimulation of cardiomyocyte proliferation.” Regarding
PAB in ccTGA, the adaptive ability of the sub-pulmonary ventricle is better the
younger the patient’s age [33]. Independent of a sub-aortic left or right ventricle,
the risk for surgical banding is lower, the younger the patient’s age, and it is
highly effective in generating right ventricular adaptation to PAB without the need
for re-banding. The patient should also have the chance to grow in the PAB. Acute
right ventricular adaption to rPAB occurs within 3–15 days, comparable to those
patients where a sub-pulmonary left ventricle is retrained [33, 34]. Regarding some
of the basic research results of PAB and its effects on the right ventricle (see
Chap. 13). In animal models with a non-diseased left ventricle the time course of
right ventricular hypertrophy development after PAB showed an exponential rise in
the RV mass during the first 3 weeks after PAB, and thereafter the RV mass reached
a plateau [41]. Published research data obtained in animal studies confirm that PAB
induced RV hypertrophy, which is accompanied by a slightly (almost 10–20 %)
hypertrophic reaction of an unaffected healthy left ventricle [42]. Additionally, there
appears to be a syncytial relationship between cardiomyocytes, fibroblasts, and the
cardiac matrix. A hypertrophy-fibrosis-angiogenesis program that initially allows a
compensated response of the RV to pressure overload and stretch seems to be essen-
tial for the adaptive mechanisms of the heart to pressure overload. In this context,
Takeda et al. [43] have provided evidence that in particular fibroblasts are essential
for the adaptive response of the heart to such pressure overload. Data from Bogaard
et al. [44] have confirmed that the hypertrophic RV after chronic PAB is character-
ized by an increase in the size of the myocardiocytes, a cell growth-directed gene
expression pattern and a maintained capillary network. During hypertrophic growth,
enhanced protein synthesis leads to an increase in the individual size of the myocar-
diocytes, whereas de-compensation is associated with proteolysis, a switch from
cell growth to cell death and replacement fibrosis.
However, in the clinical setting of reversible PAB in LV-DCM, clinical improve-
ment corresponded with an increase of the LV-EF a decrease of LVEDD and BNP-
blood levels (Video 7.2). In addition to mechanical interactions between the right
and left ventricle, we hypothesize that there are also biological signal interactions
between the right ventricle that undergoes hypertrophy and the improving LV [45].
The reversibility of the PAB is based on the specific surgical technique, which
allows percutaneous de-banding by a balloon dilation procedure with or without
residual pressure gradient [12]. Nevertheless, multicenter investigations are yet to
show whether the concept of rPAB leading to LV recovery can be expanded to older
children and whether rPAB diminishes the need for mechanical circulatory assist
devices and heart transplantation in the management of pediatric heart failure. Such
studies are necessary in order to assess long-term risks and benefits of the reported
surgical approach and to elucidate the mechanistic interactions between the hyper-
trophying right and dilated and dysfunctional left ventricle in patients with
LV-DCM. Bailey stated [36] “PAB in LV-DCM might have the potential of a game
changer if the approach is proven and based on a percutaneous procedure” [36].
The Right Ventricle in the Context of Restrictive Cardiomyopathy and

Borderline Left Ventricle: Heart Failure with Preserved Ejection Fraction
In contrast to DCM, RCM or a BLV is primarily associated with a diastolic dysfunc-

tional circulation [46, 47].
Heart failure with preserved left ventricular ejection fraction is attributed to

“abnormalities of diastolic function” [48]. Diastolic dysfunction with preserved left
ventricular ejection fraction is relatively rare but already present in a newborn,
child, or young adult, often associated with congenital or acquired myocardial
fibrosis (RCM) or a structural “borderline left ventricle” with or without additional
endocardial fibroelastosis [49, 50].
The entity of a too small ventricle as well as structural left heart diseases like
pulmonary vein stenosis, total anomalous venous return, mitral or aortic valve
diseases and aortic arch obstruction as a single disease or as a multiple structural
abnormalities disease (Shone complex), have the potential to be associated with an
out-of-proportion pulmonary hypertension and subsequent right heart failure [51].
The Right Ventricle in Context of Borderline Left Ventricle
Borderline and hypoplastic left heart structures are defined by z-score values more
than −2 SD deviating from the norm (Video 7.3). From the pathophysiological point
of view this means that the filling of the ventricle is limited, the capacity of the
end-diastolic volume at rest or during exercise is diminished and the end-systolic
volume is minimized [51]. Therefore, the ventricular compliance is reduced by its
inability to relax, but the systolic function. The therapeutic strategies are limited and
any surgical approach challenging. Trials to resect part of the endocardial fibroelas-
tosis have been performed with success in some cases [52].
One therapeutic option in newborns with BLV might be a “Hybrid approach”
which consists of bilateral pulmonary banding, duct stenting and, if necessary, inter-
atrial stenting [53, 54], which gives the right ventricle the chance to work in concert
with the diminutive left ventricle. The hybrid approach allows the delay of the final
decision of generating a bi- or uni-ventricular circulation later, which depends on
the further development of the affected left ventricle (Fig. 7.2a, b). In infancy,
patients with left heart induced “out-of-proportion” pulmonary hypertension and
right ventricular failure, might be helped by duct stenting, not only as a life saving
approach, but even as an option for recovery and delayed surgical correction.
Therefore, careful structural assessment of patients with right ventricular failure
based on pulmonary vascular suprasystemic pressures is necessary in order to
consider additional therapeutic strategies like stenting of a still, even minimal patent
ductus arteriosus to achieve a pulmonary-to-aortic (Potts-shunt-like) communica-
tion (Fig. 7.3, Video 7.4a, b). Considering such experience in newborns and infants,
“hybrid strategies” might have even survival potential in adolescent patients. Before
heart–lung transplantation is considered, which is associated with high initial mortal-
ity and a limited long-term survival [55], a diastolic dysfunctional structurally left
heart might be supported by creation of such a Potts-like shunt to establish a paral-
lel circulation in part. The timing of a “Hybrid approach” in a BLV or complex
structural left heart disease with dysfunctional global circulation is difficult. “Out-
of-proportion” pulmonary hypertension and subsequent right ventricular failure
which necessitates the listing for heart–lung transplantation might be such a criterion
Fig. 7.2 (a) MRI 4-chamber

view of newborn with
borderline left ventricle (LV),
the right ventricle (RV) is
apex forming, postnatally the
patient has a duct-dependent
systemic blood flow
guaranteed by the RV
function and persistent
pulmonary hypertension;
(b) Duct stenting and
bilateral pulmonary banding
allows survival without
prostaglandin infusion,
protection of the distal
pulmonary vasculature by
flow and pressure reducing
and gives the chance for
further LV developing by
preserving sufficient preload
and the decision for later
bi- or univentricular repair
(Cartoon is a courtesy by
Hakan Akintürk)
favoring a “hybrid approach” consisting of percutaneous atrioseptostomy, interatrial

stenting, or device implantation for a definitive interatrial fenestration combined
with a surgical [12, 56] or transcatheter [57] performed Potts-like shunt (Video 7.4).
However, whether such a strategy will indeed improve survival with improved
quality of life needs to be examined in multicenter studies. From a pathophysiology
point of view left-to-right shunt at the atrial level together with a pulmonary-
systemic right-to-left shunt leads to an unloading of the compromised right ventricle
and an economized ventricular function by allowing both ventricles to work in a
more synchronized fashion. The right-to-left shunt across the Potts-shunt offers a
pop-off valve function for a suprasystemic pulmonary artery circulation, RV pressure
unloading together with an improved systemic blood flow (see Chap. 5). It becomes
Fig. 7.3 Angiography in lateral 90° view demonstrates a right-to-left shunt through a stented
(4 × 12 mm Coronary stent) duct in an infant, who was referred after resuscitation due to suprasys-
temic pulmonary hypertension and right ventricular failure
is clear that the left ventricular preload has to be balanced by the right-to-left shunt
through a restrictive Potts-shunt combined with a restricted atrial left-to-right shunt,
such that systemic blood flow improves despite a reduced transpulmonary blood
flow to the left atrium. Both, diminishing ventricular pressure load together with a
beneficial ventricular interaction improve systemic oxygen delivery and consecu-
tively the clinical functional class. The change of the cardiac pathophysiology into
that of an Eisenmenger physiology at the arterial level does not only preserve highly
oxygenated coronary and cerebral blood flow but avoids extreme oxygen desatura-
tion of the lower body via the atrial left-to-right shunt (Chap. 5). However, creation
of a Potts-shunt has been described in children with suprasystemic idiopathic
pulmonary arterial hypertension (IPAH), as an alternative to lung transplantation [56],
and as an alternative to an interatrial communication with right–left shunt provok-
ing a global body cyanosis (see Chap. 5). This surgical procedure requires the
construction of an anastomosis between the left pulmonary artery and the
descending aorta allowing right-to-left shunting and leading to a decompression of
the failing RV without provoking oxygen desaturation in the upper part of the body.
In one of our functional class IV patients, a repertoire of surgical-interventional
procedures became necessary to treat life-threatening hemoptysis associated with
suprasystemic pulmonary hypertension ([13], see Chap. 5).
Considering the current interventional-surgical Hybrid techniques, we want to
hypothesized, that Eisenmenger patients due to intracardiac right–left shunts with
full body cyanosis (which includes the coronary as well as cerebral perfusion) might
Fig. 7.4 Cartoon of a valved Conduit between left pulmonary artery (LPA) and descending aorta
(DAO) as an additional option to repair intraoperative shunt with “fixed” pulmonary vascular resis-
tance. Hypothesis: change of total body cyanotic type I Eisenmenger-syndrome to a lower body
“harlekin” Eisenmenger type II physiology by contemporary avoiding of suprasystemic pulmo-
nary hypertension in case of an inappropriate intracardiac shunt (VSD) closure and established
Potts-shunt. The valve should avoid diastolic left–right shunt
benefit from an intracardiac repair together with a performed reverse Potts-shunt;

depending on the systolic and diastolic pulmonary-to-systemic pressure ratio, a
valved conduit might be favored as a Potts-shunt (Fig. 7.4).
The Right Ventricle in Context of a Restrictive Cardiomyopathy
RCM is a rare form of childhood cardiomyopathy, accounting for 2.5 to 5 % of all

of the idiopathic cardiomyopathies [58]. Histologic abnormalities are often present,
depending on the etiology of the RCM. Endomyocardial biopsy findings include
myocyte hypertrophy, myofibrillar disarray, and interstitial fibrosis. RCM is charac-
terized by impaired diastolic function with relatively preserved systolic function
and right ventricular wall thickness [59]. Normal systolic function and equalization
of increased ventricular end-diastolic pressures lead to abrupt premature cessation
of ventricular filling in early diastole. Therefore, ventricular filling is limited to
early diastole. The decreased compliance of the ventricle induces atrial dilation and
raises the pulmonary vascular resistance [60]. Therefore, PAPs are usually elevated.
A few small number case series have been published documenting the clinical
course after the diagnosis of childhood RCM [61, 62]; all have reported an acceler-
ated deterioration in comparison with that seen in adults. However, the natural his-
tory of the disease is not predictable and a rise of the pulmonary vascular resistance
and clinical deterioration unfolded at different rates. No consistent risk factors
predictive for progression have been identified [58]. The natural history of RCM
varies and is at least partially dependent on the etiology, if any is identified. The
mortality of children with idiopathic RCM is high, particularly in the group not
undergoing heart transplantation. Rates have been reported to be as high as 63 %
within 3 years of diagnosis and 75 % within 6 years of diagnosis [59]. The actuarial
survival range is 44–50 % at 1–2 years after presentation. The survival decreases to
29–39 % at 3–5 years after presentation [62]. Children with RCM are at a higher
risk for the development of pulmonary hypertension than children with dilated or
hypertrophic cardiomyopathy. Patients with RCM and a relatively well-preserved
clinical functional status remain stable despite already excessive systolic PAPs.
Therefore, risk stratification and the decision to list a patient for heart transplanta-
tion is problematic. Invasive hemodynamic assessment is helpful for decision mak-
ing. As mentioned above, we recommend the use of the TPG (the difference of
diastolic pulmonary blood pressure and pulmonary capillary wedge pressure, left
atrial and/or left ventricular enddiastolic pressure) as an additional valuable param-
eter for decision making of the timing of heart vs. heart–lung transplantation. Based
on our institutional experience, a non-proofed cut-off value in children might be a
difference (PAPd-PCWP/LAP) of less than 15 mmHg. Currently, the therapy for
idiopathic RCM is limited to symptomatic treatment and does not improve out-
come. However, many of the adult patients but even children are not sufficiently
treated by targeted medication; most receive only diuretics [58]. Considering that
controlled studies of medical treatment of children and young adults with RCM and
subsequent pulmonary hypertension are missing, we favor pathophysiology and
pharmacology-based medical treatments. We hypothesize that sympathetic over-
drive, renin-angiotensin, endothelin- and aldosterone as circulating as well as car-
diac tissue specific agonists or antagonists might be responsible for the progression
of a genetically anchored myocardial fibrosis. We have treated several patients, on
single case and compassionate basis without a control group. Based on our anec-
dotal experience, a cocktail of specific antagonists (β-AR, AT-II, ETI, and aldoste-
rone) starting each drug in very low, but slowly increasing dosages to avoid
hypotension continues to be our first therapeutic goal. We avoid as always-possible
diuretics in chronic treatment of DCM, and in particular of RCM; preserving a suf-
ficient blood pressure not at least for introducing the abovementioned antagonists in
sufficient dosages but even not to activate the neurohumoral axis further. We are
convinced, that such more cardiac targeted drug treatment may also induce a degree
of cardiac re-remodeling. Certainly, controlled studies are needed to support our
anecdotal experience. Currently, surgical options in children with RCM are limited
to heart transplantation [59, 63]. However, in pure left-sided RCM “interventional,
transcatheter or even surgical-interventional hybrid” strategies can be an additional
option in selected cases before cardiac transplantations is considered. In patients
with isolated left ventricular RCM or patients with left ventricular diastolic dys-
function there may be a benefit from a defined interatrial communication (PFO-like)
Atrioseptostomy (Video 7.5a, b) with or without implantation of a fenestrated atrial
septum defect occluder or a diastolic dysfunctional device (Video 7.6) should allow
a defined, restrictive left-to-right shunt to reduce an “out-of-proportion” left atrial

pressure. The global hemodynamic function should improve; the secondary pulmo-
nary hypertension decrease and atrial fibrillation might be avoided by a reduced left
atrium pressure and consecutive enlargement (see Video 7.4). Taken together, the
need of an increased demand in left ventricular preload has to be considered and
therefore preserved. Additionally, and even based on our experience in BLV, the
presence of an isolated left-sided RCM with suprasystemic pulmonary hypertension
and already started right heart failure might benefit from a hybrid like approach
consisting of an interventional performed PFO-like interatrial communication
together with a surgically created reversed Potts-shunt; this in particular in patients
in whom a heart–lung transplantation is the only alternative.
In general, special attention must be paid to a pre-transplant pulmonary hyperten-
sion; it needs to be differentiate between a genuine out-of-proportion pulmonary
hypertension by considering the diastolic PAP (see above), a fixed and/or may be still
responsive PH. In doubt, a left ventricular assist device combined with specific PH -in
particular continuous prostanoid infusion – has to be used to differentiate between a
still reactive and fixed pulmonary vasculature. Considering our own and the heart
transplant results of others [62], children and young adults suffering RCM might be
benefit from immediate and elective ECMO use after cardiac transplantation to pre-
vent post-transplant graft failure. Such a prophylactic strategy might be effective to
bridge the vulnerable period immediate after the cardiopulmonary bypass and inflam-
mation-induced endothelial stunning in particular of the pulmonary circulation. In
addition, if pulmonary hypertension persists, creation of a small ASD in the donor
heart may be of benefit to decompress the right heart in case of a postoperative pul-
monary hypertensive crisis. Susceptibility of the host pulmonary circulation together
with the 3-to-5 days lasting (endothelial, endocardial, myocardial) stunning period,
are risk factors for right ventricular failure, as the unprepared donor heart reacts to the
acute afterload increase. Such unloading and an adaptation period for the lung circu-
lation by ECMO appear to be effective in younger patients [63]. However, there
remains an increased risk of death from right heart failure after orthotopic cardiac
transplantation, sometimes for weeks and months. By utilizing modern pharmaco-
logical PH treatment, acute right heart failure can be avoided and a better outcome of
heart instead heart–lung transplantation might be achieved.
Based on our own institutional experience, we arrive at the following conclusion:
An asymptomatic child or adolescent with RCM should not receive as the first
option a heart transplantation. Post-capillary induced pulmonary hypertension with
a difference of diastolic pulmonary artery to PCWP/left atrial pressure of less than
15 mmHg is a cardiac output independent value and should be interpret different
from the mean PAP in children; if from the clinical point of view a HTX becomes
necessary heart- and not a heart-lung transplantation should be considered.
Therefore, any out-of-proportion pulmonary hypertension needs to be carefully
examined on an individual basis; age, PH etiology as well as the results of invasive
pulmonary artery testing are required for final decision-making.
Summary for the Practitioner
– Left-sided dilative cardiomyopathy in the fetus is compensated as long as a

severe regurgitation of the systemic atrioventricular valve is not observed.
– During postnatal life, left-sided systolic heart failure becomes obvious when the
pulmonary vascular resistance and increased right ventricular pressure begin to
fall (ALCAPA, LV-DCM).
– Compared to the left ventricle, the postnatal fully adapted right ventricle is
severalfold more sensitive to changes in its afterload (see Chap. 7).
– A small rise in right ventricular afterload can lead to a rapid and linear decline in
stroke volume—and therefore cardiac output—of an unprepared right ventricle; in
contrast to acute pulmonary hypertension, which is particularly poorly tolerated
by an unprepared right ventricle (after HTX, pulmonary embolism), right
ventricular adaptation can occur with passage of time.
– Rapid right or sub-pulmonary ventricular dilatation and reduced cardiac output
leads to a reciprocal change in left ventricular filling and a spiral of decline.
– The greatest tolerance to a persistently high (vascular) afterload is observed in
the setting of a right or sub-pulmonary ventricle, which never adapts to normal
postnatal low ventricular pressure circulation (PPHN, RVOTO).
– Under physiological conditions, about 60 % of the mechanical work generated
by the right side of the circulation, is a direct consequence of left ventricular
function.
– Acute right heart dilation immediately affects the left ventricular intrinsic con-
tractility as measured by preload recruitable stroke work and end-systolic elas-
tance. Pericardial effects might be responsible for the geometric interaction and
also shared myofibers.
– The right ventricular function determines the outcome of patients with left-sided
heart failure.
– Structural left-sided heart malformations (borderline left ventricle) may remain
compensated as long as the sub-pulmonary right ventricle is not overly stressed
by the presence of right–left-sided communications or out-of-proportion pulmo-
nary hypertension.
– A disease in one ventricle, if a sub-aortic or sub-pulmonary one modifies the
function of the other; techniques directed toward improving performance of one
side of the heart are likely to have beneficial effects on the contralateral side, and
vice versa.
– Considering the outcome of congenital heart disease with an Eisenmenger-
pathophysiology, it can be observed that the longevity of patient with an
Eisenmenger-syndrome based on a ventricular septal defect or arterial duct is
prolonged. The ability to shunt right-to-left across the lesions substantially
reduces the hemodynamic burden on the RV, supports the function of the second-
ary involved LV and improves survival albeit at the cost of earlier cyanosis.
Therapeutic Considerations
– Limitations to increase oxygen delivery (DO2) might be compensated by strate-

gies to reduce oxygen consumption (heart rate, work load).
– Left ventricular DCM with significant reduced left ventricular ejection fraction
(LV-EF <25 %) but preserved right ventricular function might be considered for
PAB to avoid or delay the need for HTX.
– Diastolic dysfunctional left heart disease with out-of-proportion left atrial pres-
sure and consecutive induced atrial fibrillation left ventricular low cardiac output
with associated pulmonary hypertension might benefit from a definitive (restric-
tive) atrial left–right shunt if a mandatory increased left ventricular preload is
preserved.
– Establishing an Eisenmenger physiology in a restrictive or borderline left ven-
tricle consisting of a left pulmonary artery descending aorta Potts-right–left
shunt and restrictive atrial left–right shunt might be considered as an alternative
of a heart–lung transplantation.
References
1. Schwarz K, Singh S, Dawson D, Frenneaux MP. Right ventricular function in left ventricular
disease: pathophysiology and implications. Heart Lung Circ. 2013;12:172–8.
2. Dickstein M, Todaka K, Burkhoff D. Left-to-right systolic and diastolic ventricular interac-
tions are dependent on right ventricular volume. Am J Physiol Heart Circ Physiol. 1997;272:
H2869–74.
3. Sanchez-Quintana D, Anderson RH, Ho SY. Ventricular myoarchitecture in tetralogy of Fallot.
Heart. 1996;76:280–6.
4. Damiano Jr R, La Follette Jr P, Cox J, Lowe J, Santamore W. Significant left ventricular con-
tribution to right ventricular systolic function. Am J Physiol Heart Circ Physiol. 1991;261:
H1514–24.
5. Redington AN. Pathophysiology of right ventricular failure. Seminars in thoracic and cardio-
vascular surgery. Pediatr Card Surg Ann. 2006;9:3–10.
6. Groner A, Yau J, Lytrivi ID, Ko HH, Nielsen JC, Parness IA, Srivastava S. The role of right
ventricular function in pediatric idiopathic dilated cardiomyopathy. Cardiol Young. 2013;
23(3):409–15.
7. Guazzi M, Borlaug BA. Pulmonary hypertension due to left heart disease. Circulation.
2012;126:975–90.
8. Berger G, Hardak E, Obaid W, Shaham B, Carasso S, Kerner A, Yigla M, Azzam
ZS. Characterization of pulmonary venous hypertension patients with reactive pulmonary
hypertension as compared to proportional pulmonary hypertension. Respiration. 2012;83:
494–8.
9. Adir Y, Humbert M, Sitbon O, Wolf R, Lador F, Jaïs X, Simonneau G, Amir O. Out-of-
proportion pulmonary hypertension and heart failure with preserved ejection function.
Respiration. 2012;9:1–7.
10. Bonnet D, Humpel T. Out of proportion pulmonary hypertension and other forms of the
disease. In: Beghetti M, Barst RJ, Berger RMF, Humpel T, Ivy D, Schulze-Neick I, editors.
Pediatric pulmonary hypertension, Chap 16. Amsterdam: Elsevier. 2011.
10. Schranz D, Veldman A, Bartram U, Michel-Behnke I, Bauer J, Akintürk H. Pulmonary artery

banding for idiopathic dilative cardiomyopathy: a novel therapeutic strategy using an old
surgical procedure. J Thorac Cardiovasc Surg. 2007;134:796–7.
11. Schranz D, Rupp S, Muller M, et al. Pulmonary artery banding in infants and young children
with left ventricular dilated cardiomyopathy: a novel therapeutic strategy before heart trans-
plantation. J Heart Lung Transplant. 2013;32:475–81.
12. Latus H, Apitz C, Schmidt D, Jux C, Müller M, Bauer J, Akintuerk H, Schneider M, Schranz
D. Potts shunt and atrial septostomy in pulmonary hypertension due to left ventricular disease.
Ann Thorac Surg. 2013;96(1):317–9.
13. Recla S, Steinbrenner B, Schreier J, Fichtlscherer S, Schmidt D, Apitz C, Müller M, Bauer J,
Akintuerk H, Schranz D. Surgical-interventional hybrid orchestra consisting of Potts shunt,
transcatheter tricuspid valve repair by Edwards-valve in a 26-years old patient with suprasys-
temic pulmonary hypertension and right ventricular failure. WJCD. 2031;3:1–4.
14. Lipshultz SE, Sleeper LA, Towbin JA, Lowe AM, Orav EJ, Cox GF, Lurie PR, McCoy KL,
McDonald MA, Messare JE, Colan SD. The incidence of pediatric cardiomyopathy in two
regions of the United States. N Engl J Med. 2003;348:1647–55.
15. Jefferies JL, Towbin JA. Dilated cardiomyopathy. Lancet. 2010;375(9716):752–62.
16. Watkins H, Ashrafian H, Redwood C. Inherited cardiomyopathies. N Engl J Med. 2011;364:
1643–56.
17. Sanbe A. Dilated cardiomyopathy: a disease of the myocardium. Biol Pharm Bull. 2013;
36(1):18–22.
18. Bonnet D, Humpel T. Out of proportion pulmonary hypertension and other forms of the dis-
ease. In: Beghetti M, Barst RJ, Berger RMF, Humpel T, Ivy D, Schulze-Neick I, editors.
Pediatric pulmonary hypertension, Chap 16. Amsterdam: Elsevier.
19. Towbin JA, Lowe AM, Colan SD, Sleeper LA, Orav EJ, Clunie S, Messere J, Cox GF, Lurie
PR, Hsu D, Canter C, Wilkinson JD, Lipshultz SE. Incidence, causes, and outcomes of dilated
cardiomyopathy in children. JAMA. 2006;296:1867–76.
20. Nugent AW, Daubeney PE, Chondros P, Carlin JB, Cheung M, Wilkinson LC, Davis AM,
Kahler SG, Chow CW, Wilkinson JL. The epidemiology of childhood cardiomyopathy in
Australia. N Engl J Med. 2003;348:1639–46.
21. Canter CE, Shaddy RE, Bernstein D, Hsu DT, Chrisant MR, Kirklin JK, Kanter KR, Higgins RS,
Blume ED, Rosenthal DN, Boucek MM, Uzark KC, Friedman AH, Young JK. Indications for
heart transplantation in pediatric heart disease: a scientific statement from the American Heart
Association Council on Cardiovascular Disease in the Young; the Councils on Clinical Cardiology,
Cardiovascular Nursing, and Cardiovascular Surgery and Anesthesia; and the Quality of Care and
Outcomes Research Interdisciplinary Working Group. Circulation. 2007;115:658–76.
22. Alvarez JA, Orav EJ, Wilkinson JD, Fleming LE, Lee DJ, Sleeper GF, Rusconi PG, Colan SD,
Hsu DT, Canter CE, Webber SA, Cox GF, Jefferies JL, Towbin JA, Lipschütz SE. Pediatric
cardiomyopathy Registry Investigators. Circulation. 2011;124:814–23.
23. Oyama S, Sakuma M, Komaki K, Ishigaki H, Nakagawa M, Hozawa H, Yamamoto Y, Kagaya
Y, Watanabe J, Shirato K. Right ventricular systolic function and the manner of transformation
of the right ventricle in patients with dilated cardiomyopathy. Circ J. 2004;68(10):933–7.
24. Meyer P, Filippatos GS, Ahmed MI, Iskandrian AE, Bittner V, Perry GJ, White M, Aban IB,
Mujib M, Dell’Italia LJ, Ahmed A. Effects of right ventricular ejection fraction on outcomes
in chronic systolic heart failure. Circulation. 2010;121:252–8.
25. Kaufman BD, Shaddy RE, Shirali GS, Tanel R, Towbin JA. Assessment and management of
the failing heart in children. Cardiol Young. 2008;18 Suppl 3:63–71.
26. Daubeney PEF, Nugent AW, Chondros P, Carlin JB, Colan SD, Cheung M, Davis AM, Chow
CW, Weintraub RG. Clinical features and outcomes of childhood dilated cardiomyopathy.
Results from a national Population-Based Study. Circ. 2006;114:2671–8.
27. Singh TP, Sleeper LA, Lipshultz S, Cinar A, Canter C, Webber SA, Bernstein D, Pahl E,
Alvarez JA, Wilkinson JD, Towbin JA, Colan SD. Association of left ventricular dilation at
listing for heart transplant with postlisting and early posttransplant mortality in children with
dilated cardiomyopathy. Circ Heart Fail. 2009;2:591–59813.
28. Kirk R, Edwards LB, Aurora P, Taylor DO, Christie J, Dobbels F, Kucheryavaya AY, Rahmel
AO, Hertz MI. Registry of the International Society for Heart and Lung Transplantation: eleventh
official pediatric heart transplantation report—2008. J Heart Lung Transplant. 2008;27:970–7.
29. Hauser J, Michel-Behnke I, Khazen C, Laufer G, Pees C. Successful cardiac resynchronization
therapy in a 1.5-year-old girl with dilated cardiomyopathy and functional mitral regurgitation.
Int J Cardiol. 2013;167:e83–4.
30. Rupp S, Jux C, Bönig H, Bauer J, Tonn T, Seifried E, Dimmeler S, Zeiher AM, Schranz
D. Intracoronary bone marrow cell application for terminal heart failure in children. Cardiol
Young. 2012;22(5):558–63.
31. Graham Jr TP, Bernard YD, Mellen BG, Celermajer D, Baumgartner H, Cetta F, Connolly HM,
Davidson WR, Dellborg M, Foster E, Gersony WM, Gessner IH, Hurwitz RA, Kaemmerer H,
Kugler JD, Murphy DJ, Noonan JA, Morris C, Perloff JK, Sanders SP, Sutherland JL. Long-
term outcome in congenitally corrected transposition of the great arteries: a multi-institutional
study. J Am Coll Cardiol. 2000;36(1):255–61.
32. Muller WH, Dammann JF. The treatment of certain congenital malformations of the heart by
the creation of pulmonic stenosis to reduce pulmonary hypertension and excessive pulmonary
blood flow: a preliminary report. Surg Gynecol Obstet. 1952;95:213.
33. Winlaw DS, McGuirk SP, Balmer C, Langley SM, Griselli M, Stümper O, De Giovanni JV,
Wright JG, Thorne S, Barron DJ, Brawn WJ. Intention-to-treat analysis of pulmonary artery
banding in conditions with a morphological right ventricle in the systemic circulation with a
view to anatomic biventricular repair. Circulation. 2005;111:405–11.
34. Murtuza B, Barron DJ, Stumper O, Stickley J, Eaton S, Jones TJ, Brawn WJ. Anatomic repair
for congenitally corrected transposition of the great arteries: a single-institution 19-year expe-
rience. J Thorac Cardiovasc Surg. 2011;142:1348–57.
35. Metton O, Gaudin R, Ou P, Geelli S, Mussa S, Sidi D, Vouhe P, Raisky O. Early prophylactic
pulmonary artery banding in isolated congenitally corrected transposition of the great arteries.
Eur J Cardiothorac Surg. 2010;38:728–34.
36. Bailey LL. Back to the future! Bold new indication for pulmonary artery banding. J Heart
Lung Transplant. 2013;32:482–3.
37. Amir G, Ma X, Reddy VM, et al. Dynamics of human myocardial progenitor cell populations
in the neonatal period. Ann Thorac Surg. 2008;86:1311–9.
38. Mishra R, Vijayan K, Colletti EJ, et al. Characterization and functionality of cardiac progenitor
cells in congenital heart patients. Circulation. 2011;123:364–73.
39. Rupp S, Bauer J, von Gerlach S, Fichtlscherer S, Zeiher AM, Dimmeler S, Schranz D. Pressure
overload leads to an increase of cardiac resident stem cells. Basic Res Cardiol. 2012;107(2):252.
40. Mollovaa M, Bersella K, Walsha S, Savlaa S, Tanmoy Dasa L, Park S-Y, Silbersteine SL, dos
Remediosg DG, Grahama D, Colana D, Kühn B. Cardiomyocyte proliferation contributes to
heart growth in young humans. Proc Natl Acad Sci U S A. 2013;110:1446–51.
41. Baicu CF, et al. Time course of right ventricular pressure-overload induced myocardial fibro-
sis: relationship to changes in fibroblast postsynthetic procollagen processing. Am J Physiol
Heart Circ Physiol. 2012;303(9):H1128–34.
42. Grosse-Kreimburg K, Uchida S, Gellert P, Schneider A, Boettger T, Voswinckel R, Wietelmann
A, Szibor M, Weissmann N, Ghofrani AH, Schermuly R, Schranz D, Seeger W, Braun
T. Identification of right heart-enriched genes in a murine model of chronic outflow tract
obstruction. J Mol Cell Cardiol. 2010;49(4):598–605.
43. Takeda N, et al. Cardiac fibroblasts are essential for the adaptive response of the murine heart
to pressure overload. J Clin Invest. 2010;120(1):254–65.
45. Roncon-Albuquerque Jr R, Vasconcelos M, Lourenco AP, et al. Acute changes of biventricular
gene expression in volume and right ventricular pressure overload. Life Sci. 2006;78:2633–42.
46. Nihoyannopoulos P, Dawson D. Restrictive cardiomyopathies. Eur J Echocardiogr.
2009;10(8):23–33.
47. Corno AF. Borderline left ventricle. Eur J Cardiothorac Surg. 2005;27(1):67–73.
48. Hamdani N, Paulus WJ. Myocardial titin and collagen in cardiac diastolic dysfunction: partners
in crime! Circulation. 2013;128:5–8.
49. Kearney DL. The pathological spectrum of left-ventricular hypoplasia. Semin Cardiothorac
Vasc Anesth. 2013;17(2):105–16.
50. Seki A, Patel S, Ashraf S, Perens G, Fishbein MC. Primary endocardial fibroelastosis: an
underappreciated cause of cardiomyopathy in children. Cardiovasc Pathol. 2013;22:345–50.
51. Grosse-Wortmann L, Yun TJ, Al-Radi O, Kim S, Nii M, Lee KJ, Redington A, Yoo SJ, van
Arsdell G. Borderline hypoplasia of the left ventricle in neonates: insights for decision-making
from functional assessment with magnetic resonance imaging. J Thorac Cardiovasc Surg.
2008;136(6):1429–36.
52. Emani SM, McElhinney DB, Tworetzky W, Myers PO, Schroeder B, Zurakowski D, Pigula FA,
Marx GR, Lock JE, Del Nido PJ. Staged left ventricular recruitment after single-ventricle pal-
liation in patients with borderline left heart hypoplasia. J Am Coll Cardiol. 2012;60:1966–74.
53. Michel-Behnke I, Akintuerk H, Marquardt I, Mueller M, Thul J, Bauer J, Hagel KJ, Kreuder J,
Vogt P, Schranz D. Stenting of the ductus arteriosus and banding of the pulmonary arteries:
basis for various surgical strategies in newborns with multiple left heart obstructive lesions.
Heart. 2003;89(6):645–50.
54. Davis CK, Pastuszko P, Lamberti J, Moore J, Hanley F, El Said H. The hybrid procedure for
the borderline left ventricle. Cardiol Young. 2011;21(1):26–30.
55. Webber SA, Lipshultz SE, Sleeper LA, Lu M, Wilkinson JD, Addonizio LJ, Canter CE, Colan
SD, Everitt MD, Jefferies JL, Kantor PF, Lamour JM, Margossian R, Pahl E, Rusconi PG,
Towbin JA. Outcomes of restrictive cardiomyopathy in childhood and the influence of pheno-
type: a report from the Pediatric Cardiomyopathy Registry. Pediatric Cardiomyopathy Registry
Investigators. Circulation. 2012;126(10):1237–44.
56. Blanc J, Vouhé P, Bonnet D. Potts shunt in patients with pulmonary hypertension. N Engl J
Med. 2004;350:623.
57. Esch JJ, Shah PB, Cockrill BA, Farber HW, Landzberg MJ, Mehra MR, Mullen MP, Opotowsky
AR, Waxman AB, Lock JE, Marshall AC. Transcatheter Potts shunt creation in patients with
severe pulmonary arterial hypertension: initial clinical experience. J Heart Lung Transplant.
2013;32(4):381–7.
58. Recla S, Steinbrenner B, Schreier J, Fichtlscherer S, Schmidt D, Apitz C, Müller M, Bauer J,
Akintuerk H, Schranz D. Surgical-interventional hybrid orchestra consisting of Potts shunt,
transcatheter tricuspid valve repair by Edwards-valve in a 26-year-old patient with pulmonary
hypertension and right ventricular failure. World J Cardiovasc Dis. 2013;3:1–4.
59. Fenton MJ, Chubb H, McMahon AM, Rees P, Elliott MJ, Burch M. Heart and heart–lung
transplantation for idiopathic restrictive cardiomyopathy in children. Heart. 2006;92(1):85–9.
60. McCartan C, Mason R, Jayasinghe R, Griffiths LR. Cardiomyopathy classification: ongoing
debate in the genomics era. Biochem Res Int. 2012;2012:796926.
61. Dragulescu A, Mertens L, Friedberg MK. Interpretation of left ventricular diastolic dysfunc-
tion in children with cardiomyopathy by echocardiography: problems and limitations. Circ
Cardiovasc Imaging. 2013;6(2):254–61.
62. Maskatia SA, Decker JA, Spinner JA, Kim JJ, Price JF, Jefferies JL, Dreyer WJ, Smith EO,
Rossano JW, Denfield SW. Restrictive physiology is associated with poor outcomes in children
with hypertrophic cardiomyopathy. Pediatr Cardiol. 2012;33(1):141–9.
63. Murtuza B, Fenton M, Burch M, Gupta A, Muthialu N, Elliott MJ, Hsia TY, Tsang VT,
Kostolny M. Pediatric heart transplantation for congenital and restrictive cardiomyopathy. Ann
Thorac Surg. 2013;95(5):1675–84.
Chapter 8
Missing a Sub-pulmonary Ventricle:
The Fontan Circulation
Marc Gewillig and Derize E. Boshoff
The “Fontan” Concept
A normal mammal cardiovascular system consists of a double circuit, pulmonary

and systemic, connected in series and powered by a double chamber pump. In the
absence of congenital heart disease, the right ventricle pumps through the pulmo-
nary circulation and the left ventricle through the systemic circulation (Fig. 8.1a).
Many complex cardiac malformations are characterized by the existence of only
one functional ventricle (Fig. 8.2). This “single” ventricle has to maintain both the
systemic and the pulmonary circulations, which during fetal life and at birth are not
connected in series but remain in parallel (Fig. 8.1b). Such a circuit has two major
disadvantages: diminished oxygen saturation of the systemic arterial blood and a
chronic volume load of the single ventricle. The chronic ventricular volume load
leads to a progressive ventricular dysfunction and remodeled pulmonary vascula-
ture, causing a gradual attrition due to congestive heart failure and pulmonary
hypertension from the third decade of life, with few survivors beyond the fourth
decade.
In 1971 Francis Fontan [1] from Bordeaux, France, reported a new approach to
the operative treatment of these malformations, separating the systemic and pulmo-
nary circulations. In a “Fontan circulation” the systemic venous return is connected
to the pulmonary arteries without the interposition of a pumping chamber (Fig. 8.1c).
In this construct, residual post-capillary transit energy is used to push blood through
the lungs in a new portal circulation-like system [2]. Advantages of a Fontan circuit
include (near-) normalization of the arterial oxygen saturation and abolishment of
the chronic volume load on the single ventricle. However, because the pulmonary
M. Gewillig, M.D., Ph.D. (*) • D.E. Boshoff, M.D., Ph.D.

Department of Paediatric Cardiology, University Hospital Leuven,
Herestraat 49, Leuven 3000, Belgium
e-mail: marc.gewillig@uzleuven.be

136 M. Gewillig and D.E. Boshoff
a b Ao
Ao
S
LV
LV V P
S
PA
RV
P
RA LA
c
Ao
V V
CV PA
F
LA
Fig. 8.1 Schematic representation of the normal cardiovascular circulation (a), shunted palliation
(b), and Fontan circulation (c). (a) Normal circulation: the pulmonary circulation (P) is connected
in series with the systemic circulation (S). The right ventricle maintains the right atrial pressure
lower than the left atrial pressure, and provides enough energy for the blood to pass through the
pulmonary resistance. (b) The systemic (S) and pulmonary (P) circuits are connected in parallel,
with a considerable volume overload to the single ventricle (V). There is complete admixture of
systemic and pulmonary venous blood, causing arterial oxygen desaturation. (c) Fontan circuit: the
systemic veins are connected to the pulmonary artery (PA), without a subpulmonary ventricle or
systemic atrium: the lungs are thereby converted into a neo-portal system which limits flow to the
ventricle. In the absence of a fenestration, there is no admixture of systemic and pulmonary venous
blood, but the systemic venous pressures are markedly elevated. A fenestration (F) allows the sys-
temic venous blood to bypass the Fontan portal system and limits the damming effect, thereby
increasing output and decreasing congestion, but also arterial saturation. Ao aorta, CV caval veins,
F fenestration, LA left atrium, LV left ventricle, PA Pulmonary artery, RV right ventricle, V single
ventricle. Line thickness reflects output, color reflects oxygen saturation
impedance hinders venous return through the pulmonary vasculature, this circulation
creates a state of chronic “hypertension” and congestion of the systemic veins, and
results in a decreased cardiac output, both at rest and during exercise [3, 4] (Fig. 8.3).
These two features of the Fontan circulation, elevated systemic venous pressure and
chronically low cardiac output, are the root cause of the majority of the physiologic
impairments of this circulation.
8 Missing a Sub-pulmonary Ventricle: The Fontan Circulation 137
Fig. 8.2 Different examples of functional single ventricles: (a) tricuspid valve atresia with hypo-
plastic right heart, ductal flow to pulmonary artery; (b) double inlet right ventricle DIRV through
an unbalanced atrioventricular septal defect with common atrioventricular valve, double outlet
right ventricle DORV and hypoplasia of the left ventricle; (c) double inlet left ventricle DILV with
left-sided hypoplastic right ventricle, restrictive ventricular septal defect VSD acting as subaortic
stenosis, transposition of the great arteries TGA, small aortic arch and coarctation of aorta; (d)
hypoplastic left heart syndrome HLHS due to aortic valve atresia
Cardiac Output % of nl baseline
500 Normal
400
300
200 Fontan best
100
Fontan worst
0
Exercise level
Fig. 8.3 Exercise and output: normal versus Fontan circulation: A normal subject with a biven-
tricular circuit can increase his output by a factor of 5 (black line). In Fontan patients, output is
significantly impaired both at rest and during exercise; at best (green line) the output is mildly
decreased at rest, with moderate capacity to increase flow during moderate exercise. At worst (red
line), the output is severely reduced at rest and barely augments during minimal exercise
Is Every Fontan Circuit the Same?
Since its original description, the Fontan circuit has undergone numerous
modifications. Early on surgeons used valves (cavo-atrial, atrioventricular, or atrio-
pulmonary) and created various connections between the right atrium and the
pulmonary artery (anterior atrio-pulmonary connection, with or without inclusion
of a small hypoplastic right ventricle, posterior atrio-pulmonary connection), with

different materials (valved conduits, homografts, patches, direct anastomosis).
The very high incidence of late reoperations, reaching 40 % in some series, does
reflect the poor design of the first Fontan circuits and the less than ideal surgical
techniques used in the early series. Most of the older circuits are no longer created
and considered obsolete; however, many patients still survive with such circuits.
When assessing a patient with a “Fontan circuit,” the clinician needs to know exactly
which connection has been made and what material has been used.
During the last decade, the total cavo-pulmonary connection (TCPC) has
emerged as being superior [5]. The caval veins are connected to the pulmonary
artery, bypassing not only the right ventricle but also the right atrium (Fig. 8.4a–c).
a
TA VSD: stent < PCPC < TCPC
b
DIRV DORV: band < PCPC < TCPC
Fig. 8.4 Schematic representation of treatment strategy from birth to Fontan circulation. (a) Patient
of with tricuspid valve atresia and hypoplastic right heart (cf. Fig. 8.2a): first palliation consists of
stenting the arterial duct, followed by partial cavo-pulmonary connection (PCPC); at the age of
about 3 years the Fontan circulation or total cavo-pulmonary connection (TCPC) is completed by
connecting the inferior caval vein through an extracardiac conduit to the pulmonary artery; a small
fenestration is created between the conduit and the right atrium. (b) Patient of Fig. 8.2b (DIRV
DORV AVSD): initial palliation consists of banding of the pulmonary artery at the age of 4–6
c DILV –TGA: band & coarc < DKS & PCPC < TCPC
d
HLHS: Norwood < PCPC < TCPC
vs hybrid
weeks; Fig. 8.4 (continued) PCPC at 6 months; TCPC at 3 years. (c) Patient of Fig. 8.2c (DILV
TGA coarctation): initial palliation consists of neonatal banding of the pulmonary artery with arch
reconstruction; PCPC with Damus-Kaye-Stansel operation at 6 months; TCPC at 3 years. (d)
Patient of Fig. 8.2d (HLHS): initial palliation consists of either Norwood operation (complex arch
reconstruction, atrial septectomy, Sano shunt from RV to pulmonary artery) or hybrid procedure
(stent in duct, bilateral banding branch pulmonary arteries); PCPC ± Norwood arch repair at 6
months; TCPC at 3 years
The superior caval vein is connected to the pulmonary artery (bidirectional Glenn
shunt or partial cavo-pulmonary connection [PCPC]). There are two variants to con-
nect the inferior caval vein: the lateral tunnel and the extra cardiac conduit.
Introduced in the mid-1980s, the lateral tunnel provides a tubular path between the
inferior caval vein and the pulmonary artery, consisting of a prosthetic baffle and a
portion of the lateral atrial wall. This circuit has growth potential and can therefore
be created in children as young as 1 year; it leaves a minimal amount of atrial tissue
exposed to high pressure, which over time may cause atrial arrhythmias. The extra
cardiac conduit was introduced in 1990, and consists of a tube graft between the
transected inferior caval vein and the pulmonary artery. This circuit leaves the entire
atrium at a low pressure, has no or minimal atrial suture lines, and can be performed
without aortic cross clamping or even cardiopulmonary bypass; however, this con-
duit has no growth potential and therefore will be offered to patients large enough
to accept a graft adequate for an adult’s inferior caval vein flow.
How to Build a Fontan Circuit?
At birth, it is impossible to create a Fontan circulation. The pulmonary vascular

resistance (PVR) is still elevated for several weeks, and the vessels—caval veins
and pulmonary arteries—are usually too small, making any cavo-pulmonary shunt
impossible during that period. Even when resistance has fallen, a staged approach is
preferred connecting the superior and inferior caval veins at separate occasions.
Such a staged approach allows the body to adapt progressively to the different
hemodynamic conditions, and reduces the overall operative morbidity and mortality.
A staged approach also allows a better patient selection and intermediate prepara-
tory interventions.
Initially in the neonatal period, management must focus on—if not provided to
some degree by nature-unrestricted flow from the heart to the aorta (if required:
coarctectomy, Damus-Kaye-Stansel, Norwood repair), a well-balanced limited flow
to the lungs (if required: pulmonary artery banding, shunt (modified Blalock-
Taussig, central), stent in duct), and unrestricted return of blood to the ventricle (if
required: Rashkind balloon septostomy, atrial septectomy) (Fig. 8.4a–c). The infant
is then allowed to grow for several months. During this time, the heart is submitted
to a chronic volume overload which is beneficial for development of the pulmonary
vasculature, but if excessive detrimental for ventricular function (see below). The
infant will have mild oxygen desaturation which is inversely related to mild cardiac
failure (Fig. 8.1b).
At the age of several months (4–12 months old), most centers will introduce a
partial cavopulmonary connection (PCPC) or bidirectional Glenn shunt: the
superior caval vein is connected to the pulmonary artery (bilateral if present). If no
other blood flow is directed to the lungs, the volume load for the heart is signifi-
cantly decreased to half or even less than normal for the body surface area (BSA).
The patient at this stage will remain slightly cyanotic, as the desaturated blood from
the inferior caval vein is still allowed to flow to the aorta.
At the age of several years (1–5 years, depending on the preference of the center,
growth of vascular structures, and cyanosis at rest and during exercise), the Fontan
circuit is completed by connecting the inferior caval vein to the pulmonary artery.
As mentioned above, two techniques are currently used: the lateral tunnel and the
extra cardiac conduit. Frequently a small fenestration is created between the
tunnel-conduit and the pulmonary atrium, either routinely or only in “high risk”
patients [6]. Such fenestration will allow a residual right-to-left shunt, thereby limit-
ing caval pressure and congestion, and increasing the preload of the systemic ven-
tricle and cardiac output, at the expense of cyanosis. Such fenestration has been
shown to reduce the operative mortality and morbidity associated with pleural
drainage; the fenestration can later be closed percutaneously (weeks-months) after
adaptation of the body to the new hemodynamic condition.
Cardiac Output in the Setting of a Fontan Circulation
By creating a TCPC, a new portal system is made. A portal system occurs when one
capillary bed pools blood into another capillary bed through veins without passing
through the heart, as for example in the hepatic portal system and the pituitary portal
system. The Fontan neo-portal system dams off and pools the systemic venous
blood. As a result, transit of blood through this neo-portal system is dependent on
the pressure gradient from the systemic post-capillary vessels to the pulmonary
post-capillary vessels (Fig. 8.1c). Since there is no pump to transmit energy to the
system, small changes in the static resistances and dynamic impedances of the
structures within this portal system have a profound impact on the blood flow.
Although the heart itself may function well, the inherent limitations of the Fontan
neo-portal system determine the degree of circulatory compromise. It is this neo-
portal system that is the major limiting factor of flow and the underlying cause of
venous congestion and diminished cardiac output. The heart, while still the engine
of the circuit, cannot compensate for this major flow restriction: the suction required
to compensate for the damming effect of the Fontan portal system cannot be
generated [7]. The heart therefore no longer controls cardiac output nor can it alter
the degree of systemic venous congestion. However, in cases in which the systemic
ventricle functions poorly, the heart can make an already compromised circulation
worse. Figure 8.5a, b illustrates the relationship between output, ventricular con-
tractility, and PVR in a normal and a Fontan circulation. In a normal subject, output
at rest is minimally influenced by ventricular function, except when severely
depressed; mild changes of the PVR will not influence the output as these changes
are neutralized by the right ventricle. In Fontan patients, the PVR is the primary
modulator of cardiac output: small changes have a profound impact; systolic perfor-
mance will only impact output at rest when cardiac function is severely depressed.
If the ventricular function is not severely depressed, squeezing harder will not result
in more output.
The components that make up the Fontan neo-portal system are thus critically
important in the overall function of the Fontan circuit. These include the veno-arterial
Fontan connection itself (atrio-pulmonary in older patients), pulmonary arteries,
pulmonary capillary network (including precapillary sphincters), pulmonary veins,
100 normal LV
Circulatory
Output 70 F PVR low
% of nl F PVR med
50
at rest
F PVR high
30
0
30 40 50 60 70
Ejection fraction of ventricle %
100 normal LV
Circulatory
Output 70
% of nl
50
at rest
30 F UVH 70%
F UVH 50%
F UVH 30%
0
1 2 3 4 5
PVR
Fig. 8.5 Relationship of output at rest, ventricular function and PVR. (a) Modulation by PVR: in
a normal subject (black line), output at rest is minimally influenced by ventricular function, except
when severely depressed. In Fontan patients (colored lines), PVR is the primary modulator of
cardiac output. As in a two-ventricle system, systolic performance will only impact output at rest
when cardiac function is severely depressed. If ventricular function is not severely depressed,
squeezing harder will not result in more output. (b) Modulation by ventricular function. In a nor-
mal subject (black line), cardiac output is not influenced by a mild increase of PVR up to 5 Woods
Units. In all Fontan patients (colored lines), an increase in PVR is invariably associated with a
decrease in cardiac output. If PVR is low, a reasonable output is achieved in patients with normal
or moderately depressed ventricular function (green and yellow lines). However, severely depressed
ventricular function invariably results in low output (red). EF ejection fraction, F Fontan, LV nor-
mal left ventricle, PVR pulmonary vascular resistance, UVH univentricular heart
and the veno-atrial connection. Impairment at any level of this portal system will
have profound consequences on the output of the Fontan circuit, much more than a
comparable dysfunction in a two-ventricle circulation. These impairments include,
but are not limited to: stenosis, hypoplasia, distortion, vasoconstriction, pulmonary
vascular disease, loss or exclusion of large vessels or microvessels, turbulence and
flow collision, flow mismatch and obstruction by external compression.
Glenn Fontan
Systemic
100
Output
% of nl BSA
80
saturation
% 60
40
20
CVP
mmHg
0
0 50 100
Fenestration size % of conduit
Fig. 8.6 Effect of various degrees of pulmonary bypassing in a Fontan circuit on systemic output,
saturation, and systemic venous congestion. A “good Fontan” with low neo-portal resistance
(green lines) has an output (thick solid line) of about 80 % of normal for BSA, with a high satura-
tion (dotted line) and a mildly elevated CVP (thin line). The “bad Fontan” with a high portal
resistance has an output with a similar saturation but with a very low to unacceptable output despite
a high CVP. Partial bypassing of the Fontan portal system by a fenestration invariably increases
systemic output and decreases systemic congestion, but in the “bad Fontan,” this occurs at an unac-
ceptable degree of cyanosis. CVP central venous pressure
The restriction of the cardiac output imposed by the neo-portal system can be
partially reversed by bypassing the pulmonary vasculature. A Fontan fenestration
allows flow to bypass the Fontan neo-portal system and results in an increase in
cardiac output and a decrease in venous congestion. However, while a fenestration
can increase the overall output, it does so at the expense of diminished arterial
oxygen saturation. Nevertheless, in the setting of a fenestration, the increase in
cardiac output can result in an increase in peripheral oxygen delivery even if the
saturation is mildly diminished. Figure 8.6 shows the relationship between output,
congestion, and arterial saturation in a successful and a failing Fontan circuit, and
the effect of partial improvement by a fenestration. In a successful Fontan circuit,
the low resistance portal system will cause a mild decrease of output with a modest
increase in the systemic venous pressures, making a fenestration unnecessary. In a
failing Fontan circuit, inclusion of a high vascular resistance portal system will
decrease the cardiac output and create venous congestion of an unacceptable degree;
a fenestration will attenuate these changes, but in patients with an increased PVR an
acceptable compromise may not be possible.
Functional Impairment After the Fontan Operation
The restriction of the cardiac output and the inability to power the blood through the
pulmonary vasculature results in a circulation in which the ability to perform exer-
cise is reduced. Under resting conditions, the cardiac output in a patient with a
Fontan circulation is approximately 70–80 % of normal. During exercise, the limita-
tions of the Fontan circuit are substantially magnified such that the small difference
in cardiac output at rest becomes a large difference during activity (Fig. 8.2).
At peak exercise, a well-trained athlete with a normal heart can increase blood flow
through the lungs by up to fivefold (see also Chap. 15). This is accomplished through
a substantial increase in the right ventricular systolic pressure (up to 70 mmHg! [5])
as well as with pulmonary blood flow acceleration coupled with a decrease in the
PVR. In a patient with Fontan physiology, there is no physiologic mechanism to
allow for a similar increase in cardiac output. The maximal mean venous pressure
rarely reaches 30 mmHg; there is no blood acceleration and the pulmonary vascular
reactivity and the ability to recruit reserve vessels is attenuated or absent [8].
Together, these limitations result in a diminished ability to augment cardiac output
in response to increased metabolic demand, and therefore limit the ability of a
patient with a Fontan circulation to perform exercise.
Through childhood and until puberty, the mean maximal exercise capacity for
patients with a Fontan circulation is in the range of 65 % predicted for gender and
age [9]. While successful Fontan patients may remain stable for many years, poor
Fontan patients suffer an accelerated increase of PVR, and increasing filling pres-
sures of the ventricle as a result of chronic preload deprivation and disuse dysfunc-
tion. Longitudinal studies of late adolescents and young adults demonstrate this
point well; as patients progress to late adolescence and early adulthood, exercise
capacity tends to continue to decline by about 2.6 % per year [10–12].
There are several reasons why adults with a Fontan circuit in the current era do
not represent the current cohort of patients. Many of the original candidates for a
Fontan operation, the now adult cohort, were suboptimal for this type of surgery
from a hemodynamic standpoint, with many significant residual lesions and sequelae
related to the original cardiac malformation and palliative procedures. A shunt pro-
cedure performed during the period from the 1960s to the 1980s was evaluated
based on the goal of the long-term relief of cyanosis: “the pinker the better.” Often
a second aortapulmonary shunt was created to augment pulmonary blood flow after
the first shunt was deemed inadequate. The potential that these shunts could induce
pulmonary vascular disease, ventricular hypertrophy and dysfunction, or pulmonary
artery distortion was not—as it is now—a principal concern of the surgeon.
Currently, the success of a shunt is evaluated by obtaining acceptable relief of cya-
nosis without significant volume overload of the ventricle and by the induction of
adequate pulmonary growth without causing changes of the PVR. In addition, in the
modern era of palliation, the systemic to pulmonary shunt is designed to last 4–6
months, enough time for the PVR to drop such that a PCPC can safely be created.
Figure 8.7a–c illustrates the different loading conditions of the single ventricle at the
various stages of palliation, highlighting the differences in management before the
1990s (typically two aortapulmonary shunts prior to the full Fontan circulation) and
after (typically one shunt, then partial and later complete Fontan circulation).
However, with the current staged strategy for functionally single ventricle, only a
limited period of controlled pulmonary “overflow” is allowed to stimulate pulmo-
nary arterial growth. The only time of significant pulmonary overflow is immediately
after birth when a shunt or band is placed. In many situations the systemic to pulmo-
nary shunt is made as small as possible to avoid volume overload of the ventricle
and potential cardiac damage. If flow to the lungs is too low for too short a period,
it may lead to inadequate development of the pulmonary vascular bed, high PVR
and, eventually a poorly functioning Fontan circulation (Fig. 8.8). Similarly, hybrid
procedures involving neonatal banding of branch pulmonary arteries may cause
distortion and inadequate growth or even loss of the distal pulmonary arteries.
The Heart and Pulmonary Vasculature in the Fontan

Circulation
The Heart
In the Fontan construct, the heart is exposed to a number of stressors that can change
structure and impair function. Chronic preload deprivation and increased systemic
vascular resistance create a milieu, which favors the development of both systolic
and diastolic dysfunction. The effects of chronic preload deprivation are signifi-
cantly aggravated by the fact that the ventricle is overgrown by the time it reaches
the Fontan state [4]. This combination leads to a situation in which the optimal point
for systolic contractility and diastolic suction according to the Frank Starling
preload-contractility curve cannot be achieved: the ventricle has evolved from
stretched and overloaded while shunted to overgrown and underloaded or even col-
lapsed, at the time of completion of the Fontan circulation [13]. Figure 8.9 depicts
the pressure-volume loops of the ventricle at the different phases of palliation,
clearly showing the effect of unloading on an overgrown ventricle. Moreover the
single ventricle may also exhibit systolic dysfunction as a result of the malformation
itself (right versus left ventricle and fiber disarray) or as a result of dilation and dam-
age by the volume or pressure overload state that had been present early during the
palliative phase.
Diastolic function after the Fontan procedure is also typically abnormal, and the
impairment is unfortunately progressive. The unloading of the ventricle at the time
of the Fontan procedure results in less recoil, impaired compliance, and decreased
suction in the acute phase [14]. Due to persistent preload deprivation, the pressure-
volume curve may show a “reversed creep” with an upward shift and increasing
filling pressures (Fig. 8.10). The ventricle may now enter a vicious cycle whereby
shunt
a Fontan
Output
ml/min
shunt
normal
>1990’s
<1990’s
Fontan
Glenn
birth
time
b
preload Shunt 1 Shunt 2
/ BSA
Fontan
100% normal
>1990’s
Glenn Fontan <1990’s
birth
time
c
preload shunt shunt
/ size
ventricle
Fontan
100% normal
>1990’s
Glenn Fontan <1990’s
birth
time
Fig. 8.7 Cardiac output versus time in the normal left ventricle and the univentricular heart (UVH)
managed before and after the 1990s: the same story but expressed with different reference frame:
in absolute value (a), related to BSA (b), and to ventricular size (c). (a) Cardiac output expressed in
absolute value: The black line shows output of a normal ventricle which increases proportional to
growth. At birth the volume load to the UVH is about 250–300 % of that of a normal left ventricle.
Prior to the 1990s, a neonatal and infant large shunt was created with significant increase in output
(red line); the shunts were abolished at the time of the Fontan operation, and the Fontan portal dam
reduced even further preload. After the 1990s, a small neonatal shunt is created for a short time, and
the ventricle is progressively unloaded both at the Glenn and the Fontan operation (green line).
(b) Cardiac output related to BSA. Black line: output of normal remains at 100 % for BSA.
This representation assumes only dilation and stretch without any overgrowth of the ventricle.
Glenn
Pulmonary volume load

shunt Fontan
100% A
B
C
birth
time
Fig. 8.8 Pulmonary volume load (and outcome) of Fontan since 1990s. In the normal circulation,
pulmonary blood flow increases at birth and remains at 100 % of normal for BSA (A, black line).
In a univentricular heart, a phase of significant pulmonary overflow exists immediately after birth
until a shunt or band is placed to limit blood flow. With adequate pulmonary growth (B, green line),
pulmonary blood flow is reduced to about 50 % of normal for BSA after the superior cavopulmo-
nary connection (stage 2 palliation). Pulmonary flow is then increased by completion of the total
cavo-pulmonary connection (the Fontan operation). If flow to the lungs is too low after the initial
palliation, this may result in inadequate growth (C, orange line). The cyanosis from low pulmonary
blood flow may lead to early referral for superior cavopulmonary connection, which may further
reduce flow and growth. When the Fontan circuit is created, the Fontan portal system will have a
high impedance, resulting in a poor Fontan circulation irrespective the ventricular function, with
low cardiac output and a progressive functional impairment
Fig. 8.7 (continued) The patient with a UVH is born with a large ventricle (volume load of 250 %
of normal for BSA). Prior to the 1990s (red line), the preload to the ventricle is augmented shortly
after birth by a shunt procedure to ±350 % of normal for BSA. The patient slowly outgrows his
shunt, thereby gradually reducing the volume overload. A second shunt was created, augmenting
the volume overload again. As this patient again outgrows his shunt, a Fontan circuit is made,
reducing the volume load to <80 %. After the 1990s (green line), a small neonatal shunt was created
for a short time; the patient slowly outgrows his shunt; the ventricle is progressively unloaded both
at the Glenn and Fontan operation (green line). (c) Cardiac output related to ventricular size in
univentricular heart (UVH) managed before and after the 1990s. This representation assumes
adapted overgrowth of the ventricle in every stage in function of chronic preload, A: output of nor-
mal remains at 100 % for ventricular size. The patient with a UVH is born with an appropriate
ventricle for volume load (100 % of normal for ventricular size). Prior to the 1990s (red line), the
preload to the ventricle was augmented shortly after birth by a shunt procedure to ±150 %. The
patient slowly outgrows his shunt, and adapts his ventricle, thereby gradually reducing the volume
overload to ±100 % for its size. A second shunt was created, augmenting the volume overload again
to 150 %. As this patient again outgrows his shunt, a Fontan circuit is made, reducing the volume
load to 25 % of its “due” preload. After the 1990s (green line), a small neonatal shunt was created
for a short time; the patient slowly outgrows his shunt; the ventricle is progressively unloaded both
at the Glenn and Fontan operation in much milder steps avoiding acute unloading and severe depri-
vation (green line)
pressure/volume loop
C
E
Pressure
B
D
A
Volume
Fig. 8.9 Pressure-volume loops: normal left ventricle (A) versus single ventricle at various stages
of palliation (B–E). A: PV loop of normal LV. At birth, the neonatal ventricle (B) of the UVH had
an intrauterine volume overload of approximately 250 of normal for BSA. In the first months a
systemic to pulmonary shunt is necessary to maintain oxygen saturations of above 85 %; the ven-
tricle will now have a volume overload of about 250–350 % of a normal for BSA (C: large stroke
volume with increasing filling pressures). When a “Fontan” type procedure is performed, all sys-
temic to pulmonary shunts are removed, and the volume preload of the ventricle is acutely reduced
to levels that may vary between at best 80 % of normal for BSA (D) down to the worst end of 30 %
(E: small stroke volume, elevated filling pressure). If the Fontan ventricle is compared to a normal
LV it will be called “stretched & dilated” (E versus A), but when compared to the pre-Fontan state
it is “collapsed and deprived” (E versus C)
D
C
Ventricular EDP mmHg
20
15
A
B
10
0
0
0 50 100 150 200 250

Preload % of normal for BSA
Fig. 8.10 Ventricular end-diastolic pressure in various phases of ventricle. A: normal ventricle; B:
shunted ventricle with chronic volume overload leading to enhanced compliance; C: Fontan ven-
tricle after acute phase: mild preload deprivation of the overgrown ventricle; D: Fontan ventricle
with low output as result of severe chronic preload deprivation leading to elevated filling pressures
the chronic low preload results in remodeling, reduced compliance with increasing
diastolic pressures, poor ventricular filling, and eventually progressively declining
cardiac output. This phenomenon of progressive “disuse hypofunction” occurs at a
chronic preload of less than 70 % of the preload expected for ventricular size [15].
The response of the heart to the stressors associated with the Fontan operation
appears to be variable. In some patients the heart can appear quite normal for many
years and cardiac function may be relatively well preserved, while in other patients
the ventricle appears heavily trabeculated and “overgrown” even before the time of
the Fontan surgery. The variability may be related in part to the native anatomy or
myocardial structural disarray due to changes resulting from the palliative surgeries
preceding the Fontan procedure, but there may also be a genetic heterogeneity in
the response to the stressors associated with the single ventricle physiology.
Polymorphisms in the renin-angiotensin-aldosterone system have been shown to
have a measureable impact on ventricular hypertrophy and on the response of the
myocardium to treatment with angiotensin converting enzyme inhibitors [16]. It is
possible that these and other unknown genetic variants are in part responsible for the
variable response of the heart to the Fontan circulation.
The clinician will thus observe many abnormal features in the Fontan ventricle:
a large cavity, thick wall, decreased systolic and diastolic function, not responsive
to classic measures that should increase the cardiac output. Many of these abnor-
malities are “secondary” and not the primary cause for the low flow observed in the
Fontan circuit. When a ventricle is large, our management will however differ
whether we consider this a stretched ventricle, or rather a collapsed underloaded but
overgrown pump. Similarly, when a ventricle is hypocontractile, our management
will differ whether we contribute this dysfunction to a damaged burned-out ventri-
cle, or rather to underfilling of an overgrown chronically deprived pump with disuse
hypofunction. Assessing the contribution of ventricular overgrowth, dilation, hyper-
trophy, dysfunction due to intrinsic myopathy or due to relative underfilling (con-
trolled by pulmonary vasculature) is difficult. Due to this complexity, most if not all
analyses are based on simplified and incomplete models.
The Pulmonary Vasculature
Abnormal growth and development of the pulmonary vasculature are a hallmark of

single ventricle congenital heart disease. Decreased flow to the pulmonary arterial
tree may begin during fetal life, depending on the specific lesion, and will certainly
exist by necessity after the first stage of palliation during partial or complete cavo-
pulmonary connection (Fig. 8.8). The initial shunting procedure(s) may cause sym-
metric or asymmetric over- or underflow. As a result, hypoplasia or mild pulmonary
vascular disease of the pulmonary vascular bed is common. Stenosis resulting from
abnormal connections, (bilateral) ductal constriction, or surgical scarring can further
compromise the normal pulmonary architecture. The Fontan circulation creates for
the pulmonary vasculature a condition with chronically decreased flow, mild desat-
uration, increased collateral flow, suboptimal mixing of inferior and superior caval
normal
PVR 3
0
10 20 30 40 50 60 70
Age in years
Fig. 8.11 Evolution of PVR with age. In normal subjects (black line), PVR remains low for many
decades, and will increase only at old age without significant cardiovascular limitation. In “good”
Fontan patients with low PVR (green line), resistance remains low for many decades, but is
expected to increase at older age (dotted line). In “poor or bad” Fontan patients with increased
PVR (orange and red line), PVR trends to increase faster with poor clinical outcome at resistances
beyond four units
flow, absence of pulsatility, endothelial dysfunction, absence of episodes of high flow

and high pressure as is normally seen during exercise. These changes can further
alter the vasculature, which underwent abnormal growth and development both
during fetal and postnatal life.
The chronic low flow conditions will induce an overall state of pulmonary (and
systemic) vasoconstriction, causing the whole circuit to fail (Fig. 8.11). Failing
Fontan circuits typically have a high and increasing PVR, although this is often
reversible after transplantation (higher output of pulsatile flow) [17].
Complications after Fontan repair are common and related to the continuously
increased venous pressure and congestion, and chronic low cardiac output.
Complications include early and late mortality, exercise intolerance, ventricular dys-
function, rhythm and conduction disturbances, hepatomegaly with secondary fibro-
sis and cirrhosis [18, 19], lymphatic dysfunction with protein losing enteropathy
[20] and bronchial casts [21, 22], systemic venous thrombi, ascites, and peripheral
edema.
Treatment of Circulatory Failure in Fontan Circulation
In the world of “classical cardiology” with primary myocardial disease, such as

ischemic heart disease or cardiomyopathy, ventricular function is most frequently
the limiting factor of the cardiac output; typically ventricular preload is abundant.
Most cardiac algorithms and treatment strategies have focused on augmenting
systolic performance. However in some conditions the systemic ventricle is not the
limiting factor but the preload of that ventricle: obstructed inflow is a problem after
Mustard repair, in primary pulmonary hypertension, constrictive pericarditis, supra-
valvar and valvular mitral stenosis, and in the setting of the Fontan circuit.
The circulatory problem in a Fontan circuit is primarily created by the dam effect
of the Fontan neo-portal system and the subsequent limited cardiac preload. It has
become clear that once created, the Fontan circuit runs on “autopilot” and allows
little modulation. The ventricular enlargement and dysfunction are initially epiphe-
nomena secondary to the previous palliation and Fontan physiology itself; the state
of volume deprivation—when sufficiently profound or long-lasting—may aggra-
vate ventricular dysfunction and circulatory failure. As such, strategies aimed at
maximizing the efficiency of this portal system will conceptually be more effective
than “traditional” heart failure therapies. Such modulation may consist of increas-
ing the pressure before the dam (systemic venous pressure), lowering the height
(resistance of Fontan neo-portal system) of the dam, enhancing the runoff after the
dam (ventricular suction), or bypassing the dam (fenestration).
Elevated Systemic Venous Pressure (Increasing Pressure

Before the Dam)
An acute increase of systemic venous pressure, as is achieved during exercise (up to

30 mmHg), can temporarily increase output [23]. However, such an elevation can-
not be maintained for a long time. A chronic elevation of venous pressures above
18–20 mmHg, as in patients with a high resistance Fontan portal circuit, will result
in unacceptable side effects such as vascular congestion, edema, ascites, and lym-
phatic failure. Diuretics can partially control these complications of congestion, but
may further increase the problems of chronic low output. General aerobic fitness
may play a role in the transient ability to increase central venous pressure, but even
then, the venous pressure cannot sustain the driving pressure that can be achieved
by a sub-pulmonary ventricle.
Impedance and Pulmonary Vascular Resistance

(Lowering the Height of the Dam)
In the current era, the surgical technique used to create a TCPC is usually quite
good with minimal focal stenosis, reduced turbulence, and flow of the inferior caval
vein blood to both lungs [5, 24]. Previous connections, including valved pathways
and atrioventricular pulmonary connections, are now considered obsolete. For
those patients who received older style Fontan operations, conversion to cavo-pul-
monary connection should be considered when the patient becomes symptomatic,
or as a prevention strategy, to limit any energy loss in the Fontan portal system [25, 26]
and to avoid recurrent atrial arrhythmias. Furthermore, even in patients who are
“doing well,” care should be taken to ensure that focal areas of stenosis, hypoplasia,
distortion, or abundant collateral flow are repaired when possible.
The total cross-sectional area of the pulmonary vascular bed and the impedance
both at rest and during exercise are important factors for the efficiency of the Fontan
circulation. The first palliative procedure is probably the most important and crucial
intervention in the development of the pulmonary vasculature in patients with single
ventricle physiology (Fig. 8.8). It is during these early days that pulmonary vascular
arterial development and “catch-up” growth occurs. The volume requirements for
optimal growth and development of the ventricle and the lungs during infancy are
different and opposed. Avoiding significant overload of the ventricle is important,
but excessive protection from volume overload may cause pulmonary vascular
hypoplasia, which in turn will severely affect the outcome of the final Fontan cir-
cuit. Current strategies place much emphasis on preserving cardiac function, which
is important in the short term whereas for a good long-term outcome, adequate
growth and development of the lungs are more important.
In the last few years, the pulmonary vasculature itself has emerged as a therapeu-
tic target to improve output. In the Fontan circuit, PVR is generally mildly elevated
at baseline but, in the absence of pulsatile flow, it does not decrease normally with
increased cardiac output. Treatment effects of several agents have been reported
(oxygen at altitude, sildenafil, bosentan, inhaled ilosprost); however, the short-term
improvements have been modest [27–30]. Longer-term studies with pulmonary
vasodilators are needed to understand whether these agents can impact the long-
term outcomes of patients after Fontan surgery, and impact on what is characteristi-
cally a slow, downward slope of exercise capacity and cardiovascular functionality.
Ventricular Suction (Enhancing Runoff Past the Dam)
In order to minimize the hemodynamic effect of the Fontan portal system, the ven-
tricle must keep pulmonary venous atrial pressure as low as possible. However, in
mammals ventricular filling is a nearly passive phenomenon and no ventricle will
generate adequate suction, let alone build up the negative pressures required to pull
the blood through the neo-portal Fontan system. Moreover, the Fontan ventricle is
already in a state of chronic severe preload restriction, making it work at the low end
of its pressure–volume relationship. Aging [31] and the progressive “disuse hypo-
function” remodeling may further reduce its compliance as on diastolic pressures.
The effect on the pulmonary venous atrial pressure of agents which alter contrac-
tility, heart rate, and afterload is frequently minimal:
• Contractility: The contraction of the ventricle itself has a role in helping blood
flow through the pulmonary vascular bed. As the atrioventricular annulus con-
tracts toward the apex of the heart, a vacuum is created to “pull” blood into the
pulmonary atrium; as the ventricular myocardium relaxes and the atrioventricular
valve opens, blood is further pulled into the ventricle. The total contribution of
this “suction” is hard to quantify, but is clearly lost in the setting of atrioventricular
dyssynchrony or in the setting of an enlarged previously overgrown atrium.

Inotropic agents can make the Fontan ventricle squeeze harder, but in the setting
of an already preload deprived ventricle, will not effectively change the pulmo-
nary atrial pressure, and hence will not result in a clinically significant cardiac
output increase! Only in the Fontan patient with extreme ventricular dysfunction
(not due to underloading), or if enhanced contractility results in decreased pul-
monary venous pressure (and thus transpulmonary flow) some increase in the
cardiac output may be observed after application of inotropic agents.
• Heart rate: in a ventricle with preload reserve, an increase of heart rate will
result in increased output. In a Fontan circuit with no ventricular preload reserve,
an increase in heart rate will result in a proportional decrease of stroke volume,
and subsequently no change in output [32]. If there is excessive bradycardia, pac-
ing to drive the heart rate into the physiologic range will increase the cardiac
output and decrease congestion [33]. Fontan patients exhibit what is called “chro-
notropic incompetence” during exercise with a heart rate consistently lower than
normal controls; this has typically been attributed to an abnormal reflex control of
heart rate or adrenergic dysfunction. However, adequate ventricular preload dur-
ing exercise is crucial and a major determinant of an increase in heart rate. The
“chronotropic incompetence” is probably not detrimental, or perhaps lifesaving:
tachycardia out of proportion to the cardiac output is poorly tolerated in patients
with limited preload, such as in patients with a Mustard or Fontan circuit.
• Afterload: Any patient who is in a chronically low cardiac output state will
invariably generate an increased systemic vascular resistance in order to main-
tain blood pressure. In a failing but normally connected biventricular circulation
with a hypocontractile ventricle and preload reserve, a decrease of afterload
results in an increase in the cardiac output. The increase in output will counter
the tendency for hypotension, thus resulting in a favorable clinical response. In a
Fontan patient a decrease of afterload without preload reserve will not result in
an increased cardiac output, but may be detrimental by causing severe hypoten-
sion. Whether there is a role for chronic low dose afterload reduction in an
attempt to modulate ventricular diastolic function, remains unknown. In the only
randomized trial of enalapril in patients with the circulation Fontan, no beneficial
effect was observed [34]. However, the duration of this trial was only 10 weeks;
it is still possible that the benefit of afterload reducing agents may be a chronic
impact on diastolic function as opposed to a short-term impact on systemic, vas-
cular resistance.
Fenestration (Bypassing the Dam)
A proven strategy to improve cardiac output in patients with the Fontan procedure
is to create a bypass of the pulmonary circuit in the form of a small fenestration.
This concept had originally been reported as a means to aid the physiologic adjust-
ment in the perioperative state following the Fontan surgery itself [6]. Following the
establishment of the fenestration, the incidence of prolonged pleural effusions and
long hospitalizations decreased significantly. In addition, a limited bypass of the

Fontan portal system also results in chronic improvement of congestion and circula-
tory output. The downside of a fenestration is decreased arterial oxygen saturation
(Fig. 8.6). Nevertheless, the improved cardiac output may result in a better overall
oxygen delivery, and will also help to alleviate the congestive symptoms, particu-
larly of the liver.
While a fenestration at the time of the Fontan surgery is well tolerated and may
be viable for years or decades after surgery, the creation of a fenestration late in a
patient who has not previously had a fenestration is not well tolerated. These patients
are referred for fenestration creation because of the failure of their Fontan circuit,
often characterized by elevated PVR and a high transpulmonary gradient. In this
setting, achieving the proper balance in the creation of a fenestration is quite diffi-
cult and may not be possible. A small fenestration will not generate the degree of
decompression necessary to alleviate symptoms, and a larger fenestration might
alleviate congestion and augment cardiac output, but in so doing will result in an
unacceptable level of cyanosis. Nevertheless, fenestration creation may have a role
in a failing Fontan as a bridge to heart transplantation and to avoid cardiac cachexia.
Mechanical Support and Heart Transplantation
Mechanical support for the failing single ventricle is still in its infancy. The usual
ventricular assist devices are designed to aid a failing systemic ventricle. In the fail-
ing Fontan circulation, the problem is typically not systolic performance, but rather
the physiology as it relates to the neo-portal system and chronic preload deprivation.
In this setting, the interposition of a sub-pulmonary assist device is needed. This has
been reported in one instance as a bridge to transplantation [35].
In many cases of Fontan circulation failure, heart transplantation is likely to be
the final outcome. Heart transplantation in the Fontan patients is associated with a
higher risk than that in patients without congenital heart disease, and may be even
higher in those patients with Fontan circulation failure but preserved ventricular
function [4, 36].
Summary
The Fontan construct has allowed the survival of countless children born with con-
genital heart disease. However, this palliation creates a form of man-made circula-
tion failure characterized by a neo-portal system that leads to chronic preload
deprivation resulting in a low cardiac output and systemic venous congestion.
The careful attention to pulmonary blood flow and pulmonary arterial growth in the
initial stages of palliation are crucial, as are the technical details of the geometry of
the Fontan connections. Avoiding overload of the systemic ventricle during initial
palliation is important, while excessive protection from volume overload may result
in pulmonary vascular hypoplasia [37]. Nevertheless, even in a “perfect” Fontan, it
is difficult to predict how durable this man-made form of circulation failure will be
over the long term.
The overall treatment options for circulatory failure of a Fontan circuit are disap-
pointing; avoidance of problems is most important, because once the Fontan circuit
is created it runs on “auto-pilot,” and allows little modulation. However, clinical
trials are underway to evaluate the potential benefits of modulators of PVR and to
determine whether aerobic training may help to forestall the insidious onset of cir-
culatory failure.
References
1. Fontan F, Baudet E. Surgical repair of tricuspid atresia. Thorax. 1971;26:240–8.

2. Gewillig M. The Fontan circulation. Heart. 2005;91:839–46.
3. Gewillig M, Brown SC, Eyskens B, Heying R, Ganame J, Budts W, La Gerche A, Gorenflo M.
The Fontan circulation: who controls cardiac output? Interact Cardiovasc Thorac Surg.
2010;10:428–33.
4. Gewillig M, Kalis N. Pathophysiological aspects after cavopulmonary anastomosis. Thorac
5. De Leval M, Kilner P, Gewillig M, Bull C. Total cavopulmonary connection: a logical alterna-
tive to atriopulmonary connection for complex Fontan operations. Experimental studies and
early clinical experience. J Thorac Cardiovasc Surg. 1988;96:682–95.
6. Bridges ND, Lock JE, Castaneda AR. Baffle fenestration with subsequent transcatheter closure.
Modification of the Fontan operation for patients at increased risk. Circulation. 1990;82(5):
1681–9.
7. La Gerche A, Gewillig M. What limits cardiac performance during exercise in normal subjects
and in healthy Fontan patients? Int J of Pediatr 2010:ID 791291.
8. Van de Bruaene A, La Gerche A, Claessen G, De Meester P, Devroe S, Bogaert J, Claus P,
Heidbuchel H, Gewillig M, Budts W. Sildanafil improves exercise hemodynamics in Fontan
patients. (abstract). Circ Cardiovasc Imaging. 2014;7(2):265–73.
9. Paridon SM, Mitchell PD, Colan SD, Williams RV, Blaufox A, Li JS, Margossian R, Mital S,
Russell J, Rhodes J. A cross-sectional study of exercise performance during the first 2 decades
of life after the Fontan operation. J Am Coll Cardiol. 2008;52:99–107.
10. Giardini A, Hager A, Pace Napoleone C, Picchio FM. Natural history of exercise capacity after
the Fontan operation: a longitudinal study. Ann Thorac Surg. 2008;85:818–21.
11. Diller GP, Dimopoulos K, Okonko D, Li W, Babu-Narayan SV, Broberg CS, Johansson B,
Bouzas B, Mullen MJ, Poole-Wilson PA, Francis DP, Gatzoulis MA. Exercise intolerance in
adult congenital heart disease: comparative severity, correlates, and prognostic implication.
Circulation. 2005;112:828–35.
12. Diller GP, Giardini A, Dimopoulos K, Gargiulo G, Muller J, Derrick G, Giannakoulas G,
Khambadkone S, Lammers AE, Picchio FM, Gatzoulis MA, Hager A. Predictors of morbidity
and mortality in contemporary Fontan patients: results from a multicenter study including
cardiopulmonary exercise testing in 321 patients. Eur Heart J. 2010;31:3073–83.
13. Gewillig MH, Lundstrom UR, Deanfield JE, Bull C, Franklin RC, Graham Jr TP, Wyse
RK. Impact of Fontan operation on left ventricular size and contractility in tricuspid atresia.
Circulation. 1990;81:118–27.
14. Gewillig M, Daenen W, Aubert A, Van der Hauwaert L. Abolishment of chronic volume overload.
Implications for diastolic function of the systemic ventricle immediately after Fontan repair.
Circulation. 1992;86:II93–9.
15. Silverstein DM, Hansen DP, Ojiambo HP, Griswold HE. Left ventricular function in severe
pure mitral stenosis as seen at the Kenyatta national hospital. Am Heart J. 1980;99:727–33.
16. Mital S, Chung WK, Colan SD, Sleeper LA, Manlhiot C, Arrington CB, Cnota JF, Graham
EM, Mitchell ME, Goldmuntz E, Li JS, Levine JC, Lee TM, Margossian R, Hsu DT. Renin-
angiotensin-aldosterone genotype influences ventricular remodeling in infants with single ven-
tricle. Circulation. 2011;123:2353–62.
17. Mitchell MB, Campbell DN, Ivy D, Boucek MM, Sondheimer HM, Pietra B, Das BB, Coll
JR. Evidence of pulmonary vascular disease after heart transplantation for Fontan circulation
failure. J Thorac Cardiovasc Surg. 2004;128:693–702.
18. Rychik J, Veldtman G, Rand E, Russo P, Rome JJ, Krok K, Goldberg DJ, Cahill AM, Wells
RG. The precarious state of the liver after a Fontan operation: summary of a multidisciplinary
symposium. Pediatr Cardiol. 2012;33:1001–12.
19. Wu FM, Ukomadu C, Odze RD, Valente AM, Mayer Jr JE, Earing MG. Liver disease in the
patient with Fontan circulation. Congenit Heart Dis. 2011;6:190–201.
20. Rychik J. Protein-losing enteropathy after Fontan operation. Congenit Heart Dis. 2007;2:
288–300.
21. Heath L, Ling S, Racz J, Mane G, Schmidt L, Myers JL, Tsai WC, Caruthers RL, Hirsch JC,
Stringer KA. Prospective, longitudinal study of plastic bronchitis cast pathology and respon-
siveness to tissue plasminogen activator. Pediatr Cardiol. 2011;32:1182–9.
22. Chaudhari M, Stumper O. Plastic bronchitis after Fontan operation: treatment with stent fen-
estration of the Fontan circuit. Heart. 2004;90:801.
23. Shachar GB, Fuhrman BP, Wang Y, Lucas Jr RV, Lock JE. Rest and exercise hemodynamics
after the Fontan procedure. Circulation. 1982;65:1043–8.
24. Van Haesdonck JM, Mertens L, Sizaire R, Montas G, Purnode B, Daenen W, Crochet M,
Gewillig M. Comparison by computerized numeric modeling of energy losses in different
Fontan connections. Circulation. 1995;92:II322–6.
25. Mavroudis C, Deal BJ, Backer CL, Johnsrude CL. The favorable impact of arrhythmia surgery
on total cavopulmonary artery Fontan conversion. Semin Thorac Cardiovasc Surg Pediatr Card
Surg Annu. 1999;2:143–56.
26. Conte S, Gewillig M, Eyskens B, Dumoulin M, Daenen W. Management of late complications
after classic Fontan procedure by conversion to total cavopulmonary connection. Cardiovasc
Surg. 1999;7:651–5.
27. Darst JR, Vezmar M, McCrindle BW, Manlhiot C, Taylor A, Russell J, Yetman AT. Living at an
altitude adversely affects exercise capacity in Fontan patients. Cardiol Young. 2010;20:
593–601.
28. Goldberg DJ, French B, McBride MG, Marino BS, Mirarchi N, Hanna BD, Wernovsky G,
Paridon SM, Rychik J. Impact of oral sildenafil on exercise performance in children and young
adults after the Fontan operation: a randomized, double-blind, placebo-controlled, crossover
trial. Circulation. 2011;123:1185–93.
29. Ovaert C, Thijs D, Dewolf D, Ottenkamp J, Dessy H, Moons P, Gewillig M, Mertens L. The
effect of bosentan in patients with a failing Fontan circulation. Cardiol Young. 2009;19:
331–9.
30. Rhodes J, Ubeda-Tikkanen A, Clair M, Fernandes SM, Graham DA, Milliren CE, Daly KP,
Mullen MP, Landzberg MJ. Effect of inhaled iloprost on the exercise function of Fontan
patients: a demonstration of concept. Int J Cardiol. 2013;168:2435–40.
31. Cheitlin MD. Cardiovascular physiology-changes with aging. Am J Geriatr Cardiol. 2003;12:
9–13.
32. Barber G, Di Sessa T, Child JS, Perloff JK, Laks H, George BL, Williams RG. Hemodynamic
responses to isolated increments in heart rate by atrial pacing after a Fontan procedure. Am
Heart J. 1988;115:837–41.
33. Cohen MI, Rhodes LA, Wernovsky G, Gaynor JW, Spray TL, Rychik J. Atrial pacing: an
alternative treatment for protein-losing enteropathy after the Fontan operation. J Thorac
34. Kouatli AA, Garcia JA, Zellers TM, Weinstein EM, Mahony L. Enalapril does not enhance
exercise capacity in patients after Fontan procedure. Circulation. 1997;96:1507–12.
35. Pretre R, Haussler A, Bettex D, Genoni M. Right-sided univentricular cardiac assistance in a
failing Fontan circulation. Ann Thorac Surg. 2008;86:1018–20.
36. Seddio F, Gorislavets N, Iacovoni A, Cugola D, Fontana A, Galletti L, Terzi A, Ferrazzi P. Is
heart transplantation for complex congenital heart disease a good option? A 25-year single
centre experience. Eur J Cardiothorac Surg. 2013;43:605–11.
37. Gewillig M, Brown SC, Heying R, Eyskens B, Ganame J, Boshoff DE, Budts W, Gorenflo M.
Volume load paradox while preparing for the Fontan: not too much for the ventricle, not too
little for the lungs. Interact Cardiovasc Thorac Surg. 2010;10(2):262–5.
Part III
Acute Right Heart Failure
Chapter 9
Acute Right Ventricular Failure
Anthony R. Cucci, Jeffrey A. Kline, and Tim Lahm
Introduction
Acute right ventricular failure (RVF) is a frequent and formidable challenge to

practicing clinicians. Despite a growing understanding of the physiology of the
acutely failing RV, this syndrome continues to carry substantial morbidity and mor-
tality [1–5]. Much of the current knowledge regarding the management of acute
RVF stems from studies focused on left ventricular failure (LVF). However, due to
embryological, anatomical, physiological, biochemical, and electrophysiological
differences between the RV and the left ventricle (LV) [6–8], insights gained from
and studies of LVF cannot be extrapolated to the failing RV. The following chapter
will (1) provide a definition of acute RV dysfunction and acute RVF, (2) highlight
the underlying pathophysiology of the acutely failing RV, (3) discuss the etiologies
behind the development of acute and acute-on-chronic RVF, (4) review diagnostic
tools that aid in diagnosis and risk stratification, and (5) describe current treatment
strategies for acute RVF.
A.R. Cucci, M.D. (*)

Department of Internal Medicine, Division of Pulmonary/Critical Care,
Indian University, 550 University Blvd, Indianapolis, IN 46202, USA
e-mail: acucci@iu.edu
J.A. Kline, M.D.
Emergency Medicine, Indiana University School of Medicine,
720 Eskenazi Ave, Indianapolis, IN 46202, USA
e-mail: jefkline@iupui.edu
T. Lahm, M.D.
Department of Medicine, Division of Pulmonary, Allergy, Critical care,
occupational and Sleep Medicine, Indiana University School of Medicine
and Richard L. Roudebush VA Medical Center, 980 W Walnut Street,
Room C-400, Indianapolis, IN 46202, USA
e-mail: tlahm@iu.edu

162 A.R. Cucci et al.
Acute RV Failure: Definitions and Clinical Challenges
Broadly defined, acute RVF results from impaired RV myocardial energy metabo-
lism and contractility, producing a clinical syndrome characterized by an RV that
cannot adequately respond to work demand, which in turn causes vital organ
hypoperfusion. Prior to abject failure, the RV manifests clinical evidence of acute
RV dysfunction, which is defined by the AHA Scientific Statement on the
Management of Massive and Submassive Pulmonary Embolism [9] as at least one of
the following:
• RV dilation (apical four-chamber RV diameter divided by LV diameter >0.9) or
RV systolic dysfunction on echocardiography
• RV dilation (four-chamber RV diameter divided by LV diameter >0.9) on com-
puter tomography
• Increased B-type natriuretic peptide (BNP; >90 pg/mL) or N-terminal pro-BNP
(>500 pg/mL)
• Electrocardiographic changes (new complete or incomplete right bundle branch
block, anteroseptal ST elevation or depression, or anteroseptal T-wave inversion;
a pattern commonly referred to as “RV strain”)
The biochemical and mechanical changes underpinning transition from acute RV
dysfunction to failure remain a subject of intense study. Extrapolating from the
definitions for submassive and massive pulmonary embolism (PE) [9], one may
propose to define acute RV failure as acute RV dysfunction that is accompanied by
hemodynamic compromise (defined as systolic blood pressure <90 mmHg for at
least 15 min or the requirement of inotropic support). Because organ hypoperfusion
may occur even in the absence of hypotension [10, 11], and because mortality
increases sharply when hypotension supervenes, it is logical to define early acute
RVF based upon biomarkers of circulatory shock that precede hypotension, includ-
ing elevations in blood lactate concentrations or decreases in central venous or
mixed SvO2 [12]. Additional evidence of organ hypoperfusion would include an
otherwise unexplained increase in creatinine, as well as oliguria or mental status
changes [10, 11].
Biomarkers that define RV dysfunction include the natriuretic peptides and
markers of myocardial necrosis. While BNP or N-terminal pro-BNP is used to
define RV dysfunction, these biomarkers may be elevated as a consequence of
sepsis, volume overload, or LV failure [13, 14]. RV dysfunction should thus be
confirmed by imaging methods or electrocardiography. On the other hand, BNP
levels can be falsely low in obese patients [15], and RV dysfunction in this popula-
tion may occur even if BNP levels are within normal limits.
Evidence of cardiomyocyte death strongly predicts severe RV dysfunction. The
AHA Scientific Statement defines the latter as an elevation of troponin I (>0.4 ng/mL)
or troponin T (>0.1 ng/mL) [9]. While evidence of cardiomyocyte death can be seen
in the absence of RV dysfunction, such patients are at high risk for progression to
circulatory shock [9].
9 Acute Right Ventricular Failure 163
Some authors differentiate between “compensated” and “decompensated RV

failure.” We prefer to use the terms “RV dysfunction” and “RV failure,” setting the
term “decompensated RV failure” aside for patients with chronic RV failure that
experience an acute worsening (a scenario that can be seen in patients with chronic
pulmonary hypertension [PH] [8, 16, 17], see Chaps. 13, 17, and 19). For the
remainder of this chapter, we will define acute RV dysfunction as the acute occur-
rence of RV dilation, otherwise unexplained increases in BNP or NT-pro-BNP lev-
els, or electrocardiographic signs of RV strain as detailed above. We will define
acute RVF as acute RV dysfunction plus otherwise unexplained hypotension or
organ hypoperfusion.
The most obvious causes of acute RV dysfunction and failure are diseases and
processes that abruptly increase RV afterload, such as embolism syndromes (from
thrombus, tumor, fat, air, or other particles) and PH, or diseases that interrupt coro-
nary blood flow (e.g., acute myocardial infarction). Defining RV failure becomes
difficult in patients with comorbid conditions that may cause hypotension or organ
hypoperfusion even in the absence of RV dysfunction (e.g., hypovolemia, sepsis,
LV dysfunction, or arrhythmias). In these complex patients, it can be extremely dif-
ficult to determine the cause or causes most responsible for the hypoperfusion.
However, from a treatment standpoint, the mere fact of RV dysfunction predicts a
worsened prognosis in patients with chronic lung disease, PH, LV dysfunction,
sepsis, acute respiratory distress syndrome [ARDS], or PE [18–24].
Pathophysiologic Concepts in Acute RV Failure
Acute RVF results from any structural or functional alteration that reduces the RV’s
ability to propel blood into the pulmonary circulation. The RV generally fails as a
consequence of (1) alterations in preload, (2) decrease in contractility, or (3) increase
in afterload (Fig. 9.1). Ventricular interdependence and myocardial ischemia make
the RV particularly prone to failure.
Preload dependence: The RV is perfectly adapted to generate an adequate and
appropriate cardiac output (CO) into the low-pressure pulmonary circulation [7,
25]. As a result of its high compliance, the RV is well adapted to accommodate
sudden and significant changes in preload [25–27]. In fact, it is the premier function
of the RV—to guarantee a sufficient amount of blood flow through the pulmonary
vasculature and into the LV, in order to allow for the required changes in CO in the
setting of positional changes, exercise, or disease. However, even though the RV is
custom-built to accommodate large changes in preload, at either end of the Frank–
Starling curve (significant underfilling or overdistension), the RV can lose this
capacity. Acute RVF from underfilling may occur during hypovolemia, sepsis, supe-
rior vena cava obstruction (e.g., SVC syndrome), mechanical ventilation (MV), or
arrhythmias. On the other hand, RV failure from overfilling and overdistension can
occur during hypervolemia or overzealous volume resuscitation. Preload sensitivity
Fig. 9.1 Mechanisms of acute RV failure. Acute RVF frequently is multifactorial and includes a
number of pathological conditions that result in reductions in RV contractility and preload, in addi-
tion to increases in RV afterload. Note that several mechanisms may cause acute RV failure by two
or more of these components. Asterisks and hashtags indicate mechanisms not directly demon-
strated in the schematic: *Pulmonary microthrombi can also be seen in sepsis/SIRS. #Sepsis/SIRS
may cause acute pulmonary hypertension due to pulmonary artery endothelial cell dysfunction.
**
LV dysfunction may also increase preload. ##Valvular heart disease may also affect RV function
by increasing afterload (e.g., pulmonary stenosis). ARDS acute respiratory distress syndrome,
IL-1β interleukin-1β, IL-6 interleukin-6, LV left ventricle, TNF tumor necrosis factor
is particularly pronounced in the setting of increased pulmonary vascular resistance

(PVR), including embolic syndromes, hypoxic pulmonary vasoconstriction (HPV),
or mechanical ventilation [2, 8].
Contractility: The RV acutely responds to afterload stress by enhancing contractility
via the Frank–Starling mechanism, the Anrep mechanism (see Chap. 2), and neuro-
hormonal activation [8, 25, 28]. RV contractility can be reduced acutely as a conse-
quence of impaired energy metabolism, cytokine activation, and/or endotoxin
release during sepsis, acidosis, ischemia, electrolyte disturbances, drug overdose
(e.g., beta blockers, calcium channel blockers), or substrate depletion [2, 5, 8, 29,
30]. Several of these processes may simultaneously affect LV function, thus leading
to biventricular failure.
Afterload sensitivity: While the RV responds well to demand for volume work from
preload increase, the RV responds poorly to pressure work demand from increased
afterload [8, 26, 31–34]. This principle is particularly important in the setting of
acute afterload increase; acute PE is the prototype of such an insult. In general, a
previously healthy and non-hypertrophied RV cannot acutely overcome a systolic
pulmonary arterial pressure (PAP) of more than 50–60; it will decompensate [2, 8,
35]. Consequentially, any condition that leads to a significant loss of pulmonary
vascular cross-sectional area (e.g., acute embolism syndromes, severe acute PH,
acute HPV, pulmonary microthrombi in sepsis, or ARDS) may result in profound
RVF, as the RV will not be able to generate a high enough PAP to maintain pulmo-
nary vascular perfusion and CO. On the other hand, in the setting of a chronically
elevated afterload, the presence of RV hypertrophy allows for the RV to generate
much higher pulmonary pressures, making it more resilient to afterload stress [8].
Even though RV contractility initially increases as a compensatory response to after-
load stress, if the rise in contractility is not sustained or sufficient for the degree of
afterload increase, this results in RV–PA uncoupling [36] (see Chap. 2). Pressure–
volume measurements in the RV allow for accurate measurements of RV contractil-
ity and RV–pulmonary artery (PA) coupling in the setting of RV afterload stress, in
the research setting [36–38].
Ventricular interdependence and dependence upon perfusion during systole also
contribute to the RV’s vulnerability. While alterations in preload, contractility, or
afterload usually initiate acute RV dysfunction, ventricular interdependence and a
drop of the perfusion pressure are causes of rapid RV failure. Ventricular interde-
pendence is due to three distinct phenomena: (1) the connection of RV and LV
superficial muscle layers in the ventricular groove, (2) the shared interventricular
septum (IVS), and (3) the poorly compliant pericardial sac limiting the expansion of
one ventricle in expense of the other ventricle’s filling [39–41]. Due to connected
superficial muscle layers and shared IVS, LV contraction contributes to roughly
20–40 % of the RV systolic pressure (RVSP) and ejection fraction [42–44]. In acute
RV pressure- or volume overload however, both distortion of the RV shape and
leftward shift of the IVS significantly compromise the contractile contributions of
the LV to RV function [8, 39, 40, 42]. Importantly, due to constraints of the pericar-
dial sac, the “bowing” of the IVS towards the LV also impinges on that ventricle,
leading to LV underfilling and diastolic dysfunction, thus further impairing overall
CO [39, 42, 45]. Similarly, ventricular interdependence can lead to acute RV dys-
function in the setting of LV failure, with the IVS being shifted to the right, and thus
impinging on the RV [46].
RV perfusion: Muscle ischemia plays a difficult to assess role in the development of
acute RVF. While RV coronary perfusion under normal conditions is characterized
by coronary flow during both systole and diastole [38, 47, 48], with increasing wall
stress and a subsequent rise in myocardial transmural pressure, coronary perfusion
via the right coronary artery (RCA) is reduced, leading to an overall decrease in
oxygen delivery and subsequent regional ischemia with the subendocardium most
severely affected [49–52]. This decreased oxygen delivery is further compounded
by an increase in myocardial oxygen demand secondary to increases in both RV
wall stress and workload [50]. The tachycardia that is frequently observed in the
setting of RV dysfunction further contributes to decreased oxygen delivery and

increased oxygen demand. In the chronically dysfunctional RV, remodeling may
promote adaptive changes in the microvasculature with increased capillarization
and compensatory biochemical and molecular changes [30, 53]. However, in the
setting of acute RV dysfunction or failure, these adaptive mechanisms are not avail-
able [53]. As a result, profound myocardial ischemia ensues leading to impaired RV
contractility. This reduction in contractility further impairs overall CO and conse-
quently reduces oxygen delivery to an already substrate-deprived RV, leading to a
viscous cycle until its ultimate collapse (Fig. 9.2). Many authors believe that it is the
myocardial ischemia that accounts for the ultimate transition from RV dysfunction
to failure [30, 51, 53].
Other components of RV performance that may contribute to an acute deteriora-
tion in RV function include loss of normal sinus rhythm, loss of RV intraventricular
synchrony, and loss of valvular competency [25, 45, 54, 55]. In particular, the acute
onset of tricuspid regurgitation (either as a result of papillary muscle rupture in
acute myocardial infarction or as a result of significant RV dilation from pressure or
volume overload) can have detrimental consequences [26].
Biochemical and Molecular Changes in the Acutely

Failing RV
Biochemical and molecular correlates of acute RVF include cardiomyocyte death,

influx of pro-inflammatory cells, chemokine/cytokine activation, and oxidative
stress. Cardiomyocyte death is a consequence of ischemia, substrate depletion, and
impaired mitochondrial energy metabolism. Intracellular calcium overload and
oxidative stress are additional contributors to cell death. Significant biochemical
alterations are observed within 24 h of RV injury.
PE is the prototype of acute RV injury. The abrupt increase in the afterload
results in RV muscle stretch and shear stress, increased wall tension and dilation,
elevated heart rate, and increased oxygen demand in the face of decreased RV coro-
nary perfusion. The result is a poorly contractile, dilated, thinned, and pale-appearing
RV [56] (Fig. 9.3a + b). Histologically, these changes are accompanied by cardio-
myocyte lysis and an inflammation. Influx of neutrophils, lymphocytes, and macro-
phages occurs within hours of the insult [57–59] (Fig. 9.3e–g). Macrophages exhibit
an M1 pro-inflammatory phenotype, and compared to neutrophils (which decrease
within 1 week) they are still present at 6 weeks (then characterized by a M2 wound
repair phenotype) [57]. Myeloperoxidase, MCP1, CINC1, CINC2, MIP1α, and
MIP2 are activated/increased within 18 h of the insult, and are accompanied by
matrix metalloproteinase activation, cardiomyocyte necrosis, and mitochondrial
damage [56, 60]. Similar changes with activation of pro-apoptotic pathways and
local overexpression of TNF-alpha were also seen in an acute PA constriction
model, where these changes occurred within 2 h of RV injury [61]. Pro-inflammatory
biomarkers (e.g., myeloperoxidase) can also be detected in the serum of patients
Fig. 9.2 Vicious cycle in the transition from RV dysfunction to failure. Alterations in preload,
increases in afterload, and/or decreases in contractility are the causative factors in the development
of RV dysfunction. If the stimulus is severe and/or sustained, increased wall stress and increased
oxygen demand will result in local ischemia. Systemic hypoxemia caused directly by the underly-
ing disease triggering the RV dysfunction (e.g., ARDS, pulmonary hypertension, sepsis, systemic
inflammatory response syndromes, exacerbations of chronic lung disease, or congestive heart fail-
ure) may contribute to the development of local ischemia in the RV. Once RV cardiomyocyte
ischemia ensues and contractility decreases, a vicious cycle of increased oxygen demand in the
setting of decreased oxygen delivery occurs, leading to worsening RV failure and its eventual col-
lapse. RV right ventricle, R → L right-to-left shunt
with acute PE [62–64]. Inflammation is pathogenetically relevant, since treatment

with anti-PMN or anti-CINC (CXCL1) antibodies or with the nonsteroidal anti-
inflammatory drug ketorolac reduces RV inflammation and improve contractile
function [56, 65, 66]. Reactive oxygen species (ROS) can be demonstrated within
24 h of acute PE [60]. The RV outflow tract is particularly affected by acute afterload
Fig. 9.3 Macroscopic and microscopic correlates as well as long-term consequence of acute RV
failure due to pulmonary embolism (PE). (a–d) Images of both whole heart (a, c) and RV free wall
(b, d), respectively, of isolated perfused rat hearts 18 h after experimental acute PE (a, b) or sham
procedure (c, d). Note the pale appearance of the RV outflow tract (RVOT) in (a) and (b), rep-
resenting significant myocardial injury. (e–g) Staining for neutrophils (PMNs) in RVOT tissue
from animals treated with PE at 2 h (e), 6 h (f), and 18 h (g) shows marked time-dependent infiltra-
tion with PMNs. (h) Long-term consequences of acute severe PE. Contrasted chest computer
tomography (CT) image from a 79-year-old male with a severe acute PE 6 months prior. Symptoms
at the time of imaging were lower extremity edema and dyspnea on exertion. CT shows a markedly
dilated RV and right atrium (RA). Of note, this patient did not have any evidence of chronic
thromboembolic pulmonary hypertension on ventilation/perfusion scanning and right heart
catheterization. (a–d) Reproduced with permission from Watts JA et al. [56]; (e–h) reproduced
with permission from Watts JA et al. [303]
stress [57, 67] (Fig. 9.3a–f). RV deformation normalizes with time in cases of less
severe cases of acute PE; however, in more severe PE, RV dilation, thinning, and
scarring may remain permanent, leading to persistently impaired contraction [68]
(Fig. 9.3h).
Though not specifically described for the RV, experimental data suggest that
cardiomyocyte stretch leads to activation of an angiotensin II- and endothelin (ET)-
mediated increase in cytosolic calcium and subsequent activation of NFAT, Ca2+/
calmodulin-dependent kinase II, and PKC signaling [69]. Calpain activation con-
tributes to contractile dysfunction in acute RVF and is associated with decreased
abundance and organization of the adhesion protein talin [70, 71]. Lastly, a switch
to the fetal gene program similar to what is observed in chronic RVF has also been
described for acute RV injury. For example, in a rat model of acute PE, a decrease
in the expression of genes, encoding proteins involved in fatty acid transport, activa-
tion, and β-oxidation occurs within 18 h of injury [72]. This is accompanied by
activation of hypoxia-inducible factor (HIF)-1α, suggesting that—as in chronic
RVF [53]—HIF-1α activation is a key regulator of these metabolic changes.
Etiologies of Acute RV Failure
In general, the RV fails as a consequence of alterations in preload, contractility, and/

or afterload [2, 8, 26]. While a separation into these three entities helps understand
and identify etiologies of RV dysfunction or failure, many conditions can alter sev-
eral of these components simultaneously (e.g., sepsis, which may alter preload, con-
tractility, and afterload [11]). The following section discusses the clinically most
relevant etiologies of acute RVF. A detailed overview of the various etiologies is
provided in Table 9.1 and Fig. 9.1.
The most common etiology underlying acute RV failure is decompensated LVF
[8]. The development of RVF in LV disease is multifactorial, and includes pulmo-
nary venous congestion, ventricular interdependence, left-sided arrhythmias, and/or
myocardial ischemia [8, 29, 73].
Acute PE and acute PH are also common causes of acute RVF [2, 8, 19, 26, 35,
74]. In many ways, these two syndromes are the prototypes of acute RV dysfunction
caused by an excessive increase in afterload. In the early 1970s, McIntyre and col-
leagues documented, using pulmonary angiography, the tight correlation between
pulmonary vascular occlusion and pulmonary hypertension in patients without pre-
existing lung disease [75, 76]. In previously healthy patients, at least 40 % of the
cross-sectional area must be obstructed to significantly increase the PAP and pro-
duce abnormalities in RV morphology and function on echocardiography [77, 78].
However, in patients with preexisting lung disease, the size and mass of the PE
affects the PVR and RV injury. In general, the degree of pulmonary vascular obstruc-
tion on CT pulmonary angiography is a poor predictor of outcome, although a cen-
tral location of clots tends to worsen prognosis [79]. Cardiogenic shock occurs in
10 % of acute PE cases, with a mortality rate of up 52 % [80]. RV dysfunction is
observed in about 40–60 % of normotensive patients with PE. While mortality in
the latter patients is only 8–10 % [35, 81, 82], RV dysfunction persists in approxi-
mately 40 % of previously healthy patients, manifesting itself as an abnormal RV on
echocardiogram and/or as persistent exercise intolerance [83, 84]. While it has tra-
ditionally been thought that acute PE increases the afterload by mechanically
obstructing the pulmonary vasculature, it has now been established that the release
of platelet- and endothelial-derived mediators (e.g., serotonin, endothelin-1, throm-
boxane-A2, prostaglandin F2α) exerts vasoconstrictor effects even in non-obstructed
areas and further contributes to the increase in PAP [65, 85, 86]. Similarly,
PE-associated intracardiac hemolysis (resulting from severe tricuspid regurgitation
Table 9.1 Common etiologies of acute right ventricular failure

Preload decrease
• Hypovolemia (over-diuresis, hemorrhage)
• Acute systemic vasodilatation (sepsisa)
• Mechanical ventilationa
• SVC syndrome
• Acute pericardial disease (constrictive pericarditis, cardiac tamponade)
Inotropic impairment
• Left ventricular systolic or diastolic dysfunction (via ventricular interdependence; possibly
also via arrhythmias)
• RV myocardial infarction/ischemia
• Acute myocarditis
• Sepsisa
• LVAD placement
• High-intensity exercise
• Brain death
• Arrhythmias
• Metabolic derangements (electrolyte disorders, acid base disturbances)
Afterload increase
• Pulmonary hypertension (PH)
– Pulmonary arterial hypertension (PAH: WHO group 1)
– Pulmonary venous hypertension (WHO group 2)
– PH due to chronic lung disease/hypoxemia (WHO group 3)
– CTEPH (WHO group 4)
– Other causes of PH (WHO group 5)
• Acute pulmonary embolism
• Acute embolism syndromes (Fat, amniotic fluid, cement, tumor)
• Hypoxic pulmonary vasoconstriction (ARDS)
• Mechanical ventilationa
• Pulmonary vein stenosis/RV outflow tract obstruction
• Post-cardiothoracic surgery (CABG, heart or lung transplantation, corrective surgery for
CHD)
• Acute chest syndrome
• Pulmonary microthrombi (sepsisa, DIC, ARDS)
• High-intensity exercise
Complex heart diseases
• Valvular heart disease (aortic, mitral, pulmonary, or tricuspid valve)
• Congenital heart disease (atrial/ventricular septal defect, Ebstein’s anomaly, tetralogy of
Fallot, transposition of great vessels, Uhl’s anomaly, anomalous pulmonary venous return)
• Chronic restrictive cardiomyopathies (amyloidosis, sarcoidosis, idiopathic)
ARDS acute respiratory distress syndrome, CABG coronary artery bypass grafting, CHD congenital
heart disease, DIC disseminated intravascular coagulation, LV left ventricle, LVAD left ventricular
assist device, PAH pulmonary arterial hypertension, PH pulmonary hypertension, SVC superior
vena cava, WHO World Health Organization
a
Impairment of RV function due to sepsis and mechanical ventilation is multifactorial
and turbulent flow across the pulmonary valve) contributes to vasoconstriction and
an increase in the afterload via nitric oxide scavenging by free hemoglobin and via
L-arginine depletion (the latter via release of erythrocyte arginase) [87–89]. In fact,
plasma haptoglobin concentrations decrease as the severity of PE and the elevations
in RVSP increase [87]. Other embolism syndromes associated with acute RV dys-
function include fat, amniotic fluid, cement, or tumor emboli [90–92].
Although any form of chronic PH can result in acute RV dysfunction, overt RVF
is frequently encountered in patients with pulmonary arterial hypertension (PAH) or
chronic thromboembolic pulmonary hypertension (CTEPH) [31, 93, 94]. In both
syndromes, acute RVF can be the initial presentation of the disease, or present as
acute-on-chronic RV failure. Acute PH and RVF are serious problems after cardio-
thoracic surgery. Mechanisms are multifactorial and include depression of preload
and cardiac contractile strength in response to a systemic inflammatory response
syndrome, as well as increased afterload from lung vascular microembolism, effects
of mechanical ventilation, cardiac restrictive physiology, and the superimposed
negative inotropy by drugs required for sedation or heart rate control [95–97].
Specific risk factors for the development of perioperative RVF include the use of
cardiopulmonary bypass, RV ischemia-reperfusion injury, and placement of left
ventricular assist devices (LVADs) [98, 99]. The etiology for RV dysfunction in the
latter case has not been fully characterized; changes in geometry and contraction
patterns after LVAD placement have been proposed (see below) [100–102]. Sickle
cell crisis, specifically the acute chest syndrome (ACS), has also been characterized
by marked elevation in tricuspid regurgitant jet velocity in as many as 60 % of
patients [103]. Cor pulmonale has been described in as many as 13 % of ACS
patients [103]. The mechanism underlying the development of PH and subsequent
RVF in the setting of ACS is multifactorial and includes hyperhemolysis, HPV,
pulmonary microvascular embolism and thrombosis, bone marrow emboli, and
coronary hypoperfusion [103–105]. Importantly, ACS-associated PH and RV
dysfunction are associated with cardiac biomarker elevation and a higher risk of
death [105].
Hypotensive states, such as sepsis, shock, hemorrhage, or severe hypovolemia,
compromise both RV filling as well as RV coronary perfusion [2]. Sepsis and shock
have complex effects on RV function, as they—in addition to decreasing preload—
can directly decrease RV contractility via negative inotropic effects of bacterial
endotoxins and/or pro-inflammatory cytokines (e.g., TNF-alpha, IL-1beta, IL-6)
[4, 106]. Furthermore, sepsis-induced endothelial dysfunction with pulmonary
vasoconstriction and pulmonary microthrombi can significantly increase RV after-
load [4, 107]. Lastly, treatments employed for sepsis and/or shock (MV, overzealous
volume resuscitation) can negatively affect RV function [2, 8, 31].
Severe respiratory disease can cause significant RV dysfunction, as hypoxemia
and hypercapnea may impair RV performance via vasoconstrictor effects, and
potentially also via direct effects on the myocardium [2, 8, 31, 108, 109]. ARDS has
been associated with increased transpulmonary gradients in 73 % of patients in the
ARDSnet cohort [110], and acute cor pulmonale occurs in 25–50 % of ARDS
patients, depending on the severity of the syndrome [21, 111, 112]. In addition to
hypoxic/hypercarbic vasoconstriction, mechanisms of ARDS-induced RV dysfunc-

tion include pulmonary microthrombi, pro-inflammatory cytokine activation, and
negative effects of MV (see below) [21, 111, 113, 114]. An increased alveolar dead
space, resulting from either precapillary occlusion or globally reduced lung perfu-
sion from RV failure, independently increases the risk of death from ARDS [115,
116]. A recent study identified infection-induced ARDS and airway pressures as
independent predictors of ARDS-induced cor pulmonale [112]. Another study iden-
tified a PaCO2 ≥ 60 mmHg as a risk factor [113]. However, while ARDS-induced
PH and cor pulmonale have been identified as risk factors for death, these results
have not been uniformly confirmed [110, 112, 113]. Lastly, exacerbations of chronic
obstructive airway diseases may be accompanied by air trapping; the letter may
negatively impact pulmonary venous return to the RV (see also Chap. 18).
Mechanical ventilation may also adversely affect RV function, especially in the
setting of preexisting chronic RV dysfunction, and if high pressures and/or high
tidal volumes are employed. The dynamics of the effects of positive pressure venti-
lation on RV mechanics are complex and involve reduction in RV preload, increase
in afterload (by converting West zone 3 to zone 1 or 2 conditions), and impaired LV
filling [117–119]. Severe hypoxemia and/or hypercapnea are commonly encoun-
tered in patients requiring MV and likely contribute to RV dysfunction [113].
In LVAD recipients, both short- and long-term outcomes largely depend on RV
performance after installation of the circulatory support device [98, 100, 120, 121].
Unfortunately, the development of RVF after LVAD implantation occurs in up to
30 % of cases [98, 122]. Whether this is the result of inducible RV dysfunction or
simply “uncovering” a preexisting RV dysfunction remains controversial. Some
earlier experimental models suggest that during LVAD support, despite initial
improvements in reduction in RV afterload, RV contractility is significantly impaired
due to geometrical changes in the LV and subsequent leftward shift of the IVS [100,
101]. However, a recent study of 130 patients with chronic LVF who underwent
placement of continuous-flow LVAD actually showed significant improvements in
RV performance as determined by an increase in RVEF, RV stroke work index, tri-
cuspid annular plane systolic excursion (TAPSE), and reduction in RV end-diastolic
dimensions [120].
Because of these conflicting findings, there has been a strong interest in predict-
ing which patients are at risk of developing progressive RVF after initiation of
LVAD support. It is known that patients requiring late biventricular VAD (BiVAD)
support have poor outcomes [123–126]. For example, among LVAD recipients who
eventually required additional RVAD support, only 35.7 % were bridged to
transplantation when compared to 89.9 % of those with LVAD therapy alone [124].
Similar outcomes (40 % survival at time of transplant in those needing BiVAD
support vs. 100 % in the LVAD group) were reported in another study [ 126 ].
Early installment of BiVAD therapy in high-risk patients significantly improves
survival compared to patients with delayed insertion of RVAD support (51 % vs.
29 %) [123]. Patients requiring aggressive inotropic support or intra-aortic balloon
counterpulsation devices prior to installation of VAD therapy are among the highest
risk patients for developing deterioration of RV function post-VAD placement [99].
Obesity, severe hemodynamic alterations such as elevated PVR, and use of LVAD
as destination therapy were also found to be strongly associated with development
of RVF [99].
Intrinsic cardiac disease, including acute RV myocardial infarction (RVMI),
acute valvulopathies (e.g., mitral or tricuspid regurgitation), viral myocarditis, sep-
tic cardiomyopathy, and pericardial disease (e.g., cardiac tamponade) can be com-
plicated by acute RVF [8, 127, 128]. RVMI has been traditionally associated with
hypotension, distended jugular veins, and clear lung fields in patients suffering from
an acute MI [129]; however, hemodynamically significant RVMI presenting with
hypotension actually occurs less than 10 % of the time [129]. Typically the RCA is
the culprit vessel, with more extensive RV myocardial necrosis associated with the
proximity of the occlusion [130]. The prognosis of RVMI largely depends on pres-
ence of complications, such as ventricular arrhythmias or a high-grade atrioven-
tricular block, underlying RV dysfunction, and the success of angioplasty to restore
coronary reperfusion [8, 130–132].
An interesting recently identified cause of acute RV dysfunction and sudden
cardiac death is the syndrome of arrhythmogenic RV dysfunction in endurance ath-
letes [133] (see Chap. 16). Similarly, it has recently been demonstrated that acute,
high-intensity exercise can result in acute dysfunction and cardiomyocyte damage
of the RV, but not the LV [134] (see Chap. 15). A decrease in RV function can also
be seen after brain death and—in case of heart transplantation—may contribute to
early postoperative RV failure in the recipient [135, 136].
Lastly, patients with comorbidities associated with chronic RV dysfunction (e.g.,
obstructive sleep apnea, chronic lung disease, chronic LV dysfunction, PAH) are at
risk for acute decompensation of RV function either due to progression of their
underlying disease, or as a consequence of an additional insult to the RV (Table 9.2).
Diagnosis and Risk Stratification
The management of acute RVF begins with recognizing the key signs and symp-
toms to make the initial diagnosis. Currently available tools include history and
physical examination, electrocardiography, biomarkers, imaging studies, noninva-
sive hemodynamic monitoring devices, and invasive cardiopulmonary hemody-
namic monitoring. Importantly, the same tools used for diagnosing RV dysfunction
have also been applied to predicting patient outcomes, and are being used for both
risk stratification and management of acute RVF (Table 9.3).
History, Patient Factors, and Physical Examination: As in chronic RVF, signs and
symptoms of acute RVF tend to be nonspecific and late. While patients typically
present with new onset signs and symptoms of RVF, in cases of acute-on-chronic
RVF patients likely have preexisting symptoms and physical examination findings.
As in chronic RVF, symptoms of chest pain, lightheadedness, and syncope, as well
Table 9.2 Common causes of acute-on-chronic right ventricular failure

New onset atrial/ventricular arrhythmias
Acute pulmonary embolism
Acute myocardial ischemia/infarction
Progression of underlying disease
• PAH
• Chronic lung disease
• CHF
Acute hypoxemia and/or hypercarbia
• COPD/IPF exacerbation
• Pneumonia
• ARDS
• High altitude
Untreated or worsening sleep disorders
• Obstructive sleep apnea
• Obesity hypoventilation syndrome
• Nocturnal hypoxemia
New or worsening anemia
Infection
• Sepsis
• Catheter-related bloodstream infection in PAH patients on chronic prostacyclin therapy
Iatrogenic
• Mechanical ventilation
• Over-diuresis
• Aggressive fluid resuscitation
Medications
• NSAIDs
• Nondihydropyridine calcium channel blockers
• Nitrates
Behavioral
• Medication nonadherence
• Dietary nonadherence
CHF congestive heart failure, COPD chronic obstructive pulmonary disease, IPF idiopathic
pulmonary fibrosis, NSAIDs nonsteroidal anti-inflammatory drugs, PAH pulmonary arterial
hypertension
as findings such as hypotension, cyanosis, and cool extremities represent severe and
advanced RV dysfunction [137–139].
Over recent years, the patterns of clinical presentations of acute RVF have been
included in the risk stratification and management strategies of these patients. For
example, syncope in patients with acute PE or advanced PAH strongly correlates
with severe RV dysfunction and is associated with increased overall mortality [19,
139, 140]. Signs of hemodynamic instability (i.e., hypotension and tachycardia)
also are strong predictors of poor outcomes in patients with PAH [141] or acute PE
[19, 35, 142]. Similarly, an altered mental status predicts poor outcomes in acute PE
and is included as a component of a recently published severity index [143].

Age and comorbidities influence the prognosis in acute PE [35, 81, 144], and have
been included in both the Geneva and pulmonary embolism severity index (PESI)
scores [145, 146]. Male sex is a risk factor for death in PAH [147]. Connective tis-
sue disease is a risk factor for death in PAH patients admitted with RVF [141].
Knowledge of these prognostic findings is fundamental in early risk stratification
and allows the opportunity for initiation of appropriate therapies.
Invasive and Noninvasive Studies for Diagnosis

and Risk Stratification
Though direct hemodynamic assessment via right heart catheterization is critical for
the diagnosis, classification, and management of acute RVF, this is frequently com-
plemented by important noninvasive tests including biomarkers, echocardiography,
and radiographic imaging.
Biomarkers: Though nonspecific and potentially confounded by other disease states
(e.g., LV disease, renal failure, obesity), increased levels of biomarker can allow
assessment of the RV dysfunction. Used in conjunction with the clinical presenta-
tion, biomarkers have also been invaluable in assessing disease severity and guiding
therapy. A major advantage of the use of serum biomarkers is their high negative
predictive value (NPV); biomarkers in the normal range essentially rule out RVF
(with obesity being a potential exception to this rule).
BNP and NT-proBNP are well established in both diagnosis and management in
LVF [148]; however their role in RV disease is increasingly being recognized.
Regardless of the cause of RV dysfunction, in the absence of LV or renal disease,
elevated natriuretic peptide concentrations predict the severity of RV dysfunction
observed on echocardiography [19, 149–152]. In patients with PAH or PE, elevated
NT-proBNP has a strong prognostic value predicting death from decompensated RV
function. For example, in PAH, proBNP concentrations >1,400 pg/mL have a sensi-
tivity and specificity of 88 % and 53 %, respectively, and a NPV of 91 % for predict-
ing fatal outcomes [152]. Similarly, BNP levels >180 pg/mL have been associated
with poor outcomes [153]. Increased BNP also predicts adverse clinical events and
increased mortality in patients with acute RVF secondary to acute PE [19, 149].
Recent meta-analyses identified elevated BNP levels as significantly associated
with increased short-term all-cause mortality, death resulting from PE, and serious
adverse events [149, 154–156]. For example, in a meta-analysis by Sanchez et al.
[156], the odds ratios for short-term mortality for BNP or N-terminal pro-BNP ele-
vations in patients with submassive PE were 9.51 and 5.74, respectively. The recent
AHA Statement on Massive and Submassive Pulmonary Embolism considers BNP
>100 pg/mL or NT-pro-BNP >900 pg/mL as strong markers of moderate-to-severe
RV strain [9].
176
Table 9.3 Overview of commonly used tools for diagnostic testing and risk stratification in acute right ventricular failure
Serum biomarkers
B-type natriuretic peptide (BNP), • NT-proBNP >1,400 pg/mL association with increased mortality in RVF in PAH [152]
NT-proBNP • BNP >180 pg/mL associated with significant increase risk of death in PAH [153]
• BNP >90–100 pg/mL associated with increased mortality and adverse clinical events in RVF in acute PE [149]
• BNP >168 pg/mL indicates severe RV dysfunction in patients with CTEPH [151]
Cardiac troponins • Independent predictor of death in acute PE; elevated levels associated with increase in short-term mortality, death
secondary to PE, and adverse outcomes [157]
• Also predictor of mortality in PAH [152]
C-reactive protein (CRP) • Predicts survival in PAH patients with acute RVF due to CTEPH and PAH [17, 302]
• CRP >5 mg/dL is associated with decreased survival and event-free survival in patients with PAH [302]
• Correlates with severity of PAH [302]
Sodium (Na), glomerular filtration • Na <135 mmol/L associated with increased 30-day mortality and an independent predictor for hospital readmission
rate (GFR) in acute PE [161]
• Na <136 mmol/L predicts frank RVF and increase risk of death in PAH patients [160]
• GFR <45 mL/min per 1.73 m2 associated with increased likelihood of death or urgent transplantation in acute
PAH-induced RVF [159]
Echocardiographic parameters
Pericardial effusion • Echocardiographic findings which predict poor outcomes in PAH [153]
RA, RV enlargement • RVSP >50 mmHg at time of diagnosis of acute PE predicts persistent elevations in RVSP [182–185]
Septal displacement or “bowing” • RV/LV diameter >0.9 predicts increased mortality in acute PE [143]
RV hypokinesis • Bowing of the IVS associated with short-term mortality [186]
A.R. Cucci et al.
Severe tricuspid regurgitation
RV diameter/LV diameter ratio
Tricuspid annular plane systolic • TAPSE ≤1.5 cm predicts increased mortality, re-infarction rates, and hospitalization at 2-year follow-up in setting
excursion (TAPSE) of RVMI [188]
• TAPSE ≤1.8 cm indicates more severe RV dysfunction and worse overall prognosis [189]
• TAPSE ≤1.8 cm in setting of acute PE predicts worse 1-year survival [190]
Presence of RV notching • Mid-systolic notching predicts increased PVR and more severe RV dysfunction in PAH [194]
Tissue Doppler, Tei index, RV • Newer indices reliable for assessing RVF; less preload dependent [25]
myocardial performance index
(RVMPI)
9 Acute Right Ventricular Failure
Hemodynamic parameters
Right atrial pressure (RAP) • RAP >15 mmHg indication for transplant referral for PAH [200]
• RAP >20 mmHg associated with significant increased risk of death in PAH [153]
• RAP >20 mmHg contraindication for balloon atrial septostomy [200]
RV stroke work index (RVSWI) • RVSWI ≤0.25 mmHg × mL/m2 strong predictor of RVF after LVAD placement [123]
CI cardiac index, CTEPH chronic thromboembolic pulmonary hypertension, LV left ventricle, LVAD left ventricular assist device, PAH pulmonary arterial
hypertension, PE pulmonary embolism, RV right ventricle, RVF right ventricular failure, RVSP right ventricular systolic pressure
177
Cardiac troponins indicate cardiomyocyte death and as such, represent a rela-

tively late finding in the progression of RV dysfunction toward frank RVF. An
abnormally elevated troponin I or T (generally defined as higher than the 99th per-
centile for the coefficient of variability <10 %), has a strong positive predictive
value for poor global RV contractile function and death, in normotensive patients
[19, 142, 157, 158]. In submassive PE, troponin elevations are associated with an
odds ratio for mortality of 5.9 [19]. Interestingly, in acute PE, the combination of
RV dysfunction as judged by echocardiography and elevated troponin seems to be
more predictive of inhospital death or clinical deterioration, than either parameter
alone [142].
Other biomarkers have been shown to be important prognostic markers in PAH
patients with acute RVF admitted to the ICU [17]. These include elevated liver func-
tion tests, increased creatinine, and elevated C-reactive protein. In particular, an
increase in serum creatinine is associated with poor outcomes [17, 159].
Hyponatremia, a sentinel marker of increased neurohormonal activation, is associ-
ated with poor outcomes in both RVF secondary to acute PE as well as patients with
acute RVF from decompensated PAH [17, 141, 159–161].
Emerging biomarkers: Heart-type fatty acid-binding protein (H-FABP) has recently
been suggested as a marker of RV stress in normotensive patients with acute
PE. H-FABP levels ≥6 ng/mL were associated with a 36.6-fold increase in death or
complication risk [162]. Elevated levels predicted worse clinical outcomes even in
the setting of a normal echocardiogram at the time of PE diagnosis [163]. However,
in patients with an abnormal echocardiogram, high levels of H-FABP seemed to be
even more predictive of a worse clinical outcome [163]. Growth differentiation fac-
tor-15 (GDF-15) is a member of the transforming growth factor-β cytokine family
that is produced by pressure-overloaded or ischemic myocardial tissue [164, 165].
GDF-15 > 1,200 ng/L is strongly associated with hemodynamic abnormalities and
increased risk of death or lung transplantation in RVF secondary to PAH [166]. In
acute PE, concentrations >4,600 ng/L have a prognostic sensitivity of 71 %, speci-
ficity of 90 %, and NPV of 95 % for complicated 30-day clinical outcomes, and also
predict increased long-term mortality [167].
Electrocardiography: The electrocardiogram (ECG) may suggest an underlying RV
etiology if it demonstrates right axis deviation, P pulmonale, RV hypertrophy, right-
sided conduction delay, or RV strain pattern (e.g., S1Q3 pattern or T-wave inversion
in the precordial leads; Fig. 9.4d). ECG patterns have also been demonstrated to
correlate with disease severity. For example, atrial arrhythmias, new right bundle
branch block (complete or incomplete), Qr pattern in V1, S1Q3T3, negative T-waves
in V1 through V4, and ST-segment shift over V1 through V4 have been associated
with worse outcomes, including inhospital deaths, in patients presenting with acute
PE [9, 19, 168]. However, while specific, the use of ECG in acute RV dysfunction
is limited by a lack of sensitivity [2]. In the setting of acute PE, a numeric score has
been derived and validated that predicts the PAP and degree of perfusion defects on
the lung scan [169–171].
Fig. 9.4 Noninvasive diagnostic methods for acute right ventricular failure (RVF). (a, b)
Echocardiographic images from a 40-year-old female with acute RVF from scleroderma-associated
PAH demonstrating incomplete tricuspid valve coaptation (white arrow) during systole (a) and
compression of the LV during diastole (b; known as the “D-sign” [white arrowhead]), both consis-
tent with severe RV pressure overload. Note presence of severe right atrial (RA) enlargement and
left atrial (LA) underfilling. (c) Color tissue Doppler sampling of the tricuspid annulus in four-
chamber view of the same patient reveals significant reduction in RV systolic velocity suggestive
of severe RV systolic dysfunction. (d) EKG from the same patient is demonstrating right axis
deviation, peaked p-waves in lead II, and significant T-wave inversions in precordial leads sugges-
tive of severe right atrial enlargement and RV strain, respectively. Precordial leads also demon-
strate evidence of RV hypertrophy. (e, f) Contrasted chest computer tomography (CT) images of a
46-year-old male presenting with acute massive pulmonary embolism. Note significant RA
enlargement and RV dilatation with reversal of appropriate RV to LV size ratio (e; RV/LV ratio >1)
and severe hepatojugular reflux of intravenous contrast into inferior vena cava and hepatic veins
(asterisk in f). The latter finding has been associated with turbulent flow in the RV and subsequent
hemolysis [87, 172]. LA left atrium, LV left ventricle, PA pulmonary artery, RA right atrium, RV
right ventricle
Radiographic Studies: Plain chest radiography lacks sensitivity, but may have some
utility in determining the etiology of acute RVF. For example, cardiomegaly, pleural
effusions, and pulmonary edema can be suggestive of LVF as the cause of
RVF. Pulmonary infiltrates may suggest a primary lung pathology. Clear lung fields
with prominent pulmonary vasculature on the other hand may suggest decompen-
sated PAH as the underlying etiology. Findings of RV dysfunction on chest com-
puted tomography (CT), such as right atrial (RA) and RV dilatation, leftward shift of
the IVS, or reflux of intravenous contrast into the hepatic veins, are often late find-
ings of disease and may suggest increased mortality [2, 172] (Fig. 9.4e + f ). Since
chest CT is often performed for other reasons, such findings are not infrequently
picked up incidentally. In acute PE, CT evidence of RV dilation (RV/LV diameter
>0.9 in a four-chamber view [9]) predicts worsened findings on echocardiography,
but prospective studies have failed to find an independent association with adverse
short-term events, including death in the hospital, at 30 days, or at 3 months [79, 173].
Chest CT with intravenous contrast is frequently obtained during the initial evaluation
of acute PE. However, for the evaluation of CTEPH as the cause of acute RV dys-
function, chest CT with intravenous contrast lacks sensitivity, and ventilation/
perfusion scanning appears to be more sensitive [174]. Chest CT may also help to
identify pulmonary parenchymal or cardiovascular causes of RVF. Cardiac magnetic
resonance imaging (cMRI) is considered the gold standard for the noninvasive
evaluation of RV and LV function and structure [25, 175]. However, due to practical
reasons, its use for the diagnosis and management of acute RVF is limited, as these
patients are frequently not stable.
Echocardiography: Echocardiography is an invaluable tool for both diagnosis and
management of acute RV dysfunction [2]. Traditional parameters of RV dysfunction
such as RA enlargement, RV dilatation, RV hypokinesis, leftward shift of the IVS,
significant tricuspid regurgitation, and dilatation of the inferior vena cava with lack
of respiratory variation predict adverse outcomes in patients with acute PE or
decompensated PAH (Fig. 9.4a–c) [19, 175–178]. The estimation of RVSP via the
modified Bernoulli equation is fundamental in screening patients for elevated PAPs.
However, RVSP, as estimated by echocardiography, may over- or underestimate the
true systolic PAP in PH patients by >10 mmHg in almost 50 % of cases, especially
when patients have intrinsic lung disease [179, 180]. To further complicate the use
of estimated RVSP, in the setting of acute RVF, a decrease often reflects worsening
RV dysfunction and a low CO [181]. Therefore, in decompensated RV disease,
RVSP values should be considered a screening step and additional markers of RV
performance are required. Despite these limitations, in acute PE, very high RVSP
(e.g., >50 mmHg) at diagnosis predicts a high probability of the patient experienc-
ing persistently elevated PAPs with standard anticoagulation [182–185].
In patients with acute PE, the increased RV/LV diameter ratio has been identified
as an independent predictor of mortality [143]. While this ratio was not identified as
a predictor of death in acute PE patients previously, that study identified bowing of
the IVS as a predictor of short-term mortality [186]. In patients with acute myocar-
dial infarction, presence of RV free wall hypokinesis, decreased TAPSE, and
reduced lateral tricuspid annular velocity on tissue Doppler imaging (TDI) may be
suggestive of RV involvement [3, 175, 187]. A TAPSE ≤1.5 cm and presence of RV
strain independently predict mortality, re-infarction rates, and hospitalization at
2-year follow-up in patients with acute MI [188]. In patients with PAH, TAPSE
<1.8 cm reflects more severe RV dysfunction and a poorer prognosis [189]. The
TAPSE may also indicate RV dysfunction in patients with acute PE, as lower values
indicate elevated RV pressures [190]. Newer indices such as tissue Doppler, Tei
index, and RV myocardial performance index (RVMPI) are being evaluated in
patients with PH and/or acute PE [191–193]. A detailed overview of prognostic
echocardiographic parameters is provided in Table 9.3.
Echocardiography also offers clues that help uncover the etiology behind decom-
pensated RVF. For example, injection of agitated saline allows for detection of
intracardiac shunts as a possible cause or consequence of RVF. Findings of left
atrial enlargement and LV hypertrophy are more suggestive of LV pathology as the
cause of RV failure. Notching of the Doppler signal in the RV outflow tract reflects
significant pulmonary vascular remodeling and is suggestive of PAH [194]. Once
thought to be a specific finding for acute PE, the McConnell sign refers to a distinct
pattern of RV mid-free wall hypokinesis with preserved contraction of the apical
segments; however, this sign has been increasingly identified in other forms of RVF
[195–197]. Transesophageal echocardiography (TEE) has been proposed as a supe-
rior method when compared to transthoracic echocardiography for detecting RV
dysfunction in ARDS [113], but further studies are needed before such a strategy
can be recommended.
Invasive Hemodynamic Assessment: Right heart catheterization remains the gold
standard for diagnosing and thoroughly characterizing acute RVF and determining
its etiology. It also provides significant insight into both disease severity and prog-
nosis [198]. While right heart catheterization in general is a very safe procedure
[199], PA catheters (PACs) may be more difficult to float in patients with RVF, and
their placement is associated with a higher rate of complications [5], a potential
problem in patients with already compromised cardiopulmonary hemodynamics.
PAC placement-associated tachyarrhythmias may be particularly devastating. Thus,
the procedure should ideally be performed in the cardiac catheterization lab, but if
the patient is too unstable to be transported, PA catheterization can be performed in
the ICU. In addition to directly measuring RA pressure, PAP, and pulmonary artery
wedge pressure (PAWP), right heart catheterization allows the measurement and/or
calculation of right atrial pressure (RAP), CO and cardiac index (CI), mixed SvO2,
PVR, and RV stroke work index [74, 200–202]. Measurement of these parameters
in the setting of acute RVF assists with guiding the therapy (inotropic agents, pul-
monary vasodilators, and diuretics). Assessment of oxygen saturation in sequential
right heart chambers (e.g., RA and RV) help determine the presence of a significant
left-to-right shunt as a possible cause of RVF. Again as a reduction in PAP may
reflect decreasing RVEF and worsening RVF [181].
While determination of Pcwp as a surrogate for LV end-diastolic pressure
(LVEDP) is critical in the evaluation of RV dysfunction, one needs to keep in mind
that the Pcwp can be poorly calibrated to LVEDP. Even in regular outpatient popula-
tions, the Pcwp over- or underestimates the LVEDP in a large percentage of patients
[203, 204]. Since the presence of tachyarrhythmias, respiratory excursions, and MV
may negate the assumption of a static blood column between the catheter tip and LV,
the agreement between Pcwp and LVEDP may be even less robust in acute RVF
patients. For example, accurate measurement of Pcwp in patients in the ICU is often
complicated by the presence of intrinsic lung disease, incorrect catheter placement,
and MV (e.g., presence of positive end-expiratory pressure [PEEP]) [205, 206].
Specifically, in the presence of higher levels of PEEP, Pcwp can be falsely elevated.
A more accurate approximation of Pcwp in a patient on MV and high level of PEEP
can be made by subtracting about one-half the PEEP level from the Pcwp. Acidosis,
hypoxemia, and administration of vasoactive drugs may also influence the accuracy
of Pcwp measurements [206]. Depending on the stability of the patient, perfor-
mance of left heart catheterization may be desirable, as it allows a direct measure-
ment of the LVEDP and assessment of coronary artery disease.
Novel methods for assessment of afterload and RV–PA coupling include the use
of impedance catheters and the measurement of pressure–volume loops in the RV
[36]. While these techniques are highly promising and while they may provide criti-
cal information their use is currently limited to research.
Noninvasive Hemodynamic Monitoring: Recently, there has been an increasing use
of noninvasive hemodynamic monitoring techniques during the management of
hemodynamically unstable patients (e.g., measurement of variations in pulse pres-
sure, systolic blood pressure, or stroke volume) [207–209]. In studies evaluating
mechanically ventilated hypotensive patients with an absence of arrhythmias, these
techniques appear to be promising. However, since patients with RVF frequently
exhibit increased respiratory efforts and/or tachyarrhythmias, extrapolation of these
data to patients with RVF is problematic. Passive leg raising may better predict fluid
responsiveness in patients with arrhythmias and spontaneous respiration [210]. A
recent study evaluated a bioreactance-based noninvasive CO monitoring method,
and found this to be precise and reliable in a stable PH population [211]. However,
the validation in patients with acute RVF is needed.
Management of Acute RVF
The key principle in the management of acute RVF focuses on determination and
treatment of the underlying etiology. Specific therapies are usually complemented
by supportive strategies focused on improving RV function via volume optimiza-
tion, enhancing contractility, and reducing afterload (Fig. 9.5). These goals are
achieved through a combination of appropriate volume management, vasopressors
and/or inotropic agents, pulmonary vasodilators, and interventional or surgical
strategies [2]. Unfortunately, no RV-specific therapies exist, and most of the inter-
ventions aimed at improving RV performance and/or PA vasomotor tone concomi-
tantly affect the systemic vasculature and/or the LV. In addition, studies specifically
evaluating patients with RVF are few, limited by small patient numbers and they are
usually not prospective. The management of patients with acute RVF should always
incorporate general preventative measures, supportive care, and specific interven-
tions aimed at the underlying cause.
General Management and Supportive Care
General measures: The initial focus in any patient with acute RVF, irrespective of
the underlying etiology, is early evaluation of any underlying reversible factors that
are either primarily responsible for or contributing to the deterioration of RV func-
tion [2, 17, 31, 212, 213]. Infections are one of the strongest predictors of mortality
in patients with RVF secondary to PAH [17, 31]. Similarly, infection has been
Fig. 9.5 Treatment of acute RV failure. Treatment of the failing RV focuses on attenuation of
pathophysiologic alterations in preload, contractility, and afterload by a combination of general
methods and specific therapies directed against the underlying, as well as pharmacological and
interventional approaches directed against the failing RV. Recent studies suggest potential role for
epoprostenol and PDE-5 inhibitors to improve RV contractility, the later through concomitant
PDE-3 inhibition. Use of milrinone, dobutamine, and levosimendan also have concurrent benefits
in afterload reduction. Importantly, management of acute RVF depends on general supportive care
including oxygen therapy, volume optimization, and correcting anemia, if present. Specific thera-
pies, such as thrombolytic therapy for acute pulmonary embolism, early percutaneous coronary
intervention for acute RV myocardial infarction, or antibiotic therapy and volume resuscitation for
patients with sepsis are indicated in the appropriate clinical setting for additional management of
RVF. BiVAD biventricular assist device, NO nitric oxide, RVAD right ventricular assist device
identified as a risk factor for ARDS-induced cor pulmonale [112]. Thus, the
importance of preventative measures, aggressive monitoring for infections, and
early use of appropriate antibiotics and source control measures cannot be overem-
phasized. Anemia can be deleterious to RV function, as it may result in decreased
oxygen carrying capacity and reduced oxygen delivery to the failing RV, while
simultaneously increasing the oxygen demand as a consequence of anemia-induced
tachycardia. The optimal hemoglobin (Hb) level for patients with acute RVF is not
well defined [31]. While typical ICU patients may benefit from a conservative
transfusion strategy [214], this specific patient population may require higher
hemoglobin levels in order to maintain appropriate oxygen delivery [215].
Monitoring serum lactate levels and central or mixed venous oxygen saturation
(ScvO2 or SvO2) may assist in guiding decisions regarding the need for transfusions
[10, 216].
Management of supraventricular arrhythmias: Supraventricular arrhythmias can be
highly detrimental to RV performance, thus reflecting the importance of atrial con-
traction in maintaining RV diastolic filling and RV stroke volume [25]; a recent
study in a PAH and CTEPH cohort with atrial flutter or fibrillation demonstrated
benefit from a rhythm control strategy [55]. In particular, both atrial flutter and
fibrillation were strongly associated with clinical worsening, RVF, and death [55].
Whether these data can be extrapolated to other populations with RV dysfunction is
unknown; however, immediate cardioversion in patients with significant RV dys-
function should be considered [5, 31].
Volume management is fundamental in acute RVF. Typically, patients with RVF
present with volume overload and require sodium restriction and diuresis; thus the
use of diuretics or renal replacement therapy is frequently required during the initial
management [31]. Continuous infusion of diuretics may be preferable over bolus
dosing, and the combination of a loop diuretic with a thiazide or thiazide-like diuretic
(e.g., metolazone) may confer additional benefits [217, 218]. RVF is characterized
by significant neurohormonal activation [17, 160], and emerging data indicate that
inhibition of the renin–angiotensin–aldosterone system may provide significant clin-
ical benefits [219–221]. While initial data suggested a role for ultrafiltration for
patients with LVF and cardiorenal syndrome, the recent CARRESS-HF trial found
that ultrafiltration was inferior to pharmacological therapy in this population, and
resulted in a significant increase in serum creatinine and serious adverse events
[222]. The routine use of this strategy for acute RVF can thus not be recommended.
Over-diuresis, however, may be detrimental to RV function, leading to electrolyte
imbalances, reduced CO, pre-renal azotemia, and systemic hypotension. A com-
monly used strategy is to diurese until BUN or creatinine is starting to rise [223].
On the other hand, volume administration to an already overloaded RV will fur-
ther impair CO through ventricular interdependence and subsequent underfilling of
the LV [26]. In hypotensive patients with suspected hypovolemia, careful fluid
boluses of 500 mL are recommended, but should be discontinued if no improvement
in blood pressure or CO occurs after 1,000 mL [2, 5]. Use of clinical history, physical
exam, bedside echocardiography, and serum biomarkers cannot be overemphasized
in guiding volume management for RV dysfunction and failure. Frequently, invasive
monitoring of hemodynamics is required.
The diabolical effect of preload reduction: The failing RV requires an adequate
preload to sustain forward flow. However, many patients with severe afterload-
induced RV dysfunction will have chest pain suggestive of angina. Usual care often
prescribes the use of nitroglycerine in effort to improve coronary perfusion.
Regrettably, nitrates have the opposite effect. Although clinical studies are lacking,
in our experience, the use of nitrates in afterload-induced RV failure can produce a
deleterious reduction in arterial blood pressure, especially in patients with acute
PE. A similar phenomenon has been described for patients with acute RVMI.
Ventilation and oxygenation strategies: Maintaining oxygen saturation >90–92 % is

crucial to avoid HPV. Similarly, excessive hypercapnia and acidosis should be
avoided [5, 109]. On the other hand, due to its potential for reducing CO, causing
hypotension and hemodynamic collapse, MV—if at all possible—should be avoided
[117–119]. If MV is unavoidable, the lowest possible PEEP and tidal volume (VT)
required to provide adequate oxygenation and ventilation, respectively, should be
applied, and use of an ARDSnet strategy has been recommended [2, 5, 31, 224,
225]. However, a small VT may lead to hypercapnia with subsequent pulmonary
vasoconstriction and increased afterload. While this may be overcome by increasing
the respiratory rate, that maneuver may result in excessive auto-PEEP, air trapping,
and preload reduction. Prone position ventilation may unload the RV [21, 226, 227],
and a decrease in RV dysfunction has been proposed as one of the reasons for the
positive results of a recent proning trial [226, 227]. However, this hypothesis will
need a prospective evaluation. The complexities reviewed here emphasize why MV
in acute RVF is associated with high morbidity and mortality [97, 141, 228]. For
this reason, we recommend avoiding MV altogether by using extracorporeal mem-
brane oxygenation (ECMO) in awake patients with RVF (see below) [31, 228, 229].
Specific therapies: A key principle in the management of acute RVF focuses on
determination and treatment of the underlying etiology. Sepsis is treated with anti-
biotics, source control measures, volume replacement and, if needed, hemodynamic
support [11]. ARDS treatment requires appropriate MV strategies (see above). PH
crisis and RVF in PAH and in the postoperative setting are treated with the pulmo-
nary vasodilators and inotropes (reviewed below). Patients with sickle cell crisis
and ACS require blood transfusions and supportive care [230]. Patients with RVMI
benefit from immediate administration of both anti-platelet and anticoagulation
therapy in conjunction with early percutaneous coronary intervention (PCI) [8, 129,
132, 231]. Successful revascularization with normalization of blood flow within the
RCA results in prompt recovery of RV function and decreased inhospital mortality
[132]. LVF is treated with inotropes, afterload reduction and volume management
strategies [73]. Mechanical support (intraaortic balloon counterpulsation or LVAD
therapy) is needed in severe cases. Treatment of RVF following LVAD requires sup-
portive care, volume optimization, and inotropic support with or without use of
pulmonary vasodilators [98]. Patients unresponsive to such medical therapies may
require installment of an RVAD for additional support. Valvular heart disease is
treated with percutaneous or surgical interventions.
Unless contraindications exist, acute PE is treated with anticoagulation. In patients
with massive PE (systolic BP <90 mmHg for at least 15 min or requiring inotropic
support not due to a cause other than a PE), thrombolytic therapy is a reasonable deci-
sion in the setting of acceptable risk of bleeding [9]. However, in the setting of sub-
massive PE, defined as the presence of PE without systemic hypotension but with
evidence of either RV dysfunction or myocardial necrosis (see definition section) [9],
treatment with thrombolytic therapy remains currently controversial.
Meta-analyses of randomized controlled trials have consistently failed to find an
improvement in mortality for patients with submassive pulmonary embolism [232].
However, considerable evidence suggests that fibrinolytics can improve patient

outcomes related to RV dysfunction at two timepoints: short term (inhospital) and
longer term (3–6 month follow-up). For example, an earlier randomized trial sug-
gested that in selected patients with echocardiographic evidence of RV dysfunction
and a low risk of bleeding, early treatment with alteplase plus heparin (as compared
with conventional anticoagulation therapy) reduced the need for emergency thera-
peutic measures during the hospital stay [233]. A large, multinational, randomized
trial to determine whether normotensive patients with RV dysfunction (detected on
echocardiogram or CT scan), and evidence of myocardial injury (indicated by a
positive troponin) may benefit from early thrombolytic treatment (PEITHO;
ClinicalTrials.gov number NCT00639743) has completed enrollment. Preliminary
results of this large randomized controlled trial of fibrinolysis for PE demonstrated
a significant reduction in the rate of inhospital deterioration (defined by the compos-
ite endpoint of shock, hypotension or death) [234]. Four independent studies,
including one observational study and two randomized controlled trials have
demonstrated lower rates of echocardiographically defined PH and RV dysfunction
with fibrinolysis [183, 184, 235, 236]. A recent randomized trial found improved
functional capacity and quality of life measures with fibrinolysis treatment after
submassive PE [237]. Moreover, in the aggregate of randomized controlled trials of
fibrinolysis that performed right heart catheterization have demonstrated a more
complete and significant reduction in mean PAP compared with placebo
(Fig. 9.6a + b). Taken together, these studies suggest that treatment of submassive
PE with fibrinolytics may reduce inhospital deterioration and the development of
pulmonary hypertension, and may improve functional capacity and quality of life.
Inotropes and Vasopressors: While a retrospective study identified inotropic therapy
in PAH-induced RVF as a risk factor for death [141], this may be due to the fact that
sicker patients require more inotropic support. Based on the data reviewed below,
the authors and others [2, 5, 8, 26, 31] strongly believe that inotropic support is one
of the cornerstones of the treatment of acute RVF.
Dobutamine, a β1/β2-receptor agonist, augments ventricular contractility and
promotes pulmonary and systemic vasodilatation, thus reducing both RV and LV
afterload. In patients with acute or chronic PH, the combination of dobutamine and
inhaled nitric oxide (iNO) improved CO, decreased PVR, and increased the PaO2/
FiO2 ratio [238, 239], making dobutamine an attractive agent for treatment of acute
RVF. Preclinical trials have demonstrated more improvement in RV contractility
and RV–PA coupling with dobutamine than with norepinephrine therapy [240].
Beneficial effects are usually seen with doses in the 2–5 μg/kg/min range; doses
>5 μg/kg/min should be avoided in order to prevent tachyarrhythmias and increased
myocardial oxygen consumption [2, 5, 31]. Like all vasoactive agents, titration of
dobutamine is guided by hemodynamic and echocardiographic data, as well as by
lactate levels and SvO2 or ScvO2. Due to its peripheral β2-mediated vasodilator
effects, dobutamine may need to be used in combination with vasopressor agents,
such as norepinephrine, to avoid systemic hypotension [2].
Fig. 9.6 Effect of fibrinolysis on mean pulmonary artery pressure (mPAP) in patients with acute
pulmonary embolism. (a) Summary of PAP data from randomized placebo-controlled trials. (b)
Forest plot of effect size based upon magnitude and direction of change in mPAP after fibrinolysis.
The pooled effect size (white diamond) demonstrates benefit for fibrinolysis in reducing
mPAP. Note that the pooled effect size demonstrates benefit for fibrinolysis in reducing mean PAP.
PAG pulmonary angiogram, SD standard deviation, SK streptokinase, TPA tissue plasminogen acti-
vator, UK urokinase, VQ ventilation perfusion scan
Milrinone, a PDE-3 inhibitor that prevents breakdown of cyclic AMP, also has
inotropic and vasodilatory properties. Similar to dobutamine, systemic vasodilatation
may limit its use [241]. This effect is minimized by the use of inhaled milrinone,
which results in localized pulmonary vasodilatation, while maintaining its benefi-
cial effects on improving RVEF [242]. Due to the lack of β-receptor effects, milrinone
is typically not associated with development of tachyarrhythmias and may be for
patients on chronic β-blocker therapy. Both milrinone and dobutamine can be used
in conjunction with inhaled pulmonary vasodilators, such as iNO [243]. This com-
bination provides additive effects on pulmonary vasodilatation while allowing for
lower inotrope doses, thus minimizing the risk of hypotension [244].
Levosimendan, a calcium sensitizer that is available in Europe, increases RV
contractility without increasing oxygen consumption [245]. The drug also has a
variety of other potential beneficial effects for patients with RVF (e.g., anti-ischemic
properties) [246]. Recent preclinical trials show significant improvements in both
RV contractility and afterload reduction compared to dobutamine [247, 248], but
the clinical experience in acute RVF is limited.
While dopamine increases RV contractility, it may also paradoxically increase
RV end-diastolic volumes [136]. In addition, its tendency to induce tachyarrhythmias
and increase overall mortality in cardiogenic shock [249] make it a less ideal agent
in the setting of decompensated RVF.
Norepinephrine is an α1/β1-receptor agonist that offers a number of benefits in
the treatment of acute RVF: (1) it may allow with the use of inotropes in the setting
of hypotension, (2) it exerts β1-mediated positive inotropic effects [240], and (3) it
exerts the α1-mediated increase in LV afterload and coronary perfusion pressure
that improve both LV and RV function [240, 250]. The latter is of particular impor-
tance, since increased RV transmural pressure frequently compromises RCA perfu-
sion. Norepinephrine can thus help break the vicious cycle of the decompensated
RVF hemodynamic demise [251] (Fig. 9.2). Importantly, the drug does not appear
to increase PAP or PVR. Experimental studies using aortic constriction for acute
RVF suggest that increasing afterload may also exert protective effects indepen-
dently of coronary perfusion pressure elevation [252], possibly mediated by
improved septal mechanics. Vasopressin may be an alternative to norepinephrine as
it has systemic vasoconstrictive properties while concurrently resulting in pulmo-
nary vasodilatation [253, 254]. However, its use for RVF has not been systemati-
cally investigated.
Pulmonary vasodilators: Reducing RV afterload is one of the cornerstones in the
treatment of acute RVF, and pulmonary vasodilators are an attractive class of drugs
for this syndrome. Typically, iNO and/or PAH-targeted therapies such as prostacy-
clin derivatives, phosphodiesterase-5 (PDE5) inhibitors, and endothelin receptor
antagonists (ERAs) are used.
iNO stimulates soluble guanylate cyclase (sGC) and increases cyclic GMP,
thereby mediating pulmonary vasodilatation [255]. Rapid hemoglobin-mediated
inactivation in the pulmonary capillaries prevents systemic vasodilatation [256].
Effects are limited to ventilated lung areas, therefore attenuating HPV, decreasing
PAP and PVR, and improving oxygenation without increasing shunt physiology
[257, 258]. In addition, iNO has anti-inflammatory effects and decreases inflamma-
tory cytokine production [259]; this may be of particular importance in RVF associ-
ated with significant RV or lung inflammation. Typical concentrations range from
20 to 40 ppm. Results are not uniform, however; in a study of 26 ICU patients with
acute RVF, 14 patients experienced a significant increase in CO and oxygenation as
well as a decrease of the PVR with iNO (35 ppm) [260]. One study in patients
undergoing heart or lung transplantation demonstrated decreased mortality if iNO
was used for PH and/or RVF rather than as a treatment for hypoxemia [261].
Improvements in PVR and RV dysfunction were confirmed in another study of heart
transplant recipients [262], and in patients with PH after mitral valve replacement
[263]. iNO’s properties make it an attractive agent for the treatment of severe acute
PE, and in a recent phase I study of eight patients with severe submassive PE, iNO
reduced dyspnea without adverse events [264]. A phase II study evaluating iNO in
acute submassive PE with RV strain is currently ongoing (ClinicalTrials.gov identi-
fier NCT01939301). Use of iNO is limited by expense, potential methemoglobinemia,
production or reactive nitrogen species, acute kidney injury, and rebound PH after
sudden discontinuation [5, 265]. iNO appears to be of particular benefit when com-
bined with inotropic agents, such as dobutamine or milrinone [243].
Epoprostenol, due to its short half-life (3–6 min) and potent vasodilator effects,
is the preferred prostacyclin in patients with severe RVF. Initiated at 1–2 ng/kg/min,
the drug can be increased by 0.5–1 ng/kg/min every 15–30 min. A more cautious
approach is often warranted in critically ill patients with significant comorbidities,
hypoxemia, and/or labile hemodynamics. Epoprostenol, by increasing cAMP,
decreases PAP and PVR and increases CO, but its use is frequently limited by sys-
temic hypotension, worsening ventilation/perfusion mismatch, and dose-dependent
side effects (e.g., gastrointestinal symptoms, headaches) [2, 266]. Intravenous epo-
prostenol should therefore be avoided in shock that is not due to RVF and in severe
respiratory failure [2]. Use in LV dysfunction is contraindicated, due to its associa-
tion with increased mortality [267] and potential to precipitate acute pulmonary
edema [73]. Despite its conceptual appeal, in patients with acute PE and RV dys-
function, treatment with epoprostenol did not improve RV dilatation or any other
measured variables of RV function [268]. While epoprostenol may exert inotropic
effects in patients with idiopathic PAH [269], improvements of the CO in acute RVF
appear to be primarily due to pulmonary vasodilatory effects [270]. Importantly,
abrupt discontinuation of epoprostenol may result in rebound PH and even death
[271, 272]. Treprostinil also reduces PAP and PVR [273], but has a longer half-life
than epoprostenol. Intravenous rather than subcutaneous administration should be
pursued in unstable patients, in order to avoid problems due to unpredictable absorp-
tion. Aerosolized prostacyclins offer the benefit of reducing systemic side effects
(e.g., hypotension), minimizing ventilation/perfusion mismatch, and decreasing
cost as compared to iNO. In particular, aerosolized epoprostenol is increasingly
used in the acute setting [274]. For example, in heart or lung transplant recipients
with PH, refractory hypoxemia, and RV dysfunction, inhaled prostacyclin therapy
reduced PAP and improved CI and ScvO2 similar to iNO [275]. Similarly, inhaled
iloprost improves PH and RV function during/after mitral valve surgery, cardio-
pulmonary bypass, or heart transplantation [276–278]. One study found it to be
more potent than iNO [279]. Clearly the management of these agents requires
close monitoring of cardiopulmonary hemodynamics (usually by PAC and/or
echocardiography).
Due to concerns about unreliable absorption in decompensated RVF, oral
vasodilators are less frequently used. However, they are useful for (1) less severe
forms of acute RVF and (2) when patients that have become more hemodynamically
stable, with plans to withdraw parenteral agents [31]. ERA use in the ICU is limited
by relatively long half-lives and potential hepatotoxicity in case of bosentan [272,
280]. In general, more data are available for PDE5 inhibitors. In patients undergoing
mitral valve repair or LVAD placement, sildenafil reduces PAP and PVR and facilitates
weaning of parenteral pulmonary vasodilators while only minimally affecting the

systemic blood pressure [281]. Sildenafil and its precursor zaprinast may act syner-
gistically with inhaled pulmonary vasodilators such as iNO [282–285]. Sildenafil
also decreases the rebound PH after iNO withdrawal [286]. In LVAD patients, silde-
nafil facilitates weaning from iNO and inotropes while providing additive reduc-
tions in PAP. PDE5 inhibitors also decrease PVR, maintain systemic blood pressure,
and improve myocardial perfusion after coronary artery bypass grafting [287, 288].
Preclinical data and one single case report suggest beneficial effects of sildenafil in
acute PE [289–291]. Sildenafil also exerts inotropic effects that are mediated at least
in part throughout concomitant PDE3 inhibition (similar to milrinone) [292]. Like
other PAH drugs, use of sildenafil may be limited by thrombocytopenia [293].
While sGC stimulators (e.g., riociguat) have shown benefit in PAH or CTEPH
patients with chronic RV dysfunction [294, 295], experience in patients with acute
RV dysfunction is limited, and its use may be limited by hypotensive properties.
Surgical and interventional strategies are typically indicated for patients with
acute RVF that progresses despite maximal medical therapy. Such interventions
range from balloon atrial septostomy (BAS), to installation of VADs, and initiation
of ECMO and artificial lung systems. In the setting of potentially salvageable or
reversible RVF, such surgical interventions can be used to help support the failing
RV until the underlying etiology underlying the development of RVF resolves
(e.g., ARDS). However, most frequently, invasive strategies are reserved for bridg-
ing patients to heart, lung, or heart–lung transplantation or occasionally purely for
palliative purposes. Unfortunately in the setting of advanced RVF with significant
end-organ damage, surgical approaches may not be beneficial and can even be
detrimental [124, 200].
Use of extracorporeal therapy in the management of critically ill patients has
evolved significantly over the last few decades. ECMO may be considered for
patients with reversible RVF due to severe hypoxemic respiratory failure in whom
conventional ventilator support is failing [296–298]. However, since MV may lead
to devastating cardiopulmonary collapse, there is considerable interest in using
ECMO instead of MV. This has been successfully demonstrated for PAH patients
with advanced RVF, where awake ECMO is increasingly used for bridging non-
intubated to lung transplantation [228]. Experience with awake ECMO is now
evolving in ARDS patients [299]. Veno-arterial ECMO is generally the preferred
mode for patients with RVF and without significant lung disease [297]. The pump-
less Novalung interventional lung assist device represents a promising strategy to
bridge patients with advanced PAH and RVF to transplantation [300, 301].
Conclusion
Acute RVF is a devastating emergency caused by a variety of common diseases and

conditions. Invasive hemodynamic assessment and echocardiography remain the
most valuable methods to diagnose and manage acute RVF in critically ill patients.
These strategies are complemented by biomarker assessment, radiographic studies,
and incorporation of clinical parameters into validated risk scores. The key principle
in the management of acute RVF is the treatment of the underlying etiology,
complemented by supportive strategies focused on improving RV function via opti-
mization of the volume status, enhancing contractility, and reducing afterload. The
latter two are achieved through use of vasopressors, inotropes, pulmonary vasodila-
tors, and interventional or surgical therapies. Unfortunately, most of the interven-
tions aimed at improving RV performance and/or PA vasomotor tone concomitantly
affect the systemic vasculature and/or the LV. Future research should focus on better
defining the molecular mechanisms of cellular dysfunction and cardiomyocyte
death in acute RVF, as a better understanding of these mechanisms will lead to the
ultimate goal of developing novel therapies that directly target the failing RV and
may salvage injured myocardium.
References
1. Lin BW, Schreiber DH, Liu G, et al. Therapy and outcomes in massive pulmonary embolism
from the Emergency Medicine Pulmonary Embolism in the Real World Registry. Am J
Emerg Med. 2012;30(9):1774–81.
2. Lahm T, McCaslin CA, Wozniak TC, et al. Medical and surgical treatment of acute right
ventricular failure. J Am Coll Cardiol. 2010;56(18):1435–46.
3. Engstrom AE, Vis MM, Bouma BJ, et al. Right ventricular dysfunction is an independent
predictor for mortality in ST-elevation myocardial infarction patients presenting with cardio-
genic shock on admission. Eur J Heart Fail. 2010;12(3):276–82.
4. Chan CM, Klinger JR. The right ventricle in sepsis. Clin Chest Med. 2008;29(4):661–76, ix.
5. Zamanian RT, Haddad F, Doyle RL, Weinacker AB. Management strategies for patients with
pulmonary hypertension in the intensive care unit. Crit Care Med. 2007;35(9):2037–50.
6. Voelkel NF, Gomez-Arroyo J, Abbate A, Bogaard HJ. Mechanisms of right heart failure-a
work in progress and a plea for failure prevention. Pulm Circ. 2013;3(1):137–43.
7. Voelkel NF, Quaife RA, Leinwand LA, et al. Right ventricular function and failure: report of
a National Heart, Lung, and Blood Institute working group on cellular and molecular mecha-
nisms of right heart failure. Circulation. 2006;114(17):1883–91.
8. Haddad F, Doyle R, Murphy DJ, Hunt SA. Right ventricular function in cardiovascular dis-
ease, part II: pathophysiology, clinical importance, and management of right ventricular fail-
ure. Circulation. 2008;117(13):1717–31.
9. Jaff MR, McMurtry MS, Archer SL, et al. Management of massive and submassive pulmo-
nary embolism, iliofemoral deep vein thrombosis, and chronic thromboembolic pulmonary
hypertension: a scientific statement from the American Heart Association. Circulation.
2011;123(16):1788–830.
10. Dellinger RP, Levy MM, Rhodes A, et al. Surviving sepsis campaign: international guide-
lines for management of severe sepsis and septic shock: 2012. Crit Care Med. 2013;41(2):
580–637.
11. Hotchkiss RS, Karl IE. The pathophysiology and treatment of sepsis. N Engl J Med. 2003;
348(2):138–50.
12. Vanni S, Viviani G, Baioni M, et al. Prognostic value of plasma lactate levels among patients
with acute pulmonary embolism: the thrombo-embolism lactate outcome study. Ann Emerg
Med. 2013;61(3):330–8.
13. Omland T. Advances in congestive heart failure management in the intensive care unit:
B-type natriuretic peptides in evaluation of acute heart failure. Crit Care Med. 2008;
36(1 Suppl):S17–27.
14. de Cal M, Haapio M, Cruz DN, et al. B-type natriuretic peptide in the critically ill with acute
kidney injury. Int J Nephrol. 2011;2011:951629.
15. Burke MA, Cotts WG. Interpretation of B-type natriuretic peptide in cardiac disease and
other comorbid conditions. Heart Fail Rev. 2007;12(1):23–36.
16. Tonelli AR, Arelli V, Minai OA, et al. Causes and circumstances of death in pulmonary arte-
rial hypertension. Am J Respir Crit Care Med. 2013;188(3):365–9.
17. Sztrymf B, Souza R, Bertoletti L, et al. Prognostic factors of acute heart failure in patients
with pulmonary arterial hypertension. Eur Respir J. 2010;35(6):1286–93.
18. ten Wolde M, Sohne M, Quak E, Mac Gillavry MR, Buller HR. Prognostic value of echocar-
diographically assessed right ventricular dysfunction in patients with pulmonary embolism.
Arch Intern Med. 2004;164(15):1685–9.
19. Becattini C, Agnelli G. Acute pulmonary embolism: risk stratification in the emergency
department. Intern Emerg Med. 2007;2(2):119–29.
20. Matthews JC, McLaughlin V. Acute right ventricular failure in the setting of acute pulmonary
embolism or chronic pulmonary hypertension: a detailed review of the pathophysiology,
diagnosis, and management. Curr Cardiol Rev. 2008;4(1):49–59.
21. Vieillard-Baron A, Price LC, Matthay MA. Acute cor pulmonale in ARDS. Intensive Care
Med. 2013;39(10):1836–8.
22. Segers VF, Brutsaert DL, De Keulenaer GW. Pulmonary hypertension and right heart failure
in heart failure with preserved left ventricular ejection fraction: pathophysiology and natural
history. Curr Opin Cardiol. 2012;27(3):273–80.
23. Alon D, Stein GY, Korenfeld R, Fuchs S. Predictors and outcomes of infection-related hospi-
tal admissions of heart failure patients. PLoS One. 2013;8(8):e72476.
24. Singanayagam A, Schembri S, Chalmers JD. Predictors of mortality in hospitalized adults
with acute exacerbation of chronic obstructive pulmonary disease. Ann Am Thorac Soc.
2013;10(2):81–9.
Circulation. 2008;117(11):1436–48.
26. Greyson CR. Pathophysiology of right ventricular failure. Crit Care Med. 2008;36(1
Suppl):S57–65.
27. Naeije R. Physiology of the pulmonary circulation and the right heart. Curr Hypertens Rep.
2013;15:623–31.
28. Kiely DG, Cargill RI, Lipworth BJ. Angiotensin II receptor blockade and effects on pulmo-
nary hemodynamics and hypoxic pulmonary vasoconstriction in humans. Chest.
1996;110(3):698–703.
29. Bogaard HJ, Abe K, Vonk Noordegraaf A, Voelkel NF. The right ventricle under pressure:
cellular and molecular mechanisms of right-heart failure in pulmonary hypertension. Chest.
2009;135(3):794–804.
30. Drake JI, Bogaard HJ, Mizuno S, et al. Molecular signature of a right heart failure program
in chronic severe pulmonary hypertension. Am J Respir Cell Mol Biol. 2011;45(6):
1239–47.
hypertension and right heart failure. Am J Respir Crit Care Med. 2011;184(10):1114–24.
32. Tan JL, Prati D, Gatzoulis MA, Gibson D, Henein MY, Li W. The right ventricular response
to high afterload: comparison between atrial switch procedure, congenitally corrected trans-
position of the great arteries, and idiopathic pulmonary arterial hypertension. Am Heart
J. 2007;153(4):681–8.
33. Mebazaa A, Karpati P, Renaud E, Algotsson L. Acute right ventricular failure–from patho-
physiology to new treatments. Intensive Care Med. 2004;30(2):185–96.
34. Chin KM, Kim NH, Rubin LJ. The right ventricle in pulmonary hypertension. Coron Artery
Dis. 2005;16(1):13–8.
35. Goldhaber SZ, Visani L, De Rosa M. Acute pulmonary embolism: clinical outcomes in the
International Cooperative Pulmonary Embolism Registry (ICOPER). Lancet. 1999;353(9162):
1386–9.
36. Champion HC, Michelakis ED, Hassoun PM. Comprehensive invasive and noninvasive
approach to the right ventricle-pulmonary circulation unit: state of the art and clinical and
research implications. Circulation. 2009;120(11):992–1007.
37. Dell’Italia LJ. The right ventricle: anatomy, physiology, and clinical importance. Curr Probl
Cardiol. 1991;16(10):653–720.
38. Dell’Italia LJ. Anatomy and physiology of the right ventricle. Cardiol Clin. 2012;30(2):
167–87.
39. Hsia HH, Haddad F. Pulmonary hypertension: a stage for ventricular interdependence? J Am
Coll Cardiol. 2012;59(24):2203–5.
40. Cucci AR, Lahm T. Resynchronization therapy for right ventricular failure: restoring har-
mony in left ventricular contractility. J Surg Res. 2013;185:493–5.
41. Alpert JS. The effect of right ventricular dysfunction on left ventricular form and function.
Chest. 2001;119(6):1632–3.
butions to right ventricular systolic function. Prog Cardiovasc Dis. 1998;40(4):289–308.
43. Klima U, Guerrero JL, Vlahakes GJ. Contribution of the interventricular septum to maximal
right ventricular function. Eur J Cardiothorac Surg. 1998;14(3):250–5.
44. Feneley MP, Gavaghan TP, Baron DW, Branson JA, Roy PR, Morgan JJ. Contribution of left
ventricular contraction to the generation of right ventricular systolic pressure in the human
heart. Circulation. 1985;71(3):473–80.
45. Lopez-Candales A, Dohi K, Rajagopalan N, et al. Right ventricular dyssynchrony in patients
with pulmonary hypertension is associated with disease severity and functional class.
Cardiovasc Ultrasound. 2005;3:23.
46. Majos E, Dabrowski R, Szwed H. The right ventricle in patients with chronic heart failure
and atrial fibrillation. Cardiol J. 2013;20(3):220–6.
47. Kinch JW, Ryan TJ. Right ventricular infarction. N Engl J Med. 1994;330(17):1211–7.
48. Marcus JT, Smeenk HG, Kuijer JP, Van der Geest RJ, Heethaar RM, Van Rossum AC. Flow
profiles in the left anterior descending and the right coronary artery assessed by MR velocity
quantification: effects of through-plane and in-plane motion of the heart. J Comput Assist
Tomogr. 1999;23(4):567–76.
49. Sharma GV, Sasahara AA. Regional and transmural myocardial blood flow studies in experi-
mental pulmonary embolism. Prog Cardiovasc Dis. 1974;17(3):191–8.
50. Vlahakes GJ, Turley K, Hoffman JI. The pathophysiology of failure in acute right ventricular
hypertension: hemodynamic and biochemical correlations. Circulation. 1981;63(1):87–95.
51. van Wolferen SA, Marcus JT, Westerhof N, et al. Right coronary artery flow impairment in
patients with pulmonary hypertension. Eur Heart J. 2008;29(1):120–7.
52. Gold FL, Bache RJ. Transmural right ventricular blood flow during acute pulmonary artery
hypertension in the sedated dog. Evidence for subendocardial ischemia despite residual vaso-
dilator reserve. Circ Res. 1982;51(2):196–204.
53. Bogaard HJ, Natarajan R, Henderson SC, et al. Chronic pulmonary artery pressure elevation
is insufficient to explain right heart failure. Circulation. 2009;120(20):1951–60.
54. Goldstein JA, Barzilai B, Rosamond TL, Eisenberg PR, Jaffe AS. Determinants of hemody-
namic compromise with severe right ventricular infarction. Circulation. 1990;82(2):359–68.
55. Olsson KM, Nickel NP, Tongers J, Hoeper MM. Atrial flutter and fibrillation in patients with
pulmonary hypertension. Int J Cardiol. 2013;167(5):2300–5.
56. Watts JA, Zagorski J, Gellar MA, Stevinson BG, Kline JA. Cardiac inflammation contributes
to right ventricular dysfunction following experimental pulmonary embolism in rats. J Mol
Cell Cardiol. 2006;41(2):296–307.
57. Watts JA, Gellar MA, Obraztsova M, Kline JA, Zagorski J. Role of inflammation in right
ventricular damage and repair following experimental pulmonary embolism in rats. Int J Exp
Pathol. 2008;89(5):389–99.
58. Iwadate K, Doi M, Tanno K, et al. Right ventricular damage due to pulmonary embolism:
examination of the number of infiltrating macrophages. Forensic Sci Int. 2003;134(2–3):
147–53.
59. Begieneman MP, van de Goot FR, van der Bilt IA, et al. Pulmonary embolism causes
endomyocarditis in the human heart. Heart. 2008;94(4):450–6.
60. Cau SB, Barato RC, Celes MR, Muniz JJ, Rossi MA, Tanus-Santos JE. Doxycycline prevents
acute pulmonary embolism-induced mortality and right ventricular deformation in rats.
Cardiovasc Drugs Ther. 2013;27(4):259–67.
61. Dewachter C, Dewachter L, Rondelet B, et al. Activation of apoptotic pathways in experi-
mental acute afterload-induced right ventricular failure. Crit Care Med. 2010;38(6):
1405–13.
62. Nordenholz KE, Mitchell AM, Kline JA. Direct comparison of the diagnostic accuracy of
fifty protein biological markers of pulmonary embolism for use in the emergency department.
Acad Emerg Med. 2008;15(9):795–9.
63. Kline JA, Zeitouni R, Marchick MR, Hernandez-Nino J, Rose GA. Comparison of 8 bio-
markers for prediction of right ventricular hypokinesis 6 months after submassive pulmonary
embolism. Am Heart J. 2008;156(2):308–14.
64. Mitchell AM, Nordenholz KE, Kline JA. Tandem measurement of D-dimer and myeloperoxi-
dase or C-reactive protein to effectively screen for pulmonary embolism in the emergency
department. Acad Emerg Med. 2008;15(9):800–5.
65. Jones AE, Watts JA, Debelak JP, Thornton LR, Younger JG, Kline JA. Inhibition of prosta-
glandin synthesis during polystyrene microsphere-induced pulmonary embolism in the rat.
Am J Physiol Lung Cell Mol Physiol. 2003;284(6):L1072–81.
66. Zagorski J, Wahl SM. Inhibition of acute peritoneal inflammation in rats by a cytokine-
induced neutrophil chemoattractant receptor antagonist. J Immunol. 1997;159(3):1059–62.
67. Zagorski J, Obraztsova M, Gellar MA, Kline JA, Watts JA. Transcriptional changes in right
ventricular tissues are enriched in the outflow tract compared with the apex during chronic
pulmonary embolism in rats. Physiol Genomics. 2009;39(1):61–71.
68. Kaczynska A, Szulc M, Styczynski G, Kostrubiec M, Pacho R, Pruszczyk P. Right ventricle
injury during acute pulmonary embolism leads to its remodeling. Int J Cardiol. 2008;
125(1):120–1.
69. Cingolani HE, Perez NG, Aiello EA, et al. Early signals after stretch leading to cardiac hyper-
trophy. Key role of NHE-1. Front Biosci. 2008;13:7096–114.
70. Ahmad HA, Lu L, Ye S, Schwartz GG, Greyson CR. Calpain inhibition preserves talin and
attenuates right heart failure in acute pulmonary hypertension. Am J Respir Cell Mol Biol.
2012;47(3):379–86.
71. Greyson CR, Schwartz GG, Lu L, et al. Calpain inhibition attenuates right ventricular con-
tractile dysfunction after acute pressure overload. J Mol Cell Cardiol. 2008;44(1):59–68.
72. Zagorski J, Sanapareddy N, Gellar MA, Kline JA, Watts JA. Transcriptional profile of right
ventricular tissue during acute pulmonary embolism in rats. Physiol Genomics.
2008;34(1):101–11.
73. Guazzi M, Borlaug BA. Pulmonary hypertension due to left heart disease. Circulation.
2012;126(8):975–90.
74. Hoeper MM, Barbera JA, Channick RN, et al. Diagnosis, assessment, and treatment of non-
pulmonary arterial hypertension pulmonary hypertension. J Am Coll Cardiol. 2009;54(1
Suppl):S85–96.
75. McIntyre KM, Sasahara AA. Correlation of pulmonary photoscan and angiogram as mea-
sures of the severity of pulmonary embolic involvement. J Nucl Med. 1971;12(11):732–8.
76. McIntyre KM, Sasahara AA. Hemodynamic and ventricular responses to pulmonary embo-
lism. Prog Cardiovasc Dis. 1974;17(3):175–90.
77. Wolfe MW, Lee RT, Feldstein ML, Parker JA, Come PC, Goldhaber SZ. Prognostic signifi-
cance of right ventricular hypokinesis and perfusion lung scan defects in pulmonary embo-
lism. Am Heart J. 1994;127(5):1371–5.
78. Ribeiro A, Juhlin-Dannfelt A, Brodin LA, Holmgren A, Jorfeldt L. Pulmonary embolism:
relation between the degree of right ventricle overload and the extent of perfusion defects.
Am Heart J. 1998;135(5 Pt 1):868–74.
79. Vedovati MC, Becattini C, Agnelli G, et al. Multidetector CT scan for acute pulmonary
embolism: embolic burden and clinical outcome. Chest. 2012;142(6):1417–24.
80. Kucher N, Rossi E, De Rosa M, Goldhaber SZ. Massive pulmonary embolism. Circulation.
2006;113(4):577–82.
81. Laporte S, Mismetti P, Decousus H, et al. Clinical predictors for fatal pulmonary embolism
in 15,520 patients with venous thromboembolism: findings from the Registro Informatizado
de la Enfermedad TromboEmbolica venosa (RIETE) Registry. Circulation. 2008;117(13):
1711–6.
82. Pollack CV, Schreiber D, Goldhaber SZ, et al. Clinical characteristics, management, and
outcomes of patients diagnosed with acute pulmonary embolism in the emergency depart-
ment: initial report of EMPEROR (Multicenter Emergency Medicine Pulmonary Embolism
in the Real World Registry). J Am Coll Cardiol. 2011;57(6):700–6.
83. Kline JA, Hernandez-Nino J, Rose GA, Norton HJ, Camargo Jr CA. Surrogate markers for
adverse outcomes in normotensive patients with pulmonary embolism. Crit Care Med.
2006;34(11):2773–80.
84. Stevinson BG, Hernandez-Nino J, Rose G, Kline JA. Echocardiographic and functional car-
diopulmonary problems 6 months after first-time pulmonary embolism in previously healthy
patients. Eur Heart J. 2007;28(20):2517–24.
85. Smulders YM. Pathophysiology and treatment of haemodynamic instability in acute pulmo-
nary embolism: the pivotal role of pulmonary vasoconstriction. Cardiovasc Res.
2000;48(1):23–33.
86. Kapsch DN, Metzler M, Silver D. Contributions of prostaglandin F2alpha and thromboxane
A2 to the acute cardiopulmonary changes of pulmonary embolism. J Surg Res. 1981;30(5):
522–9.
87. Kline JA, Marchick MR, Hogg MM. Reduction in plasma haptoglobin in humans with acute
pulmonary embolism causing tricuspid regurgitation. J Thromb Haemost. 2009;7(9):
1597–9.
88. Sousa-Santos O, Neto-Neves EM, Ferraz KC, Sertorio JT, Portella RL, Tanus-Santos JE. The
antioxidant tempol decreases acute pulmonary thromboembolism-induced hemolysis and
nitric oxide consumption. Thromb Res. 2013;132:578–83.
89. Morris CR, Kato GJ, Poljakovic M, et al. Dysregulated arginine metabolism, hemolysis-
associated pulmonary hypertension, and mortality in sickle cell disease. JAMA.
2005;294(1):81–90.
90. McDonnell NJ, Percival V, Paech MJ. Amniotic fluid embolism: a leading cause of maternal
death yet still a medical conundrum. Int J Obstet Anesth. 2013;22:329–36.
91. Telford L, Harris J. A traumatic case of fat embolism. BMJ Case Rep. 2013;2013.
92. Abd El-Rahman AM, Lazzarotti AG, Cosottini M, Puglioli M. Pulmonary embolism caused
by cement leakage during percutaneous vertebroplasty. A case report of successful conserva-
tive management. Neuroradiol J. 2012;25(4):481–5.
93. Simonneau G, Robbins IM, Beghetti M, et al. Updated clinical classification of pulmonary
hypertension. J Am Coll Cardiol. 2009;54(1 Suppl):S43–54.
94. Fedullo P, Kerr KM, Kim NH, Auger WR. Chronic thromboembolic pulmonary hyperten-
sion. Am J Respir Crit Care Med. 2011;183(12):1605–13.
95. Brookes CI, White PA, Bishop AJ, Oldershaw PJ, Redington AN, Moat NE. Validation of a
new intraoperative technique to evaluate load-independent indices of right ventricular perfor-
mance in patients undergoing cardiac operations. J Thorac Cardiovasc Surg. 1998;116(3):
468–76.
96. Brookes C, Ravn H, White P, Moeldrup U, Oldershaw P, Redington A. Acute right ventricu-
lar dilatation in response to ischemia significantly impairs left ventricular systolic perfor-
mance. Circulation. 1999;100(7):761–7.
97. Cullen S, Shore D, Redington A. Characterization of right ventricular diastolic performance
after complete repair of tetralogy of Fallot. Restrictive physiology predicts slow postoperative
recovery. Circulation. 1995;91(6):1782–9.
98. Patlolla B, Beygui R, Haddad F. Right-ventricular failure following left ventricle assist device
implantation. Curr Opin Cardiol. 2013;28(2):223–33.
99. Drakos SG, Janicki L, Horne BD, et al. Risk factors predictive of right ventricular failure
after left ventricular assist device implantation. Am J Cardiol. 2010;105(7):1030–5.
100. Santamore WP, Gray Jr LA. Left ventricular contributions to right ventricular systolic func-
tion during LVAD support. Ann Thorac Surg. 1996;61(1):350–6.
101. Moon MR, Castro LJ, DeAnda A, et al. Right ventricular dynamics during left ventricular
assistance in closed-chest dogs. Ann Thorac Surg. 1993;56(1):54–66, discussion 66–7.
102. Miller LW, Guglin M. Patient selection for ventricular assist devices: a moving target. J Am
Coll Cardiol. 2013;61(12):1209–21.
103. Mekontso Dessap A, Leon R, Habibi A, et al. Pulmonary hypertension and cor pulmonale
during severe acute chest syndrome in sickle cell disease. Am J Respir Crit Care Med.
2008;177(6):646–53.
104. Bhalla M, Abboud MR, McLoud TC, et al. Acute chest syndrome in sickle cell disease: CT
evidence of microvascular occlusion. Radiology. 1993;187(1):45–9.
105. Mekontso Dessap A, Deux JF, Abidi N, et al. Pulmonary artery thrombosis during acute chest
syndrome in sickle cell disease. Am J Respir Crit Care Med. 2011;184(9):1022–9.
106. Meldrum DR. Tumor necrosis factor in the heart. Am J Physiol. 1998;274(3 Pt 2):R577–95.
107. Wort SJ, Ito M, Chou PC, et al. Synergistic induction of endothelin-1 by tumor necrosis factor
alpha and interferon gamma is due to enhanced NF-kappaB binding and histone acetylation
at specific kappaB sites. J Biol Chem. 2009;284(36):24297–305.
108. Sylvester JT, Shimoda LA, Aaronson PI, Ward JP. Hypoxic pulmonary vasoconstriction.
Physiol Rev. 2012;92(1):367–520.
109. Balanos GM, Talbot NP, Dorrington KL, Robbins PA. Human pulmonary vascular response
to 4 h of hypercapnia and hypocapnia measured using Doppler echocardiography. J Appl
Physiol. 2003;94(4):1543–51.
110. Bull TM, Clark B, McFann K, Moss M. Pulmonary vascular dysfunction is associated with
poor outcomes in patients with acute lung injury. Am J Respir Crit Care Med. 2010;
182(9):1123–8.
111. Vieillard-Baron A, Schmitt JM, Augarde R, et al. Acute cor pulmonale in acute respiratory
distress syndrome submitted to protective ventilation: incidence, clinical implications, and
prognosis. Crit Care Med. 2001;29(8):1551–5.
112. Boissier F, Katsahian S, Razazi K, et al. Prevalence and prognosis of cor pulmonale during
protective ventilation for acute respiratory distress syndrome. Intensive Care Med. 2013;
39(10):1725–33.
113. Lheritier G, Legras A, Caille A, et al. Prevalence and prognostic value of acute cor pulmonale
and patent foramen ovale in ventilated patients with early acute respiratory distress syn-
drome: a multicenter study. Intensive Care Med. 2013;39(10):1734–42.
114. Mekontso Dessap A, Charron C, Devaquet J, et al. Impact of acute hypercapnia and aug-
mented positive end-expiratory pressure on right ventricle function in severe acute respira-
tory distress syndrome. Intensive Care Med. 2009;35(11):1850–8.
115. Her C, Lees DE. Accurate assessment of right ventricular function in acute respiratory fail-
ure. Crit Care Med. 1993;21(11):1665–72.
116. Nuckton TJ, Alonso JA, Kallet RH, et al. Pulmonary dead-space fraction as a risk factor for
death in the acute respiratory distress syndrome. N Engl J Med. 2002;346(17):1281–6.
117. Henning RJ. Effects of positive end-expiratory pressure on the right ventricle. J Appl Physiol.
1986;61(3):819–26.
118. Cassidy SS, Eschenbacher WL, Robertson Jr CH, Nixon JV, Blomqvist G, Johnson Jr
RL. Cardiovascular effects of positive-pressure ventilation in normal subjects. J Appl Physiol.
1979;47(2):453–61.
119. Cassidy SS, Mitchell JH. Effects of positive pressure breathing on right and left ventricular
preload and afterload. Fed Proc. 1981;40(8):2178–81.
120. Morgan JA, Paone G, Nemeh HW, et al. Impact of continuous-flow left ventricular assist
device support on right ventricular function. J Heart Lung Transpl. 2013;32(4):398–403.
121. Maeder MT, Leet A, Ross A, Esmore D, Kaye DM. Changes in right ventricular function
during continuous-flow left ventricular assist device support [corrected]. J Heart Lung
Transpl. 2009;28(4):360–6.
122. Furukawa K, Motomura T, Nose Y. Right ventricular failure after left ventricular assist device
implantation: the need for an implantable right ventricular assist device. Artif Organs.
2005;29(5):369–77.
123. Fitzpatrick III JR, Frederick JR, Hiesinger W, et al. Early planned institution of biventricular
mechanical circulatory support results in improved outcomes compared with delayed conver-
sion of a left ventricular assist device to a biventricular assist device. J Thorac Cardiovasc
Surg. 2009;137(4):971–7.
124. Dang NC, Topkara VK, Mercando M, et al. Right heart failure after left ventricular assist
device implantation in patients with chronic congestive heart failure. J Heart Lung Transpl.
2006;25(1):1–6.
125. Farrar DJ, Hill JD, Pennington DG, et al. Preoperative and postoperative comparison of
patients with univentricular and biventricular support with the thoratec ventricular assist
device as a bridge to cardiac transplantation. J Thorac Cardiovasc Surg. 1997;113(1):202–9.
126. Kormos RL, Gasior TA, Kawai A, et al. Transplant candidate’s clinical status rather than right
ventricular function defines need for univentricular versus biventricular support. J Thorac
Cardiovasc Surg. 1996;111(4):773–82, discussion 782–3.
127. Schultz JC, Hilliard AA, Cooper Jr LT, Rihal CS. Diagnosis and treatment of viral myocardi-
tis. Mayo Clin Proc. 2009;84(11):1001–9.
128. Gaffney FA, Keller AM, Peshock RM, Lin JC, Firth BG. Pathophysiologic mechanisms of
cardiac tamponade and pulsus alternans shown by echocardiography. Am J Cardiol.
1984;53(11):1662–6.
129. O’Rourke RA, Dell’Italia LJ. Diagnosis and management of right ventricular myocardial
infarction. Curr Probl Cardiol. 2004;29(1):6–47.
130. Anderson NE, Ali MR, Simpson IJ. The clinical significance of right ventricular infarction.
N Z Med J. 1981;94(691):174–6.
131. Mehta SR, Eikelboom JW, Natarajan MK, et al. Impact of right ventricular involvement on
mortality and morbidity in patients with inferior myocardial infarction. J Am Coll Cardiol.
2001;37(1):37–43.
132. Bowers TR, O’Neill WW, Grines C, Pica MC, Safian RD, Goldstein JA. Effect of reperfusion
on biventricular function and survival after right ventricular infarction. N Engl J Med.
1998;338(14):933–40.
133. Heidbuchel H, Hoogsteen J, Fagard R, et al. High prevalence of right ventricular involvement
in endurance athletes with ventricular arrhythmias. Role of an electrophysiologic study in
risk stratification. Eur Heart J. 2003;24(16):1473–80.
134. La Gerche A, Burns AT, Mooney DJ, et al. Exercise-induced right ventricular dysfunction
and structural remodelling in endurance athletes. Eur Heart J. 2012;33(8):998–1006.
135. Bittner HB, Chen EP, Milano CA, et al. Myocardial beta-adrenergic receptor function and
high-energy phosphates in brain death–related cardiac dysfunction. Circulation. 1995;92(9
Suppl):II472–8.
136. Stoica SC, Satchithananda DK, White PA, et al. Brain death leads to abnormal contractile
properties of the human donor right ventricle. J Thorac Cardiovasc Surg. 2006;132(1):
116–23.
137. Piazza G, Goldhaber SZ. The acutely decompensated right ventricle: pathways for diagnosis
and management. Chest. 2005;128(3):1836–52.
138. Kelder JC, Cramer MJ, van Wijngaarden J, et al. The diagnostic value of physical examina-
tion and additional testing in primary care patients with suspected heart failure. Circulation.
2011;124(25):2865–73.
139. Le RJ, Fenstad ER, Maradit-Kremers H, et al. Syncope in adults with pulmonary arterial
hypertension. J Am Coll Cardiol. 2011;58(8):863–7.
140. Konstantinides S, Geibel A, Olschewski M, et al. Association between thrombolytic treat-
ment and the prognosis of hemodynamically stable patients with major pulmonary embolism:
results of a multicenter registry. Circulation. 1997;96(3):882–8.
141. Campo A, Mathai SC, Le Pavec J, et al. Outcomes of hospitalisation for right heart failure in
pulmonary arterial hypertension. Eur Respir J. 2011;38(2):359–67.
142. Becattini C, Casazza F, Forgione C, et al. Acute pulmonary embolism: external validation of
an integrated risk stratification model. Chest. 2013;144:1539–45.
143. Sanchez O, Trinquart L, Caille V, et al. Prognostic factors for pulmonary embolism: the prep
study, a prospective multicenter cohort study. Am J Respir Crit Care Med. 2010;181(2):
168–73.
144. Grifoni S, Olivotto I, Cecchini P, et al. Short-term clinical outcome of patients with acute
pulmonary embolism, normal blood pressure, and echocardiographic right ventricular dys-
function. Circulation. 2000;101(24):2817–22.
145. Aujesky D, Obrosky DS, Stone RA, et al. Derivation and validation of a prognostic model for
pulmonary embolism. Am J Respir Crit Care Med. 2005;172(8):1041–6.
146. Wicki J, Perrier A, Perneger TV, Bounameaux H, Junod AF. Predicting adverse outcome in
patients with acute pulmonary embolism: a risk score. Thromb Haemost. 2000;84(4):
548–52.
147. Humbert M, Sitbon O, Chaouat A, et al. Survival in patients with idiopathic, familial, and
anorexigen-associated pulmonary arterial hypertension in the modern management era.
Circulation. 2010;122(2):156–63.
148. Weintraub NL, Collins SP, Pang PS, et al. Acute heart failure syndromes: emergency depart-
ment presentation, treatment, and disposition: current approaches and future aims: a scientific
statement from the American Heart Association. Circulation. 2010;122(19):1975–96.
149. Klok FA, Mos IC, Huisman MV. Brain-type natriuretic peptide levels in the prediction of
adverse outcome in patients with pulmonary embolism: a systematic review and meta-
analysis. Am J Respir Crit Care Med. 2008;178(4):425–30.
150. Nagaya N, Nishikimi T, Okano Y, et al. Plasma brain natriuretic peptide levels increase in
proportion to the extent of right ventricular dysfunction in pulmonary hypertension. J Am
Coll Cardiol. 1998;31(1):202–8.
151. Reesink HJ, Tulevski II, Marcus JT, et al. Brain natriuretic peptide as noninvasive marker of
the severity of right ventricular dysfunction in chronic thromboembolic pulmonary hyperten-
sion. Ann Thorac Surg. 2007;84(2):537–43.
152. Fijalkowska A, Kurzyna M, Torbicki A, et al. Serum N-terminal brain natriuretic peptide as
a prognostic parameter in patients with pulmonary hypertension. Chest. 2006;129(5):
1313–21.
153. Benza RL, Miller DP, Gomberg-Maitland M, et al. Predicting survival in pulmonary arterial
hypertension: insights from the Registry to Evaluate Early and Long-Term Pulmonary
Arterial Hypertension Disease Management (REVEAL). Circulation. 2010;122(2):164–72.
154. Coutance G, Le Page O, Lo T, Hamon M. Prognostic value of brain natriuretic peptide in
acute pulmonary embolism. Crit Care. 2008;12(4):R109.
155. Cavallazzi R, Nair A, Vasu T, Marik PE. Natriuretic peptides in acute pulmonary embolism:
a systematic review. Intensive Care Med. 2008;34(12):2147–56.
156. Sanchez O, Trinquart L, Colombet I, et al. Prognostic value of right ventricular dysfunction
in patients with haemodynamically stable pulmonary embolism: a systematic review. Eur
Heart J. 2008;29(12):1569–77.
157. Becattini C, Vedovati MC, Agnelli G. Prognostic value of troponins in acute pulmonary
embolism: a meta-analysis. Circulation. 2007;116(4):427–33.
158. Heresi GA, Tang WH, Aytekin M, Hammel J, Hazen SL, Dweik RA. Sensitive cardiac tropo-
nin I predicts poor outcomes in pulmonary arterial hypertension. Eur Respir J. 2012;39(4):
939–44.
159. Haddad F, Peterson T, Fuh E, et al. Characteristics and outcome after hospitalization for acute
right heart failure in patients with pulmonary arterial hypertension. Circ Heart Fail.
2011;4(6):692–9.
160. Forfia PR, Mathai SC, Fisher MR, et al. Hyponatremia predicts right heart failure and
poor survival in pulmonary arterial hypertension. Am J Respir Crit Care Med. 2008;
177(12):1364–9.
161. Scherz N, Labarere J, Mean M, Ibrahim SA, Fine MJ, Aujesky D. Prognostic importance of
hyponatremia in patients with acute pulmonary embolism. Am J Respir Crit Care Med.
2010;182(9):1178–83.
162. Dellas C, Puls M, Lankeit M, et al. Elevated heart-type fatty acid-binding protein levels on
admission predict an adverse outcome in normotensive patients with acute pulmonary embo-
lism. J Am Coll Cardiol. 2010;55(19):2150–7.
163. Puls M, Dellas C, Lankeit M, et al. Heart-type fatty acid-binding protein permits early risk
stratification of pulmonary embolism. Eur Heart J. 2007;28(2):224–9.
164. Kempf T, Eden M, Strelau J, et al. The transforming growth factor-beta superfamily member
growth-differentiation factor-15 protects the heart from ischemia/reperfusion injury. Circ
Res. 2006;98(3):351–60.
165. Xu J, Kimball TR, Lorenz JN, et al. GDF15/MIC-1 functions as a protective and antihyper-
trophic factor released from the myocardium in association with SMAD protein activation.
Circ Res. 2006;98(3):342–50.
166. Nickel N, Kempf T, Tapken H, et al. Growth differentiation factor-15 in idiopathic pulmonary
arterial hypertension. Am J Respir Crit Care Med. 2008;178(5):534–41.
167. Lankeit M, Kempf T, Dellas C, et al. Growth differentiation factor-15 for prognostic assess-
ment of patients with acute pulmonary embolism. Am J Respir Crit Care Med. 2008;
177(9):1018–25.
168. Geibel A, Zehender M, Kasper W, Olschewski M, Klima C, Konstantinides SV. Prognostic
value of the ECG on admission in patients with acute major pulmonary embolism. Eur Respir
J. 2005;25(5):843–8.
169. Daniel KR, Courtney DM, Kline JA. Assessment of cardiac stress from massive pulmonary
embolism with 12-lead ECG. Chest. 2001;120(2):474–81.
170. Toosi MS, Merlino JD, Leeper KV. Electrocardiographic score and short-term outcomes of
acute pulmonary embolism. Am J Cardiol. 2007;100(7):1172–6.
171. Iles S, Le Heron CJ, Davies G, Turner JG, Beckert LE. ECG score predicts those with the
greatest percentage of perfusion defects due to acute pulmonary thromboembolic disease.
Chest. 2004;125(5):1651–6.
172. Aviram G, Rogowski O, Gotler Y, et al. Real-time risk stratification of patients with acute
pulmonary embolism by grading the reflux of contrast into the inferior vena cava on comput-
erized tomographic pulmonary angiography. J Thromb Haemost. 2008;6(9):1488–93.
173. Jimenez D, Lobo JL, Monreal M, et al. Prognostic significance of multidetector CT in nor-
motensive patients with pulmonary embolism: results of the protect study. Thorax. 2014;69:
109–15.
174. Tunariu N, Gibbs SJ, Win Z, et al. Ventilation-perfusion scintigraphy is more sensitive than
multidetector CTPA in detecting chronic thromboembolic pulmonary disease as a treatable
cause of pulmonary hypertension. J Nucl Med. 2007;48(5):680–4.
175. Brittain EL, Hemnes AR, Keebler M, Lawson M, Byrd III BF, Disalvo T. Right ventricular
plasticity and functional imaging. Pulm Circ. 2012;2(3):309–26.
176. Kasper W, Konstantinides S, Geibel A, Tiede N, Krause T, Just H. Prognostic significance of
right ventricular afterload stress detected by echocardiography in patients with clinically sus-
pected pulmonary embolism. Heart. 1997;77(4):346–9.
177. Jardin F, Vieillard-Baron A. Monitoring of right-sided heart function. Curr Opin Crit Care.
2005;11(3):271–9.
178. Vieillard-Baron A, Prin S, Chergui K, Dubourg O, Jardin F. Echo-Doppler demonstration of
acute cor pulmonale at the bedside in the medical intensive care unit. Am J Respir Crit Care
Med. 2002;166(10):1310–9.
179. Fisher MR, Forfia PR, Chamera E, et al. Accuracy of Doppler echocardiography in the hemo-
dynamic assessment of pulmonary hypertension. Am J Respir Crit Care Med. 2009;179(7):
615–21.
180. Rich JD, Shah SJ, Swamy RS, Kamp A, Rich S. Inaccuracy of Doppler echocardiographic
estimates of pulmonary artery pressures in patients with pulmonary hypertension: implica-
tions for clinical practice. Chest. 2011;139(5):988–93.
181. MacNee W. Pathophysiology of cor pulmonale in chronic obstructive pulmonary disease.

Part two. Am J Respir Crit Care Med. 1994;150(4):1158–68.
182. Otero R, Oribe M, Ballaz A, et al. Echocardiographic assessment of pulmonary arterial pres-
sure in the follow-up of patients with pulmonary embolism. Thromb Res. 2011;
127(4):303–8.
183. Kline JA, Steuerwald MT, Marchick MR, Hernandez-Nino J, Rose GA. Prospective evalua-
tion of right ventricular function and functional status 6 months after acute submassive pul-
monary embolism: frequency of persistent or subsequent elevation in estimated pulmonary
artery pressure. Chest. 2009;136(5):1202–10.
184. Sharifi M, Bay C, Skrocki L, Rahimi F, Mehdipour M. Moderate pulmonary embolism
treated with thrombolysis (from the “MOPETT” Trial). Am J Cardiol. 2013;111(2):273–7.
185. Ribeiro A, Lindmarker P, Johnsson H, Juhlin-Dannfelt A, Jorfeldt L. Pulmonary embolism:
one-year follow-up with echocardiography Doppler and five-year survival analysis.
Circulation. 1999;99(10):1325–30.
186. Jardin F, Dubourg O, Gueret P, Delorme G, Bourdarias JP. Quantitative two-dimensional
echocardiography in massive pulmonary embolism: emphasis on ventricular interdependence
and leftward septal displacement. J Am Coll Cardiol. 1987;10(6):1201–6.
187. Oguzhan A, Abaci A, Eryol NK, Topsakal R, Seyfeli E. Colour tissue Doppler echocardio-
graphic evaluation of right ventricular function in patients with right ventricular infarction.
Cardiology. 2003;100(1):41–6.
188. Antoni ML, Scherptong RW, Atary JZ, et al. Prognostic value of right ventricular function in
patients after acute myocardial infarction treated with primary percutaneous coronary inter-
vention. Circ Cardiovasc Imaging. 2010;3(3):264–71.
189. Forfia PR, Fisher MR, Mathai SC, et al. Tricuspid annular displacement predicts survival in
pulmonary hypertension. Am J Respir Crit Care Med. 2006;174(9):1034–41.
190. Rydman R, Soderberg M, Larsen F, Caidahl K, Alam M. Echocardiographic evaluation of
right ventricular function in patients with acute pulmonary embolism: a study using tricuspid
annular motion. Echocardiography. 2010;27(3):286–93.
191. Badano LP, Ginghina C, Easaw J, et al. Right ventricle in pulmonary arterial hypertension:
haemodynamics, structural changes, imaging, and proposal of a study protocol aimed to
assess remodelling and treatment effects. Eur J Echocardiogr. 2010;11(1):27–37.
192. Park JH, Park YS, Park SJ, et al. Midventricular peak systolic strain and Tei index of the right
ventricle correlated with decreased right ventricular systolic function in patients with acute
pulmonary thromboembolism. Int J Cardiol. 2008;125(3):319–24.
193. Dentali F, Bertolini A, Nicolini E, et al. Evaluation of right ventricular function in patients
with a previous episode of pulmonary embolism using tissue Doppler imaging. Intern Emerg
Med. 2013;8:689–94.
194. Arkles JS, Opotowsky AR, Ojeda J, et al. Shape of the right ventricular Doppler envelope
predicts hemodynamics and right heart function in pulmonary hypertension. Am J Respir Crit
Care Med. 2011;183(2):268–76.
195. Platz E, Hassanein AH, Shah A, Goldhaber SZ, Solomon SD. Regional right ventricular
strain pattern in patients with acute pulmonary embolism. Echocardiography. 2012;
29(4):464–70.
196. McConnell MV, Solomon SD, Rayan ME, Come PC, Goldhaber SZ, Lee RT. Regional right
ventricular dysfunction detected by echocardiography in acute pulmonary embolism. Am J
Cardiol. 1996;78(4):469–73.
197. Casazza F, Bongarzoni A, Capozi A, Agostoni O. Regional right ventricular dysfunction in
acute pulmonary embolism and right ventricular infarction. Eur J Echocardiogr. 2005;
6(1):11–4.
198. Chemla D, Castelain V, Herve P, Lecarpentier Y, Brimioulle S. Haemodynamic evaluation of
pulmonary hypertension. Eur Respir J. 2002;20(5):1314–31.
199. Hoeper MM, Lee SH, Voswinckel R, et al. Complications of right heart catheterization pro-
cedures in patients with pulmonary hypertension in experienced centers. J Am Coll Cardiol.
2006;48(12):2546–52.
200. Keogh AM, Mayer E, Benza RL, et al. Interventional and surgical modalities of treatment in
pulmonary hypertension. J Am Coll Cardiol. 2009;54(1 Suppl):S67–77.
201. La Vecchia L, Varotto L, Zanolla L, Spadaro GL, Fontanelli A. Right ventricular function
predicts transplant-free survival in idiopathic dilated cardiomyopathy. J Cardiovasc Med
(Hagerstown). 2006;7(9):706–10.
202. Badesch DB, Champion HC, Sanchez MA, et al. Diagnosis and assessment of pulmonary
arterial hypertension. J Am Coll Cardiol. 2009;54(1 Suppl):S55–66.
203. Ryan JJ, Rich JD, Thiruvoipati T, Swamy R, Kim GH, Rich S. Current practice for determin-
ing pulmonary capillary wedge pressure predisposes to serious errors in the classification of
patients with pulmonary hypertension. Am Heart J. 2012;163(4):589–94.
204. Halpern SD, Taichman DB. Misclassification of pulmonary hypertension due to reliance on
pulmonary capillary wedge pressure rather than left ventricular end-diastolic pressure. Chest.
2009;136(1):37–43.
205. Matthay MA. Invasive hemodynamic monitoring in critically ill patients. Clin Chest Med.
1983;4(2):233–49.
206. Vender JS, Franklin M. Hemodynamic assessment of the critically ill patient. Int Anesthesiol
Clin. 2004;42(1):31–58.
207. Daudel F, Tuller D, Krahenbuhl S, Jakob SM, Takala J. Pulse pressure variation and volume
responsiveness during acutely increased pulmonary artery pressure: an experimental study.
Crit Care. 2010;14(3):R122.
208. Michard F, Richards G, Biais M, Lopes M, Auler JO. Using pulse pressure variation or stroke
volume variation to diagnose right ventricular failure? Crit Care. 2010;14(6):451, author
reply 451.
209. Wyler von Ballmoos M, Takala J, Roeck M, et al. Pulse-pressure variation and hemodynamic
response in patients with elevated pulmonary artery pressure: a clinical study. Crit Care.
2010;14(3):R111.
210. Monnet X, Rienzo M, Osman D, et al. Passive leg raising predicts fluid responsiveness in the
critically ill. Crit Care Med. 2006;34(5):1402–7.
211. Rich JD, Archer SL, Rich S. Noninvasive cardiac output measurements in patients with pul-
monary hypertension. Eur Respir J. 2013;42(1):125–33.
212. Tongers J, Schwerdtfeger B, Klein G, et al. Incidence and clinical relevance of supraventricu-
lar tachyarrhythmias in pulmonary hypertension. Am Heart J. 2007;153(1):127–32.
213. Goldstein JA, Harada A, Yagi Y, Barzilai B, Cox JL. Hemodynamic importance of systolic
ventricular interaction, augmented right atrial contractility and atrioventricular synchrony in
acute right ventricular dysfunction. J Am Coll Cardiol. 1990;16(1):181–9.
214. Hebert PC, Wells G, Blajchman MA, et al. A multicenter, randomized, controlled clinical
trial of transfusion requirements in critical care. Transfusion requirements in Critical Care
Investigators, Canadian Critical Care Trials Group. N Engl J Med. 1999;340(6):409–17.
215. Groenveld HF, Januzzi JL, Damman K, et al. Anemia and mortality in heart failure patients a
systematic review and meta-analysis. J Am Coll Cardiol. 2008;52(10):818–27.
216. Rivers E, Nguyen B, Havstad S, et al. Early goal-directed therapy in the treatment of severe
sepsis and septic shock. N Engl J Med. 2001;345(19):1368–77.
217. Amer M, Adomaityte J, Qayyum R. Continuous infusion versus intermittent bolus furose-
mide in ADHF: an updated meta-analysis of randomized control trials. J Hosp Med.
2012;7(3):270–5.
218. Ng TM, Konopka E, Hyderi AF, et al. Comparison of bumetanide- and metolazone-based
diuretic regimens to furosemide in acute heart failure. J Cardiovasc Pharmacol Ther.
2013;18(4):345–53.
219. Maron BA, Zhang YY, White K, et al. Aldosterone inactivates the endothelin-B receptor via
a cysteinyl thiol redox switch to decrease pulmonary endothelial nitric oxide levels and mod-
ulate pulmonary arterial hypertension. Circulation. 2012;126(8):963–74.
220. Maron BA, Opotowsky AR, Landzberg MJ, Loscalzo J, Waxman AB, Leopold JA. Plasma
aldosterone levels are elevated in patients with pulmonary arterial hypertension in the absence
of left ventricular heart failure: a pilot study. Eur J Heart Fail. 2013;15(3):277–83.
221. de Man FS, Tu L, Handoko ML, et al. Dysregulated renin-angiotensin-aldosterone system

contributes to pulmonary arterial hypertension. Am J Respir Crit Care Med. 2012;
186(8):780–9.
222. Bart BA, Goldsmith SR, Lee KL, et al. Ultrafiltration in decompensated heart failure with
cardiorenal syndrome. N Engl J Med. 2012;367(24):2296–304.
223. Testani JM, Chen J, McCauley BD, Kimmel SE, Shannon RP. Potential effects of aggressive
decongestion during the treatment of decompensated heart failure on renal function and sur-
vival. Circulation. 2010;122(3):265–72.
224. Vieillard-Baron A, Jardin F. Why protect the right ventricle in patients with acute respiratory
distress syndrome? Curr Opin Crit Care. 2003;9(1):15–21.
225. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute
lung injury and the acute respiratory Distress syndrome. The Acute Respiratory Distress
Syndrome Network. New Engl J Med. 2000;342(18):1301–8.
226. Vieillard-Baron A, Charron C, Caille V, Belliard G, Page B, Jardin F. Prone positioning
unloads the right ventricle in severe ARDS. Chest. 2007;132(5):1440–6.
227. Guerin C, Reignier J, Richard JC. Prone positioning in the acute respiratory distress syn-
drome. N Engl J Med. 2013;369(10):980–1.
228. Fuehner T, Kuehn C, Hadem J, et al. Extracorporeal membrane oxygenation in awake patients
as bridge to lung transplantation. Am J Respir Crit Care Med. 2012;185(7):763–8.
229. Wiesner O, Hadem J, Sommer W, Kuhn C, Welte T, Hoeper MM. Extracorporeal membrane
oxygenation in a nonintubated patient with acute respiratory distress syndrome. Eur Respir
J. 2012;40(5):1296–8.
230. Miller AC, Gladwin MT. Pulmonary complications of sickle cell disease. Am J Respir Crit
Care Med. 2012;185(11):1154–65.
231. Braunwald E, Antman EM, Beasley JW, et al. ACC/AHA guideline update for the manage-
ment of patients with unstable angina and non-ST-segment elevation myocardial infarc-
tion–2002: summary article: a report of the American College of Cardiology/American Heart
Association Task Force on Practice Guidelines (Committee on the Management of Patients
with Unstable Angina). Circulation. 2002;106(14):1893–900.
232. Wan S, Quinlan DJ, Agnelli G, Eikelboom JW. Thrombolysis compared with heparin for the
initial treatment of pulmonary embolism: a meta-analysis of the randomized controlled trials.
Circulation. 2004;110(6):744–9.
233. Konstantinides S, Geibel A, Heusel G, Heinrich F, Kasper W. Heparin plus alteplase com-
pared with heparin alone in patients with submassive pulmonary embolism. N Engl J Med.
2002;347(15):1143–50.
234. Konstantinides S. Tenecteplase for patients with submassive pulmonary embolism. 2013.
235. Fasullo S, Scalzo S, Maringhini G, et al. Six-month echocardiographic study in patients with
submassive pulmonary embolism and right ventricle dysfunction: comparison of thromboly-
sis with heparin. Am J Med Sci. 2011;341(1):33–9.
236. Kline JA. Randomized trial of tenecteplase or placebo with low molecular weight heparin for
acute submassive pulmonary embolism: assessment of patient oriented cardiopulmonary out-
comes at three months. J Am Coll Cardiol. 2013;61(10):E2074.
237. Kline JA KC, Courtney DM et al. Randomized trial of tenecteplase or placebo with low
molecular weight heparin for acute submassive pulmonary embolism: assessment of patient-
oriented cardiopulmonary outcomes at three months. J Am Coll Cardiol. 2013;61(10 S).
238. Bradford KK, Deb B, Pearl RG. Combination therapy with inhaled nitric oxide and intrave-
nous dobutamine during pulmonary hypertension in the rabbit. J Cardiovasc Pharmacol.
2000;36(2):146–51.
239. Vizza CD, Rocca GD, Roma AD, et al. Acute hemodynamic effects of inhaled nitric oxide,
dobutamine and a combination of the two in patients with mild to moderate secondary pul-
monary hypertension. Crit Care. 2001;5(6):355–61.
240. Kerbaul F, Rondelet B, Motte S, et al. Effects of norepinephrine and dobutamine on pressure
load-induced right ventricular failure. Crit Care Med. 2004;32(4):1035–40.
241. Chen EP, Bittner HB, Davis Jr RD, Van Trigt III P. Milrinone improves pulmonary hemody-
namics and right ventricular function in chronic pulmonary hypertension. Ann Thorac Surg.
1997;63(3):814–21.
242. Hentschel T, Yin N, Riad A, et al. Inhalation of the phosphodiesterase-3 inhibitor milrinone
attenuates pulmonary hypertension in a rat model of congestive heart failure. Anesthesiology.
2007;106(1):124–31.
243. Solina A, Papp D, Ginsberg S, et al. A comparison of inhaled nitric oxide and milrinone for
the treatment of pulmonary hypertension in adult cardiac surgery patients. J Cardiothorac
Vasc Anesth. 2000;14(1):12–7.
244. Khazin V, Kaufman Y, Zabeeda D, et al. Milrinone and nitric oxide: combined effect on pul-
monary artery pressures after cardiopulmonary bypass in children. J Cardiothorac Vasc
Anesth. 2004;18(2):156–9.
245. Innes CA, Wagstaff AJ. Levosimendan: a review of its use in the management of acute
decompensated heart failure. Drugs. 2003;63(23):2651–71.
246. Gruhn N, Nielsen-Kudsk JE, Theilgaard S, Bang L, Olesen SP, Aldershvile J. Coronary
vasorelaxant effect of levosimendan, a new inodilator with calcium-sensitizing properties.
J Cardiovasc Pharmacol. 1998;31(5):741–9.
247. Kerbaul F, Rondelet B, Demester JP, et al. Effects of levosimendan versus dobutamine on
pressure load-induced right ventricular failure. Crit Care Med. 2006;34(11):2814–9.
248. Missant C, Rex S, Segers P, Wouters PF. Levosimendan improves right ventriculovascular
coupling in a porcine model of right ventricular dysfunction. Crit Care Med. 2007;35(3):
707–15.
249. De Backer D, Biston P, Devriendt J, et al. Comparison of dopamine and norepinephrine in the
treatment of shock. N Engl J Med. 2010;362(9):779–89.
250. Angle MR, Molloy DW, Penner B, Jones D, Prewitt RM. The cardiopulmonary and renal
hemodynamic effects of norepinephrine in canine pulmonary embolism. Chest. 1989;95(6):
1333–7.
251. Apitz C, Honjo O, Friedberg MK, et al. Beneficial effects of vasopressors on right ventricular
function in experimental acute right ventricular failure in a rabbit model. Thorac Cardiovasc
Surg. 2012;60(1):17–23.
252. Belenkie I, Horne SG, Dani R, Smith ER, Tyberg JV. Effects of aortic constriction during
experimental acute right ventricular pressure loading. Further insights into diastolic and sys-
tolic ventricular interaction. Circulation. 1995;92(3):546–54.
253. Braun EB, Palin CA, Hogue CW. Vasopressin during spinal anesthesia in a patient with pri-
mary pulmonary hypertension treated with intravenous epoprostenol. Anesth Analg.
2004;99(1):36–7.
254. Price LC, Forrest P, Sodhi V, et al. Use of vasopressin after Caesarean section in idiopathic
pulmonary arterial hypertension. Br J Anaesth. 2007;99(4):552–5.
255. Griffiths MJ, Evans TW. Inhaled nitric oxide therapy in adults. N Engl J Med. 2005;353(25):
2683–95.
256. Lei J, Vodovotz Y, Tzeng E, Billiar TR. Nitric oxide, a protective molecule in the cardiovas-
cular system. Nitric Oxide. 2013;35:175–85.
257. Rossaint R, Gerlach H, Schmidt-Ruhnke H, et al. Efficacy of inhaled nitric oxide in patients
with severe ARDS. Chest. 1995;107(4):1107–15.
258. Kaisers U, Busch T, Deja M, Donaubauer B, Falke KJ. Selective pulmonary vasodilation in
acute respiratory distress syndrome. Crit Care Med. 2003;31(4 Suppl):S337–42.
259. Meldrum DR, Shames BD, Meng X, et al. Nitric oxide downregulates lung macrophage
inflammatory cytokine production. Ann Thorac Surg. 1998;66(2):313–7.
260. Bhorade S, Christenson J, O’Connor M, Lavoie A, Pohlman A, Hall JB. Response to inhaled
nitric oxide in patients with acute right heart syndrome. Am J Respir Crit Care Med.
1999;159(2):571–9.
261. George I, Xydas S, Topkara VK, et al. Clinical indication for use and outcomes after inhaled
nitric oxide therapy. Ann Thorac Surg. 2006;82(6):2161–9.
262. Ardehali A, Hughes K, Sadeghi A, et al. Inhaled nitric oxide for pulmonary hypertension
after heart transplantation. Transplantation. 2001;72(4):638–41.
263. Fattouch K, Sbraga F, Bianco G, et al. Inhaled prostacyclin, nitric oxide, and nitroprusside in
pulmonary hypertension after mitral valve replacement. J Card Surg. 2005;20(2):171–6.
264. Kline JA, Hernandez J, Garrett JS, Jones AE. Pilot study of a protocol to administer inhaled
nitric oxide to treat severe acute submassive pulmonary embolism. Emerg Med
J. 2014;31:459–62.
265. Christenson J, Lavoie A, O’Connor M, Bhorade S, Pohlman A, Hall JB. The incidence and
pathogenesis of cardiopulmonary deterioration after abrupt withdrawal of inhaled nitric
oxide. Am J Respir Crit Care Med. 2000;161(5):1443–9.
266. Badesch DB, McLaughlin VV, Delcroix M, et al. Prostanoid therapy for pulmonary arterial
hypertension. J Am Coll Cardiol. 2004;43(12 Suppl S):56S–61.
267. Califf RM, Adams KF, McKenna WJ, et al. A randomized controlled trial of epoprostenol
therapy for severe congestive heart failure: The Flolan International Randomized Survival
Trial (FIRST). Am Heart J. 1997;134(1):44–54.
268. Kooter AJ, Ijzerman RG, Kamp O, Boonstra AB, Smulders YM. No effect of epoprostenol
on right ventricular diameter in patients with acute pulmonary embolism: a randomized con-
trolled trial. BMC Pulm Med. 2010;10:18.
269. Rich S, McLaughlin VV. The effects of chronic prostacyclin therapy on cardiac output and
symptoms in primary pulmonary hypertension. J Am Coll Cardiol. 1999;34(4):1184–7.
270. Kerbaul F, Brimioulle S, Rondelet B, Dewachter C, Hubloue I, Naeije R. How prostacyclin
improves cardiac output in right heart failure in conjunction with pulmonary hypertension.
Am J Respir Crit Care Med. 2007;175(8):846–50.
271. Barst RJ, Rubin LJ, Long WA, et al. A comparison of continuous intravenous epoprostenol
(prostacyclin) with conventional therapy for primary pulmonary hypertension. N Engl J Med.
1996;334(5):296–301.
272. Badesch DB, Abman SH, Ahearn GS, et al. Medical therapy for pulmonary arterial hyperten-
sion: ACCP evidence-based clinical practice guidelines. Chest. 2004;126(1 Suppl):35S–62.
273. Gomberg-Maitland M, Preston IR. Prostacyclin therapy for pulmonary arterial hypertension:
new directions. Semin Respir Crit Care Med. 2005;26(4):394–401.
274. Haraldsson A, Kieler-Jensen N, Ricksten SE. Inhaled prostacyclin for treatment of pulmo-
nary hypertension after cardiac surgery or heart transplantation: a pharmacodynamic study.
J Cardiothorac Vasc Anesth. 1996;10(7):864–8.
275. Khan TA, Schnickel G, Ross D, et al. A prospective, randomized, crossover pilot study of
inhaled nitric oxide versus inhaled prostacyclin in heart transplant and lung transplant recipi-
ents. J Thorac Cardiovasc Surg. 2009;138(6):1417–24.
276. Rex S, Schaelte G, Metzelder S, et al. Inhaled iloprost to control pulmonary artery hyperten-
sion in patients undergoing mitral valve surgery: a prospective, randomized-controlled trial.
Acta Anaesthesiol Scand. 2008;52(1):65–72.
277. De Wet CJ, Affleck DG, Jacobsohn E, et al. Inhaled prostacyclin is safe, effective, and afford-
able in patients with pulmonary hypertension, right heart dysfunction, and refractory hypox-
emia after cardiothoracic surgery. J Thorac Cardiovasc Surg. 2004;127(4):1058–67.
278. Theodoraki K, Rellia P, Thanopoulos A, et al. Inhaled iloprost controls pulmonary hyperten-
sion after cardiopulmonary bypass. Can J Anaesth. 2002;49(9):963–7.
279. Winterhalter M, Simon A, Fischer S, et al. Comparison of inhaled iloprost and nitric oxide in
patients with pulmonary hypertension during weaning from cardiopulmonary bypass in cardiac
surgery: a prospective randomized trial. J Cardiothorac Vasc Anesth. 2008;22(3):406–13.
280. Rubin LJ, Badesch DB, Barst RJ, et al. Bosentan therapy for pulmonary arterial hypertension.
N Engl J Med. 2002;346(12):896–903.
281. Trachte AL, Lobato EB, Urdaneta F, et al. Oral sildenafil reduces pulmonary hypertension
after cardiac surgery. Ann Thorac Surg. 2005;79(1):194–7, discussion 194–7.
282. Lepore JJ, Maroo A, Pereira NL, et al. Effect of sildenafil on the acute pulmonary vasodilator
response to inhaled nitric oxide in adults with primary pulmonary hypertension. Am J
Cardiol. 2002;90(6):677–80.
283. Lepore JJ, Maroo A, Bigatello LM, et al. Hemodynamic effects of sildenafil in patients with
congestive heart failure and pulmonary hypertension: combined administration with inhaled
nitric oxide. Chest. 2005;127(5):1647–53.
284. Ghofrani HA, Wiedemann R, Rose F, et al. Combination therapy with oral sildenafil and
inhaled iloprost for severe pulmonary hypertension. Ann Intern Med. 2002;136(7):515–22.
285. Nagamine J, Hill LL, Pearl RG. Combined therapy with zaprinast and inhaled nitric oxide
abolishes hypoxic pulmonary hypertension. Crit Care Med. 2000;28(7):2420–4.
286. Lee JE, Hillier SC, Knoderer CA. Use of sildenafil to facilitate weaning from inhaled nitric
oxide in children with pulmonary hypertension following surgery for congenital heart dis-
ease. J Intensive Care Med. 2008;23(5):329–34.
287. Fung E, Fiscus RR, Yim AP, Angelini GD, Arifi AA. The potential use of type-5 phosphodi-
esterase inhibitors in coronary artery bypass graft surgery. Chest. 2005;128(4):3065–73.
288. Urdaneta F, Lobato EB, Beaver T, et al. Treating pulmonary hypertension post cardiopulmo-
nary bypass in pigs: milrinone vs. sildenafil analog. Perfusion. 2008;23(2):117–25.
289. Neto-Neves EM, Dias-Junior CA, Uzuelli JA, et al. Sildenafil improves the beneficial hemo-
dynamic effects exerted by atorvastatin during acute pulmonary thromboembolism. Eur J
Pharmacol. 2011;670(2–3):554–60.
290. Dias-Junior CA, Neto-Neves EM, Montenegro MF, Tanus-Santos JE. Hemodynamic effects
of inducible nitric oxide synthase inhibition combined with sildenafil during acute pulmonary
embolism. Nitric Oxide. 2010;23(4):284–8.
291. Bonatti HJ, Harris T, Bauer T, et al. Transfemoral catheter thrombolysis and use of sildenafil
in acute massive pulmonary embolism. J Cardiothorac Vasc Anesth. 2010;24(6):980–4.
292. Nagendran J, Archer SL, Soliman D, et al. Phosphodiesterase type 5 is highly expressed in
the hypertrophied human right ventricle, and acute inhibition of phosphodiesterase type 5
improves contractility. Circulation. 2007;116(3):238–48.
293. Philip A, Ramchandani S, Dorrance K, Dorrance C. Sildenafil-induced thrombocytopenia.
Ann Intern Med. 2008;149(6):437–9.
294. Ghofrani HA, Galie N, Grimminger F, et al. Riociguat for the treatment of pulmonary arterial
hypertension. N Engl J Med. 2013;369(4):330–40.
295. Ghofrani HA, D’Armini AM, Grimminger F, et al. Riociguat for the treatment of chronic
thromboembolic pulmonary hypertension. N Engl J Med. 2013;369(4):319–29.
296. Conrad SA, Rycus PT, Dalton H. Extracorporeal Life Support Registry report 2004. ASAIO
J. 2005;51(1):4–10.
297. Brodie D, Bacchetta M. Extracorporeal membrane oxygenation for ARDS in adults. N Engl
J Med. 2011;365(20):1905–14.
298. Peek GJ, Mugford M, Tiruvoipati R, et al. Efficacy and economic assessment of conventional
ventilatory support versus extracorporeal membrane oxygenation for severe adult respiratory
failure (CESAR): a multicentre randomised controlled trial. Lancet. 2009;374(9698):
1351–63.
299. Hoeper MM, Wiesner O, Hadem J, et al. Extracorporeal membrane oxygenation instead of
invasive mechanical ventilation in patients with acute respiratory distress syndrome. Intensive
Care Med. 2013;39(11):2056–7.
300. de Perrot M, Granton JT, McRae K, et al. Impact of extracorporeal life support on outcome
in patients with idiopathic pulmonary arterial hypertension awaiting lung transplantation.
J Heart Lung Transpl. 2011;30(9):997–1002.
301. Hoeper MM, Welte T. Extracorporeal lung assist: more than kicking a dead horse? Eur Respir
J. 2008;32(6):1431–2.
302. Quarck R, Nawrot T, Meyns B, Delcroix M. C-reactive protein: a new predictor of adverse
outcome in pulmonary arterial hypertension. J Am Coll Cardiol. 2009;53(14):1211–8.
303. Watts JA, Marchick MR, Kline JA. Right ventricular heart failure from pulmonary embolism:
key distinctions from chronic pulmonary hypertension. J Card Fail. 2010;16(3):250–9.
Part IV
Chronic Right Ventricular Failure
Chapter 10
Echocardiography of Chronic Right
Heart Failure
Florence H. Sheehan and Per Lindqvist
Introduction
Right heart failure most commonly develops from pressure overload, volume overload,
and ischemic heart disease. It is rarely caused by cardiomyopathies or infiltrative
myocardial disease (e.g., amyloid heart disease). Pressure overload can be caused
by pulmonary artery hypertension (pre-capillary hypertension) but far more com-
monly from elevation of left heart filling pressures (post-capillary hypertension).
In general, the right ventricle (RV) manages pressure overload less efficiently than
volume overload. Examples of RV volume overload are atrial septum defect (ASD),
severe tricuspid regurgitation, and anomalous pulmonary venous drainage [1].
Acute ischemia or infarction with occlusion of the proximal part of the RV
branches often generates RV dysfunction, low cardiac output, and fluid retention in
the acute phase. However, with rapid treatment including fluid treatment and reper-
fusion, and sometimes inotropic stimulation, the RV often recovers well [2].
In addition, problems in one ventricle can be transmitted to the other one, an exam-
ple of this is an increased pressure overload of the RV which results in reduced LV
volume and diastolic dysfunction. On the other hand, RV diastolic dysfunction can be
seen in patients with volume or pressure overloaded LV as in dilated cardiomyopathy
(Fig. 10.1). In those conditions the ventricular septum plays an important role in
F.H. Sheehan, M.D. (*)

Department of Medicine/Cardiology, University of Washington,
1959 Northeast Pacific Street, Seattle, WA 98195-6422, USA
e-mail: sheehan@uw.edu
P. Lindqvist
Departments of Surgical and Peri-operative Sciences/Heart Center, Clinical Physiology,
Umeå University Hospital, Umeå S-901 85, Sweden
e-mail: per.lindqvist@medicin.umu.se

210 F.H. Sheehan and P. Lindqvist
Fig. 10.1 Upper left and right; LV D-shape and LV mitral filling pattern (LV relaxation distur-
bance) in a patient (age of 40 years) with pressure overloaded RV due to PAH. Lower left and right;
right ventricular filling pattern (relaxation disturbance) in a patient with DCM (45 years old). E
early diastolic filling velocity, A atrial diastolic filling velocity
maintaining optimum stroke volume (Fig. 10.2), and Doppler echocardiography is

extremely useful to determine and quantify the degree of chamber interaction.
Another clinical picture similar to right heart failure, that is caused by ventricular
interaction, is when the pericardium is involved with either rapid fluid collection or
pericardial stiffness, cardiac tamponade or pericardial constriction, respectively. In
tamponade, the rise in intrathoracic and intra-pericardial pressures above RV pres-
sure makes its filling and ejection very sensitive to respiration especially during
inspiration. If this condition is ignored, it eventually reduces LV filling and ejection
during inspiration until blood pressure reduction >10 mmHg and lack of a palpable
arterial pulse produce the clinical picture of pulsus paradoxus. Similar ventricular
interaction disturbances with flow velocity variations with respiration can be seen
with massive left pleural effusion and, to a lesser extent, in constrictive pericarditis.
Echocardiography
Patients with right heart failure may be managed using a combination of imaging
modalities. This chapter presents the advantages and applications of ultrasound.
Unlike for the LV, however, the classic metrics for assessing the status of the failing RV,
10 Echocardiography of Chronic Right Heart Failure 211
Fig. 10.2 Septal motion during inspiration and expiration in a patient with pulmonary hypertension
volume and systolic function, cannot be measured accurately from two-dimensional

(2D) echocardiograms. To compensate, a multiplicity of methods has been devel-
oped for evaluating RV status using Doppler and innovative approaches for 2D
echo. In addition, three-dimensional (3D) echo imaging and analysis is increasingly
available, and provide a more comprehensive view that helps to unite the informa-
tion obtained from multiple 2D views and Doppler measurements (Fig. 10.3). As a
result there are many metrics at hand from which the most appropriate can be
selected and applied.
RV Volume and Other Dimensions
Visualization of the Right Ventricle
To evaluate the RV it is often necessary to adjust the technique from an adult cardi-
ology laboratory’s usual “LV-centric” approach. When the RV is dilated, the sector
width in current ultrasound equipment is too narrow to contain both ventricles.
Therefore the view must be centered on the RV to ensure that the RV is completely
visualized [3].
The LV maintains its ellipsoid geometry in both volume and pressure overload
(Fig. 10.4) [4]. In contrast the RV does not remodel along a shape continuum [5].
Fig. 10.3 Reconstruction of

the heart of a normal subject
from multiple two-
dimensional echo images by
the piecewise smooth
subdivision surface method.
The anatomy illustrated is
that of the left ventricle (LV),
right ventricle (RV), left
atrium (LA), and right
atrium (RA)
Fig. 10.4 The left ventricle retains its ellipsoidal shape in the face of hemodynamic overload.
(From Grossman W, Carabello BA, Gunther S, Fifer MA. Ventricular wall stress and the develop-
ment of cardiac hypertrophy and failure. Perspectives in Cardiovasc Res 7:1–18. 1983)
Patients with heart failure due to idiopathic dilated cardiomyopathy may exhibit
transition to a more spherical shape in both ventricles (Fig. 10.5). RV shape in pul-
monary hypertension (PH) is characterized by septal flattening or curvature reversal
on short axis images [6]. More recent studies have shown that the RV may also
exhibit bulging at the base with tilting of the tricuspid annulus and/or bulging at the
apex without central rounding in response to volume or pressure overload (Figs. 10.6
and 10.7) [5, 7, 8].
To capture these shape changes additional, nonstandard views may be needed to
fully visualize the RV patients with dilated RVs [3, 9]. Truncation of the parasternal
Fig. 10.5 Reconstruction of the left (red) and right (blue) ventricles of a patient with idiopathic
dilated cardiomyopathy and heart failure (left ventricular ejection fraction 17 %, RV ejection frac-
tion 12 %) showing the spherical shape adopted by the left ventricle. See Fig. 13.3 for comparison
with the reconstruction of a normal subject’s ventricles

the right (RV) and left (LV)
ventricles in a patient with
pulmonary artery
hypertension illustrating the
bulging at the base (BB) and
apex (*)

the left (red) and right (blue)
ventricles of a patient with
repaired tetralogy of Fallot
and wide open pulmonary
regurgitation showing the
basal bulge and tricuspid
annular tilt as well as
rounding of the apex
Fig. 10.8 (a) Truncation of the right ventricle (blue) in the parasternal short axis view may give
the false impression of a crescent shape when the image is centered on the left ventricle (red). (b)
Care in visualizing the entire right ventricle (blue) shows its true shape to be triangular (arrow)
short axis view may cause the RV to appear crescent shaped when actually it is often
triangular in cross section (Fig. 10.8). Truncation of apical views may conceal the
apical bulging (Fig. 10.9), an indicator of RV dysfunction [8]. For a good discussion
of technique in imaging the RV, see Horton et al. [10].
RV Volume
Visual Assessment
In clinical practice, visual assessment is performed to gauge RV size relative to that

of the LV. The advantages are its simplicity and avoidance of measurement vari-
ability. Normally the RV is only two-thirds the size of the LV in the apical four-
chamber view, the LV forms the apex of the heart, and the LV is round in short axis
views throughout the cardiac cycle. Deviations from this pattern may indicate RV
dilatation but careful examination of multiple views is recommended for confirma-
tion of the diagnosis because the apparent size of the RV varies with the angle of the
plane (Fig. 10.10) [3]. In the presence of LV dilatation the RV should be compared
to additional anatomic landmarks.
Quantitation from Two-Dimensional Echocardiography
Much research has gone into attempting to find a method for quantifying RV volume.
These efforts have been frustrated by the complex shape of the RV. The LV can be
compared to an ellipsoid of revolution not only in normal hearts but also in patients
with volume or pressure overload (Fig. 10.4). This uniformity of shape enables
Fig. 10.9 Representative four-chamber apical views in end systole showing the right ventricular
apical angle in an individual with normal pulmonary pressures (a), patient with mild to moderate
pulmonary hypertension (b), and a patient with severe pulmonary hypertension (c). A significant
degree of right ventricular hypertrophy is noted in both (b and c) cases. (From Lopez-Candales A,
Dohi K, Iliescu A, Peterson RC, Edelman K, Bazaz R. An abnormal right ventricular apical angle
is indicative of global right ventricular impairment. Echocardiography 2006;23:361–368)
accurate measurement of its volume from a single view. In contrast, the RV has
resisted easy comparison to a geometric reference model. The models that have
been tried fall into three types. Both the multiple slice and area–length methods
were originally applied to contours traced from biplane contrast ventriculograms.
The third type utilizes the formula V = AL, where A is the area in one view and L
spans the length of the RV in the other view; this formula computes the volumes of
numerous geometric figures ranging from a prism to a crescent [11, 12]. However
the subcostal views that are required may be obtainable in only 52 % of children
older than 5 years [13].
Other limitations of 2D echocardiography for RV volume quantification are dif-
ficulty in locating and acquiring views that yield the maximal area and long axis
length measurements, and RV remodeling in response to the hemodynamic over-
load. As a consequence of the shape change, a given model may better fit diseased
hearts than normal subjects, resulting in variable accuracy. For example, the obser-
vation that error in RV volume determination by both ellipsoidal approximation and
multiple slice methods was significantly higher in normal subjects compared to
patients with congenital heart disease [13] may be attributable to RV remodeling
Fig. 10.10 Diagram showing the recommended apical four-chamber (A4C) view with focus on
the right ventricle (RV)(1*), and the sensitivity of right ventricular size with angular change (2, 3)
despite similar size and appearance of the left ventricle (LV). The lines of intersection of the A4C
planes (1*, 2, 3) with a mid left ventricular short axis are shown above and corresponding A4C
views below. (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.
J Am Soc Echocardiogr 2010;23:685–713)
to a more ellipsoid shape in the latter. It is therefore not surprising that RV volume
measurement from 2D echocardiograms has proven inaccurate in comparison with
magnetic resonance imaging (MRI) [13, 14]. In addition, the dearth of clear ana-
tomic landmarks in the RV reduces reproducibility in volume determination because
it is so difficult to locate and image the same anatomical image planes on serial
studies. The problem is exacerbated when the RV dilates because this chamber may
change position and rotate within the thorax [15]. For a good discussion of 2D echo
methods and their limitations the reader is referred to Jiang et al. [16].
Quantitation from Three-Dimensional Echocardiography
Three-dimensional (3D) echocardiography enables accurate analysis of RV volume

by avoiding the need to match the RV to a geometric reference figure. Instead the
RV is analyzed in its entirety, and even pathologically misshapen ventricles can be
measured accurately, even those in congenital heart defects.
Volumetric 3D Echo. Most commonly 3D echocardiography refers to acquisition of
a volume of image data using a matrix array transducer. The image data are viewed
and the RV endocardial contour is delineated in multiple parallel, evenly spaced
planes, the area of each contour is multiplied by the interplane distance, and the
products are summed to provide a true multiple slice analysis of volume (Fig. 10.11).
Fig. 10.11 Offline analysis of real-time three-dimensional echocardiographic data using disk
summation algorithm for right ventricular (RV) volume calculations at end diastole. Top left, Four-
chamber view of RV. Top right, Two-chamber view of RV perpendicular to four-chamber view.
Bottom left, Series of short axis slices were used to trace RV endocardial borders to derive RV
volumes and ejection fraction (EF). Tricuspid annulus, apex, interventricular septum, and free wall
in other panels were used as references for measurements of RV indexes. Bottom right, Cine short
axis image displayed in this panel to add to four- and two-chamber views as references for border
identification and tracing. (From Lu X, Nadvoretskiy V, Bu L, et al. Accuracy and reproducibility
of real-time three-dimensional echocardiography for assessment of right ventricular volumes and
ejection fraction in children. J Am Soc Echocardiogr. 2008;21:84–89)
Studies have shown excellent accuracy for RV volume measurement from 3D echo
image data when compared with MRI or with direct volume measurement [17–20].
The RV is usually “sliced” into short axis views, like the LV. As for MRI or com-
puted tomography, image quality is poorer due to partial volume effects at the first
and last slices where the RV wall is nearly tangential to the image plane. As a result,
the apex and basal limit of the RV may be difficult to delineate. Some investigators
have attempted to solve the problem by using alternate slice orientations [21, 22].
Another approach is to utilize information from orthogonal views to assist in delin-
eating the endocardium, e.g., by tracing the short axis contours with guidance from
one or two long axis views [23].
Fig. 10.12 Assessment of right ventricular volume using two different protocols for analyzing the
short axis view from a multiphase steady-state free precision magnetic resonance imaging sequence
in end systole (left) and end diastole (right) obtained in a patient with an atrially switched transpo-
sition of the great arteries. Top, Inclusion of trabeculations and papillary muscles in the ventricular
cavity. Bottom, Exclusion of trabeculations and papillary muscles from the ventricular cavity. LV
left ventricle. (From Winter MM, Bernink FJP, Groenink M, et al: Evaluating the systemic right
ventricle by CMR: The importance of consistent and reproducible delineation of the cavity. J
Cardiovasc Magn Res 10:40, 2008)
A limitation of current matrix array transducers is that the sector width does not
allow imaging of the RV in its entirety in a significant proportion of adult patients
within the single apical scan that is most commonly employed to acquire the image
data [24]. This disadvantage is particularly present when the RV is enlarged, the
very situation where quantification of RV function is important.
The biggest source of variability derives from delineating the endocardium,
which is particularly difficult in heavily trabeculated RVs at end systole. One area
of previous controversy has been resolved by an MRI study, which recommended
tracing the contour outside rather than around the trabeculations to maximize repro-
ducibility (Fig. 10.12) [25]. Another issue is the definition of end systole. Because
of the RV’s peristaltic pattern of contraction the timing of minimum chamber area
varies from region to region and from slice to slice [26]. One approach is to select
the time at which minimum chamber area occurs in the greatest number of views.
Another approach is to select this time point from the four-chamber view; applica-
tion of its systolic interval to the entire RV has been shown to provide a highly
accurate measurement of end-systolic volume [27]. Volume analysis by 3D echo is
more reproducible than by 2D echo [18].
3D Analysis of Multiple 2D Views. A 3D reconstruction of the RV surface can be
generated by analyzing multiple 2D views acquired while tracking the spatial loca-
tion and orientation of the view planes [28, 29]. The RV endocardial surface is
reconstructed after tracing the images, and volume is computed from the 3D sur-
face. An advantage of this approach is the use of freehand scanning, so that views
providing optimal image quality are acquired. As for multiple slice analysis of
volumetric data sets, multiple views must be traced. Several methods have been
validated for 3D reconstruction of the RV from manually traced borders. The
method of Jiang et al. was based on deforming a spherical template to fit traced
borders (Fig. 10.12) [30]. Buckey et al. swept the RV from a single fixed transducer
location in angular increments that defined a series of wedges whose volumes were
computed and summed to determine RV volume [31]. The piecewise smooth subdi-
vision surface (PSSS) method fits a model mesh to traced borders (Fig. 10.3) [32].
The PSSS method is the only method shown to reproduce the 3D shape of the LV
and RV with anatomical accuracy [33].
Despite these methods’ demonstrated accuracy for measuring RV volume,
clinical application has been discouraged by the labor required to trace the RV bor-
der in multiple images. In a comparison of accuracy when volume is measured
using the multiple slice method from 2 to 16 slices, Chen et al. found 8 slices to be
the “optimum choice for accurate and convenient measurement” of mass as well as
volume [34]. Since analysis must be performed at both end diastole and end systole,
the effort is nearly prohibitive for clinical application. Indeed one author opined that
an “easily applicable, real-time, three-dimensional assessment of right ventricular
volume is the Holy Grail of cardiographic assessment” [35].
Current Commercial 3D Echo Products for RV Analysis. Development of methods
for automatically delineating the RV endocardial contour was slowed behind that of
the LV by the heavier trabeculation of the RV compared to the LV, and by the diverse
shape abnormalities adopted as the RV remodels in response to hemodynamic over-
load. Tomtec Imaging Systems (Unterschleissheim, Germany) markets a product
that employs semiautomated analysis of volumetric 3D echo data sets (Fig. 10.13);
its accuracy and reproducibility have been extensively validated by comparison
with MRI [17, 18, 20, 24].
An alternative approach to reducing the workload of manual tracing is to utilize
knowledge of the expected shape of the RV and of the range of shapes that it can
adopt in disease processes. The method marketed by VentriPoint, Inc. (Seattle, WA)
generates PSSS surface reconstructions from user-entered points at anatomic land-
marks (Fig. 10.14) and does not require whole borders be traced. Its accuracy has
been verified by comparison with MRI [36, 37].
Fig. 10.13 Reconstruction of the RV using commercially available analysis software. After the
user traces the endocardial contour (green) in three orthogonal views at end diastole and at end
systole, the right ventricle is automatically delineated in all remaining time points through the car-
diac cycle. (Reproduced with permission from Tomtec Imaging Systems GmbH, Unterschleissheim,
Germany)
RV Function
Global RV Function
Because of the inaccuracy in volume measurement [13, 14], assessment of RV

ejection fraction (EF) based on two-dimensional (2D) echocardiography is not
recommended [3]. Before 3D echo became as available as it is today, RV global
function was estimated using surrogate parameters based on a single 2D view. The
apical four-chamber view is used due to the predominantly longitudinal contractile
pattern of the RV [38, 39], which lacks the LV’s middle layer of circumferential
fibers. The most commonly used parameters are fractional area change (FAC), the
Fig. 10.14 The Ventripoint method. (a) Reconstruction of the right ventricle showing the points
entered by the user at anatomic landmarks as colored spheres. The green contours represent sharp
edges in the surface at the tricuspid and pulmonary annuli and around the insertion of the right
ventricle into the interventricular septum. (b) Verification that the right ventricle was adequately
interrogated by the images: the intersections of each image plane with the reconstructed surface
produces a contour (yellow). (c) Reconstructions of a patient’s right ventricle at end diastole (mesh)
and end systole (solid surface) shown overlaid for assessment of regional right ventricular wall
motion. (d) Overlay of the reconstructed surface on the image. (From Dragulescu A, Grosse-
Wortmann L, Fackoury C, et al. Echocardiographic assessment of right ventricular volumes after
surgical repair of Tetralogy of Fallot: Clinical validation of a new echocardiographic method. J Am
Soc Echocardiogr. 2011;24:1191–1198)
2D equivalent of the RV EF, and tricuspid annular plane systolic excursion (TAPSE)
[40], which measures the RV’s longitudinal contraction. TAPSE can be assessed by
M-mode, 2D echo, tissue Doppler, or speckle tracking echo, and is discussed below
(see “Tricuspid Annular Plane Systolic Excursion”).
FAC is computed as the percent change in the area of the RV between end diastole
and end systole. FAC correlates more closely with RV EF than either longitudinal or
Fig. 10.15 Evaluation of the right ventricular systolic function using modified short axis view.
The long axis view of aorta must be shown from modified short axis view. AO aorta, RA right
atrium, RVOT right ventricular outflow tract, TOF tetralogy of Fallot
transverse contraction in PH patients, probably because FAC is an area metric and

therefore integrates contributions from both [41, 42]. The normal mean is 49 % [3].
The disadvantage of the FAC is its failure to consider the function of the RV outflow
tract (RVOT). Because akinesis of the RV outflow track is associated with a poor
prognosis in repaired tetralogy of Fallot [43], some advocate measuring FAC from
a modified short axis view that includes the outflow tract (Fig. 10.15) [44].
Regional RV Function
Analysis in 2D. Very few of the geometric models developed for 2D images of the
LV can be applied to the RV due to their assumptions regarding the right ventricular
shape. For example radial coordinate systems cannot be applied to short axis views
of the RV because the septal and free walls meet at an acute angle, except in severe
PH with inversion of septal curvature. Rectangular coordinate systems do not fit the
RV’s triangular or crescent-shaped long or short axis contours either. In contrast, the
centerline method has been successfully applied for measuring regional RV func-
tion in both long axis and short axis views because it does not rely on geometric
assumptions about RV shape; the centerline method has been applied to projection as
well as tomographic imaging modalities (angiograms, echo images, and MRI) [45–48].
Fig. 10.16 (a) Schematic diagram of the apical four-chamber view from a transthoracic two-
dimensional echocardiogram. Qualitative wall motion scores were assigned at four locations of the
right ventricular free wall (shaded areas). (b) Segmental right ventricular free wall excursion
(mean ± 1 SEM) by centerline analysis as a function of right ventricular free wall segment.
Centerline excursion in patients with acute pulmonary embolism (PE) was near normal (p = NS
versus normal), p greater than 0.03 versus primary pulmonary hypertension (PPH) at the apex
(hatched area), but abnormal at the mid-free wall and base (p < 0.02 versus normal). Centerline
excursion in patients with primary pulmonary hypertension was reduced compared with that in
normal subjects in all segments (p < 0.03). LV left ventricle, RV right ventricle. (From McConnell
MV, Solomon SD, Rayan ME, et al: Am J Cardiol 78(4):469–473, 1996; redrawn for publication
in Sheehan FH. Ventricular shape and function. In: Otto CM, ed. Clinical Echocardiography. 3rd
ed. Philadelphia: W.B. Saunders Company, 2007)
This method was used to identify a pattern of regional RV dysfunction peculiar to

acute pulmonary embolism (Fig. 10.16) [49].
Like the LV the RV may develop regional hypokinesis due to coronary occlusion,
and a more proximal occlusion of the right coronary artery produces a larger wall
motion defect in experimental studies. In the RV, however, the size of the dyskinetic
segment is excessive for the size of the infarction [50]. Despite severe free wall
dysfunction, global RV function recovers early after occlusion due to stiffening of
the free wall. Clinically most patients recover regardless of whether the right coro-
nary artery is reperfused [51]. For assessment of ischemic heart disease a road map
for visual assessment of regional function has been developed that reflects the per-
fusion territories of the left and right coronary arteries (Fig. 10.17) [3].
Analysis in 3D. Most of what we know about 3D regional RV function derives
from MR tagging studies, which have documented the regional heterogeneity of RV
wall motion [52, 53], confirmed the greater long axis than short axis shortening
[38, 39], quantified torsion [54], and evaluated functional abnormality in a few disease
conditions [38, 55].
Fig. 10.17 Segmental nomenclature of the right ventricular walls, along with their coronary supply.
Ao Aorta, CS coronary sinus, LA left atrium, LAD left anterior descending artery, LV left ventricle,
PA pulmonary artery, RA right atrium, RCA right coronary artery, RV right ventricle, RVOT right
ventricular outflow tract. (From Rudski LG, Lai WW, Afilalo J, et al. Guidelines for the echocar-
diographic assessment of the right heart in adults: A report from the American Society of
Echocardiography. J Am Soc Echocardiogr. 2010;23:685–713)
Investigators have developed a multiplicity of methods for assessing regional RV

function from 3D images using MRI or echocardiography, and a multiplicity of
segmentation models dividing the RV into 2, 3, 4, 9, 10, or 12 regions [26, 48, 53,
55–58]. Some analyzed multiple short axis views, dividing the RV free wall geo-
metrically into circumferential regions (superior, middle, inferior), vertical regions
(apical, mid, basal), or both [48, 57, 58]. Others followed the tripartite model of the
RV [59, 60] and calculated regional EFs or wall motion after using anatomic land-
marks to subdivide the RV volume into inlet, apical or trabecular, and outlet por-
tions (Fig. 10.18) [26, 56, 61]. However the normative data from the tripartite model
vary widely, with two studies finding relatively reduced function in the apical
region, and the third study showing a higher EF in the apical region than in the inlet
and outflow regions. The studies varied in the software source, imaging modality
(3D echo vs. MRI), and age of the normal subjects; nevertheless the discrepant
results suggest that the model is difficult to apply reproducibly, perhaps due to the
requirement for identification of anatomic landmarks in the images.
The centersurface method measures RV wall motion from 3D surface recon-
structions along vectors orthogonal to the endocardium at end diastole (Fig. 10.19)
[58]. It is a 3D analog of the centerline method developed for analysis of 2D image
Fig. 10.18 Tripartite model of the right ventricle illustrating division into inflow, outflow, and
apical regions. (From Calcutteea A, Chung R, Lindqvist P, Hodson M, Henein MY. Differential
right ventricular regional function and the effect of pulmonary hypertension: three-dimensional
echo study. Heart. Jun 2011;97(12):1004–1011)

the right ventricle (blue) of a
patient illustrating the
direction of motion measured
by the centersurface method
from an inferior view.
Anatomic landmarks are the
aortic valve (AoV), left
ventricle (LV), mitral valve
(MV), and tricuspid valve
(TV). The basal bulge (BB) is
also indicated. (From Morcos
M, Sheehan FH. Regional
right ventricular wall motion
in Tetralogy of Fallot: A
three-dimensional analysis.
Intl J Cardiovasc Imag.
2013;in press)
data, and displays the same flexibility for defining regions of interest. Analysis of
wall motion in patients with repaired tetralogy of Fallot showed that a larger number
of regions than the three defined by the tripartite model are needed to characterize
the heterogeneity of RV regional function [58].
In summary, the methodology for measuring regional RV function is still in
development. A number of models for segmenting the RV into regions have been
proposed, but it is unclear which will prove most informative for a given disease
condition.
Hemodynamics
The RV’s sensitivity to pressure and volume overload mandates hemodynamic

examination. Doppler echocardiography has proved a very powerful tool for assess-
ing such disturbances and therefore plays an important role in early diagnosis.
Doppler techniques also provide additional metrics of RV function.
Pulmonary Hypertension
Assessment
As the RV tolerates badly a long-standing increased afterload, assessing pulmonary

pressures and their early changes is of great importance. By using continuous wave
Doppler technique to measure the peak retrograde pressure drop across the tricuspid
valve (tricuspid regurgitation velocity), applying the modified Bernoulli equation,
and adding right atrial pressure (RAP), peak systolic pulmonary artery pressure
(sPAP) can be estimated. A multiview approach should be used to secure the clear-
est tricuspid regurgitation velocity profile (Fig. 10.20).
Although transtricuspid regurgitation peak gradient is currently the most accu-
rate measure of PA systolic pressure it has its limitations. It tends to underestimate
the severity of PH in patients [62] with elevated RAP, e.g., due to a stiff right
ventricle and raised end-diastolic pressure [63]. Also, it tends to underestimate the
PA pressure in patients with significant tricuspid regurgitation, even in the absence
of obvious organic tricuspid valve disease. Finally, the transtricuspid pressure drop
by continuous wave Doppler can be accurately recorded in approximately 50–70 %
of patients, hence the need for an alternative similarly accurate marker for PH
assessment (Fig. 10.21) [64]. In the remaining cases the pulmonary regurgitant
velocity curve can be useful in measuring the early and late diastolic pressure drops
that reflect the mean and end-diastolic PA pressures (Fig. 10.22) [65].
Estimation of RAP is an ongoing topic of discussion and a number of measures
[3] as well as a fixed value of 7 or 10 mmHg in patients without right heart failure
have been proposed [66, 67]. Inferior vena cava diameter and collapsibility with
inspiration have also been found to correlate with RAP and are probably the most
Fig. 10.20 Color and peak continuous wave Doppler signals illustrating tricuspid regurgitation
from different projections. The peak tricuspid regurgitation velocity (lower right) in this patient is
4 m/s; the peak pressure gradient between the right ventricle and right atrium is 64 mmHg. A4CH
apical four chamber, PLAX parasternal long axis
commonly used [68], but have limited value in the presence of mechanical ventilation
or hypovolemia [69]. The ratio of E from tricuspid flow to e′ from RV free wall
(E/e′) using tissue Doppler imaging (TDI) can also be used to estimate the RAP.
Pulmonary artery acceleration time (PAcT) has been shown to be related to both
pulmonary pressures and pulmonary vascular resistance (PVR), and a cutoff value
of less than 90 ms identifies patients having a PVR more than 3 Wood units with
high sensitivity and specificity (Fig. 10.23) [70]. However PAcT is less reliable at
higher heart rates and not useful for detecting an optimal flow signal when the out-
flow tract is dilated.
Furthermore, a prolonged isovolume relaxation time (IVRT) from pulsed TDI
(>75 ms corrected for heart rate) accurately identified patients with sPAP > 40 mmHg,
Fig. 10.21 Tricuspid regurgitation with peak gradient of 4 m/s measured with continuous wave
Doppler giving a peak pressure gradient of 64 mmHg
Fig. 10.22 Pulmonary regurgitation with a peak early diastolic (marked +1 in figure) of 18 mmHg
and late diastolic pressure gradient (marked +2 in figure) of 4 mmHg measured with continuous
wave Doppler
Fig. 10.23 Pulmonary artery acceleration time in a normal subject (right, mean 131 ms) and in
pulmonary arterial hypertension with elevated pulmonary vascular resistance (left, mean 50 ms).
Acceleration time is measured as the time from onset to peak velocity on the pulmonary artery
flow measured with pulsed Doppler in a central position of the pulmonary artery within the pulmo-
nary valves
Fig. 10.24 Pulsed tissue Doppler-based myocardial velocities in normal subject (left) and in
patient with pulmonary hypertension (right). Right ventricular (RV) isovolumic relaxation time
(IVRT) is measured from the end of systole (s′) to the onset of early diastole (e′)
a marker that has proved the best in predicting patients with raised pulmonary artery
pressure (Fig. 10.24) [71]. However increased RV IVRT is not specific for PH as it
also increases with increased wall thickness in hypertrophic cardiomyopathy and
ischemic heart disease [72, 73].
The myocardial performance (or Tei) index is a non-volumetric method using the
sum of isovolumic time intervals (relaxation and contraction) in relation to RV ejec-
tion time. This index has been shown to be useful in determining both RV function
and pulmonary hemodynamics and can be assessed using both conventional Doppler
and tissue Doppler [74].
All these methods are complementary in identifying patients with PH.
Mechanisms of Pulmonary Hypertension
The next question that should be answered is the cause of the raised PA pressure.
The guidelines for diagnosing PH classify it into four levels; with level 4 caused by
pre-capillary pathologies and level 1 due to post-capillary hypertension [75]. Pre-
capillary PH is defined as a mean PAP ≥ 25 mmHg and pulmonary capillary wedge
pressure (PCWP) ≤ 15 mmHg. Post-capillary PAH is defined as mean
PAP ≥ 25 mmHg and PCWP >15 mmHg. The pre-capillary PH can be caused by (1)
idiopathic forms of pulmonary arterial hypertension, (2) lung diseases with and
without hypoxia, (3) collagen vascular diseases, (4) HIV-AIDs, (5) chronic throm-
boembolism, or (6) unclear or multifactorial reasons, whereas the post-capillary
type is caused by various forms of left heart disease and venooclusive pathology.
In both types cardiac output at rest can be normal or reduced.
Post-capillary pulmonary hypertension (left heart dysfunction). In post-capillary
hypertension, whether due to valve disease or LV dysfunction, RV function may be
preserved in patients with mild to moderate disease. It is only when left atrial pres-
sure or PCWP rises significantly, as a result of increased LV stiffness or significant
mitral or aortic valve diseases, that RV dysfunction is seen [76, 77]. It may take time
for the increased left atrial pressure to affect the pulmonary pressures and for the RV
to develop a restrictive filling pattern. This process can easily be determined and
followed up closely by Doppler echocardiography [78].
Patients with well-established raised left atrial pressure (restrictive LV filling pat-
tern) usually present with raised RV systolic pressure, assessed by tricuspid regurgi-
tation velocities, with values exceeding 35 mmHg but rarely as high as in pre-capillary
PH [77, 79]. In such patients, long-standing post-capillary PH may result in irrevers-
ibly raised pulmonary pressure but also increased PVR and stiff pulmonary circula-
tion, defined as reactive or combined pre- and post capillary PH [80, 81].
Doubling RV afterload (from 25 to 50 mmHg) has been shown to reduce its EF
by approximately 10 %. The RV can tolerate even moderate degrees of PH but even-
tually the tricuspid annulus dilates and secondary tricuspid regurgitation develops
which itself, if significant, adds to the clinical deterioration by further decreasing
RV stroke volume and increasing diastolic pressures and fluid retention.
Pre-capillary pulmonary hypertension (pulmonary vascular disease). The most
common cause of RV dysfunction in this scenario is chronic obstructive pulmonary
disease (COPD, see Chap. 18). Long-standing COPD may result in various degrees
of RV hypertrophy with systolic and diastolic dysfunction, but it rarely causes PH at
rest [82]. Systemic sclerosis (scleroderma) is another parenchymal or pulmonary
arterial venous disease that causes PAH and LV and RV subendocardial fibrosis and
dysfunction [83]. Severe cases may present with significant PH associated with poor
clinical outcome [84]. Finally, other parenchymal fibrotic diseases such as cystic
fibrosis may also involve the RV myocardium and cause significant systolic and
diastolic dysfunction even in the absence of PH [85]. Patients with end-stage cystic
fibrosis may present with a picture resembling cardiac tamponade as a result of the
increased intrathoracic pressure. Although RV function in most lung diseases may
appear to be normal at rest, RV function at fast heart rates needs to be determined.
Table 10.1 Hemodynamic measurements using Doppler echocardiography

Estimation Formula Abnormal level
sPAP (mmHg) 4 × TRPG2 + RAP >36 mmHg
mPAP (mmHg) sPAP × 0.61 + 2
4 × PREDG2 + RAP >25 mmHg
79–0.45 × (PAcT)
dPAP (mmHg) 4 × PRLDG2 + RAP >15 mmHg
PVR (WU) TRPG/PA VTI × 10 + 0.16 [91]
mPAP (sPAP × 0.61 + 2) − PCWP/CO (LVOT) [92] >3 WU
Abbreviations: sPAP systolic pulmonary artery pressures, TR tricuspid regurgitation, pd peak drop,
RAP right atrial pressures, PAcT pulmonary artery acceleration time, PRed pulmonary regurgita-
tion at early diastole, PRld pulmonary regurgitation at late diastole, pv peak velocity, PA VTI pul-
monary artery velocity time integral, mPAP mean pulmonary artery pressures, PCWP pulmonary
capillary wedge pressures, CO cardiac output, LVOT left ventricular outflow tract
The most common pulmonary vascular disease that affects the RV is pulmonary
embolism which represents an acute increase in afterload. As for the left heart, acute
changes in the pulmonary circulation at any level are poorly tolerated. A small pul-
monary embolism may be compensated for but a massive one can be fatal [86] (see
Chap. 9). The RV systolic pressure will acutely increase, its cavity dilates, and sys-
tolic function deteriorates rapidly [87].
pecific Hemodynamic Patterns of Pre- and Post-capillary Pulmonary

S
Hypertension
In addition to the investigations mentioned above, assessment of PVR is necessary

when PH is suspected [88, 89]. A number of equations have been developed over the
years for estimating PVR (Table 10.1) with varying sensitivities and specificities.
A simple measurement is by analyzing the PAcT: if PAcT is shorter than
80–90 ms it discriminates between pre- and post-capillary PH by identifying
patients with PVR >3 Woods units (Fig. 10.23) [70, 90].
Estimation of PVR can also be assessed more specifically from the ratio of peak
tricuspid regurgitant velocity (TRV) to RVOT time–velocity integral (TVIRVOT)
using the following simplified formula [91]:
PVR = TRV / TVI RVOT ´ 10 + 0.16
Another relatively simple Doppler echocardiography-based method that can be

used to estimate PVR first calculates mean PA pressure (mPAP) = sPAP × 0.61 + 2,
and then computes PVR = mPAP − PCWP/cardiac output (from LVOT) [92].
However, the main limitation of both methods is lack of accurate estimation of
PCWP, which reflects left atrial pressure.
A number of different echocardiography-based methods have been developed to
estimate LV filling pressures. The EAE/ASE guidelines recommend the following
parameters for assessing elevated LV filling pressures in patients with depressed

LVEF; (1) E/A > 2 and mitral deceleration time <150 ms, (2) E/A 1–2 and E/e′(average
e′) > 15, pulmonary flow systolic and diastolic flow velocity ratio <1, and (3) A wave
duration from pulmonary venous flow >30 ms longer than A wave duration from
transmitral flow and estimated PA systolic pressure >35 mmHg.
In patients with preserved LVEF, E/e′ (average e′) 9–14, left atrial volume
≥34 mL/m [2], A wave duration from pulmonary venous flow >30 ms longer than A
wave duration from transmitral flow, and estimated PA systolic pressure >35 mmHg
indicate elevated LV filling pressures [93].
Primary Right Ventricular Dysfunction
The commonest cause of primary dysfunction is RV infarction. It occurs in approxi-

mately 30 % of patients presenting with acute inferior myocardial infarction and
may result in severe haemodynamic compromise with occasionally poor clinical
outcome [94]. Acute right coronary artery occlusion proximal to the RV branch
often causes RV free wall dysfunction.
ssessing RV Function Using Doppler Echocardiography

A
in Clinical Practice
Tricuspid Annular Plane Systolic Excursion
Having established the anatomical features, more detailed assessment of its various
compartments can be obtained using Doppler echocardiography. Quantification of
global and regional RV function is still challenging due to its complex geometry and
also due to its thin walled myocardium, particularly in normal subjects. Systolic
function of the inflow tract of the RV is easily studied from the systolic excursion of
the tricuspid valve annulus movement (TAPSE) towards the apex (longitudinal
function) and can be measured by several techniques. [95] Using M-mode
(Fig. 10.25), a value less than 20 mm and measured at the level of amplitude at Q on
ECG to the maximal amplitude within systole (excluding postsystolic amplitude)
suggests a degree of dysfunction. Recently a value >18 mm has been proposed as
the lower limit of normal, irrespective of age [96]. TAPSE has also been found to
correlate well with the RV ejection fraction as measured by radionuclide angiogra-
phy [40], although less well when measured by MRI [97]. Values <15 mm are con-
sistent with an overall ejection fraction of less than 45 % [97]. A value <14 mm is
associated with poor prognosis in heart failure due to LV dysfunction [78], and a
value <18 mm with poor prognosis in PH [97]. However, TAPSE has some limitations:
(a) TAPSE can remain within normal values despite severely increased pulmonary
pressures [97], (b) TAPSE can erroneously overestimate RV function in patients
with a dilated cavity and volume overload, e.g., severe tricuspid regurgitation [98],
Fig. 10.25 Right ventricular outflow tract fractional shortening (RVOT fs, left) and tricuspid
annular plane systolic excursion (TAPSE, right) in a normal subject (upper) and in a patient with
pulmonary hypertension (lower). RVOT fs is measured as dimensions at end-diastole (Q on ECG)
and end systole (aortic valve closure and/or end of T on ECG). TAPSE is measured as amplitude
between at end-diastole (Q on ECG) and end systole (aortic valve closure and /or end of T on ECG)
(c) being load and angle dependent, and (d) TAPSE is subject to the influence by
right atrial size, function, and pressure. Since TAPSE only measures the motion of
a single segment of the RV, its value in predicting RV EF is reduced when regional
function differs in other segments [99].
Fractional Shortening of the Outflow Tract
An additional measure of regional RV function is the diameter change or fractional

shortening of the outflow tract (RVOT fs). RVOT fs has been shown to be more
sensitive to elevation in pulmonary pressure than TAPSE and of prognostic value in
heart failure (Fig. 10.25) [100, 101]. Its limitation is that it is a measure of only one
segment of the RV, the RVOT, which contributes less to overall RV function than the
inflow tract [102].
Right Atrial Size and Function
The right atrium plays an important role in maintaining cardiac performance and its
size increases in atrial arrhythmias, heart failure, and pulmonary hypertension as
well as in congenital heart diseases [103, 104]. An increased right atrial end-systolic
area is also a strong predictor for mortality in PH [105, 106]. Furthermore, its function
is altered in PH [107] as well as after open heart surgery [108]. At present, the right
atrial area is the recommended method to assess right atrial size [109], but recent
reports have shown that one can assess the right atrium with 3D as well as speckle
tracking echocardiography (STE) [110].
Tissue Doppler Imaging
Right ventricular free wall systolic velocities and time relations can be measured
using different echo techniques, such as myocardial TDI and STE [111, 112]. TDI
velocities are measured by using a Doppler-based algorithm (which is angle depen-
dent) which detects myocardial motion with high frequencies and low velocities
compared to the spectral Doppler measurements. TDI is a robust method for repro-
ducibly assessing RV lateral free wall systolic and diastolic movement velocities, and
is therefore highly recommended for routine follow-up of PH patients [112]. Using
pulsed or color TDI the systolic (s′), early diastolic (e′), and late atrial velocities (a′)
can reliably be measured as well as the time intervals of isovolumic contraction and
relaxation (IVCT and IVRT) (Fig. 10.24) [109]. From color TDI off-line analysis of
velocities and amplitudes, as well as one-dimensional strain and strain rate, values
can be derived, that have been shown to be modestly useful in estimating the PVR
[113]. This method has also been shown useful for assessing the dyssynchrony
between the RV and septal segments and disease severity (Fig. 10.26) [114].
As this method is Doppler based, the applications of strain measurements are
limited by its angle dependency and significant signal-to-noise ratio. From our own
data, we have found normal RV free wall myocardial velocities to be approximately
15–16 cm/s with a reduction of the diastolic velocities with increasing age [115].
However TDI of the RV inlet has the limitations of assessing only one segment,
being load and angle dependent, and sometimes has a poor signal-to-noise ratio.
Fig. 10.26 Color tissue Doppler-based myocardial strain (ɛ) in a normal subject (left) and in a
patient with pulmonary hypertension (right). In pulmonary hypertension, peak strain in the right
ventricular (RV) free wall occurs after peak strain in the septum. This is the reverse of the normal
sequence
Fig. 10.27 Myocardial strain (ɛ) from speckle tracking echocardiography (three segment model
including right ventricular (RV) free wall) in a normal subject (left) and a patient with pulmonary
hypertension (right). Note the lower strain in pulmonary hypertension
Speckle Tracking
STE is a relatively new method that detects the motion of acoustic markers or speck-
les in the myocardium. STE is determined from the grey scale images and is consid-
ered to be angle independent. This method has been found useful for assessing RV
myocardial deformation or strain function. Strain and strain rate measure ampli-
tude- and velocity differences between two segments defined from a chosen region
of interest; they can be measured from both TDI and STE. Although speckle track-
ing measurement of strain and strain rate of the RV is still under investigation, this
methodology is being clinically adopted (Fig. 10.27). However, the thinness of the
RV wall limits the reliability with which the RV can be tracked. In addition there is
still no consensus whether the septum should or should not be included when assess-
ing the overall function of the RV.
V Failure in Difficult Conditions: The Value of Assessing

R
Diastolic Dysfunction
The assessment of diastolic RV function, particularly in patients with fluid retention

is very important and STE is the main stay in this scenario. Functional markers are
generally very similar to those conventionally used on the left side of the heart but
less commonly measured today in clinical practice. Myocardial diastolic velocities
from TDI and STE, particularly those of the RV inlet compartment, are quite easy
to measure and have acceptable reproducibility. Signs of RV dyssynchrony are simi-
lar to those on the left, and delayed onset of long axis diastolic motion in compari-
son to the one from the septum, commonly seen in PH (Fig. 10.26). Spectral Doppler
assessment of the RA and RV filling patterns reflects phasic tension and pressure
changes and hence provides an accurate diagnosis particularly in patients with sig-
nificant RV dysfunction. A dominant transtricuspid “A” wave along with a blunted
or reversed diastolic filling phase and increased atrial reversal components during
the right atrial filling phase from the hepatic venous flow component are commonly
seen in PH (Fig. 10.28).
Fig. 10.28 Dominant A tricuspid flow filling pattern (right) from pulsed Doppler and a blunted
diastolic flow component and increased atrial reversal component, especially during expiration, in
vena hepatic flow from pulsed Doppler (left) in patients with abnormal relaxation RV caused by
pulmonary hypertension. Exp expiration; insp inspiration
Fig. 10.29 Dominated E tricuspid flow filling pattern from pulsed Doppler (right) with a blunted
systolic flow component in vena hepatic flow from pulsed Doppler (left) in a patient with restrictive
right ventricular function
A dominant “E” wave with short deceleration time and blunted systolic phase in
right atrial filling from hepatic venous flow are all markers consistent with restric-
tive RV physiology (Fig. 10.29) [116]. However, it is important to remember that
there are normal variations from age and respiration in both tricuspid flow and
hepatic vein flow velocities (Table 10.2). With inspiration there is an increase in
tricuspid inflow velocity and E/A, whereas no change should normally be seen for
Table 10.2 Reference values for Doppler echocardiography

Age correlation,
Variable n Mean (SD) coefficient References
2D/M-mode dimension
RVIT end-diastolic area/BSA, cm2/m2 255 9.5 ± 2.5 −0.22, p < 0.001 [134]
RVIT end-systolic area, cm2 255 4.6 ± 1.6 −0.13, p < 0.05 [134]
RA end-systolic area/BSA, cm2/m2 255 8.2 ± 1.9 – [134]
RVOT end-diastolic diameter/BSA, 255 17.9 ± 3.3 0.16, p < 0.05 [134]
mm/m2
RVOT wall thickness, mm 255 3.8 ± 1.4 0.42, p < 0.001 [134]
2D/M-mode systolic function
RVOT fs, % 255 61.5 ± 14.6 −0.14, p < 0.05 [134]
RVIT fractional area change, % 255 52 ± 11 – [134]
TAPSE, mm 255 25 ± 4 – [134]
Spectral Doppler
Tricuspid E, cm/s 255 43 ± 11 −0.39, p < 0.001 [134]
Tricuspid A, cm/s 255 31 ± 9 0.35, p < 0.001 [134]
E/A 255 1.5 ± 0.6 −0.57, p < 0.001 [134]
DT, ms 255 187 ± 58 0.35, p <0.001 [134]
IVRT, ms 255 31 ± 16 0.38, p < 0.001 [134]
RV-RA peak gradient, mmHg 255 22 ± 6 0.29, p < 0.001 [134]
PAcT, ms 255 133 ± 27 −0.47, p < 0.001 [134]
PAcTcorr, ms 255 142 ± 27 −0.46, p < 0.001 [134]
Pulsed tissue Doppler
S, base, cm/s 255 15.2 ± 2.8 – [134]
E′ base, cm/s 255 14.5 ± 3.5 −0.39, p < 0.001 [134]
E/e′, cm/s 359 4 (2–6) – [109]
A′ base, cm/s 255 16.2 ± 3.1 0.49, p < 0.001 [134]
S′ mid, cm/s 255 14.5 ± 2.6 −0.29, p < 0.001 [134]
E′ mid, cm/s 255 14.1 ± 3.7 0.52, p < 0.001 [134]
A′ mid, cm/s 255 16.6 ± 5.5 −0.62, p < 0.001 [134]
Strain, systole, % base 385 29 (13–45)a – [109]
Strain, systole, %, mid 269 31 (13–48)a – [109]
Speckle tracking echocardiography
Strain, systole, %, base 183 28 (18–39) – [109]
Strain, systole, %, mid 125 29 (20–38) – [109]
a
Upper and lower 95 % CI
the tricuspid E velocity deceleration time. Hepatic venous flow could also increase
with inspiration but no variations are expected during the atrial reversal. The varia-
tion from expiration to inspiration is normally in the order of 17–20 % [117].
Thus a >25 % increase in RV filling and ejection velocities in a patient with fluid
retention reflects raised intrathoracic pressure, irrespective of its cause.
Constrictive Pericarditis
Pericardial constriction is characterized by pericardial thickening due to fibrosis

causing adhesion between the two pericardial layers and thus an unstretchable peri-
cardium. This noncompliance of the pericardium limits its ability to handle varia-
tions in preload, which normally occur during respiration, and causes abnormal
intracardiac pressures in both left and right heart cavities. Figure 10.29 illustrates an
abnormal increase in right heart pressures during inspiration as shown by increased
RV filling E velocities and simultaneous decrease in LV filling pressures and its fill-
ing E velocities. This alteration in filling pressures creates a shift in septal motion
and configuration. As the endocardium is not involved in the pericardial pathology of
constriction it remains free to move as it does in normal hearts. This is demonstrated
by normal systolic long axis motion of the ventricles, which can be measured by
simple M-mode, TDI, or STE techniques. Therefore, the systolic filling function
from the central venous system (i.e., vena cava or hepatic flow) is preserved giving a
dominant “X” descent in the jugular venous pulse curve. In contrast, with restrictive
cardiomyopathy the subendocardium is involved with the transmural myocardial
pathology and its systolic function is limited. This results in predominant filling of
the heart in early diastole “Y descent” along with the classical restrictive filling
pattern. However, the diagnosis of constrictive pericarditis is often complicated as
many patients also have restrictive filling pattern due to subendocardial dysfunction,
e.g., due to ischemia, which reduces the long axis function. Therefore, a compre-
hensive cardiac imaging and right heart catheterization diagnostic approach is
recommended.
Cardiac Tamponade
The pattern of LV and RV filling velocities follows the pattern in constrictive peri-
carditis. However, in pericardial tamponade the main cause of variations in the LV
and RV inflow velocities is the elevation in the intra-pericardial pressure rather than
intra-cavity pressure. In tamponade, RV and right atrial collapse in response to the
massive pericardial effusion are the main diagnostic features. However, in acute
tamponade the rapid fluid collection is of serious clinical importance. Additionally,
during inspiration the RV filling velocities increase whereas LV filling velocities
decrease causing a significant drop in stroke volume as shown by the aortic velocity:
pulsus paradoxus.
Severity of Tricuspid Regurgitation
Secondary tricuspid valve dysfunction is common in severe right heart disease.

In these conditions color and pulsed wave Doppler techniques are useful in quanti-
fying the severity of tricuspid regurgitation and its hemodynamic consequences.
Quantifying TR severity by assessing the size of a color Doppler regurgitant jet in
Fig. 10.30 Pulsed Doppler echocardiography in patient with a component of constrictive pericarditis
which is illustrated by abnormal increase in right heart pressures during inspiration as shown by
increased right ventricular E filling velocities and simultaneous decrease in left ventricular filling
pressures and E filling velocities
the right atrium is not recommended. It is more important to evaluate the central jet
diameter in the vena contracta or proximal to the tricuspid valve leaflets (PISA
radius). A vena contracta jet diameter ≥7 mm (at a Nyquist limit of 50–60 cm/s)
and/or PISA radius ≥9 mm (Nyquist limit shift of 28 cm/s) indicates severe tricus-
pid regurgitation [69]. An increased E peak velocity (>1 m/s) from tricuspid inflow
and hepatic vein systolic flow reversal are also strong predictors of severe TR,
Fig. 10.30 [69]. In addition, large variations in peak TR gradients with respiration,
increased RV and right atrial volumes, and dilatation of the proximal part of the
inferior vena cava are important supportive evidence in the assessment of RV func-
tion (Fig. 10.31) [69, 118].
Prognostic Value of Assessing RV Function
Despite being often ignored during patient care and management, RV dysfunction
has been shown to carry significant prognostic value in various cardiac conditions:
ischemic [119] and non-ischemic cardiomyopathy [120], acute myocardial infarction
[121], and myocarditis [122]. An RV ejection fraction <35 % carries a poor progno-
sis, whereas patients with values above 35 % usually have satisfactory oxygen uptake
levels with exercise [123]. In fact, RV EF has been shown to better correlate with
myocardial oxygen consumption than that of the LV [124]. RV long axis amplitude
(TAPSE) >14 mm and RV strain >18 % are associated with better survival than val-
ues <14 mm and <18 %, respectively [125]. This applies not only to patients with
various myocardial pathologies but also to patients with PH [126] and to those
receiving cardiac resynchronization therapy who do not demonstrate significant func-
tional improvement [127, 128]. Moreover, severe tricuspid regurgitation is of prog-
nostic significance in mild to moderate chronic heart failure [129] (see Chap. 17).
Fig. 10.31 Hepatic vein systolic flow reversal (red circles) from pulsed Doppler due to severe
tricuspid regurgitation
Right Heart Function Before and After Cardiac Surgery
The finding of RV dysfunction before coronary artery bypass graft surgery in

patients with severe LV dysfunction may be associated with poorer short- and long-
term prognosis. In a retrospective study, patients with severe LV dysfunction and
RV FAC <35 % had a higher 30 day and 2 year mortality, higher perioperative mor-
bidity, and poorer LV functional recovery [130].
After open cardiac surgery the right heart is commonly functionally impaired
mainly because of reduced long axis function. However, its overall function, includ-
ing the interventricular septum, plays an important role in maintaining stroke vol-
ume after surgery. One week after surgery there is a marked reduction in long axis
function which does not fully recover even at 6 months after surgery. RV dysfunc-
tion measured as free wall strain preoperatively and during cardiac surgery has
been shown to be associated with high morbidity and mortality [108, 131, 132].
Modern catheter procedures for valve replacement appear to cause much less dam-
age to RV function than traditional aortic valve surgery procedure [133]. In sum-
mary, a well-planned strategy would include detailed Doppler echocardiographic
examination before, during, and after cardiac surgery in patients with RV dysfunction
(Fig. 10.32).
Fig. 10.32 RV strain (tissue Doppler) of the right ventricular free wall and septal motion before
aortic valve surgery (left) and 1 week after surgery for aortic valve replacement (AVR; right). Note
the reduced right ventricular strain and septal motion towards the right ventricular cavity during
systole
References
1. Simon MA. Assessment and treatment of right ventricular failure. Nat Rev Cardiol. 2013;
10(4):204–18.
2. Goldstein JA. Acute right ventricular infarction: insights for the interventional era. Curr Probl
Cardiol. 2012;37(12):533–57.
3. 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. J Am Soc
Echocardiogr. 2010;23:685–713.
4. Grossman W, Carabello BA, Gunther S, Fifer MA. Ventricular wall stress and the develop-
ment of cardiac hypertrophy and failure. Perspect Cardiovasc Res. 1983;7:1–18.
5. Sheehan FH, Ge S, Vick III GW, et al. Three-dimensional shape analysis of right ventricular
remodeling in repaired tetralogy of Fallot. Am J Cardiol. 2008;101:107–13.
6. King ME, Braun H, Goldblatt A, Liberthson R, Weyman AE. Interventricular septal configu-
ration as a predictor of right ventricular systolic hypertension in children: a cross-sectional
echocardiographic study. Circulation. 1983;68:68–75.
7. Leary PJ, Kurtz CE, Hough CL, Waiss M-P, Ralph DD, Sheehan FH. Three-dimensional
analysis of right ventricular shape and function in pulmonary hypertension. Pulm Circ. 2012;
2:34–40.
8. Lopez-Candales A, Dohi K, Iliescu A, Peterson RC, Edelman K, Bazaz R. An abnormal right

ventricular apical angle is indicative of global right ventricular impairment. Echocardiography.
2006;23:361–8.
9. Sheehan FH, Waiss M-P. Right ventricular function assessment by three-dimensional echo-
cardiography. In: Gill EA, editor. Atlas of 3D echocardiography. Philadelphia, PA: Elsevier;
2012. p. 238–68.
10. Horton KD, Meece RW, Hill JC. Assessment of the right ventricle by echocardiography: a
primer for cardiac sonographers. J Am Soc Echocardiogr. 2009;22:776–92.
11. Levine RA, Gibson TC, Aretz T, et al. Echocardiographic measurement of right ventricular
volume. Circulation. 1984;69:497–505.
12. Denslow S. An ellipsoidal shell model for volume estimation of the right ventricle from mag-
netic resonance images. Acad Radiol. 1994;1:345–51.
13. Helbing WA, Bosch HG, Maliepaard C, et al. Comparison of echocardiographic methods
with magnetic resonance imaging for assessment of right ventricular function in children. Am
J Cardiol. 1995;76:589–94.
14. Aebischer N, Meuli R, Jeanrenaud X, Koerfer J, Kappenberger L. An echocardiographic and
magnetic resonance imaging comparative study of right ventricular volume determination.
Int J Card Imaging. 1998;14:271–8.
15. Badano LP, Ginghina C, Easaw J, et al. Right ventricle in pulmonary arterial hypertension:
haemodynamics, structural changes, imaging, and proposal of a study protocol aimed to
assess remodelling and treatment effects. Eur J Echocardiogr. 2010;11(1):27–37.
16. Jiang L, Levine RA, Weyman AE. Echocardiographic assessment of right ventricular volume
and function. Echocardiography. 1997;14:189–206.
17. Lu X, Nadvoretskiy V, Bu L, et al. Accuracy and reproducibility of real-time three dimen-
sional echocardiography for assessment of right ventricular volumes and ejection fraction in
children. J Am Soc Echocardiogr. 2008;21:84–9.
18. Jenkins C, Chan J, Bricknell K, Strudwick M, Marwick TH. Reproducibility of right ven-
tricular volumes and ejection fraction using real-time three-dimensional echocardiography:
comparison with cardiac MRI. Chest. 2007;131:1844–51.
19. Grison A, Maschietto N, Reffo E, et al. Three-dimensional echocardiographic evaluation of
right ventricular volume and function in pediatric patients: validation of the technique. J Am
Soc Echocardiogr. 2007;20:921–9.
20. Johnson TR, Hoch M, Huber A, et al. Quantification of right ventricular function in congeni-
tal heart disease: correlation of 3D echocardiography and MRI as complementary methods.
Rofo. 2006;178:1014–21.
21. Strugnell WE, Slaughter RE, Riley RA, Trotter AJ, Bartlett H. Modified RV short axis series—
a new method for cardiac MRI measurement of right ventricular volumes. J Cardiovasc Magn
Reson. 2005;7:769–74.
22. Atalay MK, Chang KJ, Grand DJ, Haji-Momenian S, Machan J, Sheehan FH. The transaxial
orientation is superior to both the short axis and horizontal long axis orientations for deter-
mining right ventricular volume and ejection fraction using Simpson’s method with cardiac
magnetic resonance. ISRN Cardiol. 2013 (2013), Article ID 268697.
23. Moroseos T, Mitsumori L, Kerwin WS, et al. Comparison of Simpson’s method with three-
dimensional reconstruction for measurement of right ventricular volume in patients with
complete or corrected transposition of the great arteries. Am J Cardiol. 2010;105:1603–9.
24. Iriart X, Montaudon M, Lafitte S, et al. Right ventricle three-dimensional echography in cor-
rected tetralogy of Fallot: accuracy and variability. Eur J Echocardiogr. 2009;10:784–92.
25. Winter MM, Bernink FJP, Groenink M, et al. Evaluating the systemic right ventricle by
CMR: the importance of consistent and reproducible delineation of the cavity. J Cardiovasc
Magn Reson. 2008;10:40.
26. Geva T, Powell AJ, Crawford EC, Chung T, Colan SD. Evaluation of regional differences in
right ventricular systolic function by acoustic quantification echocardiography and cine mag-
netic resonance imaging. Circulation. 1998;98:339–45.
27. Edwards R, Shurman AJ, Sahn DJ, Jerosch-Herold M, Kilner PJ, Sheehan FH. Determination
of right ventricular end systole by cardiovascular magnetic resonance imaging: a standard
method of selection. Int J Cardiovasc Imaging. 2009;25:791–6.
28. Linker D, Moritz W, Pearlman A. A new three-dimensional echocardiographic method of
right ventricular volume measurement: in vitro validation. J Am Coll Cardiol. 1986;8:101–6.
29. Jiang L, Handschumacher MD, Hibberd MG, et al. Three-dimensional echocardiographic
reconstruction of right ventricular volume: in vitro comparison with two-dimensional meth-
ods. J Am Soc Echocardiogr. 1994;7:150–8.
30. Jiang L, de Prada JAV, Handschumacher MD, et al. Three-dimensional echocardiography:
in vivo validation for right ventricular free wall mass as an index of hypertrophy. J Am Coll
Cardiol. 1994;23:1715–22.
31. Buckey JC, Beattie JM, Nixon JV, Gaffney FA, Blomqvist CG. Right and left ventricular
volumes in vitro by a new nongeometric method. Am J Card Imaging. 1987;1:227–33.
32. Legget ME, Leotta DF, Bolson EL, et al. System for quantitative three dimensional echocar-
diography of the left ventricle based on a magnetic field position and orientation sensing
system. IEEE Trans Biomed Eng. 1998;45:494–504.
33. Hubka M, Bolson EL, McDonald JA, Martin RW, Munt B, Sheehan FH. Three-dimensional
echocardiographic measurement of left and right ventricular mass and volume: in vitro vali-
dation. Int J Cardiovasc Imaging. 2002;18:111–8.
34. Chen G, Sun K, Huang G. In vitro validation of right ventricular volume and mass measure-
ment by real-time three-dimensional echocardiography. Echocardiography. 2006;23:395–9.
35. Redington AN. Right ventricular function. Cardiol Clin. 2002;20:341–9.
36. Sheehan FH, Kilner P, Sahn D, et al. Accuracy of knowledge based reconstruction for the
measurement of right ventricular volume and function in patients with tetralogy of Fallot. Am
J Cardiol. 2010;105:993–9.
37. Dragulescu A, Grosse-Wortmann L, Fackoury C, et al. Echocardiographic assessment of
right ventricular volumes after surgical repair of tetralogy of Fallot: clinical validation of a
new echocardiographic method. J Am Soc Echocardiogr. 2011;24:1191–8.
38. Fayad ZA, Ferrari VA, Kraitchman DL, et al. Right ventricular regional function using MR
tagging: normals versus chronic pulmonary hypertension. Magn Reson Med. 1998;39:
116–23.
39. Naito H, Arisawa J, Harada K, Yamagami H, Kozuka T, Tamura S. Assessment of right ven-
tricular regional contraction and comparison with the left ventricle in normal humans: a cine
magnetic resonance study with presaturation myocardial tagging. Br Heart
J. 1995;74:186–91.
40. Kaul S, Tei C, Hopkins J, Shah P. Assessment of right ventricular function using two-
dimensional echocardiography. Am Heart J. 1984;107:526–31.
41. Kind T, Mauritz G-J, Marcus T, van de Veerdonk M, Westerhof N, vonk-Noordegraaf A. Right
ventricular ejection fraction is better reflected by transverse rather than longitudinal wall
motion in pulmonary hypertension. J Cardiovasc Magn Reson. 2010;12:35.
42. Anavekar NS, Gerson D, Skali H, Kwong RY, Yucel EK, Solomon SD. Two-dimensional
assessment of right ventricular function: an echocardiographic-MRI correlative study.
Echocardiography. 2007;24:452–6.
43. Davlouros PA, Kilner PJ, Hornung TS, et al. Right ventricular function in adults with repaired
tetralogy of Fallot assessed with cardiovascular magnetic resonance imaging: detrimental
role of right ventricular outflow aneurysms or akinesia and adverse right-to-left ventricular
interaction. J Am Coll Cardiol. 2002;40:2044–52.
44. Hui W, El Rahman MYA, Dsebissowa F, et al. Comparison of modified short axis view and
apical four chamber view in evaluating right ventricular function after repair of tetralogy of
Fallot. Int J Cardiol. 2005;105:256–61.
45. Sheehan FH, Mathey DG, Wygant J, Schofer J, Bolson EL. Measurement of regional right
ventricular wall motion from biplane contrast angiograms using the centerline method. In:
KL Ripley and HG Ostrow (eds.), Computers in Cardiology. Long Beach, CA: IEEE
Computer Society; 1985. p. 149–152.
46. Nakasato M, Akiba T, Sato S, Suzuki H, Hayasaka K. Right and left ventricular function
assessed by regional wall motion analysis in patients with tetralogy of Fallot. Int J Cardiol.
1997;58:127–34.
47. Yang P, Otto C, Sheehan F. The effect of normalization in reducing variability in regional wall
thickening. J Am Soc Echocardiogr. 1997;10:197–204.
48. Tulevski II, Zijta FM, Smeijers AS, Dodge-Khatami A, van der Wall EE, Mulder
BJM. Regional and global right ventricular dysfunction in asymptomatic or minimally symp-
tomatic patients with congenitally corrected transposition. Cardiol Young. 2004;14:168–74.
49. McConnell MV, Solomon SD, Rayan ME, Come PC, Goldhaber SZ, Lee RT. Regional right
ventricular dysfunction detected by echocardiography in acute pulmonary embolism. Am J
Cardiol. 1996;78:469–73.
50. Laster SB, Shelton TJ, Barzilai B, Goldstein JA. Determinants of the recovery of right ventricu-
lar performance following experimental chronic right coronary artery occlusion. Circulation.
1993;88:696–708.
51. Goldstein JA. Right heart ischemia: pathophysiology, natural history, and clinical management.
Prog Cardiovasc Dis. 1998;40:325–41.
52. Haber I, Metaxas DN, Geva T, Axel L. Three-dimensional systolic kinematics of the right
ventricle. Am J Physiol Heart Circ Physiol. 2005;289:H1826–33.
53. Klein SS, Graham TPJ, Lorenz CH. Noninvasive delineation of normal right ventricular con-
tractile motion with magnetic resonance imaging myocardial tagging. Ann Biomed Eng.
1998;26:756–63.
54. Young AA, Fayad ZA, Axel L. Right ventricular midwall surface motion and deformation
using magnetic resonance tagging. Am J Physiol. 1996;271:H2677–88.
55. Menteer J, Weinberg PM, Fogel MA. Quantifying regional right ventricular function in tetral-
ogy of Fallot. J Cardiovasc Magn Reson. 2005;7:753–61.
56. Bodhey NK, Beerbaum P, Sarikouch S, et al. Functional analysis of the components of the
right ventricle in the setting of tetralogy of Fallot. Circ Cardiovasc Imaging. 2008;1:141–7.
57. Bomma C, Dal D, Tandri H, et al. Regional differences in systolic and diastolic function in
arrhythmogenic right ventricular dysplasia/cardiomyopathy using magnetic resonance imag-
ing. Am J Cardiol. 2005;95:1507–11.
58. Morcos M, Sheehan FH. Regional right ventricular wall motion in Tetralogy of Fallot: a three
dimensional analysis. Int J Cardiovasc Imaging. 2013;29:1051–8.
59. Goor DA, Lillehei CW. The anatomy of the heart. Congenital malformations of the heart.
New York, NY: Grune & Stratton; 1975. p. 1–37.
60. Anderson RH, Baker EJ, Redington AN. Can we describe structure as well as function when
accounting for the arrangement of the ventricular mass? Cardiol Young. 2000;10:247–60.
61. Calcutteea A, Chung R, Lindqvist P, Hodson M, Henein MY. Differential right ventricular
regional function and the effect of pulmonary hypertension: three-dimensional echo study.
Heart. 2011;97(12):1004–11.
62. Brecker SJ, Gibbs JS, Fox KM, Yacoub MH, Gibson DG. Comparison of Doppler derived
haemodynamic variables and simultaneous high fidelity pressure measurements in severe
pulmonary hypertension. Br Heart J. 1994;72(4):384–9.
63. Lindqvist P, Henein MY, Wikstrom G. Right ventricular myocardial velocities and timing
estimate pulmonary artery systolic pressure. Int J Cardiol. 2009;137(2):130–6.
64. Barst RJ, McGoon M, Torbicki A, et al. Diagnosis and differential assessment of pulmonary
arterial hypertension. J Am Coll Cardiol. 2004;43(12 Suppl S):40S–7.
65. Posteraro A, Salustri A, Trambaiolo P, Amici E, Gambelli G. Echocardiographic estimation
of pulmonary pressures. J Cardiovasc Med. 2006;7(7):545–54.
66. Currie PJ, Seward JB, Chan KL, et al. Continuous wave Doppler determination of right ven-
tricular pressure: a simultaneous Doppler-catheterization study in 127 patients. J Am Coll
Cardiol. 1985;6(4):750–6.
67. Chan KL, Currie PJ, Seward JB, Hagler DJ, Mair DD, Tajik AJ. Comparison of three Doppler
ultrasound methods in the prediction of pulmonary artery pressure. J Am Coll Cardiol.
1987;9(3):549–54.
68. Daniels LB, Krummen DE, Blanchard DG. Echocardiography in pulmonary vascular disease.
Cardiol Clin. 2004;22(3):383–99, vi.
69. Lancellotti P, Moura L, Pierard LA, et al. European Association of Echocardiography recom-
mendations for the assessment of valvular regurgitation. Part 2: mitral and tricuspid regurgi-
tation (native valve disease). Eur J Echocardiogr. 2010;11(4):307–32.
70. Tossavainen E, Soderberg S, Gronlund C, Gonzalez M, Henein MY, Lindqvist P. Pulmonary
artery acceleration time in identifying pulmonary hypertension patients with raised pulmo-
nary vascular resistance. Eur Heart J Cardiovasc Imaging. 2013;14(9):890–7.
71. Zimbarra Cabrita I, Ruisanchez C, Grapsa J, et al. Validation of the isovolumetric relaxation
time for the estimation of pulmonary systolic arterial blood pressure in chronic pulmonary
hypertension. Eur Heart J Cardiovasc Imaging. 2013;14:51–5.
72. Morner S, Lindqvist P, Waldenstrom A, Kazzam E. Right ventricular dysfunction in hypertro-
phic cardiomyopathy as evidenced by the myocardial performance index. Int J Cardiol.
2008;124(1):57–63.
73. Moller JE, Sondergaard E, Poulsen SH, Appleton CP, Egstrup K. Serial Doppler echocardio-
graphic assessment of left and right ventricular performance after a first myocardial infarc-
tion. J Am Soc Echocardiogr. 2001;14(4):249–55.
74. Schiller NB, Kwan DM. The Tei index as an expression of right ventricular impairment and
recovery: investment grade or subprime? JACC Cardiovasc Imaging. 2009;2(2):150–2.
75. Galie N, Hoeper MM, Humbert M, et al. Guidelines for the diagnosis and treatment of pul-
monary hypertension: the Task Force for the Diagnosis and Treatment of Pulmonary
Hypertension of the European Society of Cardiology (ESC) and the European Respiratory
Society (ERS), endorsed by the International Society of Heart and Lung Transplantation
(ISHLT). Eur Heart J. 2009;30(20):2493–537.
76. Grose R, Strain J, Yipintosoi T. Right ventricular function in valvular heart disease: relation
to pulmonary artery pressure. J Am Coll Cardiol. 1983;2(2):225–32.
77. Enriquez-Sarano M, Rossi A, Seward JB, Bailey KR, Tajik AJ. Determinants of pulmonary
hypertension in left ventricular dysfunction. J Am Coll Cardiol. 1997;29:153–9.
78. Ghio S, Temporelli PL, Klersy C, et al. Prognostic relevance of a non-invasive evaluation of
right ventricular function and pulmonary artery pressure in patients with chronic heart failure.
Eur J Heart Fail. 2013;15(4):408–14.
79. Henein MY, O’Sullivan CA, Coats AJ, Gibson DG. Angiotensin-converting enzyme (ACE)
inhibitors revert abnormal right ventricular filling in patients with restrictive left ventricular
disease. J Am Coll Cardiol. 1998;32(5):1187–93.
80. Segers VF, Brutsaert DL, De Keulenaer GW. Pulmonary hypertension and right heart failure
in heart failure with preserved left ventricular ejection fraction: pathophysiology and natural
history. Curr Opin Cardiol. 2012;27(3):273–80.
81. Thenappan T, Shah SJ, Gomberg-Maitland M, et al. Clinical characteristics of pulmonary
hypertension in patients with heart failure and preserved ejection fraction. Circ Heart Fail.
2011;4(3):257–65.
82. Arcasoy SM, Christie JD, Ferrari VA, et al. Echocardiographic assessment of pulmonary
hypertension in patients with advanced lung disease. Am J Respir Crit Care Med.
2003;167(5):735–40.
83. Henein MY, Cailes J, O’Sullivan C, du Bois RM, Gibson DG. Abnormal ventricular long-axis
function in systemic sclerosis. Chest. 1995;108(6):1533–40.
84. Proudman SM, Stevens WM, Sahhar J, Celermajer D. Pulmonary arterial hypertension in
systemic sclerosis: the need for early detection and treatment. Intern Med J. 2007;37(7):
485–94.
85. Florea VG, Florea ND, Sharma R, et al. Right ventricular dysfunction in adult severe cystic
fibrosis. Chest. 2000;118(4):1063–8.
86. Kjaergaard J, Schaadt BK, Lund JO, Hassager C. Prognostic importance of quantitative echo-
cardiographic evaluation in patients suspected of first non-massive pulmonary embolism. Eur
J Echocardiogr. 2009;10(1):89–95.
87. Kjaergaard J, Schaadt BK, Lund JO, Hassager C. Quantitative measures of right ventricular
dysfunction by echocardiography in the diagnosis of acute nonmassive pulmonary embolism.
J Am Soc Echocardiogr. 2006;19(10):1264–71.
88. Chemla D, Castelain V, Humbert M, et al. New formula for predicting mean pulmonary artery
pressure using systolic pulmonary artery pressure. Chest. 2004;126(4):1313–7.
89. Bossone E, Bodini BD, Mazza A, Allegra L. Pulmonary arterial hypertension: the key role of
echocardiography. Chest. 2005;127(5):1836–43.
90. Opotowsky AR, Clair M, Afilalo J, et al. A simple echocardiographic method to estimate
pulmonary vascular resistance. Am J Cardiol. 2013;112(6):873–82.
91. Abbas AE, Fortuin FD, Schiller NB, Appleton CP, Moreno CA, Lester SJ. A simple method
for noninvasive estimation of pulmonary vascular resistance. J Am Coll Cardiol. 2003;41(6):
1021–7.
92. Lindqvist P, Soderberg S, Gonzalez MC, Tossavainen E, Henein MY. Echocardiography
based estimation of pulmonary vascular resistance in patients with pulmonary hypertension: a
simultaneous Doppler echocardiography and cardiac catheterization study. Eur J Echocardiogr.
2011;12(12):961–6.
93. Nagueh SF, Appleton CP, Gillebert TC, et al. Recommendations for the evaluation of left
ventricular diastolic function by echocardiography. Eur J Echocardiogr. 2009;10(2):165–93.
94. Goldstein JA. Right heart ischemia: pathophysiology, natural history, and clinical manage-
ment. Prog Cardiovasc Dis. 1998;40(4):325–41.
95. Kaul S, Tei C, Hopkins JM, Shah PM. Assessment of right ventricular function using two-
dimensional echocardiography. Am Heart J. 1984;107(3):526–31.
96. Innelli P, Esposito R, Olibet M, Nistri S, Galderisi M. The impact of ageing on right ventricu-
lar longitudinal function in healthy subjects: a pulsed tissue Doppler study. Eur J Echocardiogr.
2009;10(4):491–8.
97. Kjaergaard J, Petersen CL, Kjaer A, Schaadt BK, Oh JK, Hassager C. Evaluation of right
ventricular volume and function by 2D and 3D echocardiography compared to MRI. Eur J
Echocardiogr. 2006;7(6):430–8.
98. Hsiao SH, Lin SK, Wang WC, Yang SH, Gin PL, Liu CP. Severe tricuspid regurgitation shows
significant impact in the relationship among peak systolic tricuspid annular velocity, tricuspid
annular plane systolic excursion, and right ventricular ejection fraction. J Am Soc
Echocardiogr. 2006;19(7):902–10.
99. Smith JL, Bolson EL, Wong SP, Hubka M, Sheehan FH. Three-dimensional assessment of
two-dimensional technique for evaluation of right ventricular function by tricuspid annulus
motion. Int J Cardiovasc Imaging. 2003;19(3):189–97.
100. Lindqvist P, Henein M, Kazzam E. Right ventricular outflow-tract fractional shortening: an
applicable measure of right ventricular systolic function. Eur J Echocardiogr. 2003;4(1):
29–35.
101. Yamaguchi M, Tsuruda T, Watanabe Y, et al. Reduced fractional shortening of right ventricu-
lar outflow tract is associated with adverse outcomes in patients with left ventricular dysfunc-
tion. Cardiovasc Ultrasound. 2013;11:19.
102. Geva T, Powell AJ, Crawford EC, Chung T, Colan SD. Evaluation of regional differences in
right ventricular systolic function by acoustic quantification echocardiography and cine mag-
netic resonance imaging. Circulation. 1998;98(4):339–45.
103. Do DH, Therrien J, Marelli A, Martucci G, Afilalo J, Sebag IA. Right atrial size relates to
right ventricular end-diastolic pressure in an adult population with congenital heart disease.
Echocardiography. 2011;28(1):109–16.
104. Cioffi G, de Simone G, Mureddu G, Tarantini L, Stefenelli C. Right atrial size and function
in patients with pulmonary hypertension associated with disorders of respiratory system or
hypoxemia. Eur J Echocardiogr. 2007;8(5):322–31.
105. McCrory DC, Coeytaux RR, Schmit KM, et al. Pulmonary arterial hypertension: screening,
management, and treatment. Agency for Healthcare Research and Quality. Comparative
Effectiveness Reviews 13-EHC087-EF; 2013.
106. Bustamante-Labarta M, Perrone S, De La Fuente RL, et al. Right atrial size and tricuspid
regurgitation severity predict mortality or transplantation in primary pulmonary hypertension.
J Am Soc Echocardiogr. 2002;15(10 Pt 2):1160–4.
107. Sato T, Tsujino I, Oyama-Manabe N, et al. Right atrial volume and phasic function in pulmo-
nary hypertension. Int J Cardiol. 2013;168(1):420–6.
108. Lindqvist P, Holmgren A, Zhao Y, Henein MY. Effect of pericardial repair after aortic valve
replacement on septal and right ventricular function. Int J Cardiol. 2012;155(3):388–93.
109. 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):685–713. quiz 786-688.
110. Peluso D, Badano LP, Muraru D, et al. Right atrial size and function assessed with three-
dimensional and speckle-tracking echocardiography in 200 healthy volunteers. Eur Heart J
111. Hoffmann R, Hanrath P. Tricuspid annular velocity measurement. Simple and accurate solu-
tion for a delicate problem? Eur Heart J. 2001;22(4):280–2.
112. Lindqvist P, Calcutteea A, Henein M. Echocardiography in the assessment of right heart
function. Eur J Echocardiogr. 2008;9(2):225–34.
113. Rajagopalan N, Simon MA, Shah H, Mathier MA, Lopez-Candales A. Utility of right ven-
tricular tissue Doppler imaging: correlation with right heart catheterization. Echocardiography.
2008;25(7):706–11.
114. Lopez-Candales A, Dohi K, Rajagopalan N, et al. Right ventricular dyssynchrony in patients
with pulmonary hypertension is associated with disease severity and functional class.
Cardiovasc Ultrasound. 2005;3:23.
115. Lindqvist P, Waldenstrom A, Henein M, Morner S, Kazzam E. Regional and global right
ventricular function in healthy individuals aged 20-90 years: a pulsed Doppler tissue imaging
study: Umea General Population Heart Study. Echocardiography. 2005;22(4):305–14.
116. Lam YY, Kaya MG, Goktekin O, Gatzoulis MA, Li W, Henein MY. Restrictive right ventricu-
lar physiology: its presence and symptomatic contribution in patients with pulmonary valvular
stenosis. J Am Coll Cardiol. 2007;50(15):1491–7.
117. Klein AL, Leung DY, Murray RD, Urban LH, Bailey KR, Tajik AJ. Effects of age and physi-
ologic variables on right ventricular filling dynamics in normal subjects. Am J Cardiol.
1999;84(4):440–8.
118. Mutlak D, Carasso S, Lessick J, Aronson D, Reisner SA, Agmon Y. Excessive respiratory
variation in tricuspid regurgitation systolic velocities in patients with severe tricuspid regur-
gitation. Eur Heart J Cardiovasc Imaging. 2013;14(10):957–62.
119. Polak JF, Holman BL, Wynne J, Colucci WS. Right ventricular ejection fraction: an indicator
of increased mortality in patients with congestive heart failure associated with coronary
artery disease. J Am Coll Cardiol. 1983;2(2):217–24.
120. Juilliere Y, Barbier G, Feldmann L, Grentzinger A, Danchin N, Cherrier F. Additional predic-
tive value of both left and right ventricular ejection fractions on long-term survival in idio-
pathic dilated cardiomyopathy. Eur Heart J. 1997;18(2):276–80.
121. Shah PK, Maddahi J, Staniloff HM, et al. Variable spectrum and prognostic implications of
left and right ventricular ejection fractions in patients with and without clinical heart failure
after acute myocardial infarction. Am J Cardiol. 1986;58(6):387–93.
122. Mendes LA, Dec GW, Picard MH, Palacios IF, Newell J, Davidoff R. Right ventricular
dysfunction: an independent predictor of adverse outcome in patients with myocarditis. Am
Heart J. 1994;128(2):301–7.
123. Di Salvo TG, Mathier M, Semigran MJ, Dec GW. Preserved right ventricular ejection frac-
tion predicts exercise capacity and survival in advanced heart failure. J Am Coll Cardiol.
1995;25(5):1143–53.
124. Baker BJ, Wilen MM, Boyd CM, Dinh H, Franciosa JA. Relation of right ventricular ejection
fraction to exercise capacity in chronic left ventricular failure. Am J Cardiol. 1984;54(6):
596–9.
125. Kjaergaard J, Akkan D, Iversen KK, Kober L, Torp-Pedersen C, Hassager C. Right ventricular
dysfunction as an independent predictor of short- and long-term mortality in patients with
heart failure. Eur J Heart Fail. 2007;9(6–7):610–6.
126. Haeck ML, Scherptong RW, Marsan NA, et al. Prognostic value of right ventricular longitu-
dinal peak systolic strain in patients with pulmonary hypertension. Circ Cardiovasc Imaging.
2012;5(5):628–36.
127. Sade LE, Ozin B, Atar I, Demir O, Demirtas S, Muderrisoglu H. Right ventricular function Is
a determinant of long-term survival after cardiac resynchronization therapy. J Am Soc
Echocardiogr. 2013;26(7):706–13.
128. Ghio S, Freemantle N, Scelsi L, et al. Long-term left ventricular reverse remodelling with
cardiac resynchronization therapy: results from the CARE-HF trial. Eur J Heart Fail. 2009;
11(5):480–8.
129. Neuhold S, Huelsmann M, Pernicka E, et al. Impact of tricuspid regurgitation on survival in
patients with chronic heart failure: unexpected findings of a long-term observational study.
Eur Heart J. 2013;34(11):844–52.
130. Maslow AD, Regan MM, Panzica P, Heindel S, Mashikian J, Comunale ME.
Precardiopulmonary bypass right ventricular function is associated with poor outcome after
coronary artery bypass grafting in patients with severe left ventricular systolic dysfunction.
Anesth Analg. 2002;95:1507–18.
131. Ternacle J, Berry M, Cognet T, et al. Prognostic value of right ventricular two-dimensional
global strain in patients referred for cardiac surgery. J Am Soc Echocardiogr. 2013;26(7):
721–6.
132. Denault AY, Haddad F, Jacobsohn E, Deschamps A. Perioperative right ventricular dysfunc-
tion. Curr Opin Anaesthesiol. 2013;26(1):71–81.
133. Zhao Y, Lindqvist P, Nilsson J, Holmgren A, Naslund U, Henein MY. Trans-catheter aortic
valve implantation—early recovery of left and preservation of right ventricular function.
Interact Cardiovasc Thorac Surg. 2011;12(1):35–9.
134. Henein M, Waldenstrom A, Morner S, Lindqvist P. The normal impact of age and gender on
right heart structure and function. Echocardiography. 2014;31:5–11.
Chapter 11
Hemodynamic Evaluation and Exercise
Testing in Chronic Right Ventricular Failure
Onno A. Spruijt, Anton Vonk-Noordegraaf, and Harm J. Bogaard
Hemodynamic Evaluation
Introduction
After successfully and safely using the cardiac catheter technique in animals,
Dr. Werner Forssmann performed in 1929 the first recorded human cardiac catheter-
ization of his own right heart. Andre Cournand and Dickinson Richards did further
development of this technique for clinical purposes in 1944 and demonstrated the
safety and feasibility of this technique in a large cohort of patients. For their contri-
butions to the understanding of cardiac physiology, Forssmann, Cournand, and
Richards received the Nobel Prize in Physiology in 1956 (Fig. 11.1) [1].
Today, the right heart catheterization (RHC) is still the gold standard for the
hemodynamic evaluation of the right ventricle (RV) and pulmonary circulation.
During a RHC, right atrial pressure (RAP), right ventricular pressure (RVP), pul-
monary artery pressure (PAP), and pulmonary arterial wedge pressure (PAWP) are
measured and recorded. RHC can also be used to measure flow [cardiac output
(CO)] using thermodilution or (in)direct Fick methods. In addition, systemic sam-
pling of blood to determine oxygen saturations is indispensable for the evaluation of
systemic-to-pulmonary shunting.
Very important for a correct hemodynamic evaluation of patients is a precise and
standardized RHC procedure [2]. Kovacs et al. [3] showed that the choice of
different zero reference levels strongly influenced pressure measurements. It has
been recommended to set the zero reference level at the level of the right atrium.
Evaluation with CT scans showed that the height of the right atrium was best
O.A. Spruijt, M.D. (*) • A. Vonk-Noordegraaf, M.D., Ph.D. • H.J. Bogaard, M.D., Ph.D.
Department of Pulmonary Diseases, VU University Medical Center,
De Boelelaan 1117, ZH 4A-48, Amsterdam 1007 MB, The Netherlands
e-mail: o.spruijt@vumc.nl; hj.bogaard@vumc.nl

250 O.A. Spruijt et al.
Fig. 11.1 Forssmann, Richards, and Cournand receiving the Nobel Prize in Physiology. From left
to right: Richards, Forssmann Cournand, and Professor Friberg. From Werner Forssmann:
A Pioneer of Cardiology Original Journal: The American Journal of Cardiology, Volume 79, Issue
5, 1 March 1997, Pages 651–660, Fig. 4. Renate Forssmann-Falck
estimated when the zero reference level was set at 1/3 of the thoracic diameter [3].
The RHC is a relatively safe procedure and when performed in an experienced
center, morbidity (1.1 %) and mortality (0.055 %) rates are low [4].
Mean Pulmonary Arterial Pressure
Shortly after the clinical introduction of the RHC technique, it became clear that
elevated pulmonary vascular pressures were related to symptoms of dyspnea and
fatigue. Paul Wood defined in 1958 a mean pulmonary artery pressure (mPAP) of
25 mmHg as the upper limit of normal on the basis of measurements performed in
60 healthy subjects [5]. The same definition of pulmonary hypertension (PH) is still
used today and the RHC remains the gold standard for the diagnosis of PH [2].
Wood’s studies using acetylcholine in PH patients also contributed to the classi-
fication of PH (Fig. 11.2), which has been modified several times in the last five
decades. Approximately 40 causes of PH are now recognized, which are categorized
in 5 main groups (Fig. 11.3). Left-sided heart failure (WHO group 2) is the most
common cause of PH [2].
Since the cardiovascular system is a closed loop system, different (patho)physi-
ological hemodynamic changes can initiate an increase in mPAP. The hemodynamic
mechanisms resulting in an increase in mPAP are: an increase in pulmonary vascu-
lar resistance (PVR), an increase in PAWP, and an increase in cardiac output (CO).
11 Hemodynamic Evaluation and Exercise Testing in Chronic… 251
Fig. 11.2 Reaction of the pulmonary and systemic circulation to acetylcholine in a patient with
“primary pulmonary hypertension.” Using acetylcholine as a pulmonary vasodilator, Paul Wood
showed in patients with “Primary pulmonary hypertension” that the administration of acetylcho-
line led to a decrease in pulmonary artery pressure in combination with an increase in cardiac
output and systemic blood pressure proving the increased vasoconstriction in this disease. From
Wood: Pulmonary hypertension with special reference to the vasoconstrictive factor. Journal: Br
Heart J 1958;20:557–570, Fig. 8
Pulmonary Vascular Resistance
An increase in the afterload of the RV leads to an increase in mPAP since the RV

needs to build up more pressure to maintain an adequate CO. The load on the out-
flow of the RV can be divided into the resistance to steady state flow and the resis-
tance to pulsatile flow from vascular impedance [6]. The resistance to steady state
flow is known as the PVR and is defined as PVR = (mPAP − PAWP)/CO. An increase
in PVR can be due to a decrease in the pulmonary vessel radius or due to the loss of
arterial surface [6]. A decrease in pulmonary arterial vessel radius is seen in WHO
group 1 and 4 PH patients and is due to thickening of the vascular wall, intravascular
occlusions (either by exuberantly proliferating cells of the vessel wall or thrombosis
and emboli), and loss of vessel number (rarefaction). Hypoxic vasoconstriction,
also seen in WHO group 3 PH patients can contribute to a decrease in the pulmo-
nary arterial diameter. A decrease in arterial surface area is often observed in
emphysema. Vascular rarefaction as the sole cause of an increased PVR is still a
matter of debate, since even in severe emphysema, PH is rare. PVR can also be
increased in conditions associated with an increased blood viscosity.
Fig. 11.3 Five main groups of pulmonary hypertension
Resistance to pulsatile flow is mostly described by an inverse measure, the

pulmonary arterial compliance. Pulmonary arterial compliance is assessed by stroke
volume (SV) divided by the pulse pressure (PP) (SV/PP). It has been shown that in
the pulmonary circulation PVR and compliance are inversely related [7]. The prod-
uct of PVR and compliance, known as the RC time (T ), can be calculated as
T = PVR × compliance = ((mPAP − PAWP)/(SV × HR)) × (SV/PP) = T ×
((mPAP − PAWP)/PP). Over a wide range of PVR, T remains relatively stable in
healthy people and patients with precapillary PH [7–9].
The increase in afterload in PH requires the RV to generate more hydraulic power
to maintain adequate CO. The power generated by the RV can be divided into mean
(or steady) power and oscillatory (or pulsatile) power. Mean flow determines trans-
port and is mainly determined by mean power. Oscillatory power is generated for the
pulsatile component of flow. It has been shown that the ratio between mean power
and oscillatory power generated by the RV is equal among healthy people and PAH
patients and that oscillatory power counts for approximately 23 % of total power
generated by the RV [10]. Since mean power is defined as mPAP × CO, mean power,
total hydraulic power (1.3 × mean power), and oscillatory power (0.23 × total hydrau-
lic power) can be derived from RHC measurements. Mean power is related to mPAP
and therefore mean power is also related to steady state resistance (PVR) and oscil-
latory power is related to pulse pressure and therefore related to arterial compliance.
Consequently, the constant power fractions reflect the constant RC time [7–10].
Pulmonary Arterial Wedge Pressure
mPAP can also be increased due to an increased PAWP. During RHC, a balloon can
be inflated to temporarily close a small pulmonary artery branch. The pressure proxi-
mal from the inflated balloon is the PAWP and is a surrogate measure of the pressure
in the postcapillary system including the left atrial pressure (LAP). Left heart failure
or left-sided valvular disease results in an increase in PAWP, which can subsequently
increase mPAP. A PAWP >15 mmHg is defined as abnormal and is due to left heart
disease. Therefore, PH can be classified in pre- and postcapillary PH based on the
PAWP [2]. The significance of a PAWP between 12 and 15 mmHg is still unclear.
In left heart disease, the elevation of the mPAP is proportional to the increase in
PAWP and the PVR is often normal. An elevated PVR in combination with an
increase in PAWP is seen in approximately 25 % of patients with PH due to left
heart failure and has been described as “out of proportion” PH [11].
When using the PAWP to classify the PH, some shortcomings of PAWP should
be taken into account. PAWP is dependent on the volume status and can be falsely
low in WHO group 2 PH patients on diuretic therapy. Rapid fluid infusion or exer-
cise testing can increase the PAWP in WHO group 2 patients and can reveal left
heart disease. PAWP can also be falsely high in patients with precapillary PH, since
severe precapillary PH with RV dilatation, congestion, and increased RAP can
cause diastolic pressures to be transmitted across the septum causing increased left-
sided filling pressures [11, 12].
Another way to distinguish pre- from postcapillary PH is to use the transpulmo-
nary gradient (TPG) defined as TPG = mPAP − PAWP, with a TPG >12 mmHg as a
threshold for precapillary PH. However, the calculation of the TPG can be mislead-
ing, because an increase in CO can lead to an increase in distensibility of pulmonary
vessels, lowering mPAP and the TPG for any given flow. An increase in distensibil-
ity also lowers the slope of the mPAP–PAWP relation, falsely decreasing TPG with
an increase in PAWP. Moreover, the mPAP–PAWP relation is sensitive to changes in
SV and arterial compliance. An increase in SV will lead to an increase in mPAP for
any given PAWP and therefore increasing the TPG [13].
Although the RC time of the pulmonary circulation in healthy subjects is stable
and patients with precapillary PH, a recent study showed that this may not be true
in patients with postcapillary PH [9]. The upstream load of an increased PAWP
causes a relatively greater decrease in compliance than an increase in PVR, subse-
quently increasing the TPG.
It has been suggested that the diastolic pressure gradient (DPG), defined as
diastolic pulmonary artery pressure (dPAP) minus PAWP (=dPAP − PAWP), is more
accurate when it comes to distinguishing pre- from postcapillary PH, since dPAP is
less sensitive to changes in SV and arterial compliance [13].
Cardiac Output
The degree to which an increase in CO leads to an increase in mPAP depends on the

degree to which lung vessels can distend and be recruited. The magnitude of vascu-
lar distention and lung vascular recruitment during exercise is still hotly debated.
During exercise, an increased demand for oxygen will increase CO, which is usu-
ally followed by at least some increase in the mPAP [14]. Pathophysiologic changes
of the slope of the mPAP–CO relation during exercise will be further discussed in
the exercise section below. Conditions like congenital heart disease, hyperthyroid-
ism, portal hypertension, and congenital portosystemic venous shunts can also
increase CO and mPAP [15–17]. Nevertheless, overwhelmingly patients with PH
have a decreased CO as a result of the increase in PVR and RV failure.
Usage of Hemodynamics in Clinical Practice and Research
As already mentioned, RHC is the gold standard for the diagnosis of PH and PH is
defined as mPAP >25 mmHg. To distinguish pre- from postcapillary PH, the hemo-
dynamics are further evaluated on the basis of the PAWP, TPG, and DPG, not only
at baseline but preferably also after a fluid challenge or during exercise. A proper
classification is of major importance, since pre- and postcapillary PH are managed
quite differently [2] (Table 11.1).
Current PH guidelines advise, on a non-consensus basis, to repeat the RHC
12–16 weeks after initiating or changing PH treatment, once a year in stable patients
or when signs of clinical worsening are present. Neither the baseline mPAP nor
changes in mPAP during treatment have a prognostic value in PH patients [18–20].
In precapillary PH, baseline PVR has prognostic value and an increased PVR at
baseline is associated with a worse survival [18]. Treatment-related changes in PVR
Table 11.1 Diagnostic reference values of hemodynamic parameters

Normal (mmHg) Precapillary PH (mmHg) Postcapillary PH (mmHg)
mPAP <25 >25 >25
PAWP <15 <15 >15
TPG <12 >12 <12
DPG <5 >5 <5
mPAP mean pulmonary artery pressure, PAWP pulmonary arterial wedge pressure, TPG transpulmonary
gradient, DPG diastolic pressure gradient
do not predict survival or a change in RV function [20]. Only when a reduction in

PVR is very substantial, as is seen after a pulmonary thrombendarterectomy for
chronic thromboembolic PH (CTEPH), the decrease in PVR is accompanied by an
improved RV function.
Baseline CO and cardiac index (CI = CO corrected for body surface area) are of
prognostic value in PH [18, 19]. The PH guidelines describe profiles of outcome
based on multiple prognostic parameters including CI, with a CI < 2.5 L/min/m2
predicting a worse prognosis. Interestingly, at the time of the writing of the guide-
lines, there was little scientific basis for a cutoff value of CI < 2.5 L/min/m2. A recent
study in IPAH patients showed that a baseline CI > 2.5 L/min/m2 combined with a
CI > 2.5 L/min/m2 follow-up was associated with the best survival. Survival rates of
patients with a baseline CI < 2.5 L/min/m2 were almost as good, provided their CI
after follow-up was greater than >2.5 L/min/m2. Poor survival was observed when
follow-up measurements showed a CI < 2.5 L/min/m2, with little difference between
patients with a high or low baseline CI. This suggests that not only baseline CI but
also the change in CI to treatment is important in the evaluation of patients [21].
Multiple studies have shown that an increased RAP at baseline is associated with
a poor prognosis in PAH patients and a strong predictor of survival [18, 19]. The
prognostic significance of treatment associated changes in RAP is unstudied.
Exercise Testing
Pathophysiology
During exercise, the cardiopulmonary system is pushed to its upper limits. The
increased demand for oxygen delivery to the tissues is met by an almost fourfold
increase in CO. The entire CO passes through the pulmonary circulation and the
pulmonary circulation prevents a proportional increase in mPAP by vasodilatation
and vessel recruitment [22]. In other words, the slope of the mPAP–CO relationship
is determined by the magnitude of vascular recruitment and distention.
PH patients often complain of exercise-induced dyspnea and this impaired exer-
cise tolerance is mainly due to circulatory limitations. Exercise-induced dyspnea in
PH patients is primarily due to the inability to increase pulmonary blood flow dur-
ing exercise. This limited increase in CO is caused by an inability to increase SV
and due to an abnormal chronotropic response [23, 24]. The inability to increase SV
reflects an increased end-systolic volume (ESV) as a result of the increase in PVR
and RV dysfunction [23, 25]. An abnormal chronotropic response is demonstrated
as a decreased maximal heart rate (HR) in PH and is believed to be the result of an
imbalance of the autonomic nervous system [24, 26–28]. The decrease in CO for a
given workload results in insufficient oxygen delivery to peripheral tissues, anaero-
bic metabolism of glucose, and muscle weakness due to acidosis [29]. Together
these changes limit the maximal uptake of oxygen (VO2max) and result in early
exercise termination.
A second problem in PH is an increased ventilatory requirement, which is still

poorly understood, but likely contributes to the patients’ sensation of dyspnea.
In precapillary PH, dead space ventilation occurs because of hypoperfusion of
normally ventilated alveoli due to loss of the pulmonary capillary bed. Dead space
ventilation could lead to problems eliminating carbon dioxide, increasing minute
ventilation (VE). However, because PH patients are often hypocapnic at rest and
during exercise, it is assumed that in addition to dead space ventilation, alveolar
hyperventilation further contributes to the increased ventilatory requirement [30].
It is believed that exercise-induced alveolar hyperventilation in PH is due to the
summation of lactate acidosis, a hypoxemic ventilatory drive, and a sympathetic
nerve overdrive. In summary, ventilatory inefficiency is a hallmark of PH and may
contribute to the sensation of dyspnea [25, 26, 29].
Finally, diaphragm weakness can lead to a further increase of breathlessness dur-
ing exercise [31].
To evaluate a patient’s exercise capacity and exercise-related symptoms, both the
6 min walk test (6MWT) and the maximal cardiopulmonary exercise test (CPET)
are used.
Six Minute Walk Test
The 6MWT is a relatively simple and inexpensive tool to measure exercise toler-
ance. It measures the distance that a patient can walk on a flat floor in 6 min. The
6MWT is a measure of the integrated response of all physiological systems that are
necessary to perform work. The SV response and chronotropic response to exercise
are found to be the most important factors influencing the 6MWT [27].
The 6MWT is adapted from the Cooper test and is used as a surrogate for maxi-
mal oxygen consumption (VO2max). Via the Fick’s equation (VO2 = CO × arteriove-
nous oxygen difference), the 6MWT is associated with CO (and, hence, SV and
heart rate). A limitation of the 6MWT is a ceiling effect in relatively healthy indi-
viduals, since in these individuals the increase in distance during the 6MWT does
not follow the increase in VO2max [32].
6MWT in Clinical Practice and Research
In precapillary PH, baseline 6MWT is a strong predictor of survival and a baseline

distance of >440 meters is associated with a better survival [18, 19]. It is found that
the minimal important difference (MID) in 6 min walk distance to get a change in
health-related quality of life score is 41 m [33]. This is in accordance to a recent
meta-analysis using the occurrence of clinical events to assess the MID of the
change in 6 min walking distance (Δ6MWD) (41.8 m) [34].
Since the 6MWT is highly reproducible and standardized, many trials of PAH
therapies have used the Δ6MWD as a primary end point [35]. However, pooled data
from these clinical trials have shown that using the Δ6MWD as a surrogate end point
for clinical outcome is inadequate, since the effect of therapy on preventing clinical
events could only modestly be explained by Δ6MWD [34]. Therefore, future clinical
trails will use Δ6MWD as a secondary rather than a primary end point.
Cardiopulmonary Exercise Test
The disadvantage of the 6MWT is that it does not provide pathophysiological infor-
mation about the exact factors limitating exercise. During a CPET, all ventilatory
parameters, blood pressure, HR, and arterial blood gases can be measured, giving
more insight into the cardiovascular and pulmonary factors contributing to the exer-
cise limitation [36].
CPET parameters indicative of the presence of PH are a reduced VO2max, reduced
O2 pulse (calculated as the O2 uptake per heartbeat), a reduced VO2 at the anaerobic
threshold (VO2AT), an increased VE/VCO2 slope (a measure of ventilatory effi-
ciency), and a progressive decrease in oxygen saturation measured by pulse oxime-
try (Fig. 11.4). The VO2max can also be used to measure CO using the (indirect)
Fick method. According to the Fick principle, the O2 pulse (VO2/HR) is a measure of
SV [36]. In PH, a reduced VO2max, O2 pulse, and VO2AT result from a decreased
blood flow and reflect RV dysfunction. The increased VE/VCO2 slope describes the
ventilatory insufficiency and is observed in both pre- and postcapillary PH [29, 37].
A good correlation is found between CPET parameters and NYHA functional
class in PAH patients [29] and studies have also shown that VE/VCO2 at AT and
VO2max are independent predictors of survival in patients with IPAH [38–41].
Combining hemodynamic and exercise parameters increased the predicted value for
long-term survival in idiopathic and hereditary PAH [42]. Moreover, the change in
VO2max and maximal O2 pulse at follow-up are independent predictors of survival
in iPAH patients [40].
While the prognostic value of CPET parameters has been studied in some detail in
(i)PAH patients with IPAH it is still unknown whether these prognostic findings can
be extrapolated to all forms of PH [41, 43]. Groepenhoff et al. [39] showed that only
the oxygen pulse had a small added value to the 6MWT for predicting of survival.
Invasive Cardiopulmonary Exercise Test
Recently, invasive cardiopulmonary exercise testing (iCPET) has received interest in

PH studies. During iCPET, supine or upright cardiopulmonary exercise protocols are
completed with pulmonary artery and radial artery catheters in situ, giving a more
complete hemodynamic and ventilatory evaluation during exercise (Fig. 11.5) [44].
The ability to increase CO during exercise depends on the fitness of an individual
and the slope of the mPAP–CO relationship which is steeper in older subjects [45].
Prior to the 2008 World Conference on PH in Dana Point, exercise-induced PH
was recognized as a separate PH entity and was defined as an mPAP < 25 mmHg at
Fig. 11.4 Comparison of AT, VO2max, O2 pulse, and VE/VCO2 between PAH patients and healthy
controls. Caption: (a) Decrease in AT-, (b) decrease in VO2max-, (c) decrease in O2 pulse-, (d)
increase in VE/VCO2 slope in PAH patients compared to healthy controls. From Sun et al. Exercise
Pathophysiology in patients with primary pulmonary hypertension. Journal: Circulation
2001;104:429–435, Fig. 1
rest and an mPAP > 30 mmHg during exercise. The diagnosis of exercise-induced
PH was eliminated because the upper limits of normal for the rise in mPAP during
exercise are very ill defined. It has been suggested that an mPAP of 30 mmHg at a
CO <10 L/min and an mPAP-CO slope >3 mmHg per L/min represent the upper
limits of normal. A slope of >2.5 mmHg per L/min is probably abnormal in younger
individuals [14, 45–48]. Such criteria for the upper limits of normal for the mPAP–
CO relation are not yet officially endorsed in the PH guidelines because they require
external validation.
A study by Gruenig et al. [49] used the rise in systolic pulmonary artery pressure
(sPAP) during exercise, assessed with echocardiography, as a measure of the con-
tractile reserve of the RV. They showed in PAH and CTEPH patients that the increase
Fig. 11.5 The invasive cardiopulmonary exercise test. From Maron et al. The invasive cardiopul-
monary exercise test Journal: Circulation 2013;127:1157–1164, Fig. 3
of sPAP during exercise was an independent predictor of survival with a better

survival in the patients with a bigger contractile reserve [49].
Likewise, changes in PVR and PAWP from rest to exercise are poorly character-
ized. A recent meta-analysis showed that changes in PVR and PAWP during exercise
are dependent on age [50].
Despite the suggestion that evaluation of the hemodynamic response to exercise
aids the early detection of pathological cardiopulmonary changes and the distinc-
tion between exercise-induced PH and left-sided diastolic dysfunction [44, 48],
more and more widely disseminated experience with invasive CPET is necessary to
determine its value.
Conclusion
Eighty-five years after the first catheterization of the pulmonary circulation in man,
the normal hemodynamic behavior of the pulmonary circulation has been well char-
acterized and pulmonary hypertensive diseases have been recognized as a group
of clinical conditions with devastating effects on a person’s exercise capacity and
survival. The place of the RHC in the diagnosis and classification of pulmonary
hypertension is now firmly established, while the diagnostic and prognostic signifi-
cance of exercise testing are still being debated. In coming years, we can expect a
more detailed description of the limits of normal and of the pulmonary hemody-
namic response to exercise, hopefully ending controversies pertaining to the clinical
relevance of “out of proportion” and “exercise-induced” pulmonary hypertension
and RV dysfunction without PH [51].
Take Home Messages
Hemodynamic Evaluation
• Right heart catheterization is the golden standard for the assessment of hemody-
namics and for the diagnosis of PH.
• PH, defined as mPAP > 25 mmHg, can be due to three different hemodynamic
mechanisms: an increase in PVR, an increase in PAWP and an increase in CO.
• PAWP, TPG, and DPG can be used to distinguish pre- from postcapillary PH.
• CI and RAP are strong predictors of survival in PH.
Exercise Testing
• In PH, impaired exercise tolerance is mainly due to a limited increase in CO,

ventilatory insufficiency, and diaphragm weakness.
• Limited increase in CO is due to the inability to increase SV and an abnormal
chronotropic response and is leading to a decrease in VO2.
• Most frequently applied exercise tests are the 6MWT and CPET.
• Baseline 6MWD is a strong predictor of survival, although the change in 6MWD
with treatment is not.
• VO2max, the O2 pulse, and the anaerobic threshold are reduced in PH and reflect
RV dysfunction. An increased slope of the VE/VCO2 relation is a hallmark of PH.
• iCPET gives the opportunity of a complete hemodynamic and ventilatory evalu-
ation during exercise, although consensus about the upper limits of normal of
exercise hemodynamics is missing.
References
1. Nossaman BD, Scruggs BA, Nossaman VE, Murthy SN, Kadowitz PJ. History of right heart
catheterization: 100 years of experimentation and methodology development. Cardiol Rev.
2010;18(2):94–101.
2. Galie N, Hoeper MM, Humbert M, Torbicki A, Vachiery JL, Barbera JA, et al. Guidelines for
the diagnosis and treatment of pulmonary hypertension. Eur Respir J. 2009;34(6):1219–63.
3. Kovacs G, Avian A, Olschewski A, Olschewski H. Zero reference level for right heart
catheterization. Eur Respir J. 2013;42(6):1586–94.
4. Hoeper MM, Lee SH, Voswinckel R, Palazzini M, Jais X, Marinelli A, et al. Complications of
right heart catheterization procedures in patients with pulmonary hypertension in experienced
centers. J Am Coll Cardiol. 2006;48(12):2546–52.
5. Wood P. Pulmonary hypertension with special reference to the vasoconstrictive factor.
Br Heart J. 1958;20(4):557–70.
7. Lankhaar JW, Westerhof N, Faes TJ, Gan CT, Marques KM, Boonstra A, et al. Pulmonary
vascular resistance and compliance stay inversely related during treatment of pulmonary
hypertension. Eur Heart J. 2008;29(13):1688–95.
8. Lankhaar JW, Westerhof N, Faes TJ, Marques KM, Marcus JT, Postmus PE, et al. Quantification
of right ventricular afterload in patients with and without pulmonary hypertension. Am J
Physiol Heart Circ Physiol. 2006;291(4):H1731–7.
9. Tedford RJ, Hassoun PM, Mathai SC, Girgis RE, Russell SD, Thiemann DR, et al. Pulmonary
capillary wedge pressure augments right ventricular pulsatile loading. Circulation. 2012;
125(2):289–97.
10. Saouti N, Westerhof N, Helderman F, Marcus JT, Boonstra A, Postmus PE, et al. Right ven-
tricular oscillatory power is a constant fraction of total power irrespective of pulmonary artery
pressure. Am J Respir Crit Care Med. 2010;182(10):1315–20.
11. Haddad F, Kudelko K, Mercier O, Vrtovec B, Zamanian RT, de Jesus Perez V. Pulmonary
hypertension associated with left heart disease: characteristics, emerging concepts, and
treatment strategies. Prog Cardiovasc Dis. 2011;54(2):154–67.
12. Hoeper MM, Barbera JA, Channick RN, Hassoun PM, Lang IM, Manes A, et al. Diagnosis,
assessment, and treatment of non-pulmonary arterial hypertension pulmonary hypertension.
J Am Coll Cardiol. 2009;54(1 Suppl):S85–96.
13. Naeije R, Vachiery JL, Yerly P, Vanderpool R. The transpulmonary pressure gradient for the
diagnosis of pulmonary vascular disease. Eur Respir J. 2013;41(1):217–23.
14. Argiento P, Vanderpool RR, Mule M, Russo MG, D’Alto M, Bossone E, et al. Exercise stress
echocardiography of the pulmonary circulation: limits of normal and sex differences. Chest.
2012;142(5):1158–65.
15. Mehta PA, Dubrey SW. High output heart failure. QJM. 2009;102(4):235–41.
16. Hoeper MM, Krowka MJ, Strassburg CP. Portopulmonary hypertension and hepatopulmonary
syndrome. Lancet. 2004;363(9419):1461–8.
17. Spruijt OA, Bogaard HJ, Vonk-Noordegraaf A. Pulmonary arterial hypertension combined
with a high cardiac output state: three remarkable cases. Pulm Circ. 2013;3(2):440–3.
18. Humbert M, Sitbon O, Chaouat A, Bertocchi M, Habib G, Gressin V, et al. Survival in patients
with idiopathic, familial, and anorexigen-associated pulmonary arterial hypertension in the
modern management era. Circulation. 2010;122(2):156–63.
19. Benza RL, Miller DP, Gomberg-Maitland M, Frantz RP, Foreman AJ, Coffey CS, et al.
Predicting survival in pulmonary arterial hypertension: insights from the Registry to Evaluate
Early and Long-Term Pulmonary Arterial Hypertension Disease Management (REVEAL).
Circulation. 2010;122(2):164–72.
20. van de Veerdonk MC, Kind T, Marcus JT, Mauritz GJ, Heymans MW, Bogaard HJ, et al.
Progressive right ventricular dysfunction in patients with pulmonary arterial hypertension
responding to therapy. J Am Coll Cardiol. 2011;58(24):2511–9.
21. Nickel N, Golpon H, Greer M, Knudsen L, Olsson K, Westerkamp V, et al. The prognostic
impact of follow-up assessments in patients with idiopathic pulmonary arterial hypertension.
Eur Respir J. 2012;39(3):589–96.
22. Waxman AB. Exercise physiology and pulmonary arterial hypertension. Prog Cardiovasc Dis.
2012;55(2):172–9.
23. Holverda S, Gan CT, Marcus JT, Postmus PE, Boonstra A, Vonk-Noordegraaf A. Impaired
stroke volume response to exercise in pulmonary arterial hypertension. J Am Coll Cardiol.
2006;47(8):1732–3.
24. Ramos RP, Arakaki JS, Barbosa P, Treptow E, Valois FM, Ferreira EV, et al. Heart rate recov-
ery in pulmonary arterial hypertension: relationship with exercise capacity and prognosis. Am
Heart J. 2012;163(4):580–8.
25. Fowler RM, Gain KR, Gabbay E. Exercise intolerance in pulmonary arterial hypertension.
Pulm Med. 2012;2012:359204.
26. Velez-Roa S, Ciarka A, Najem B, Vachiery JL, Naeije R, van de Borne P. Increased sympa-
thetic nerve activity in pulmonary artery hypertension. Circulation. 2004;110(10):1308–12.
27. Provencher S, Chemla D, Herve P, Sitbon O, Humbert M, Simonneau G. Heart rate responses
during the 6-minute walk test in pulmonary arterial hypertension. Eur Respir J. 2006;27(1):
114–20.
28. Minai OA, Gudavalli R, Mummadi S, Liu X, McCarthy K, Dweik RA. Heart rate recovery
predicts clinical worsening in patients with pulmonary arterial hypertension. Am J Respir Crit
Care Med. 2012;185(4):400–8.
29. Sun XG, Hansen JE, Oudiz RJ, Wasserman K. Exercise pathophysiology in patients with
primary pulmonary hypertension. Circulation. 2001;104(4):429–35.
30. Hoeper MM, Pletz MW, Golpon H, Welte T. Prognostic value of blood gas analyses in patients
with idiopathic pulmonary arterial hypertension. Eur Respir J. 2007;29(5):944–50.
31. de Man FS, van Hees HW, Handoko ML, Niessen HW, Schalij I, Humbert M, et al. Diaphragm
muscle fiber weakness in pulmonary hypertension. Am J Respir Crit Care Med.
2011;183(10):1411–8.
32. Lipkin DP, Scriven AJ, Crake T, Poole-Wilson PA. Six minute walking test for assessing
exercise capacity in chronic heart failure. Br Med J (Clin Res Ed). 1986;292(6521):653–5.
33. Gilbert C, Brown MC, Cappelleri JC, Carlsson M, McKenna SP. Estimating a minimally
important difference in pulmonary arterial hypertension following treatment with sildenafil.
Chest. 2009;135(1):137–42.
34. Gabler NB, French B, Strom BL, Palevsky HI, Taichman DB, Kawut SM, et al. Validation of
6-minute walk distance as a surrogate end point in pulmonary arterial hypertension trials.
Circulation. 2012;126(3):349–56.
35. Peacock AJ, Naeije R, Galie N, Rubin L. End-points and clinical trial design in pulmonary
arterial hypertension: have we made progress? Eur Respir J. 2009;34(1):231–42.
36. Wasserman K. Principles of exercise testing and interpretation. Philadelphia: Lippincott
Williams & Wilkins; 1999.
37. Guazzi M, Cahalin LP, Arena R. Cardiopulmonary exercise testing as a diagnostic tool for the
detection of left-sided pulmonary hypertension in heart failure. J Card Fail. 2013;19(7):461–7.
38. Wensel R, Opitz CF, Anker SD, Winkler J, Hoffken G, Kleber FX, et al. Assessment of survival
in patients with primary pulmonary hypertension: importance of cardiopulmonary exercise
testing. Circulation. 2002;106(3):319–24.
39. Groepenhoff H, Vonk-Noordegraaf A, Boonstra A, Spreeuwenberg MD, Postmus PE, Bogaard
HJ. Exercise testing to estimate survival in pulmonary hypertension. Med Sci Sports Exerc.
2008;40(10):1725–32.
40. Groepenhoff H, Vonk-Noordegraaf A, van de Veerdonk MC, Boonstra A, Westerhof N,
Bogaard HJ. Prognostic relevance of changes in exercise test variables in pulmonary arterial
hypertension. PLoS One. 2013;8(9):e72013.
41. Deboeck G, Scoditti C, Huez S, Vachiery JL, Lamotte M, Sharples L, et al. Exercise testing to
predict outcome in idiopathic versus associated pulmonary arterial hypertension. Eur Respir
J. 2012;40(6):1410–9.
42. Wensel R, Francis DP, Meyer FJ, Opitz CF, Bruch L, Halank M, et al. Incremental prognostic
value of cardiopulmonary exercise testing and resting haemodynamics in pulmonary arterial
hypertension. Int J Cardiol. 2013;167(4):1193–8.
43. Zhai Z, Murphy K, Tighe H, Wang C, Wilkins MR, Gibbs JS, et al. Differences in ventilatory
inefficiency between pulmonary arterial hypertension and chronic thromboembolic pulmonary
hypertension. Chest. 2011;140(5):1284–91.
44. Maron BA, Cockrill BA, Waxman AB, Systrom DM. The invasive cardiopulmonary exercise
test. Circulation. 2013;127(10):1157–64.
45. Kovacs G, Berghold A, Scheidl S, Olschewski H. Pulmonary arterial pressure during rest and
exercise in healthy subjects: a systematic review. Eur Respir J. 2009;34(4):888–94.
46. D’Alto M, Ghio S, D’Andrea A, Pazzano AS, Argiento P, Camporotondo R, et al. Inappropriate
exercise-induced increase in pulmonary artery pressure in patients with systemic sclerosis.
Heart. 2011;97(2):112–7.
47. Naeije R. In defence of exercise stress tests for the diagnosis of pulmonary hypertension.
Heart. 2011;97(2):94–5.
48. Tolle JJ, Waxman AB, Van Horn TL, Pappagianopoulos PP, Systrom DM. Exercise-induced
pulmonary arterial hypertension. Circulation. 2008;118(21):2183–9.
49. Grunig E, Tiede H, Enyimayew EO, Ehlken N, Seyfarth HJ, Bossone E, et al. Assessment and
prognostic relevance of right ventricular contractile reserve in patients with severe pulmonary
hypertension. Circulation. 2013;128(18):2005–15.
50. Kovacs G, Olschewski A, Berghold A, Olschewski H. Pulmonary vascular resistances during
exercise in normal subjects: a systematic review. Eur Respir J. 2012;39(2):319–28.
51. Hilde JM, Skjorten I, Grotta OJ, Hansteen V, Melsom MN, Hisdal J, et al. Right ventricular
dysfunction and remodeling in chronic obstructive pulmonary disease without pulmonary
Chapter 12
Cardiac MRI and PET Scanning in Right
Ventricular Failure
Mariëlle C. van de Veerdonk, J. Tim Marcus, Harm-Jan Bogaard,

and Anton Vonk Noordegraaf
Introduction
Right ventricular (RV) failure may be defined as a complex clinical syndrome that
can result from any structural or functional cardiac disorder that impairs the ability
of the right heart to fill or eject appropriately [1]. In pulmonary arterial hypertension
(PAH), a progressive pulmonary vascular disease resulting in chronic pressure over-
load, patients die due to the consequences of RV failure [2, 3]. In the past, the RV
has been largely understudied and the pathophysiology of RV failure has remained
incompletely understood. It has become clear that increased pulmonary pressures
are insufficient to explain the development of RV failure [3–7]. Furthermore, it is
intriguing that end-stage RV failure can be completely reversed as is observed after
lung transplantation [8]. Recent advanced, noninvasive imaging techniques have
been developed that can directly study RV myocardial tissue processes and
may increase the insights into the factors contributing to the development of chronic
RV failure. Cardiac magnetic resonance imaging (MRI) and positron emission
tomography (PET) allow in vivo assessment of RV morphology, function, tissue
characterization, perfusion and blood flow, metabolism, neurohormonal activation,
and other molecular processes. These techniques may help to identify factors which
M.C. van de Veerdonk

J.T. Marcus, Ph.D.
Department of Physics & Medical Technology, VU University Medical Center,
e-mail: jt.marcus@vumc.nl
H.-J. Bogaard, M.D., Ph.D. • A.V. Noordegraaf, M.D., Ph.D. (*)
e-mail: hj.bogaard@vumc.nl; long@vumc.nl; a.vonk@vumc.nl

266 M.C. van de Veerdonk et al.
determine risk and prognosis and may allow assessment of therapeutic effects on
RV function in PAH patients.
Cardiac MRI provides high resolution imaging, does not need geometric assump-
tions and lacks ionizing radiation. It has been shown that two-dimensional and
three-dimensional cardiac MRI measures are highly accurate [9, 10] and reproduc-
ible [11]. MRI has become the gold standard to noninvasively measure RV mass,
volumes, and function [12] and has the ability to image perfusion and cellular and
molecular tissue characteristics. Although the role of MRI in establishing the diag-
nosis of PAH is limited, it allows complete RV phenotyping and is especially valu-
able in the monitoring of therapeutic effects. However because MRI is relatively
expensive and requires operator expertise, this methodology is not widely used.
Furthermore, scan times quite long-end ferromagnetic objects such as pacemakers
and defibrillators are incompatible. Nevertheless, its (clinical) relevance has been
clearly established [12]. PET is a rapidly developing technique allowing perfusion
imaging, assessment of molecular and physiologic processes, and evaluation of the
cardiac nervous system. Limitations of PET are its costs and labor intensity.
Furthermore, due to the relatively low spatial resolution, current clinical PET-
scanners are combined with computed tomography (CT). In PAH, PET has only
been recently used and broader application can be expected in the near future. In
addition, rapid developments in hybrid scanners consisting of PET and MRI are
taking place in order to allow integrated cardiac assessment.
Here we provide an overview of current and future applications of cardiac MRI
and PET for assessment of chronic RV failure and review potential contributing fac-
tors that could help considerably to understand the pathophysiology of RV failure in
the setting of chronic pressure overload. Furthermore, we demonstrate the potential
clinical relevance of these imaging techniques in patients with PAH.
RV Structural and Functional Imaging
RV Remodeling and Wall Stress
Figure 12.1 demonstrates cardiac MRI cine images obtained over time from a
35-year-old, female patient who was diagnosed as having idiopathic PAH, New York
Heart Association (NYHA) functional class II. Mean pulmonary artery pressure
was 45 mmHg and cardiac output (CO) was 4.1 L/min. At the time of diagnosis, she
showed cardiac compensation with a maintained crescent shape of the RV, RV
hypertrophy with an increased RV mass, relatively preserved cardiac dimensions
(but a small increase in RV volume), no pericardial effusion and moderate RV and
left ventricular (LV) function (Fig. 12.1a). Despite unchanged pulmonary pressures
after 7 years of follow-up, she developed symptoms of progressive RV failure, even
though the CO remained relatively stable. Figure 12.1 demonstrates the characteris-
tics of the progression to RV failure by showing the development of a spherical RV
shape, progressively enlarged RV cross sectional area, apical ballooning, thinning
12 Cardiac MRI and PET Scanning in Right Ventricular Failure 267
Fig. 12.1 Cardiac magnetic resonance imaging (MRI) four-chamber (A1–C1) and short-axis cine
images (A2–C2) obtained in a patient with pulmonary arterial hypertension (PAH) over time. The
course from right ventricular (RV) structural compensation to end-stage RV failure is demon-
strated. This patient was diagnosed with an elevated mean pulmonary artery pressure (PAP) of
45 mmHg and a cardiac output (CO) of 4.1 L/min. At baseline, the RV shows a concentric RV
remodeling pattern with increased RV mass, a crescent RV shape, small amounts of dilatation,
modest RV function (right ventricular ejection fraction (RVEF): 39 %), and preserved left ven-
tricular (LV) function (left ventricular ejection fraction (LVEF): 62 %) (A1, A2). During 7 years of
follow-up, PAP was unchanged and CO remained relatively stable. However, the RV remodeling
pattern has changed (B, C). RV end-diastolic volume (RVEDV) showed a progressive increase
from 140 to 449 mL. Smaller increases in RV mass were observed. Furthermore, the RV developed
a spherical shape, apical ballooning, bulging of the interventricular septum into the LV (dark
arrows), an enlarged right atrium, tricuspid insufficiency, and pericardial effusion (white arrows).
In addition, RVEF and LVEF showed a progressive decline to 8 % and 29 % respectively. PAP
(m/s/d) pulmonary artery pressure (mean/systole/diastole), SV stroke volume
of the RV wall, bulging of the interventricular septum (IVS) into the LV, underfilling
of the LV, an increased right atrium, tricuspid insufficiency, pericardial effusion, and
severely impaired biventricular function.
The combined assessment of multiple RV imaging parameters provides insights
into RV remodeling. According to a basic physiological principle of Guyton and
Hall, the heart primarily functions as an on-demand pump to maintain CO in order
to fulfill the needs of sufficient oxygen delivery to the body [13]. In the setting of
chronic RV pressure overload, the RV compensates enduringly (i.e., by Frank–

Starling mechanism [see also Chap. 2], RV dilatation, RV hypertrophy, tachycardia,
changes in contractility) in order to sustain the CO. However, in the long run RV
compensation mechanisms may get exhausted resulting in disturbed intrinsic RV struc-
ture and ultimately RV dysfunction and failure. Importantly, imaging of the RV might
be of clinical relevance since it is likely that early changes in the RV structure could
predict an ultimate RV functional deterioration (Fig. 12.1).
Based on the combined MRI assessment of RV mass, shape and volumes and by
measures of RV pressure, ventricular wall stress can be estimated using the law of
Laplace (i.e., wall stress = intraluminal pressure times chamber internal radius,
divided by wall thickness) [14]. According to Laplace, RV hypertrophy is considered
part of the adaptive remodeling response to increase RV pumping effectiveness by
unloading of the individual muscle fibers and lowering ventricular wall stress. In
contrast, an increased RV mass measured by cardiac MRI is associated with an
increased mortality in scleroderma-associated PAH patients [15] and might have
some prognostic relevance in idiopathic PAH [16]. These still ambiguous findings
might be explained by several aspects. First, although RV mass in patients with PAH
measured by MRI can be more than 2.5 times increased when compared to normal
reference values [17], the RV often faces at rest a fourfold increase in pulmonary
artery pressures indicating that the amount of RV hypertrophy may or may not be
insufficient to lower the wall stress and protect RV function. This is in keeping with
several MRI studies showing that, in PAH patients RV mass and pulmonary pressures
are only modestly related [15, 18, 19]. Furthermore, it has been observed that patients
with PAH associated with the Eisenmenger syndrome showed a higher amount of RV
hypertrophy despite a similar elevation in pulmonary pressure compared to idio-
pathic PAH patients; in those patients with RVH was associated with better RV func-
tion and survival [20, 21]. However, in RV autopsy tissue of PAH patients and in rat
models with pulmonary hypertension (PH) it has been found that an increase in RV
mass is not necessarily accompanied by a similar increase in the number of contrac-
tile elements [22]. Second, using MRI with gadolinium contrast it has been demon-
strated that degenerative changes occur in the hypertrophic RV of PAH patients.
It was found that delayed contrast enhancement (DCE) appears as a unique pattern at
the IVS insertion points and might be a reflection of focal fibrosis [23–26]. The
extent of DCE was most strongly correlated with increased RV mass, volumes, and
pulmonary pressures (i.e., RV wall stress) [23, 24]. Third, RV hypertrophy is associ-
ated with maladaptive changes in RV metabolism and blood flow (see below).
During chronic pressure overload, the RV phenotype changes from a more con-
centric (Fig. 12.1a) towards an eccentric remodeling pattern (Fig. 12.1b, c). The RV
shape becomes more like the LV. In contrast to the crescent shape and bellows-like
contraction pattern of the normal RV wall, a spherical RV shape in PAH might toler-
ate high pressure without generating high wall stress due to a decreased RV wall
curvature radius of end-systole [27]. In addition, the RV dilates and it has been
found by MRI that increased RV end-diastolic volume at baseline and progressive
dilatation during follow-up were among the strongest predictors of mortality in
PAH [16]. Although RV dilatation might be beneficial at first resulting in increased

preload via the Frank–Starling mechanism to increase contractility and sustain CO,
this compensatory mechanism eventually fails and results in a maladaptive course
of remodeling with increased wall stress, disturbed RV function, and ultimately
depressed RV output.
RV Contractility
Load-independent RV contractility can be assessed by right heart catheterization

according to the single-beat method [28–32]. Noninvasive MRI approaches have
also been developed to estimate RV contractility [33, 34]. In PAH patients, RV con-
tractility is increased compared to controls. However, paradoxically global RV sys-
tolic function (e.g. determined by RV ejection fraction and stroke volume) is
significantly decreased in PAH. This paradox is explained by the fact that in PAH,
RV hypercontractility augmentation is insufficient for the degree of pressure over-
load, a phenomenon which has been described as ventriculo-arterial uncoupling
[28, 29, 33, 34] (see also Chap. 2). In addition to a systolic impairment, it was
recently demonstrated that RV diastolic stiffness is increased in PAH patients and
this was related to disease severity [28].
RV Function
Imaging parameters describing global systolic RV function are all load dependent
and therefore reflect RV-arterial coupling rather than intrinsic RV contractility. In
fact, global RV systolic function is determined by multiple factors: preload, after-
load, contractility, ventricular synchrony, valvular regurgitation, and shunt fraction
[3, 35]. Low stroke volume and low RV ejection fraction at baseline and a further
decrease during follow-up were associated with worse outcome [4, 16, 36].
Furthermore, stroke volume determined by MRI has been validated as the imaging
parameter to monitor therapeutic effects [37]. In addition, after current medical
therapies, it has been found that the changes in RVEF were only modestly related to
the changes in RV load (measured by pulmonary vascular resistance (PVR)).
Moreover, despite the fact that PVR is reduced by treatment, RVEF can deteriorate.
The decrease in RVEF was associated with poor outcome, independent of the reduc-
tion in PVR (Fig. 12.2) [4].
The determination of RV ejection fraction is relatively time consuming whereas
stroke volume can be more easily obtained by phase contrast mapping MRI [38].
Other more readily applicable measures of RV function have also been explored.
RV shortening in a longitudinal plane (tricuspid annular plane excursion or TAPSE)
and transverse plane provided simple estimates of RV ejection fraction of which
transverse shortening showed the strongest correlation [39]. In addition, Mauritz
Fig. 12.2 After 1 year of

current PAH targeted medical
treatment, the changes in
pulmonary vascular
resistance (PVR) were
modestly related to the
changes in RVEF (a). In the
PAH patients with a reduced
PVR after therapy, a decrease
in RVEF was associated with
a worse survival compared to
patients with a stable/
improved RVEF. Both groups
showed a similar decrease in
PVR after treatment (mean
PVR reduction: 284 ±
248 dyne s cm5) (b) [4]
et al. showed that assessments of both parameters are valuable, but that changes in
transverse wall motion rather than changes in TAPSE reflect RV dysfunction during
end-stage disease [36].
Regional ventricular wall deformation and ventricular synchrony are important
aspects of RV function. MRI tagging techniques are considered as the reference
techniques to measure the relative amount of myocardial wall deformation (seg-
mental strain), the velocity of deformation (strain rate), and synchrony (i.e., timing
of mechanical activation and relaxation between wall segments); all of these param-
eters can be determined in a circumferential, longitudinal, and radial axis. It has
been found that in the healthy RV, there is a predominant longitudinal rather than
circumferential wall deformation, resulting in a bellows-like or peristaltic action.
Normal wall deformation is in general larger at the basal and apical segments than
at the mid-segment [40]. Patients with PH showed an altered pattern with a globally
reduced longitudinal and circumferential wall deformation [41]. Furthermore, it has
been found that regional longitudinal wall deformation can already be disturbed at
the time that global RV function is still intact, implying that changes in regional
measures could be sensitive parameters to detect early RV dysfunction in PAH [42].
In addition, it has been shown by MRI that RV asynchrony may contribute
to the development of impaired cardiac function. In PAH patients, RV mechani-
cal contraction is prolonged and continues after the pulmonary valve closes
(resulting in a so-called post-systolic contraction period) rendering RV contraction

inefficient [43, 44]. In addition, at the time that the RV still contracts, the LV in PAH
is already in its relaxation phase, leading to leftward septum bowing, a low LV
end-diastolic volume and decreased stroke volume [44–46]. In fact, a low LV
end-diastolic volume appears to be a strong predictor of poor prognosis [16].
RV Molecular and Perfusion Imaging
RV Metabolic Remodeling
PET studies have demonstrated that in LV cardiomyopathies a switch takes place

from primarily fatty acid metabolism to glucose metabolism in order to maintain the
adenosine triphosphate (ATP) supply [47, 48]. In the failing human RV under
chronic pressure overload, single photon emission computed tomography (SPECT)
has demonstrated a decreased RV uptake of fatty acids which was associated with
impaired RV function and poor prognosis [49]. Fatty acid uptake can also be esti-
mated using PET with 11C-palmitate tracers [47, 50] but such studies have yet to be
performed in PAH. In addition, RV myocardial glucose metabolism can be mea-
sured by PET with 18F-2-deoxy-2-fluoro-D-Glucose (18FDG) tracers [51]. Some
studies have demonstrated an increase in the ratio of RV to LV glucose uptake in
PAH patients. However it remains unclear whether this ratio is explained by an
increased RV glucose uptake [52–54] or a lowered LV uptake [55]. Furthermore,
inconsistent results have been reported with respect to the relevance of glucose
metabolism in relationship with RV load and function [51, 54–58]. The differences
between study results are perhaps due to differences in patient populations, scan-
ning protocols, or data analysis. At this moment, it remains unclear which changes
in metabolism occur in the RV of PAH patients and whether these changes can be
regarded as adaptive or indicative of pathological remodeling. This area of imaging
of RV metabolism will likely be further developed in the coming years.
RV Blood Flow and Oxygen Balance
By use of Using PET with a combination of 15O-labeled tracers (15O-H2O, 15O-

CO, and 15O-O2) or by a more practical method using 11C-acetate tracers, RV
myocardial oxygen consumption (MVO2) can be estimated [59, 60]. It has been
demonstrated that resting MVO2 is significantly elevated in patients with PAH
(Fig. 12.2) and this finding is primarily determined by increased pulmonary pres-
sures and an increased heart rate [58, 61]. PAH patients in NYHA class III show a
higher MVO2 compared to NYHA class II patients, despite a similar RV power
output, which implies that the RV of these patients becomes mechanically ineffi-
cient (Figs. 12.3 and 12.4) [58].
Fig. 12.3 A four-chamber (a) and short-axis (b) image obtained by positron emission tomography
(PET) with 11C-acetate tracers in the same patient with end-stage RV failure as in Fig. 1. It is
demonstrated that part of the RV wall shows an increased myocardial oxygen consumption
(MVO2) (bright, yellow) that can be even higher compared to the LV
Fig. 12.4 Impaired RV mechanical efficiency in patients with PAH is primarily determined by
increased MVO2. Light gray bars = New York Heart Association (NYHA) Functional class II
patients, dark bars = NYHA functional class III patients. Patients in NYHA II showed a higher
cardiac output (CO) (a) and similar mean pulmonary artery pressure (mPAP) (b) compared to
NYHA III patients. Consequently, RV power output (i.e., product of CO and mean PAP) was simi-
lar in both groups (e). RV myocardial blood flow determined by positron emission tomography
(PET) with H215O tracers (c) and oxygen (O2) extraction fraction estimated by PET using 15O2
tracers (d) were not statistically different in both groups. However, there was a significantly higher
MVO2 per gram of myocardial tissue in NYHA III compared to NYHA II patients (f). RV mechan-
ical efficiency was reduced by ~50 % in NYHA III in comparison with NYHA II as a result of a
similar RV power output but higher MVO2 (g). [58] (Wong et al. Circ HF 2011; Reprint Fig. 3)
The normal RV has two mechanisms which generate an increased MVO2 during
stress: (1) coronary flow reserve and (2) oxygen extraction fraction (OEF) reserve
[62–65]. In patients with PAH during resting conditions, the OEF is already ele-
vated whereas the mean resting myocardial blood flow is similar in PAH compared
to controls [58, 66, 67]. In addition, PAH patients show an impaired perfusion
reserve since myocardial blood flow did neither increase during adenosine-induced
stress MRI [66] nor during PET imaging with cycling exercise [68]. Surprisingly,
the change in myocardial blood flow during exercise was unrelated to resting
OEF. Especially in patients with a high resting OEF, an attenuated increase in blood
flow during exercise was observed and was related to a poorer clinical, hemody-
namic and RV condition [66, 68]. The findings of impaired myocardial blood flow
reserve might be explained by multiple factors. First, although mean resting coro-
nary blood flow was unchanged, coronary flow was inversely related to the amount
of RV hypertrophy [67]. Transmural blood flow may be impaired, perhaps as a
consequence of a reduced capillary density of the failing RV tissue [22]. Indeed,
impaired angiogenesis might play a role in the mismatch between hypertrophic
myocytes and capillaries. Second, the resting coronary blood flow and perfusion
reserve are both negatively associated with increased pulmonary pressures [66, 67],
which could imply that these extravascular compressive forces may restrict an
increase in blood flow. Other explanations could be impaired autoregulatory flow
mechanisms [69] and systemic hypotension resulting in reduced coronary driving
pressures. However, van Wolferen et al. showed that the latter factor is probably not
a major determinant of impaired RV flow in PAH [67].
To summarize, the increased RV oxygen demand in patients with PAH is
not adequately compensated for by an increased oxygen supply. As a potential
consequence, Gomez et al. observed RV ischemia in PAH patients by SPECT
imaging [70].
The Near Future of RV Molecular Imaging
RV Angiogenesis
In PH animal models, impaired angiogenesis in the setting of RV hypertrophy has

been demonstrated; might lead to RV ischemia and fibrosis [35, 71]. Vascular endo-
thelial growth factor (VEGF) is a major contributor to angiogenesis and integrins
serve as important mediators of angiogenesis. Novel imaging strategies have been
developed that can directly measure angiogenesis in vivo using PET with tracers
such as 64CU-labeled VEGF121 or 18F arginine–glycine–aspartic acid peptide
(RGD) with affinity for the αvβ3 integrins. Angiogenic imaging has successfully
been performed in rat models with myocardial infarction [72–74] and in a patient
2 weeks after myocardial infarction [75]. These imaging techniques may become
important in the assessment of pathophysiological mechanisms of RV disease
processes in vivo in PAH.
RV Apoptosis
Apoptosis is defined as programmed cell death and may play a causal role in the
development of cardiac hibernation and heart failure [76]. Radiolabeled annexin
can be used as an imaging protein that binds to phosphatidylserine (PS); a phospho-
lipid expressed on the outer cell membrane during apoptosis which serves as a
marker for macrophages to remove apoptotic cells [77]. It has been demonstrated by
SPECT that increased 99Tc-Labeled annexin V uptake was associated with the
deterioration of LV function in patients with LV failure [78]; increased annexin
uptake was also related to allograft rejection in cardiac transplant recipients [79].
Such studies have not yet been performed in PAH patients but in PH animal models
increased levels of SPECT cardiac annexin V uptake have been detected [80].
In addition, activated caspases are involved in the signal transduction of apoptosis
and when radiolabeled, they can be used for PET measurements of apoptosis in vivo.
In mouse models of dilated cardiomyopathies, it has been shown that although the
overall rate of myocyte apoptosis was low, persistent levels can overwhelm the
limited regenerative capacity of the myocardium contributing to heart failure [81].
RV Neurohormonal System
Preclinical studies have demonstrated that dysfunctional neuronal signaling might

be an important hallmark in the development of RV failure in PAH [82]. PET imag-
ing with radiolabeled norepinephrine (NE) analogs such as 11C-meta-
hydroxyephedrine (HED) can be applied to estimate presynaptic sympathetic
function and 11C-CGP-12177 or 11C-CGP-12388 tracers are used to estimate lev-
els of postsynaptic sympathetic β-adrenoceptors. HED reuptake and β-adrenoceptor
density were reduced in patients with LV cardiomyopathies and associated with
impaired LV function and worse survival [83–85].
The renin–angiotensin–aldosterone system (RAAS) activity in PAH is increased
and associated with disease severity [86]. By use of PET imaging with 11C-
KR31173 tracers, levels of cardiac angiotensin receptors have been detected in
healthy volunteers [87] such data might be of pathophysiological interest also in
patients with PAH.
Magnetic Resonance Spectroscopy
Magnetic resonance spectroscopy (MRS) is a technically difficult technique but can

provide insight into cardiac metabolism in vivo without requirements of an external
tracer. There is limited expertise in the field of PAH [88] but multiple studies have
been performed in patients with LV failure. Multiple 31 Phosphorus MRS studies
have demonstrated that LV levels of creatine and ATP were decreased in advanced
heart failure and related to survival [89].
Fig. 12.5 Short-axis images obtained by hybrid PET-MRI in a patient with myocardial infarction
of the septal and anteroseptal wall. MRI with late gadolinium enhancement (LGE) demonstrates
the infarct zone with a no-reflow phenomenon (arrows) (a). Fusion of 18F-2-deoxy-2-fluoro-D-
Glucose (18FDG) PET and MRI LGE images demonstrates absent 18FDG uptake in the infarcted
area (b) [91]. (Nensa et al. Radiology 2013; Reprint Fig. 2)
Hybrid PET-MRI
Currently, hybrid PET-CT has become commonplace in clinical practice and

research settings and has significantly contributed to our insights into pathophysio-
logical processes in cardiovascular diseases [90]. Although CT allows detailed
structural imaging it is less useful in RV functional assessment. Hybrid PET-MRI is
an innovative, rapidly accepted technique which does not only allow (simultaneous)
combination of PET with anatomic imaging but also provides functional imaging,
perfusion imaging, tissue characterization, and flow imaging that might provide
improved insights into the pathophysiology of RV failure. However one limitation
of hybrid systems with MRI is that information required for attenuation correction
of nuclear images is not provided. Recently, the first hybrid PET-MRI results of
patients with myocardial infarction have been published and have demonstrated
high image qualities (Fig. 12.5) [91–93].
Summary and Conclusions
We predict that in vivo cardiac MRI and PET will significantly contribute to a better
understanding of the pathophysiological processes which lead to the development
of chronic RV failure. Imaging studies have demonstrated that in the setting of
chronic pressure overload, the RV compensates enduringly to sustain CO by an
increase in wall mass, dilatation and contractility, and marked changes in the RV
shape. With passage of time, these compensation mechanisms fail, resulting in
increased wall stress and impaired global RV function. Other factors that might
contribute to disturbed RV function are a reduced wall deformation and an
inefficient RV contraction pattern. The resulting interventricular asynchrony is

associated with leftward septum bowing, impaired LV filling, and decreased stroke
volume. Furthermore, the RV becomes mechanically insufficient: more oxygen is
required for a comparable power output. At the same time, RV oxygen delivery is
impaired and tissue oxygenation is reduced. Alterations in myocardial metabolism
have been observed in PAH, but their overall relevance and cause or consequence of
RV failure remains unclear. In the near future it can be expected that the importance
of changes in cellular functions and signaling pathways will become clear and
“imageable.” This may allow a regional and quantifiable analysis of processes such
as angiogenesis, apoptosis, and neurohormonal factors impact. Fig. 12.1 provides
an overview of currently available clinical imaging tracers that could be relevant for
the assessment of molecular processes of RV diseases in patients. In addition, recent
developments in (hybrid) PET and MRI might allow an integrated RV assessment
in vivo. They will likely provide an important basis for simultaneous measurements
of multiple myocardial disease processes.
Acknowledgements We would like to thank Dr. Hans Harms for his support of the image
collection.
References
1. Hunt SA, Abraham WT, Chin MH, Feldman AM, Francis GS, Ganiats TG, et al. 2009
Focused update incorporated into the ACC/AHA 2005 guidelines for the diagnosis and man-
agement of heart failure in adults a report of the American College of Cardiology Foundation/
American Heart Association Task Force on Practice Guidelines developed in collaboration
with the International Society for Heart and Lung Transplantation. J Am Coll Cardiol.
2009;53(15):e1–90.
2. McLaughlin VV, McGoon MD. Pulmonary arterial hypertension. Circulation. 2006;114(13):
1417–31.
3. Voelkel NF, Quaife RA, Leinwand LA, Barst RJ, McGoon MD, Meldrum DR, et al. Right
ventricular function and failure: report of a National Heart, Lung, and Blood Institute working
group on cellular and molecular mechanisms of right heart failure. Circulation. 2006;
114(17):1883–91.
4. van de Veerdonk MC, Kind T, Marcus JT, Mauritz GJ, Heymans MW, Bogaard HJ, et al.
Progressive right ventricular dysfunction in patients with pulmonary arterial hypertension
responding to therapy. J Am Coll Cardiol. 2011;58(24):2511–9.
6. Bristow MR, Zisman LS, Lowes BD, Abraham WT, Badesch DB, Groves BM, et al. The
pressure-overloaded right ventricle in pulmonary hypertension. Chest. 1998;114(1 Suppl):
101S–6.
7. Morrison D, Goldman S, Wright AL, Henry R, Sorenson S, Caldwell J, et al. The effect of
pulmonary hypertension on systolic function of the right ventricle. Chest. 1983;84(3):
250–7.
8. Pasque MK, Trulock EP, Cooper JD, Triantafillou AN, Huddleston CB, Rosenbloom M, et al.
Single lung transplantation for pulmonary hypertension. Single institution experience in 34
patients. Circulation. 1995;92(8):2252–8.
9. Shors SM, Fung CW, Francois CJ, Finn JP, Fieno DS. Accurate quantification of right
ventricular mass at MR imaging by using cine true fast imaging with steady-state precession:
study in dogs. Radiology. 2004;230(2):383–8.
10. Katz J, Whang J, Boxt LM, Barst RJ. Estimation of right ventricular mass in normal subjects
and in patients with primary pulmonary hypertension by nuclear magnetic resonance imag-
ing. J Am Coll Cardiol. 1993;21(6):1475–81.
11. Grothues F, Moon JC, Bellenger NG, Smith GS, Klein HU, Pennell DJ. Interstudy reproduc-
ibility of right ventricular volumes, function, and mass with cardiovascular magnetic reso-
nance. Am Heart J. 2004;147(2):218–23.
12. Pennell DJ, Sechtem UP, Higgins CB, Manning WJ, Pohost GM, Rademakers FE, et al.
Clinical indications for cardiovascular magnetic resonance (CMR): Consensus Panel report.
Eur Heart J. 2004;25(21):1940–65.
13. Hall JE. Guyton and hall textbook of medical physiology. 12th ed. Philadelphia: Elsevier
Health Sciences; 2010.
14. Mauritz GJ, Vonk-Noordegraaf A, Kind T, Surie S, Kloek JJ, Bresser P, et al. Pulmonary
endarterectomy normalizes interventricular dyssynchrony and right ventricular systolic wall
stress. J Cardiovasc Magn Reson. 2012;14:5.
15. Hagger D, Condliffe R, Woodhouse N, Elliot CA, Armstrong IJ, Davies C, et al. Ventricular
mass index correlates with pulmonary artery pressure and predicts survival in suspected sys-
temic sclerosis-associated pulmonary arterial hypertension. Rheumatology (Oxford).
2009;48(9):1137–42.
16. van Wolferen SA, Marcus JT, Boonstra A, Marques KM, Bronzwaer JG, Spreeuwenberg
MD, et al. Prognostic value of right ventricular mass, volume, and function in idiopathic
pulmonary arterial hypertension. Eur Heart J. 2007;28(10):1250–7.
17. Kawut SM, Lima JA, Barr RG, Chahal H, Jain A, Tandri H, et al. Sex and race differences in
right ventricular structure and function: the multi-ethnic study of atherosclerosis-right
ventricle study. Circulation. 2011;123(22):2542–51.
18. Roeleveld RJ, Marcus JT, Boonstra A, Postmus PE, Marques KM, Bronzwaer JG, et al.
A comparison of noninvasive MRI-based methods of estimating pulmonary artery pressure in
pulmonary hypertension. J Magn Reson Imaging. 2005;22(1):67–72.
19. Saba TS, Foster J, Cockburn M, Cowan M, Peacock AJ. Ventricular mass index using mag-
netic resonance imaging accurately estimates pulmonary artery pressure. Eur Respir
J. 2002;20(6):1519–24.
20. Hopkins WE, Waggoner AD. Severe pulmonary hypertension without right ventricular
failure: the unique hearts of patients with Eisenmenger syndrome. Am J Cardiol. 2002;
89(1):34–8.
21. Hopkins WE, Ochoa LL, Richardson GW, Trulock EP. Comparison of the hemodynamics
and survival of adults with severe primary pulmonary hypertension or Eisenmenger syn-
drome. J Heart Lung Transplant. 1996;15(1 Pt 1):100–5.
22. Ruiter G, Ying Wong Y, de Man FS, Louis Handoko M, Jaspers RT, Postmus PE, et al. Right
ventricular oxygen supply parameters are decreased in human and experimental pulmonary
hypertension. J Heart Lung Transplant. 2013;32(2):231–40.
23. Sanz J, Dellegrottaglie S, Kariisa M, Sulica R, Poon M, O’Donnell TP, et al. Prevalence and
correlates of septal delayed contrast enhancement in patients with pulmonary hypertension.
Am J Cardiol. 2007;100(4):731–5.
in pulmonary artery hypertension. AJR Am J Roentgenol. 2007;188(2):349–55.
25. McCann GP, Beek AM, Vonk-Noordegraaf A, van Rossum AC. Delayed contrast-enhanced
magnetic resonance imaging in pulmonary arterial hypertension. Circulation. 2005;
112(16):e268.
26. Blyth KG, Groenning BA, Martin TN, Foster JE, Mark PB, Dargie HJ, et al. Contrast
enhanced-cardiovascular magnetic resonance imaging in patients with pulmonary hyperten-
sion. Eur Heart J. 2005;26(19):1993–9.
27. Greyson CR. Pathophysiology of right ventricular failure. Crit Care Med. 2008;36(1
Suppl):S57–65.
28. Rain S, Handoko ML, Trip P, Gan TJ, Westerhof N, Stienen G, et al. Right ventricular dia-
stolic impairment in patients with pulmonary arterial hypertension. Circulation. 2013;128(18):
2016–25, 1–10.
29. Tedford RJ, Mudd JO, Girgis RE, Mathai SC, Zaiman AL, Housten-Harris T, et al. Right
ventricular dysfunction in systemic sclerosis associated pulmonary arterial hypertension.
Circ Heart Fail. 2013;6(5):953–63.
30. Trip P, Kind T, van de Veerdonk MC, Marcus JT, de Man FS, Westerhof N, et al. Accurate
assessment of load-independent right ventricular systolic function in patients with pulmonary
hypertension. J Heart Lung Transplant. 2013;32(1):50–5.
31. Brimioulle S, Wauthy P, Ewalenko P, Rondelet B, Vermeulen F, Kerbaul F, et al. Single-beat
estimation of right ventricular end-systolic pressure-volume relationship. Am J Physiol Heart
Circ Physiol. 2003;284(5):H1625–30.
32. Sunagawa K, Yamada A, Senda Y, Kikuchi Y, Nakamura M, Shibahara T, et al. Estimation of
the hydromotive source pressure from ejecting beats of the left ventricle. IEEE Trans Biomed
Eng. 1980;27(6):299–305.
33. Sanz J, Garcia-Alvarez A, Fernandez-Friera L, Nair A, Mirelis JG, Sawit ST, et al. Right
ventriculo-arterial coupling in pulmonary hypertension: a magnetic resonance study. Heart.
2012;98(3):238–43.
34. Kuehne T, Yilmaz S, Steendijk P, Moore P, Groenink M, Saaed M, et al. Magnetic resonance
imaging analysis of right ventricular pressure-volume loops: in vivo validation and clinical
application in patients with pulmonary hypertension. Circulation. 2004;110(14):2010–6.
2009;135(3):794–804.
36. Mauritz GJ, Kind T, Marcus JT, Bogaard HJ, van de Veerdonk M, Postmus PE, et al.
Progressive changes in right ventricular geometric shortening and long-term survival in pul-
monary arterial hypertension. Chest. 2012;141(4):935–43.
37. van Wolferen SA, van de Veerdonk MC, Mauritz GJ, Jacobs W, Marcus JT, Marques KM,
et al. Clinically significant change in stroke volume in pulmonary hypertension. Chest.
2011;139(5):1003–9.
38. Mauritz GJ, Marcus JT, Boonstra A, Postmus PE, Westerhof N, Vonk-Noordegraaf A. Non-
invasive stroke volume assessment in patients with pulmonary arterial hypertension: left-
sided data mandatory. J Cardiovasc Magn Reson. 2008;10:51.
39. Kind T, Mauritz GJ, Marcus JT, van de Veerdonk M, Westerhof N, Vonk-Noordegraaf
A. Right ventricular ejection fraction is better reflected by transverse rather than longitudinal
wall motion in pulmonary hypertension. J Cardiovasc Magn Reson. 2010;12:35.
40. Petitjean C, Rougon N, Cluzel P. Assessment of myocardial function: a review of quantifica-
tion methods and results using tagged MRI. J Cardiovasc Magn Reson. 2005;7(2):501–16.
41. Fayad ZA, Ferrari VA, Kraitchman DL, Young AA, Palevsky HI, Bloomgarden DC, et al.
Right ventricular regional function using MR tagging: normals versus chronic pulmonary
hypertension. Magn Reson Med. 1998;39(1):116–23.
42. Shehata ML, Harouni AA, Skrok J, Basha TA, Boyce D, Lechtzin N, et al. Regional and
global biventricular function in pulmonary arterial hypertension: a cardiac MR imaging
study. Radiology. 2013;266(1):114–22.
43. Mauritz GJ, Marcus JT, Westerhof N, Postmus PE, Vonk-Noordegraaf A. Prolonged right
ventricular post-systolic isovolumic period in pulmonary arterial hypertension is not a reflec-
tion of diastolic dysfunction. Heart. 2011;97(6):473–8.
44. Marcus JT, Gan CT, Zwanenburg JJ, Boonstra A, Allaart CP, Gotte MJ, et al. Interventricular
mechanical asynchrony in pulmonary arterial hypertension: left-to-right delay in peak short-
ening is related to right ventricular overload and left ventricular underfilling. J Am Coll
Cardiol. 2008;51(7):750–7.
45. Gan CT, Holverda S, Marcus JT, Paulus WJ, Marques KM, Bronzwaer JG, et al. Right
ventricular diastolic dysfunction and the acute effects of sildenafil in pulmonary hypertension
patients. Chest. 2007;132(1):11–7.
46. Vonk-Noordegraaf A, Marcus JT, Gan CT, Boonstra A, Postmus PE. Interventricular mechan-
ical asynchrony due to right ventricular pressure overload in pulmonary hypertension plays
an important role in impaired left ventricular filling. Chest. 2005;128(6 Suppl):628S–30.
47. de las Fuentes L, Herrero P, Peterson LR, Kelly DP, Gropler RJ, Davila-Roman VG. Myocardial
fatty acid metabolism: independent predictor of left ventricular mass in hypertensive heart
disease. Hypertension. 2003;41(1):83–7.
48. Davila-Roman VG, Vedala G, Herrero P, de las Fuentes L, Rogers JG, Kelly DP, et al. Altered
myocardial fatty acid and glucose metabolism in idiopathic dilated cardiomyopathy. J Am
Coll Cardiol. 2002;40(2):271–7.
49. Nagaya N, Goto Y, Satoh T, Uematsu M, Hamada S, Kuribayashi S, et al. Impaired regional
fatty acid uptake and systolic dysfunction in hypertrophied right ventricle. J Nucl Med.
1998;39(10):1676–80.
50. Bergmann SR, Weinheimer CJ, Markham J, Herrero P. Quantitation of myocardial fatty acid
metabolism using PET. J Nucl Med. 1996;37(10):1723–30.
51. Bokhari S, Raina A, Rosenweig EB, Schulze PC, Bokhari J, Einstein AJ, et al. PET imaging
may provide a novel biomarker and understanding of right ventricular dysfunction in patients
with idiopathic pulmonary arterial hypertension. Circ Cardiovasc Imaging. 2011;4(6):641–7.
52. Lundgrin EL, Park MM, Sharp J, Tang WH, Thomas JD, Asosingh K, et al. Fasting 2-deoxy-
2-[18F]fluoro-D-glucose positron emission tomography to detect metabolic changes in
pulmonary arterial hypertension hearts over 1 year. Ann Am Thorac Soc. 2013;10(1):1–9.
53. Hagan G, Southwood M, Treacy C, Ross RM, Soon E, Coulson J, et al. (18)FDG PET
imaging can quantify increased cellular metabolism in pulmonary arterial hypertension:
a proof-of-principle study. Pulmonary. Circulation. 2011;1(4):448–55.
54. Oikawa M, Kagaya Y, Otani H, Sakuma M, Demachi J, Suzuki J, et al. Increased [18F]fluo-
rodeoxyglucose accumulation in right ventricular free wall in patients with pulmonary
hypertension and the effect of epoprostenol. J Am Coll Cardiol. 2005;45(11):1849–55.
55. Kluge R, Barthel H, Pankau H, Seese A, Schauer J, Wirtz H, et al. Different mechanisms for
changes in glucose uptake of the right and left ventricular myocardium in pulmonary hyper-
tension. J Nucl Med. 2005;46(1):25–31.
56. Can MM, Kaymaz C, Tanboga IH, Tokgoz HC, Canpolat N, Turkyilmaz E, et al. Increased
right ventricular glucose metabolism in patients with pulmonary arterial hypertension. Clin
Nucl Med. 2011;36(9):743–8.
57. Fang W, Zhao L, Xiong CM, Ni XH, He ZX, He JG, et al. Comparison of 18F-FDG uptake
by right ventricular myocardium in idiopathic pulmonary arterial hypertension and pulmo-
nary arterial hypertension associated with congenital heart disease. Pulm Circ. 2011;2(3):
365–72.
58. Wong YY, Ruiter G, Lubberink M, Raijmakers PG, Knaapen P, Marcus JT, et al. Right ven-
tricular failure in idiopathic pulmonary arterial hypertension is associated with inefficient
myocardial oxygen utilization. Circ Heart Fail. 2011;4(6):700–6.
59. Wong YY, Raijmakers P, van Campen J, van der Laarse WJ, Knaapen P, Lubberink M, et al.
11C-Acetate clearance as an index of oxygen consumption of the right myocardium in idio-
pathic pulmonary arterial hypertension: a validation study using 15O-labeled tracers and
PET. J Nucl Med. 2013;54(8):1258–62.
60. Knaapen P, van Campen LM, de Cock CC, Gotte MJ, Visser CA, Lammertsma AA, et al.
Effects of cardiac resynchronization therapy on myocardial perfusion reserve. Circulation.
2004;110(6):646–51.
61. Wong YY, Westerhof N, Ruiter G, Lubberink M, Raijmakers P, Knaapen P, et al. Systolic
pulmonary artery pressure and heart rate are main determinants of oxygen consumption in the
right ventricular myocardium of patients with idiopathic pulmonary arterial hypertension.
Eur J Heart Fail. 2011;13(12):1290–5.
62. Tune JD, Gorman MW, Feigl EO. Matching coronary blood flow to myocardial oxygen
consumption. J Appl Physiol (1985). 2004;97(1):404–15.
63. Hart BJ, Bian X, Gwirtz PA, Setty S, Downey HF. Right ventricular oxygen supply/demand
balance in exercising dogs. Am J Physiol Heart Circ Physiol. 2001;281(2):H823–30.
64. Saito D, Tani H, Kusachi S, Uchida S, Ohbayashi N, Marutani M, et al. Oxygen metabolism
of the hypertrophic right ventricle in open chest dogs. Cardiovasc Res. 1991;25(9):731–9.
65. Kusachi S, Nishiyama O, Yasuhara K, Saito D, Haraoka S, Nagashima H. Right and left
ventricular oxygen metabolism in open-chest dogs. Am J Physiol. 1982;243(5):H761–6.
66. Vogel-Claussen J, Skrok J, Shehata ML, Singh S, Sibley CT, Boyce DM, et al. Right and left
ventricular myocardial perfusion reserves correlate with right ventricular function and pul-
monary hemodynamics in patients with pulmonary arterial hypertension. Radiology. 2011;
258(1):119–27.
67. van Wolferen SA, Marcus JT, Westerhof N, Spreeuwenberg MD, Marques KM, Bronzwaer
JG, et al. Right coronary artery flow impairment in patients with pulmonary hypertension.
Eur Heart J. 2008;29(1):120–7.
68. Wong YY, Raijmakers PG, Knaapen P, Lubberink M, Ruiter G, Marcus JT, et al. Supine-
exercise-induced oxygen supply to the right myocardium is attenuated in patients with severe
idiopathic pulmonary arterial hypertension. Heart. 2011;97(24):2069–74.
69. Murray PA, Vatner SF. Reduction of maximal coronary vasodilator capacity in conscious
dogs with severe right ventricular hypertrophy. Circ Res. 1981;48(1):25–33.
70. Gomez A, Bialostozky D, Zajarias A, Santos E, Palomar A, Martinez ML, et al. Right ven-
tricular ischemia in patients with primary pulmonary hypertension. J Am Coll Cardiol.
2001;38(4):1137–42.
71. Sutendra G, Dromparis P, Paulin R, Zervopoulos S, Haromy A, Nagendran J, et al. A meta-
bolic remodeling in right ventricular hypertrophy is associated with decreased angiogenesis
and a transition from a compensated to a decompensated state in pulmonary hypertension.
J Mol Med (Berl). 2013;91(11):1315–27.
72. Rodriguez-Porcel M, Cai W, Gheysens O, Willmann JK, Chen K, Wang H, et al. Imaging of
VEGF receptor in a rat myocardial infarction model using PET. J Nucl Med.
2008;49(4):667–73.
73. Higuchi T, Bengel FM, Seidl S, Watzlowik P, Kessler H, Hegenloh R, et al. Assessment of
alphavbeta3 integrin expression after myocardial infarction by positron emission tomogra-
phy. Cardiovasc Res. 2008;78(2):395–403.
74. Meoli DF, Sadeghi MM, Krassilnikova S, Bourke BN, Giordano FJ, Dione DP, et al.
Noninvasive imaging of myocardial angiogenesis following experimental myocardial infarc-
tion. J Clin Invest. 2004;113(12):1684–91.
75. Makowski MR, Ebersberger U, Nekolla S, Schwaiger M. In vivo molecular imaging of
angiogenesis, targeting alphavbeta3 integrin expression, in a patient after acute myocardial
infarction. Eur Heart J. 2008;29(18):2201.
76. Foo RS, Mani K, Kitsis RN. Death begets failure in the heart. J Clin Invest. 2005;115(3):
565–71.
77. Danial NN, Korsmeyer SJ. Cell death: critical control points. Cell. 2004;116(2):205–19.
78. Kietselaer BL, Reutelingsperger CP, Boersma HH, Heidendal GA, Liem IH, Crijns HJ, et al.
Noninvasive detection of programmed cell loss with 99mTc-labeled annexin A5 in heart fail-
ure. J Nucl Med. 2007;48(4):562–7.
79. Narula J, Acio ER, Narula N, Samuels LE, Fyfe B, Wood D, et al. Annexin-V imaging for
noninvasive detection of cardiac allograft rejection. Nat Med. 2001;7(12):1347–52.
80. Paffett ML, Hesterman J, Candelaria G, Lucas S, Anderson T, Irwin D, et al. Longitudinal
in vivo SPECT/CT imaging reveals morphological changes and cardiopulmonary apoptosis
in a rodent model of pulmonary arterial hypertension. PLoS One. 2012;7(7):e40910.
81. Wencker D, Chandra M, Nguyen K, Miao W, Garantziotis S, Factor SM, et al. A mechanistic
role for cardiac myocyte apoptosis in heart failure. J Clin Invest. 2003;111(10):1497–504.
82. de Man FS, Handoko ML, Guignabert C, Bogaard HJ, Vonk-Noordegraaf A. Neurohormonal
axis in patients with pulmonary arterial hypertension: friend or foe? Am J Respir Crit Care
Med. 2013;187(1):14–9.
83. Caldwell JH, Link JM, Levy WC, Poole JE, Stratton JR. Evidence for pre- to postsynaptic
mismatch of the cardiac sympathetic nervous system in ischemic congestive heart failure.
J Nucl Med. 2008;49(2):234–41.
84. Pietila M, Malminiemi K, Ukkonen H, Saraste M, Nagren K, Lehikoinen P, et al. Reduced
myocardial carbon-11 hydroxyephedrine retention is associated with poor prognosis in
chronic heart failure. Eur J Nucl Med. 2001;28(3):373–6.
85. Schafers M, Dutka D, Rhodes CG, Lammertsma AA, Hermansen F, Schober O, et al.
Myocardial presynaptic and postsynaptic autonomic dysfunction in hypertrophic cardiomy-
opathy. Circ Res. 1998;82(1):57–62.
86. de Man FS, Tu L, Handoko ML, Rain S, Ruiter G, Francois C, et al. Dysregulated renin-
angiotensin-aldosterone system contributes to pulmonary arterial hypertension. Am J Respir
Crit Care Med. 2013;186(8):780–9.
87. Fukushima K, Bravo PE, Higuchi T, Schuleri KH, Lin X, Abraham MR, et al. Molecular
hybrid positron emission tomography/computed tomography imaging of cardiac angiotensin
II type 1 receptors. J Am Coll Cardiol. 2012;60(24):2527–34.
88. Spindler M, Schmidt M, Geier O, Sandstede J, Hahn D, Ertl G, et al. Functional and meta-
bolic recovery of the right ventricle during Bosentan therapy in idiopathic pulmonary arterial
hypertension. J Cardiovasc Magn Reson. 2005;7(5):853–4.
89. Hudsmith LE, Neubauer S. Magnetic resonance spectroscopy in myocardial disease. JACC
90. Kaufmann PA, Di Carli MF. Hybrid SPECT/CT and PET/CT imaging: the next step in non-
invasive cardiac imaging. Semin Nucl Med. 2009;39(5):341–7.
91. Nensa F, Poeppel TD, Beiderwellen K, Schelhorn J, Mahabadi AA, Erbel R, et al. Hybrid
PET/MR imaging of the heart: feasibility and initial results. Radiology. 2013;268(2):
366–73.
92. Schlosser T, Nensa F, Mahabadi AA, Poeppel TD. Hybrid MRI/PET of the heart: a new
complementary imaging technique for simultaneous acquisition of MRI and PET data. Heart.
2013;99(5):351–2.
93. Ibrahim T, Nekolla SG, Langwieser N, Rischpler C, Groha P, Laugwitz KL, et al. Simultaneous
positron emission tomography/magnetic resonance imaging identifies sustained regional
abnormalities in cardiac metabolism and function in stress-induced transient midventricular
ballooning syndrome: a variant of Takotsubo cardiomyopathy. Circulation. 2012;126(21):
e324–6.
94. Sosnovik DE, Schellenberger EA, Nahrendorf M, Novikov MS, Matsui T, Dai G, et al.
Magnetic resonance imaging of cardiomyocyte apoptosis with a novel magneto-optical
nanoparticle. Magn Reson Med. 2005;54(3):718–24.
95. Zhao M, Beauregard DA, Loizou L, Davletov B, Brindle KM. Non-invasive detection of
apoptosis using magnetic resonance imaging and a targeted contrast agent. Nat Med.
2001;7(11):1241–4.
96. Keen HG, Dekker BA, Disley L, Hastings D, Lyons S, Reader AJ, et al. Imaging apoptosis
in vivo using 124I-annexin V and PET. Nucl Med Biol. 2005;32(4):395–402.
97. Conway MA, Allis J, Ouwerkerk R, Niioka T, Rajagopalan B, Radda GK. Detection of low
phosphocreatine to ATP ratio in failing hypertrophied human myocardium by 31P magnetic
resonance spectroscopy. Lancet. 1991;338(8773):973–6.
98. Naya M, Tsukamoto T, Morita K, Katoh C, Nishijima K, Komatsu H, et al. Myocardial beta-
adrenergic receptor density assessed by 11C-CGP12177 PET predicts improvement of
cardiac function after carvedilol treatment in patients with idiopathic dilated cardiomyopathy.
J Nucl Med. 2009;50(2):220–5.
99. de Jong RM, Willemsen AT, Slart RH, Blanksma PK, van Waarde A, Cornel JH, et al.
Myocardial beta-adrenoceptor downregulation in idiopathic dilated cardiomyopathy mea-
sured in vivo with PET using the new radioligand (S)-[11C]CGP12388. Eur J Nucl Med Mol
Imaging. 2005;32(4):443–7.
100. Le Guludec D, Cohen-Solal A, Delforge J, Delahaye N, Syrota A, Merlet P. Increased myo-
cardial muscarinic receptor density in idiopathic dilated cardiomyopathy: an in vivo PET
study. Circulation. 1997;96(10):3416–22.
Chapter 13
The Pathobiology of Chronic Right
Ventricular Failure
Norbert F. Voelkel, Jose Gomez-Arroyo, Antonio Abbate,

and Harm J. Bogaard
Few data dealing with the measurement of right ventricular contractility in primary pulmonary
hypertension patients are available. The study of Degenring demonstrated that the maximal
rate of right ventricular pressure rise (dp/dt max) was 5–10 times normal value. The right
ventricular oxygen consumption was five times the normal value. With exercise, the right
ventricular oxygen consumption increased further and did not fall promptly when exercise
stopped. Increased myocardial norepinephrine probably contributed to the augmentation of
the rate of right ventricular contraction and to the “uneconomical” increase of the myocontrac-
tility and oxygen consumption.
The end stage of the disease is characterized by right ventricular failure. In 50 reported
fatalities, the cause of death in 15 was severe right ventricular failure. Even in the 16
patients who died of syncope and the 16 dying of surgical or diagnostic procedures, most
had signs of right ventricular failure [1].
The rationale for investing in the assessment of the root causes of right ventricu-
lar failure simply lies in the acknowledged fact that patients with severe and chronic
pulmonary hypertension die from right heart failure [2–6]. During the last two
decades, we have witnessed several paradigm shifts in the research of pulmonary
hypertension. The first shift occurred when investigators recognized that pulmonary
vascular tone and lung vessel constriction were insufficient to explain the pathobiol-
ogy of severe forms of pulmonary hypertension. A more recent shift occurred when
N.F. Voelkel, M.D. (*)

Department of Medicine, Virginia Commonwealth University,
1220 E. Broad Street, Richmond, VA 23298, USA
e-mail: nfvoelkel@gmail.com
J. Gomez-Arroyo, M.D., Ph.D.
Department of Immunology, University of Pittsburgh, Pittsburgh, VA, USA
A. Abbate, M.D., Ph.D.
VCU Pauley Heart Center, Virginia Commonwealth University, Richmond, VA, USA
H.J. Bogaard, M.D., Ph.D.
Amsterdam, The Netherlands

284 N.F. Voelkel et al.
investigators began to consider the RV as “a specific participant in the pathobiology

of pulmonary hypertension” [7] and part of the “sick lung circulation right heart
failure axis” [8], both of which can be considered as treatment targets. Because not
every patient who has a high pulmonary arterial pressure develops right heart fail-
ure, and because chronic right heart failure can be reversed (by lung transplantation,
atrial septostomy, thromboendarterectomy, and infusion of prostacyclin), we are
motivated to search for additional reversal treatment strategies and state as a goal
the prevention of RVF development.
As we accept these paradigm shifts and new goals, we are facing the burden to
explain: Why does the RV fail? What are the fundamental failure mechanisms? Just
because we cannot yet fully and scientifically rigorously explain all of the compo-
nents of the RVF syndrome, it does not mean that we should say nothing. There are
hypotheses that need to be tested, concepts that need to be confirmed, and other
concepts that need to be revisited. We should begin to develop questions that can be
tested and answered. It will be necessary at this initial phase to take some concep-
tual “leaps” and also to revise—not only describe—concepts and to replace old
explanations with new ones. A simple but hopefully not too simplistic approach to
the pathobiology of chronic RVF is to distinguish between intrinsic mechanisms
and extrinsic influences (Fig. 13.1).
Fig. 13.1 Hemodynamic

stress causes morphological
changes of the heart and the
central vessels which are
initially adaptive (upper box).
These factors affect the fate
of the myocardial cells
(lower box)
13 The Pathobiology of Chronic Right Ventricular Failure 285
Definition of Chronic Right Ventricular Failure
Chronic right heart failure, like left ventricular failure, is often defined as a syndrome
[9] and graded as “risk of developing RVF, asymptomatic RV dysfunction, symptom-
atic RVF and end-stage RVF” [9]. The 2009 ACCF/AHA Heart Failure guidelines
emphasize “that heart failure is not equivalent to cardiomyopathy or cardiac dysfunc-
tion.” Instead, heart failure is defined as a clinical syndrome that is characterized by
specific symptoms (dyspnea and fatigue) and signs (edema, gallop rhythm, rales) on
physical examination. “Heart failure is a symptomatic disorder and is not diagnosed
by a single test” and “the mechanisms responsible for the exercise intolerance of
patients with chronic heart failure have not been defined clearly” [9]. While it is not
difficult to recognize the signs and symptoms of severe RVF, it remains difficult to
define RV dysfunction and to predict when an individual patient transits from com-
pensated to decompensated RVF. Clinicians are discussing whether there are different
RV phenotypes [10, 11] and whether there are variables that can be measured to
determine whether patients have a “failure prone” or a “failure resistant” RV. The flow
diagram (Fig. 13.1) proposes that neurohormonal overdrive as well as inadequate RV
hypertrophy may lead to RVF. We believe that RV dysfunction exists when the
patient’s dyspnea can be explained hemodynamically by an elevation of the right
atrial pressure and/or a lower than normal cardiac index at rest. Perhaps the condition
of “at risk of developing RVF” describes the asymptomatic patients which demon-
strate mild abnormalities when examined by echocardiography (see Chap. 10) or car-
diac MRI (see Chap. 12). We wonder whether a mildly elevated BNP level in patients
with PAH may be a reliable marker of early RVF, however, it may be wishful to think
that BNP alone will be able to explain and predict RV dysfunction in each individual
case, and if so, this finding would violate the “no single diagnostic test” rule.
Mechanical Concepts of Right Heart Failure
In patients with pulmonary hypertension, the increase in pulmonary vascular resis-

tance impacts the RV. Analogous to chronic obstructive pulmonary diseases (COPD),
which are defined by an increased resistance to airflow, the right ventricle is chal-
lenged when working against an increased resistance to blood flow. The increase in
resistance can be in close proximity to the RV outflow tract as in the setting of pulmo-
nary artery stenosis or central pulmonary artery blood clots and modeled by main
pulmonary artery banding (PAB), however, in patients with PAH the structural
changes occur in nearly all of the small pulmonary arteries, accounting for the resis-
tance that the RV pumps against. A second component that changes the response of
the RV to increased blood flow resistance is the quality or behavior of the Windkessel
of the large central pulmonary vessels [12]. Briefly, the arterial side of the lung circu-
lation consists of the central, large capacitance vessels and the small precapillary
resistance vessels. The capacitance vessels or conduit arteries can expand and decrease
the flow wave energy that is transmitted to the resistance vessels and capillaries.
In pulmonary hypertension the conduit arteries become stiff and less compliant. As
the pressure within the RV cavity rises, so does the RV wall stress. Wall stress is
inversely proportional to wall thickness. A robustly muscular RV, as in patients with
Eisenmenger physiology, experiences less severe wall stress than a less muscularized
“stretched” RV. Increased wall stress will also compromise the perfusion of the RV
muscle. The schematic below (Fig. 13.1) integrates these various failure components.
This schematic entails two causality concepts that are still hypothetical: (1) that RV
stress and strain lead to neurohormonal activation and (2) that factors which we des-
ignate as “intrinsic to the myocardium” are of pathogenetic importance, and thus con-
tribute to RV failure development and/or progression.
It has been recognized for some time that the RV of patients with Eisenmenger
physiology does not easily fail. Again, hypothetically, the “Eisenmenger RV” is as
muscular as the LV and is characterized by a generous vessel supply.
H.A. Zimmerman, more than half a century ago, performing postmortem coronary
angiography, demonstrated an increase in the number of small coronary branches in
the right and left ventricle, “so much so in the right ventricle as to approach in num-
ber the ramifications of the left ventricle” (Fig. 13.2) [13]. We conclude that a
robustly muscular and well-vascularized RV is not ischemic and subject to less wall
stress. RV hypertrophy per se appears, indeed, not to correlate with mortality [14].
However, in PAH patients blood flow per gram of RV hypertrophy and the mean
systolic/diastolic flow ratio in the right coronary artery decline with rising RV sys-
tolic pressure [15] and with increasing RV mass (Fig. 13.3). In addition, right and
left ventricular myocardial perfusion reserves correlate with right ventricular func-
tion [16]. Thus the RV in severe PAH is likely ischemic, but the “Eisenmenger RV”
is not. As there is a strong inverse correlation between the RVSP and mean right
coronary artery blood flow, stretch/strain of the RV may be an important component
limiting coronary perfusion. Quaife et al. estimated the relative RV wall stress in
idiopathic PAH patients and found that significant RV hypertrophy tended to lower
the RV wall stress. Neither RV end-diastolic volume nor cardiac output correlated
with RV wall stress [17] (Fig. 13.4). High plasma levels of ANP and BNP may be
Fig. 13.2 Postmortem angiogram of the coronary vessels. There is an impressive increase in the num-
ber of vessels in the right ventricle of the Eisenmenger heart (right) when compared to a normal heart
(left). This image has been first published by H.A. Zimmerman ([12], reproduced with permission)
Fig. 13.3 Relationship between right coronary artery blood flow and RVSP and mass of the right
ventricle (RV). Right coronary artery blood flow decreases as the RVSP or the mass of the RV
increases (van Wolferen, [13], reproduced with permission)
Fig. 13.4 The right ventricle-free wall stress (calculated from cardiac MRI variables) shows a
poor correlation with either cardiac output (CO) (a) or the end-diastolic volume of the right ven-
tricle (RVEDV) (b), (Quaife et al. [16] reproduced with permission)
Fig. 13.5 The right

ventricular wall strain relates
to the functional class of
patients with pulmonary
arterial hypertension (left)
and to the plasma level of the
BNP (right) (Sachdev et al.
[17] reproduced with
permission)
signals which emanate from a stretched right atrium and ventricle—relatively

independent of the cardiac output. Indeed Sachdev et al. reported that high RV free
wall strain was associated with higher BNP levels [18] (Fig. 13.5).
The Importance of Right Ventricular Hypertrophy

and Fibrosis
Cardiac Hypertrophy
Hypertrophy of the RV is frequently discussed in the greater context of “heart form

and function” [19–23] and the statement which generally applies to the left ventri-
cle: “hypertrophy is mostly bad.” Coghlan and Hoffman [19] compared the round
amphibian (Romanesque) LV with the elliptical (Gothic) human and the “extreme
Gothic” LV of the giraffe which is capable of generating pressures of 300 mmHg.
The magnitude of pump pressure that can be generated and sustained is determined
by the form and the quality of the muscle. In contrast to the LV where increased
afterload is met with a percent increase in the LVSP (always less than twofold), the
increased pulmonary vascular resistance in PAH leads to a four- to fivefold increase
in the RVSP, and in order to adapt to this high pressure demands, a robust RV hyper-
trophic response. The time course of right ventricular hypertrophy development has
been recently reported in cats after pulmonary artery banding [24]. As shown in
Fig. 13.6, there is an exponential rise in the RV mass during the first 3 weeks after
PAB; thereafter, RV mass reaches a plateau. The authors were interested in myocar-
dial collagen synthesis and showed that the collagen volume fraction also increased,
but lagged behind and climbed further as the RV end-diastolic pressure became
elevated. They went on to investigate fibroblasts from the RV early and late in the
Fig. 13.6 Change of the pressure–flow relationship following the RV outflow obstruction follow-
ing pulmonary artery banding (PAB) (left). Increase of right ventricular mass after PAB in cats and
collagen amount expressed as a fraction of the tissue volume (right) (Baicu et al. [23] reproduced
with permission)
development of RVH and concluded that the collagen deposition by fibroblasts is

increased in the hypertrophic RV [24].
While many physiologic concepts apply to both the LV and RV, it is conceivable
that chamber-specific categorical differences in the programs which govern myo-
cardial hypertrophy and fibrosis exist, given the difference in chamber-specific gene
expression patterns [25–27]. In hypertrophic cardiomyopathy, mutations of a num-
ber of sarcomeric protein genes have been identified of which mutations of the
β-myosin heavy chain (β-MHC) gene were the first to be reported [28]; other
mutated genes are α-tropomyosin and titin [28]. In left ventricular hypertrophy, the
RV-free wall is equally hypertrophic and it is of interest that patients with hypertro-
phic cardiomyopathy usually do not develop heart failure. Transcription factors
which are important during cardiac development like MEF2, GATA4, NFAT, and
myocardin have been implicated as regulators of the hypertrophy program.
Mechanisms leading to left ventricular hypertrophy are complex and continue to be
discovered in genetically modified rodent models [29–33]. There are positive and
negative regulators of cardiac hypertrophy, for example, cGMP/PKG represses
hypertrophy via antagonism of ERK1/2 signaling [29]. Protein expression changes
in the pressure-overloaded RV have been reported and reflect a shift of energy
metabolism towards glycolysis and an upregulated expression of phosphorylated
HSP-27, a chaperone that plays a role in proteolysis [34]. The protein expression
changes in these PAB experiments have been interpreted as a reflection of an adap-
tive RV response to pressure overload and negative regulators of hypertrophy may
become targets for therapy.
Recent experimental studies have investigated histone deacetylase (HDAC)
inhibitors in PAB and chronic hypoxia models [35, 36] and the Sugen/hypoxia
model of RV failure [37]. The roles of the different HDAC isozymes are complex
(Table 13.1) and the topic of cardiac HDACs in hypertrophy and heart failure has
been recently reviewed [38]. HDAC inhibitors frequently induce apoptosis [39] and
several HDACs are involved in autophagy [40] (see below). Importantly, HDAC
inhibitors attenuate cardiac hypertrophy by suppression of autophagy.
The mechanism of transition from compensated hypertrophy to failure appears
to be fundamentally a matter of balance between cell survival and death (see below).
If the RV hypertrophy in PAH is initially compensatory, then factors promoting
growth and preserve the integrity of the microvessels balance cardiomyocyte hyper-
trophy and heart tissue blood flow. Impaired expression of factors promoting myo-
cardial angiogenic growth and maintenance is likely a hallmark of this transition as
discussed in greater detail below. Here it is only mentioned that myocyte-specific
deletion of the transcription factor GATA4 in adult mouse hearts decreased VEGF-A
expression and capillary density [41].
The molecular events which underlie the transition of the pressure overloaded
from compensated RV to failure have not yet been a focus of in-depth explorations
and we mostly rely on data that characterize this transition in the LV. For example,
Ling et al. documented in KO mice that CaMKIIδ deficiency ameliorated chamber
dilatation, apoptosis, and LV dysfunction after TAC [42]. Depre et al. described a
cardiac cell survival program which is induced by transient ischemia [43]. This
survival gene set includes PAI-1 and PAI-2, ANP, CTGF, and elongation-factor 1α
and 2, as well as heat-shock protein, hsp-27.
Cardiac Fibrosis
As mentioned, RV fibrosis due to pressure overload lags behind after the increase in
RV mass [24]. Cardiac fibrosis is a hallmark of maladaptive hypertrophy and is
characterized by increased deposition of the fibrillar collagens type I and III [44].
The normal heart muscle contains about 50 % fibroblasts, and elegant studies by
Takeda et al. have provided evidence that fibroblasts are essential for the adaptive
response of the heart to pressure overload. They showed that the transcription factor
KLF5 transactivates IGF-1 in fibroblasts and that the secreted protein induced car-
diomyocyte growth in a paracrine fashion [45].
Human autopsy studies have shown that the degree of fibrosis correlates with the
mass of the LV up to a weight of 250 g, after that there is a plateau of fibrosis and
no correlation [44]. Fibrosis may impair the electrical coupling between cardio-
myocytes and can reduce the capillary density and thus influence myocyte metabo-
lism. There is evidence for locally produced TGFβ, PDGF, and a role of endothelin
and catecholamines in cardiac fibrosis [44]. TGFβ1 is a critical regulator of extra-
cellular matrix metabolism and TGF-β1 levels increase during the development of
pressure-overloaded LV hypertrophy [44]. Higher plasma levels of TGFβ1 were
associated with an increased risk of incident heart failure in older adults [44].
Although there is no direct evidence for an important causal role of fibrosis in the
development of human heart failure, experimental studies suggest that fibrosis is
not merely a marker of heart failure. One of the downstream targets of TGF-β is
CTGF which is highly expressed in the failing RV from animals with severe PAH [27].
CTGF is essential for the TGF-β-induced collagen synthesis, and CTGF may also
play a role in the transformation of mesenchymal stem cells into fibroblasts [46].
Of interest, CTGF can also be expressed in cardiac myocytes under stress,while
NFkB blockade reduces cardiac fibrosis and collagen expression [47–50], suggest-
ing that inflammation and hypoxia are likely contributors to cardiac fibrosis. Based
on these experimental studies, we can postulate that fibroblasts and their secreted
proteins play a role in the transition of the RV from compensated hypertrophy to
failure. There appears to be a syncytial relationship between cardiomyocytes, fibro-
blasts and the cardiac matrix.
In the context of cardiac tissue homeostasis and maintenance of function, a publi-
cation by Aranguiz-Urroz et al. is of interest. This study reveals a regulatory connec-
tion between β2AR (adrenergic receptors), heart fibroblasts, autophagy, and collagen
degradation. Myocardial fibroblasts express more β2AR than β1AR, and stimulation
of β2AR in cardiac fibroblasts increased collagen degradation [51]; whether this col-
lagen-degrading consequence of β2AR activation is cAMP dependent is unknown.
Finally, we wish to mention that the adipocyte-derived peptide apelin inhibits cardiac
fibroblast activation and collagen production [52, 53]. Apelin expression is severely
reduced in the failing RV of rats with severe angioproliferative PAH [27].
Endothelial–Mesenchymal Transition
The work of Raghu Kalluri [54–57] points to another mechanism of cardiac fibrosis
via endothelial cell–mesenchymal transition (EMT). Although EMT is an embry-
onic mechanism that is normally dormant in adults, hypoxia, injury, inflammation,
or aging can activate this process, and it has been shown that fibroblasts formed in
fibrotic lesions in the heart can be of endothelial origin. Type I collagen can induce
EMT together with TGFβ, in particular the TGF-β2 isoform [55] and BMP2 and
BMP4, while BMP7 inhibits EMT.
Taken together, cardiomyocyte growth, fibroblast activity, and response of car-
diac microvessel EC to hypoxia and/or injury engage in a hypertrophy–fibrosis–
angiogenesis program that initially allows a compensated response of the RV to
pressure overload and stretch. This programmatic response shares many of the char-
acteristics of a wound healing program. The added layer of sympathico-endocrine
overstimulation (see below) may tip the balance and throw the switch from
compensation to failure.
Dyskinesis, Hypokinesis
Hypokinesis, dyskinesis, failure of the right ventricle to empty during systole, bow-
ing of the interventricular septum, and underfilling of the left ventricle are all
described in great detail in previous chapters. These changes are to varying degrees
due to regional abnormalities, hypertrophy, fibrosis, or dilatation and may also be
related to the different shape of the RV and the underling myoarchitecture and fiber
architecture of the RV [19, 20]. Most of the studies that investigated the relationship
between cardiac architecture and ventricular function have so far focused on the left
ventricle [22, 23] (see also Chap. 17).
Hibernation, Proteolysis, and Autophagy—the Cell Congestive

Pathobiology of Right Heart Failure
Cardiac autophagy can be a maladaptive response to chronic hemodynamic stress

[58–61] and one hallmark of myocardial hibernation [62–64]. The right ventricle,
stressed by a chronically elevated afterload, undergoes hypertrophy which is
required for successful adaptation to the chronic stress and strain. As stated, mecha-
nisms which govern the transition from hypertrophy to RV failure are still poorly
understood; however, the regulation of protein turnover—synthesis and proteolysis
during the transition phase—is critically important. During hypertrophic growth,
enhanced protein synthesis leads to an increase in the individual size of the myocar-
diocytes, whereas decompensation is associated with proteolysis, a switch from cell
growth to cell death and replacement fibrosis. Our published data confirm this con-
cept: the hypertrophic RV after chronic pulmonary artery banding is characterized
by an increase in the size of the myocardiocytes, a cell growth-directed gene expres-
sion pattern and a maintained capillary network [65]. In contrast, in the failing RV
the gene expression pattern (RV failure gene expression program) is characterized
by a depressed cell growth pattern [27], and tissue analysis reveals increased prote-
olysis and increased apoptosis. Damaged proteins and organelles, if not eliminated
from the cells via autophagy, accumulate and become toxic (proteotoxicity [66]) or
trigger apoptotic death [67]. Zhu et al. showed in 2007 that in the setting of left
ventricular pressure overload cardiac autophagy is maladaptive and contributes to
heart failure progression [58]. The authors also demonstrated increased expression
of Beclin 1 levels in pressure-overloaded LV tissues and concluded that Beclin 1
promotes autophagy and LV failure [58]. Importantly and in contrast, autophagy is
necessary for the hypertrophic adaptive response of the heart [59]. Because RV
hypertrophy is necessary for the successful adaptation of the RV to chronic pressure
afterload, inhibition of autophagy during the development of hypertrophy may be
detrimental, but inhibition may be beneficial when autophagy has become maladap-
tive and contributes to heart failure progression. Figure 13.7 is an attempt to con-
struct a mechanistic sequence of events which begins with cardiac stress and has as
an end point apoptotic cell death or alternatively a return to cellular homeostasis via
organelle and protein clearance, which counterbalances the congestion of the cells
with damaged proteins and membrane fragments.
Thus, a fundamentally important question is whether in heart diseases autophagy
is helpful or harmful. Once the cardiac stress has been initiated, the cells, in order to
become not congested or overloaded with toxic proteins, depend on autophagy.
Whereas homeostatic during the phase of adaptive hypertrophy, autophagy can
become counterproductive leading to the so-called Type II programmed cell death
Fig. 13.7 Diagram attempting to construct a mechanistic sequence of events which begins with
cardiac stress and has as an end point apoptotic cell death or alternatively a return to cellular
homeostasis via organelle and protein clearance, which counterbalances the congestion of the cells
with damaged proteins and membrane fragments
[68, 69]. Whether autophagy is increased in the failing RV of patients with severe
PAH or impaired is unknown, but can be presumed. If we can extrapolate from left
heart failure (see above), then we would expect maladaptive autophagy in RVF as a
component which contributes to RVF progression.
As mentioned, myocardial tissue hibernation is one of the conceptual models of
progressive heart failure, which, for a lack of a better explanation, should be used to
also explain progressive RVF. Global myocardial ischemia may be a consequence
of microvascular dysfunction (see below). Indeed, May et al. generated myocardial
hibernation in mice by conditional impairment of VEGF signaling [63]; in this
model autophagy activity was increased in association with capillary loss. Once the
conditional VEGF inhibition was reversed, hibernation was reversed as the capillary
network was restored. These studies are of great interest, specifically because they
indicate that microvascular dysfunction, autophagy, and hibernation are potentially
reversible. Subsequently this group of investigators applied proteomic analyses and
found, in addition to protein expression changes, that hibernation was characterized
by a reduced state of phosphorylation of the myosin light chain 2 and of cardiac
troponin I, while the abundance of these proteins was unchanged [70]. Unlike myo-
cardial infarction, the hibernating myocardium does not undergo cell death, but can
be salvaged; the mechanisms whereby hibernating myocardium survives remain to
be elucidated [64]. It is conceivable that mechanisms which control type II
programmed cell death play a critical role.
Capillary Rarefaction
Loss of myocardial capillaries is one component of heart microvascular dysfunc-

tion. Injury and loss of integrity of remaining capillary endothelial cells is an addi-
tional component. Cardiac capillary endothelial cell damage can be demonstrated
by electron microscopy (Fig. 13.8) and function defects are reflected in the altered
Fig. 13.8 Capillary in the

RV-free wall tissue of a rat
with experimentally induced
RV failure. This electron
micrograph shows vesicles
and a bleb of the endothelial
cells
pattern of protein expression that can be shown by immunohistochemistry.

As shown and discussed above, VEGF and intact signaling via its receptors is essen-
tial for cardiac capillary endothelial cell maintenance [63]. VEGF gene expression
is controlled by the transcription factors HIF-1α and PGC-1α. PGC-1α is preferen-
tially expressed in tissues with high energy metabolism; there this transcription fac-
tor coordinates genes involved in cellular uptake and mitochondrial metabolism of
fatty acids as well as mitochondrial biogenesis. Gomez-Arroyo et al. recently
reported a decreased expression in the failing, RV but not in the stressed RV, that
responded with adaptive hypertrophy after pulmonary artery banding (PAB) [71].
The altered expression of genes of the PPAR signaling pathways had been first dis-
covered as a result of the microarray gene expression screening analysis of failing
RV tissues [27]. Interestingly, HIF-1α expression is not decreased in the failing RV
[72], however, the expression of FHL2 (four and a half LIM domains 2) was
increased in the failing RV [73], a finding also reported by Mayr et al. [70] in the
hibernating myocardium. FHL2 directly interacts with HIF-1α to repress an HIF-
1α-dependent transactivation of its target genes. Taken together, one mechanism of
capillary rarefaction in the failing RV is a decrease of HIF-1α and PGC-1α-
dependent expression of the angiogenic maintenance factor VEGFA. The upstream
mechanisms which regulate PGC-1α gene and protein expression in the setting of
RVF are still unexplored. We wonder whether the global RV loss of microvessels
can be additionally explained by circulating proapoptotic factors such as cytokines
or microRNA-containing endothelial cell microparticles [70].
One important question to address is whether RV hypertrophy per se is sufficient
to cause RV ischemia. As will be discussed in Chap. 9, acute occlusion of the right
coronary artery, even for a short time, decreases the RV contractile force [74], thus
the relationship between RV ischemia and RV contractility is understood and the
question whether the hypertrophic RV is ischemic is important. In contrast to the left
ventricle, a pressure overload of the RV results in a selective increase in the resting
transmural blood flow per gram of hypertrophied RV [75] at least in dogs. Again, in
dogs, it has been shown that there is right coronary vasodilation during systemic
hypoxia which is to a large extent explained by nitric oxide [76]. Huo et al. [77]
analyzed the coronary arterial tree in RV hypertrophy and concluded that RV hyper-
trophy functionally restores the perfusion at the arteriolar and capillary level. These
data agree with older measurements of cross-sectional capillary density and numeri-
cal capillary density in RV hypertrophy [78].
Adrenergic Receptor Blockade in Chronic Right Heart Failure
We postulate that apoptosis occurs during the transition from compensated RVH to
RV failure and that maladaptive autophagy and capillary loss in the RV contribute to
the progression of the RV failure. In this scenario it makes sense to explore thera-
peutic strategies that would decrease heart cell apoptosis. Beta-adrenergic receptor
(BAR) blockers have been used for many years to treat patients with left-sided heart
failure and they are highly effective in reducing the morbidity and mortality associ-
ated with heart failure [79]. Long-term BAR blockade causes left-ventricular vol-
umes and LVEF to return to normal (reverse remodeling). BAR blockers improve LV
remodeling and the mechanisms of this effect may include protecting the myocar-
diocytes against the toxic effects of catecholamines and reversing the cellular meta-
bolic remodeling [28, 80, 81]. Alternatively BAR blockers, by decreasing heart rate
could make the pump work more economical and improve the oxygen supply/
demand ratio. Although a number of different BAR blockers have been used,
improved outcomes appear to be more frequent when the BAR blocker carvedilol had
been used [79], and the authors of the randomized placebo-controlled CHRISTMAS
trial tested the hypothesis that carvedilol might improve the function of hibernating
myocardium [82]. For more details on carvedilol and RV failure, see Chap. 19.
Metabolic Remodeling in the Failing Right Ventricle
The strained and stressed RV tissue shifts its energy production from fatty acid oxi-
dation (FAO) to glycolysis as part of a complex metabolic remodeling program
[71]. As mitochondrial number and function are impaired in the failing RV, it fol-
lows that energy metabolism is impaired. A partial explanation for the reduced fatty
acid oxidation (FAO) can be found in the reduced expression of the above intro-
duced critically important transcription factor PGC-1α and the reduced expression
of genes encoding proteins which transport FA into the cell-like CD36- and into
mitochondria. In addition, in the failing RV we found decreased numbers of intact
mitochondria which was reflected in a reduced whole RV tissue citrate synthase
activity and notably increased levels of mitochondrial DNA [71]. In contrast, treat-
ment with carvedilol of animals with established RV failure returned the PGC-1α
protein levels to normal (this effect was not seen with metoprolol, a selective beta-1
AR antagonist) and also the gene expression of the FA transporter CD36 (also called
fatty acid translocase).
Fig. 13.9 This schematic organizes the cellular and molecular mechanisms of RV failure in four
tiers. Central and critically important is the mitochondriopathy in the myocardial cells.
Cardiomyocytes and endothelial cells may be particularly vulnerable to reactive oxygen species
(ROS) and endoplasmic reticulum stress (ER stress). Accumulation of misfolded proteins and of
damaged organelles accounts for proteotoxicity and congestion of the cells. “Waste management”
may suffer because energy is in high demand, but not supplied. This in turn leads to impaired
autophagy and apoptosis, a state that has been termed “hibernation”
Recently the isoform VEGFB has been shown to be highly expressed in the myo-
cardium; VEGFB is not angiogenic but required for FA uptake [83] by endothelial
cells. Whether impaired VEGFB-dependent FA uptake is another reason for the
impaired FAO in heart failure is unclear. As mentioned, while in the failing RV tis-
sue the number of intact mitochondria is reduced, injured mitochondria may not be
removed if mitophagy is impaired (Fig. 13.9) and the amount of total mitochondrial
DNA is increased. This may be a pertinent finding because it has been demonstrated
that mitochondrial DNA can accumulate, if it escapes removal of damaged mito-
chondria via effective autophagy, and activate a sterile inflammatory response via
activation of TLR2 and TLR4 [84].
It is presently unclear whether therapy specifically directed to alter myocardial

energy metabolism can be effective in human PAB and RV failure. Piao et al.
reported that inhibition of the enzyme pyruvate dehydrogenase kinase by dichloro-
acetate improves impaired cardiac function in models of RV hypertrophy [85]. Fang
et al. explored the treatment of rats with PAB-induced RV hypertrophy with FAO
inhibitors and reported an increase in cardiac output in this model [86]. For a review
of mitochondrial metabolism and reactive oxygen species in PAH, see [87].
Synopsis and Outlook
Whereas acute RVF is an infrequent catastrophic event, chronic right heart dysfunc-
tion and acute on chronic RVF are common and central to the quality of life and
outcomes of patients with severe PAH. Patients with chronic and progressive PAH
continue to be treated with vasodilators and the impact of these drugs on RV func-
tion has not been systematically studied and remains unclear. The concept of repair-
ing the heart by pharmacologically reducing the afterload has been abandoned in
the treatment of LV failure: pure arterial vasodilators (i.e., minoxidil or hydralazine)
have been shown to have no or deleterious effects in heart failure, if not combined
with neurohormonal blockers, in particular BAR blockers, ACE-inhibitors and aldo-
sterone blockers. It is also necessary to consider that any drug or combination of
drugs prescribed with the best intentions to reduce PVR may affect the performance
of the strained RV and may be either not beneficial or detrimental.
We have no doubts that modern investigations of the causes and mechanisms of
RV failure will predictably discover how RV mechanics and myocardial metabolism
are connected. Presently, we do not yet understand which inherited or acquired con-
ditions generate and shape the particular phenotype of the pressure-overloaded RV,
and we believe that such conditions exist. The question of why and how the right
ventricle fails remains to be fully answered. This may require sequencing of genes,
exploration of posttranslational modifications of proteins, the analysis of the influ-
ence of metabolic syndromes, and gender-related epigenetic modifiers. Before
1990, as many as 60–70 % of patients died within 5 years after diagnosis of systolic
heart failure [88]. Since then effective treatment has reduced mortality and the
5-year mortality is now 20–30 %. Perhaps mortality from RV failure can be simi-
larly reduced by future concerted efforts.
References
1. Voelkel NF, Reeves JT. Primary pulmonary hypertension. In: Moser KM, editor. Pulmonary
vascular diseases. New York: Marcel Dekker; 1979. p. 573–619.
2. D’Alonzo GE, et al. Survival in patients with primary pulmonary hypertension. Results from
a national prospective registry. Ann Intern Med. 1991;115(5):343–9.
3. Campo A, et al. Hemodynamic predictors of survival in scleroderma-related pulmonary arte-
rial hypertension. Am J Respir Crit Care Med. 2010;182(2):252–60.
4. Howard LS. Prognostic factors in pulmonary arterial hypertension: assessing the course of the
disease. Eur Respir Rev. 2011;20(122):236–42.
5. van de Veerdonk MC, et al. Progressive right ventricular dysfunction in patients with pulmo-
nary arterial hypertension responding to therapy. J Am Coll Cardiol. 2011;58(24):2511–9.
6. Haddad F, et al. Right ventricular function in cardiovascular disease, part I: anatomy, physiology,
aging, and functional assessment of the right ventricle. Circulation. 2008;117(11):1436–48.
7. Maron BA. Targeting neurohumoral signaling to treat pulmonary hypertension: the right ven-
tricle coming into focus. Circulation. 2012;126(24):2806–8.
8. Erzurum S, et al. Strategic plan for lung vascular research: an NHLBI-ORDR workshop report.
Am J Respir Crit Care Med. 2010;182(12):1554–62.
9. Hunt SA, et al. 2009 Focused update incorporated into the ACC/AHA 2005 guidelines for the
diagnosis and management of heart failure in adults. A report of the American College of
Cardiology Foundation/American Heart Association Task Force on practice guidelines devel-
oped in collaboration with the International Society for Heart and Lung Transplantation. J Am
Coll Cardiol. 2009;53(15):e1–90.
10. Quaife RA, et al. Right ventricular phenotypic characteristics in subjects with primary pulmo-
nary hypertension or idiopathic dilated cardiomyopathy. J Card Fail. 1999;5(1):46–54.
11. Abraham MR, et al. Angiotensin-converting enzyme genotype modulates pulmonary function
and exercise capacity in treated patients with congestive stable heart failure. Circulation.
2002;106(14):1794–9.
12. Wang Z, Chesler NC. Pulmonary vascular wall stiffness: an important contributor to the
increased right ventricular afterload with pulmonary hypertension. Pulm Circ. 2011;1(2):
212–23.
13. Zimmerman HA. The coronary circulation in patients with severe emphysema, cor pulmonale,
cyanotic congenital heart disease, and severe anemia. Dis Chest. 1952;22(3):269–73.
14. van Wolferen SA, et al. Prognostic value of right ventricular mass, volume, and function in
idiopathic pulmonary arterial hypertension. Eur Heart J. 2007;28(10):1250–7.
15. van Wolferen SA, et al. Right coronary artery flow impairment in patients with pulmonary
hypertension. Eur Heart J. 2008;29(1):120–7.
16. Vogel-Claussen J, et al. Right and left ventricular myocardial perfusion reserves correlate with
right ventricular function and pulmonary hemodynamics in patients with pulmonary arterial
hypertension. Radiology. 2011;258(1):119–27.
17. Quaife RA, et al. Importance of right ventricular end-systolic regional wall stress in idiopathic
pulmonary arterial hypertension: a new method for estimation of right ventricular wall stress.
Eur J Med Res. 2006;11(5):214–20.
18. Sachdev A, et al. Right ventricular strain for prediction of survival in patients with pulmonary
arterial hypertension. Chest. 2011;139(6):1299–309.
19. Coghlan C, Hoffman J. Leonardo da Vinci’s flights of the mind must continue: cardiac archi-
tecture and the fundamental relation of form and function revisited. Eur J Cardiothorac Surg.
2006;29 Suppl 1:S4–17.
20. Sanchez-Quintana D, et al. Morphological changes in the normal pattern of ventricular myo-
architecture in the developing human heart. Anat Rec. 1995;243(4):483–95.
21. Chen J, et al. Regional ventricular wall thickening reflects changes in cardiac fiber and sheet
structure during contraction: quantification with diffusion tensor MRI. Am J Physiol Heart
Circ Physiol. 2005;289(5):H1898–907.
22. Savadjiev P, et al. Heart wall myofibers are arranged in minimal surfaces to optimize organ
function. Proc Natl Acad Sci U S A. 2012;109(24):9248–53.
23. Buckberg G, et al. Cardiac mechanics revisited: the relationship of cardiac architecture to
ventricular function. Circulation. 2008;118(24):2571–87.
24. Baicu CF, et al. Time course of right ventricular pressure-overload induced myocardial fibro-
sis: relationship to changes in fibroblast postsynthetic procollagen processing. Am J Physiol
25. Chugh SS, et al. Genetic basis for chamber-specific ventricular phenotypes in the rat infarct
model. Cardiovasc Res. 2003;57(2):477–85.
26. Tabibiazar R, et al. Transcriptional profiling of the heart reveals chamber-specific gene expression
patterns. Circ Res. 2003;93(12):1193–201.
27. Drake JI, et al. Molecular signature of a right heart failure program in chronic severe
pulmonary hypertension. Am J Respir Cell Mol Biol. 2011;45(6):1239–47.
28. Harvey PA, Leinwand LA. The cell biology of disease: cellular mechanisms of cardiomyopathy.
J Cell Biol. 2011;194(3):355–65.
29. Leenders JJ, Pinto YM, Creemers EE. Tapping the brake on cardiac growth-endogenous
repressors of hypertrophic signaling. J Mol Cell Cardiol. 2011;51(2):156–67.
30. Augustus AS, et al. Hearts lacking caveolin-1 develop hypertrophy with normal cardiac
substrate metabolism. Cell Cycle. 2008;7(16):2509–18.
31. Cruz JA, et al. Chronic hypoxia induces right heart failure in caveolin-1-/- mice. Am J Physiol
32. Fisch S, et al. Kruppel-like factor 15 is a regulator of cardiomyocyte hypertrophy. Proc Natl
Acad Sci U S A. 2007;104(17):7074–9.
33. Cao DJ, et al. Histone deacetylase (HDAC) inhibitors attenuate cardiac hypertrophy by
suppressing autophagy. Proc Natl Acad Sci U S A. 2011;108(10):4123–8.
34. Faber MJ, et al. Time dependent changes in cytoplasmic proteins of the right ventricle during
prolonged pressure overload. J Mol Cell Cardiol. 2007;43(2):197–209.
35. Cavasin MA, et al. Selective class I histone deacetylase inhibition suppresses hypoxia-induced
cardiopulmonary remodeling through an antiproliferative mechanism. Circ Res. 2012;
110(5):739–48.
36. Zhao L, et al. Histone deacetylation inhibition in pulmonary hypertension: therapeutic poten-
tial of valproic acid and suberoylanilide hydroxamic acid. Circulation. 2012;126(4):455–67.
37. Bogaard HJ, et al. Suppression of histone deacetylases worsens right ventricular dysfunction
after pulmonary artery banding in rats. Am J Respir Crit Care Med. 2011;183(10):1402–10.
38. McKinsey TA. Therapeutic potential for HDAC inhibitors in the heart. Annu Rev Pharmacol
Toxicol. 2012;52:303–19.
39. Gammoh N, et al. Role of autophagy in histone deacetylase inhibitor-induced apoptotic and
nonapoptotic cell death. Proc Natl Acad Sci U S A. 2012;109(17):6561–5.
40. Lee JY, et al. HDAC6 controls autophagosome maturation essential for ubiquitin-selective
quality-control autophagy. EMBO J. 2010;29(5):969–80.
41. Oka T, Komuro I. Molecular mechanisms underlying the transition of cardiac hypertrophy to
heart failure. Circ J. 2008;72(Suppl A):A13–6.
42. Ling H, et al. Requirement for Ca2+/calmodulin-dependent kinase II in the transition from
pressure overload-induced cardiac hypertrophy to heart failure in mice. J Clin Invest.
2009;119(5):1230–40.
43. Depre C, et al. Gene program for cardiac cell survival induced by transient ischemia in con-
scious pigs. Proc Natl Acad Sci U S A. 2001;98(16):9336–41.
44. Creemers EE, Pinto YM. Molecular mechanisms that control interstitial fibrosis in the pressure-
overloaded heart. Cardiovasc Res. 2011;89(2):265–72.
45. Takeda N, et al. Cardiac fibroblasts are essential for the adaptive response of the murine heart
to pressure overload. J Clin Invest. 2010;120(1):254–65.
46. Alfaro MP, et al. A physiological role for connective tissue growth factor in early wound heal-
ing. Lab Invest. 2013;93(1):81–95.
47. Kim YS, et al. BAY 11-7082, a nuclear factor-kappaB inhibitor, reduces inflammation and
apoptosis in a rat cardiac ischemia-reperfusion injury model. Int Heart J. 2010;51(5):348–53.
48. Wei C, et al. NF-kappaB mediated miR-26a regulation in cardiac fibrosis. J Cell Physiol.
2013;228(7):1433–42.
49. Duisters RF, et al. miR-133 and miR-30 regulate connective tissue growth factor: implications
for a role of microRNAs in myocardial matrix remodeling. Circ Res. 2009;104(2):170–8, 6p
following 178.
50. Matkovich SJ, et al. MicroRNA-133a protects against myocardial fibrosis and modulates elec-
trical repolarization without affecting hypertrophy in pressure-overloaded adult hearts. Circ
Res. 2010;106(1):166–75.
51. Aranguiz-Urroz P, et al. Beta(2)-adrenergic receptor regulates cardiac fibroblast autophagy

and collagen degradation. Biochim Biophys Acta. 2011;1812(1):23–31.
52. Pchejetski D, et al. Apelin prevents cardiac fibroblast activation and collagen production
through inhibition of sphingosine kinase 1. Eur Heart J. 2012;33(18):2360–9.
53. Helske S, et al. Transcardiac gradients of circulating apelin: extraction by normal hearts vs.
release by hearts failing due to pressure overload. J Appl Physiol. 2010;109(6):1744–8.
54. Zeisberg EM, et al. Endothelial-to-mesenchymal transition contributes to cardiac fibrosis.
Nat Med. 2007;13(8):952–61.
55. Medici D, Olsen BR. Transforming blood vessels into bone. Cell Cycle. 2011;10(3):362–3.
56. Medici D, et al. Conversion of vascular endothelial cells into multipotent stem-like cells. Nat
Med. 2010;16(12):1400–6.
57. Medici D, Kalluri R. Endothelial–mesenchymal transition and its contribution to the emer-
gence of stem cell phenotype. Semin Cancer Biol. 2012;22(5–6):379–84.
58. Zhu H, et al. Cardiac autophagy is a maladaptive response to hemodynamic stress. J Clin
Invest. 2007;117(7):1782–93.
59. Nemchenko A, et al. Autophagy as a therapeutic target in cardiovascular disease. J Mol Cell
Cardiol. 2011;51(4):584–93.
60. Yan L, et al. Autophagy in chronically ischemic myocardium. Proc Natl Acad Sci U S A.
2005;102(39):13807–12.
61. Matsui Y, et al. Distinct roles of autophagy in the heart during ischemia and reperfusion: roles
of AMP-activated protein kinase and Beclin 1 in mediating autophagy. Circ Res.
2007;100(6):914–22.
62. Hein S, et al. Progression from compensated hypertrophy to failure in the pressure-overloaded
human heart: structural deterioration and compensatory mechanisms. Circulation.
2003;107(7):984–91.
63. May D, et al. Transgenic system for conditional induction and rescue of chronic myocardial
hibernation provides insights into genomic programs of hibernation. Proc Natl Acad Sci U S
A. 2008;105(1):282–7.
64. Kelly RF, Sluiter W, McFalls EO. Hibernating myocardium: is the program to survive a
pathway to failure? Circ Res. 2008;102(1):3–5.
66. Willis MS, Patterson C. Proteotoxicity and cardiac dysfunction—Alzheimer's disease of the
heart? N Engl J Med. 2013;368(5):455–64.
67. Wang X, Su H, Ranek MJ. Protein quality control and degradation in cardiomyocytes. J Mol
Cell Cardiol. 2008;45(1):11–27.
68. Klionsky DJ, et al. Guidelines for the use and interpretation of assays for monitoring autoph-
agy in higher eukaryotes. Autophagy. 2008;4(2):151–75.
69. Haspel JA, Choi AM. Autophagy: a core cellular process with emerging links to pulmonary
disease. Am J Respir Crit Care Med. 2011;184(11):1237–46.
70. Mayr M, et al. Metabolic homeostasis is maintained in myocardial hibernation by adaptive
changes in the transcriptome and proteome. J Mol Cell Cardiol. 2011;50(6):982–90.
71. Gomez-Arroyo J, et al. Metabolic gene remodeling and mitochondrial dysfunction in failing
right ventricular hypertrophy due to pulmonary arterial hypertension. Circ Heart Fail.
2013;6(1):136–44.
72. Bogaard HJ, et al. Adrenergic receptor blockade reverses right heart remodeling and dysfunc-
tion in pulmonary hypertensive rats. Am J Respir Crit Care Med. 2010;182(5):652–60.
73. Drake JI, et al. Chronic carvedilol treatment partially reverses the right ventricular failure
transcriptional profile in experimental pulmonary hypertension. Am J Physiol Genomics.
2013;45(12):449–61.
74. Brooks H, et al. Performance of the right ventricle under stress: relation to right coronary flow.
J Clin Invest. 1971;50(10):2176–83.
75. Murray PA, et al. Effects of experimental right ventricular hypertrophy on myocardial blood-
flow in conscious dogs. J Clin Invest. 1979;64(2):421–7.
76. Martinez RR, et al. Nitric oxide contributes to right coronary vasodilation during systemic
hypoxia. Am J Physiol Heart Circ Physiol. 2005;288(3):H1139–46.
77. Huo Y, Linares CO, Kassab GS. Capillary perfusion and wall shear stress are restored in the
coronary circulation of hypertrophic right ventricle. Circ Res. 2007;100(2):273–83.
78. Olivetti G, et al. Long-term pressure-induced cardiac hypertrophy: capillary and mast cell
proliferation. Am J Physiol. 1989;257(6 Pt 2):H1766–72.
79. Dinicolantonio JJ, et al. Meta-analysis of carvedilol versus beta 1 selective beta-blockers
(atenolol, bisoprolol, metoprolol, and nebivolol). Am J Cardiol. 2013;111(5):765–9.
80. Maurer MS, et al. Mechanisms underlying improvements in ejection fraction with carvedilol
in heart failure. Circ Heart Fail. 2009;2(3):189–96.
81. Kurz T, et al. Differential effects of carvedilol on norepinephrine release in normoxic and
ischemic heart. J Cardiovasc Pharmacol. 2000;36(1):96–100.
82. Cleland JG, et al. Myocardial viability as a determinant of the ejection fraction response to
carvedilol in patients with heart failure (CHRISTMAS trial): randomised controlled trial.
Lancet. 2003;362(9377):14–21.
83. Hagberg C, et al. Endothelial fatty acid transport: role of vascular endothelial growth factor
B. Physiology (Bethesda). 2013;28(2):125–34.
84. Oka T, et al. Mitochondrial DNA that escapes from autophagy causes inflammation and heart
failure. Nature. 2012;485(7397):251–5.
85. Piao L, et al. The inhibition of pyruvate dehydrogenase kinase improves impaired cardiac
function and electrical remodeling in two models of right ventricular hypertrophy: resuscitat-
ing the hibernating right ventricle. J Mol Med (Berl). 2010;88(1):47–60.
86. Fang YH, et al. Therapeutic inhibition of fatty acid oxidation in right ventricular hypertrophy:
exploiting Randle’s cycle. J Mol Med (Berl). 2012;90(1):31–43.
87. Archer SL, et al. Mitochondrial metabolism, redox signaling, and fusion: a mitochondria-
ROS-HIF-1alpha-Kv1.5 O2-sensing pathway at the intersection of pulmonary hypertension
and cancer. Am J Physiol Heart Circ Physiol. 2008;294(2):H570–8.
88. McKee PA, et al. The natural history of congestive heart failure: the Framingham study. N Engl
J Med. 1971;285(26):1441–6.
Chapter 14
The Sick Lung Circulation and the Failing
Right Ventricle
Norbert F. Voelkel
As a physicist, I wonder why it is that biology and medicine

seem to have so few new theories
Murray Gell-Mann, Nature 491, 561, 2012.
The lung circulation is usually credited with its gas exchange function while its meta-
bolic properties are often neglected. Early investigators of the metabolic activities of the
large lung endothelial cell area were John Vane [1, 2], Alain Junod [3, 4], and Norman
Gillis [5]. Isolated perfused lung studies revealed that greater than 95 % of serotonin
infused into the lung circulation was removed during one passage [3]; this is also true
for prostaglandin E2 [6] and for arachidonic acid [7]. There is not only extraction of
active substances and metabolic breakdown but also release and secretion into the circu-
lating blood of mediators like prostacyclin [7] and endothelin (for a comprehensive
assessment of the functions of the endothelial cells of the pulmonary circulation, see
also [8]). When asked in 1982 whether changes in the ability of the lung microcircula-
tion to remove or metabolize any of the vasoactive compounds have an effect on the
function of the lung, Junod answered: “It is my personal and therefore biased view that
the clearance function of the pulmonary endothelium has no important physiological
consequences. However, it is interesting in terms of endothelial cell function” [9]. In the
following, the case will be made for pathobiological consequences and how a sick lung
circulation blood effluent can affect the microcirculation of the heart. Although mor-
phological changes of the lung vessels in many chronic lung diseases have been appreci-
ated for decades, only recently have measurements of circulating cells and cell fragments
provided solid data which support the general concept of “information transfer” from
the sick lung circulation to the heart. While the focus on this review and perspective is
the right ventricle in pulmonary vascular diseases, it is clear that the information released
from the sick lung circulation and entering the myocardial microcirculation, via the
coronary arteries, will be deciphered by the left ventricle as well (Fig. 14.1).
N.F. Voelkel (*)


304 N.F. Voelkel
Fig. 14.1 Pulmonary venous and arterial remodeling in left heart disease. This schematic puts the
emphasis on the damaged lung capillaries
Hypothesis of the Lung Circulation and the Heart

as a Functional Unit
The global hypothesis is that the health of the lung circulation determines the health
of the cardiac microcirculation. This postulate views the lung microcirculation as
the emitter of information which either causes or contributes to the development of
a microangiopathy of the heart and shifts the attention in severe PH from the visible
coronary arterial disease to the function of the myocardial capillaries. Applied to the
RV dysfunction or RV failure in chronic lung diseases with involvement of the pul-
monary circulation, the specific hypothesis is that pressure overload per se is insuf-
ficient to cause RV failure [10]. Instead activation of the neuroendocrine axis and of
inflammatory pathways drive the RV into failure [11, 12]. Of interest is also the
correlation between percent emphysema and impaired left ventricular filling [13].
RV failure can be histologically defined by the presence of apoptosis, capillary loss
and capillary endothelial cell dysfunction, and myocardial fibrosis.
Perhaps of equal importance is a second contribution: the reprogramming of
the cardiac microcirculation by factors emanating from the sick lung vessels [14]. The
major histological features of remodeled lung vessels are pulmonary arteriolar mus-
cularization, intima fibrosis, angioobliterative occlusions, plexiform lesions, and loss
14 The Sick Lung Circulation and the Failing Right Ventricle 305
of lung vessels including capillary rarefaction [15]. Lung endothelial dysfunction has
been documented in COPD/emphysema [16, 17] (see also Chap. 18) as well as sys-
temic endothelial cell dysfunction [18] and also in idiopathic pulmonary arterial
hypertension (IPAH) [19], thromboembolic PAH [20], and in sickle cell disease [21].
Endothelial cell dysfunction likely also alters the adhesive properties of the lung ves-
sels facilitating in situ thrombosis and impairment of the removal and breakdown of
vasoactive substances from the circulation. Another manifestation of endothelial cell
dysfunction is the decreased expression of the prostacyclin gene and protein, result-
ing in diminished prostacyclin production by the hypertensive lung vessels [22, 23].
Thus loss of prostacyclin synthase expression is a hallmark of phenotypically altered
lung vascular endothelial cells in PH. Whether prostacyclin synthase expression is
reduced or lost in the microcirculation of the failing heart is unknown. It appears that
the prevailing and understandable emphasis of contemporary interventional cardiolo-
gists on reperfusion and revascularization of acute coronary syndromes may have
overshadowed the interest in researching the coronary microvessels and their function
and dysfunction. Left and right ventricular microvascular disease has been long
appreciated as a primary myocardial involvement in scleroderma [24–26].
Contributions to the myocardial angiopathy by the sick lung circulation have not been
investigated. In a recent review [14], we have compared pulmonary emphysema, as a
primary lung parenchyma disease, with a primary mitral valve disease and hypotheti-
cally connected in both disorders lung vessel and lung capillary damage, factors pro-
duced and released from the diseased lung vessels and heart failure. Today this
concept appears plausible and almost intuitive, however, direct evidence in support of
this concept is still lacking.
Circulating Cells
Against the background of the cancer paradigm of angioproliferative PAH [27],

which is based on the hallmarks of cancer discussed by Hanahan and Weinberg [28]
and which characterizes the intrapulmonary vascular cell growth as “quasi malig-
nant,” circulating progenitor cells were postulated to perform in a quasi-metastatic
[29] fashion, in analogy to mechanisms of tumor emboli-induced PH [30]. Such
cells could be released from the remodeled lung vessels and implant in injured lung
vessels after recirculation. The first report on circulating endothelial cells in PH
appeared in 2003 [31]. About 50 % of the cells expressed CD36, a marker of micro-
vascular endothelial cells; and 25 % expressed E-selectin, a marker of endothelial
cell activation [31]. Schiavon and coworkers found higher levels of lung tissue resi-
dent, but not circulating, endothelial cell progenitors in patients with idiopathic
PAH [32]. Sickle cell disease patients with PAH have less circulating endothelial
cell precursor cells when compared with sickle cell disease patients without PAH
[33]. The peripheral blood monocytes from patients with scleroderma-associated
PAH express markers of the endoplasmic reticulum stress [34] and Hansmann et al.
[35] designed a microfluidic endothelial cell precursor chip to capture such cells in
peripheral blood samples from PAH patients. Functional studies of circulating late
306 N.F. Voelkel
outgrowth progenitor cells showed a hyperproliferative phenotype with the inability

to generate vascular networks [36]. Finally circulating endothelial cells have also
been identified in the blood from patients with congenital heart disease associated
with PAH [37] and fibroblasts were identified in blood samples from adult patients
and children with PH [38].
Circulating Cellular Microparticles
Cell fragments are produced by injured or dying cells, and it now has been widely
appreciated that such microparticles affect the function of endothelial cells. Lewis
et al. showed in 1988 that vesicles released from injured endothelium displayed
platelet activating factor (PAF)-like activity which could be blocked by PAF recep-
tor antagonists [39]; polymorphonuclear leukocytes, after adhesion, release mic-
roparticles with PAF-like phospholipids attached to them [40]. Circulating
procoagulant microparticles have been measured and found to be increased in the
lung blood effluent from patients with severe PAH [41] (Fig. 14.2). Circulating
endothelial cell microparticles may be a signal of early lung tissue destruction in
cigarette smokers (Fig. 14.3) [42] and endothelial cell microparticles were reported
in the blood from patients with COPD in the MESA COPD study [43]. Amabile and
coworkers discussed cellular microparticles in the context of the pathogenesis of
pulmonary hypertension (Fig. 14.4) [44] and Diehl et al. [45] in the context
Fig. 14.2 The gradient of procoagulant microparticles (MP) across the lung circulation. The
gradient was calculated by subtracting the jugular venous blood level of these microparticles from
the pulmonary artery blood level. The MP gradients are plotted against the mean pulmonary artery
pressure (mPAP). (Reproduced with permission from Bakouboula et al. [41])
Fig. 14.3 Endothelial cell microparticles are increased in blood samples from healthy smokers
with low diffusing capacity (reproduced with permission from Gordon et al. [42])
Fig. 14.4 This synopsis (reprinted with permission from Amabile et al. [44]) shows the relation-
ship between endothelial cell microparticles and pulmonary vascular resistance in PAH patients
and connects various kinds of cell fragments and particles with in situ thrombosis, inflammation,
and endothelial cell dysfunction
308 N.F. Voelkel
of coagulation and inflammation. Cell–cell interactions and intercellular exchange

pf proteins and RNA-containing microparticles have been recognized as part of
information transfer and signaling between different organs. A mechanistic systems
biology analysis of multi-organ dysfunction takes circulating vesicles and particles
into account as carriers of information. For example, mesenchymal stem cells
contain phospholipid-rich 55–65 mm diameter vesicles which contain miRNA;
these vesicles are taken up by cultured myocardiocytes [46]. Recently it has been
shown that circulating platelet microparticle-derived miR-223 is taken up by
endothelial cells and can likely exert heterotypic regulation of gene expression in
endothelial cells [47]—in so many words: micro particle microRNA can be taken up
by endothelial cells and reprogram these cells. Monocytic microparticles can
activate endothelial cells in an IL-1β-dependent manner [48].
Circulating Mediators of Inflammation and Cell Death
After more than 20 years of investigation of mediators circulating in the blood of

patients with PH, it is reasonable to assume that any single molecule or the combina-
tion of factors is of pathobiological importance. Elevated levels of von Willebrand
factor [49] likely reflect activation and or injury of endothelial cells and platelets, and
other signals are secreted by activated immune-and-inflammatory cells; for example,
there is release of granulysin by lymphocytes [50], a tumoricidal, chemoattractant
molecule which also can induce mitochondrial damage and apoptosis. The recogni-
tion that all of the circulating blood cells including red blood cells, in patients with
PAH are constantly exposed to the multitude of circulating microparticles and protein
and lipid mediators led to the postulate that the gene expression pattern of the periph-
eral blood monocytes would be categorically altered in patients with PAH and, per-
haps show different expressions, when the peripheral blood monocytes from different
forms of chronic PAH were compared [51]. Such circulating particles and factors
could explain observations of increased miR-145 in tissue samples from PAH
patients—downregulation of miR-145 patients protects against the development of
PAH [52]—and the observation of impaired systemic microvessel endothelium-
dependent vasodilation in patients with scleroderma-associated PAH [53]. Cell-free
double-stranded DNA has been found to be elevated in plasma in experimental acute
pulmonary embolism [54] and mitochondrial DNA that escapes from autophagy has
been shown to cause inflammation and heart failure [55]. Thus, taken together, circu-
lating protein and lipid mediators as well as circulating DNA can be injurious to
endothelial cells, including those of the myocardial microcirculation.
Connecting miRNA and Disease
Expression of miRNAs was studied in the pulmonary artery endothelial cells and
pulmonary artery smooth muscle cells from explanted lungs from patients with heri-
table PAH and in vitro cell proliferation was correlated with miR-21 levels [56].
In lung tissue samples from patients with COPD 70 miRNAs and 2,667, mRNAs
were differently expressed between smokers with and without COPD [57]. While a
number of recent studies are descriptive surveys, there are a few reports which begin
to connect miRNAs with disease. One example is the study of Kim et al. [58] who
investigated apelin deficiency in pulmonary arterial endothelial cells from patients
with PAH; they found that apelin deficiency in these cells increased the expression
of FGF2 and its receptor FGFR1 as a consequence of downregulated expression of
miR-503 and miR-424. Reconstitution of these miRNAs in animal models of PAH
ameliorated PH. Apelin levels in the serum of PAH patients are reduced [59] and
likewise in the failing right ventricle from experimental pulmonary hypertensive ani-
mals [60]. Finally, a consortium of investigators reported the association of reduced
plasma levels of miR150 with survival of PAH patients [61]. Remarkably, growth
factor receptors have been linked to miRNAs. Especially during hypoxia EGFR can
inhibit miRNA processing from precursor miRNAs to mature miRNAs [62].
Synopsis
The sick lung circulation, together with a stressed and uneconomically working RV,
generates conditions which can best be examined by applying a “systems” approach
(Fig. 14.5). Recent studies of embryonic development of mice using lineage tracing
methods have revealed the co-development of the cardiovascular and pulmonary
Fig. 14.5 The systems approach to severe pulmonary arterial—and perhaps also pulmonary
venous hypertension. Signals from the sick lung circulation are received by the microcirculation of
the heart, which by itself secretes factors including growth and differentiation factor 15 (GDF-15),
also known as ‘macrophage-inhibitory cytokine 1’. Factors secreted from the adrenal glands, like
aldosterone (also synthesized in the sick lung) influence myocardial structure and function. The
bone marrow, under the influence of factors like VEGF, releases precursor cells which can be
trapped in the lung circulation and contribute to pulmonary vascular remodeling
310 N.F. Voelkel
Fig. 14.6 Corrosion cast of

the coronary vasculature of a
rat. Numerous capillaries can
be seen adjoining venules
(V). Anastomoses (arrows)
and branching (arrow heads)
are characteristic of the
capillary bed 520×
systems. Cardiopulmonary mesoderm progenitors arise from cardiac progenitors and

they generate the lineages within the cardiac inflow tract and lung including cardio-
myocytes, pulmonary vascular and airway smooth muscle, vascular endothelium and
pericytes [63]. Thus, another rationale for a systems approach is the coordinated heart
and lung codevelopment. Signals emanating from the lung circulation are received by
the capillaries of the heart, which form a complicated network of microvessels which
are connected by anastomoses (Fig. 14.6). The heart, under pressure-and-oxidant
stress, secretes a number of factors, the cardiac secretome [64], some of which affect
the kidney function, while adrenal aldosterone participates in myocardial fibrosis.
Maron et al. [65] recently showed that aldosterone can inactivate the endothelin B
receptor which has as a consequence the decrease of pulmonary endothelial nitric
oxide generation. Whether aldosterone also affects myocardial nitric oxide produc-
tion is unknown. Lastly, angiogenic factors like VEGF promote the release of bone
marrow cells which can attach themselves to the lung vessels and vascular lesions;
such cells are endothelial and hematopoietic precursor cells, megakaryocytic, mast
cells, and dendritic cells which, under the influence of VEGF, can transdifferentiate
into endothelial cells. This system of circulating cells, circulating microRNA-con-
taining particles, mediators of cell growth and death, and mediators of inflammation
connects lungs, heart, and bone marrow through multiple feedback and feed forward
loops—many of which still undiscovered. Much can be learned from investigating
these multiple complex interactions in PAH patients before and after thromboendar-
terectomy and before and after single lung transplantation.
References
1. Thomas DP, Vane JR. 5-hydroxytryptamine in the circulation of the dog. Nature.
1967;216(5113):335–8.
2. Vane JR. The release and fate of vaso-active hormones in the circulation. Br J Pharmacol.
1969;35(2):209–42.
3. Junod AF. Uptake, metabolism and efflux of 14 C-5-hydroxytryptamine in isolated perfused

rat lungs. J Pharmacol Exp Ther. 1972;183(2):341–55.
4. Junod AF. Metabolism, production, and release of hormones and mediators in the lung. Am
Rev Respir Dis. 1975;112(1):93–108.
5. Iwasawa Y, Gillis CN. Pharmacological analysis of norepinephrine and 5-hydroxytryptamine
removal from the pulmonary circulation: differentiation of uptake sites for each amine.
J Pharmacol Exp Ther. 1974;188(2):386–93.
6. Anderson MW, Eling TE. Prostaglandin removal and metabolism by isolated perfused rat lung.
Prostaglandins. 1976;11(4):645–77.
7. Voelkel NF, et al. Release of vasodilator prostaglandin, PGI2, from isolated rat lung during
vasoconstriction. Circ Res. 1981;48(2):207–13.
8. Voelkel NF, Rounds S, editors. Lung Endothelial Cells. Function in health and disease.
Chichester: Wiley-Blackwell; 2009.
9. Junod AF. Metabolism of the intact pulmonary microcirculation. Ann N Y Acad Sci.
1982;384:66–71.
11. Bogaard HJ, et al. The right ventricle under pressure: cellular and molecular mechanisms of
right-heart failure in pulmonary hypertension. Chest. 2009;135(3):794–804.
12. de Man FS, et al. Neurohormonal axis in patients with pulmonary arterial hypertension: friend
or foe? Am J Respir Crit Care Med. 2013;187(1):14–9.
13. Barr RG, et al. Percent emphysema, airflow obstruction, and impaired left ventricular filling.
N Engl J Med. 2010;362(3):217–27.
14. Voelkel NF, et al. Right ventricle in pulmonary hypertension. Compr Physiol. 2011;1:
595–610.
15. Taraseviciene-Stewart L, Voelkel NF. Molecular pathogenesis of emphysema. J Clin Invest.
2008;118(2):394–402.
16. Dinh-Xuan AT, et al. Impairment of endothelium-dependent pulmonary-artery relaxation in
chronic obstructive lung disease. N Engl J Med. 1991;324(22):1539–47.
17. Peinado VI, et al. Endothelial dysfunction in pulmonary arteries of patients with mild
COPD. Am J Physiol. 1998;274(6 Pt 1):L908–13.
18. Barr RG, et al. Impaired flow-mediated dilation is associated with low pulmonary function and
emphysema in ex-smokers: the Emphysema and Cancer Action Project (EMCAP) Study. Am
J Respir Crit Care Med. 2007;176(12):1200–7.
19. Langleben D, et al. Pulmonary capillary endothelial metabolic dysfunction: severity in pulmo-
nary arterial hypertension related to connective tissue disease versus idiopathic pulmonary
arterial hypertension. Arthritis Rheum. 2008;58(4):1156–64.
20. Zabini D, et al. Angiostatic factors in the pulmonary endarterectomy material from chronic
thromboembolic pulmonary hypertension patients cause endothelial dysfunction. PLoS One.
2012;7(8):e43793.
21. Kassim AA, DeBaun MR. Sickle cell disease, vasculopathy, and therapeutics. Annu Rev Med.
2013;64:451–66.
22. Tuder RM, et al. Prostacyclin synthase expression is decreased in lungs from patients with
severe pulmonary hypertension. Am J Respir Crit Care Med. 1999;159(6):1925–32.
23. Nana-Sinkam SP, et al. Prostacyclin prevents pulmonary endothelial cell apoptosis induced by
cigarette smoke. Am J Respir Crit Care Med. 2007;175(7):676–85.
24. Follansbee WP, et al. Physiologic abnormalities of cardiac function in progressive systemic
sclerosis with diffuse scleroderma. N Engl J Med. 1984;310(3):142–8.
25. Steen VD, et al. Thallium perfusion defects predict subsequent cardiac dysfunction in patients
with systemic sclerosis. Arthritis Rheum. 1996;39(4):677–81.
26. Kahan A, Allanore Y. Primary myocardial involvement in systemic sclerosis. Rheumatology
(Oxford). 2006;45 Suppl 4: iv14–7.
27. Rai PR, et al. The cancer paradigm of severe pulmonary arterial hypertension. Am J Respir Crit
Care Med. 2008;178(6):558–64.
312 N.F. Voelkel
28. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):
646–74.
29. Chaffer CL, Weinberg RA. A perspective on cancer cell metastasis. Science. 2011;331(6024):
1559–64.
30. Okubo Y, et al. Pulmonary tumor thrombotic microangiopathy induced by gastric carcinoma:
morphometric and immunohistochemical analysis of six autopsy cases. Diagn Pathol.
2011;6:27.
31. Bull TM, et al. Circulating endothelial cells in pulmonary hypertension. Thromb Haemost.
2003;90(4):698–703.
32. Schiavon M, et al. Increased tissue endothelial progenitor cells in end-stage lung diseases with
pulmonary hypertension. J Heart Lung Transplant. 2012;31(9):1025–30.
33. Anjum F, et al. Characterization of altered patterns of endothelial progenitor cells in sickle cell
disease related pulmonary arterial hypertension. Pulm Circ. 2012;2(1):54–60.
34. Lenna S, et al. Increased expression of endoplasmic reticulum stress and unfolded protein
response genes in peripheral blood mononuclear cells from patients with limited cutaneous
systemic sclerosis and pulmonary arterial hypertension. Arthritis Rheum. 2013;65(5):1357–66.
35. Hansmann G, et al. Design and validation of an endothelial progenitor cell capture chip and its
application in patients with pulmonary arterial hypertension. J Mol Med (Berl). 2011;89(10):
971–83.
36. Toshner M, et al. Evidence of dysfunction of endothelial progenitors in pulmonary arterial
hypertension. Am J Respir Crit Care Med. 2009;180(8):780–7.
37. Smadja DM, et al. Circulating endothelial cells: a new candidate biomarker of irreversible
pulmonary hypertension secondary to congenital heart disease. Circulation. 2009;119(3):
374–81.
38. Yeager ME, et al. Circulating fibrocytes are increased in children and young adults with
pulmonary hypertension. Eur Respir J. 2012;39(1):104–11.
39. Lewis MS, et al. Hydrogen peroxide stimulates the synthesis of platelet-activating factor by
endothelium and induces endothelial cell-dependent neutrophil adhesion. J Clin Invest.
1988;82(6):2045–55.
40. Watanabe J, et al. Endotoxins stimulate neutrophil adhesion followed by synthesis and release
of platelet-activating factor in microparticles. J Biol Chem. 2003;278(35):33161–8.
41. Bakouboula B, et al. Procoagulant membrane microparticles correlate with the severity of
pulmonary arterial hypertension. Am J Respir Crit Care Med. 2008;177(5):536–43.
42. Gordon C, et al. Circulating endothelial microparticles as a measure of early lung destruction
in cigarette smokers. Am J Respir Crit Care Med. 2011;184(2):224–32.
43. Thomashow MA, et al. Endothelial microparticles in mild COPD and emphysema: The MESA
COPD Study. Am J Respir Crit Care Med. 2013;188(1):60–8.
44. Amabile N, et al. Cellular microparticles in the pathogenesis of pulmonary hypertension. Eur
Respir J. 2013;42(1):272–9.
45. Diehl P, et al. Increased platelet, leukocyte and endothelial microparticles predict enhanced
coagulation and vascular inflammation in pulmonary hypertension. J Thromb Thrombolysis.
2011;31(2):173–9.
46. Chen TS, et al. Mesenchymal stem cell secretes microparticles enriched in pre-microRNAs.
Nucleic Acids Res. 2010;38(1):215–24.
47. Laffont B, et al. Activated platelets can deliver mRNA regulatory Ago2{middle dot}microRNA
complexes to endothelial cells via microparticles. Blood. 2013;122(2):253–61.
48. Wang JG, et al. Monocytic microparticles activate endothelial cells in an IL-1beta-dependent
manner. Blood. 2011;118(8):2366–74.
49. Kawut SM, et al. von Willebrand factor independently predicts long-term survival in patients
with pulmonary arterial hypertension. Chest. 2005;128(4):2355–62.
50. Perros F, et al. Cytotoxic cells and granulysin in pulmonary arterial hypertension and pulmo-
nary veno-occlusive disease. Am J Respir Crit Care Med. 2013;187(2):189–96.
51. Bull TM, et al. Gene microarray analysis of peripheral blood cells in pulmonary arterial hyper-
tension. Am J Respir Crit Care Med. 2004;170(8):911–9.
52. Caruso P, et al. A role for miR-145 in pulmonary arterial hypertension: evidence from mouse
models and patient samples. Circ Res. 2012;111(3):290–300.
53. Hofstee HM, et al. Pulmonary arterial hypertension in systemic sclerosis is associated with
profound impairment of microvascular endothelium-dependent vasodilatation. J Rheumatol.
2012;39(1):100–5.
54. Uzuelli JA, et al. Circulating cell-free DNA levels in plasma increase with severity in
experimental acute pulmonary thromboembolism. Clin Chim Acta. 2009;409(1–2):112–6.
55. Oka T, et al. Mitochondrial DNA that escapes from autophagy causes inflammation and heart
failure. Nature. 2012;485(7397):251–5.
56. Drake KM, et al. Altered MicroRNA processing in heritable pulmonary arterial hypertension:
an important role for Smad-8. Am J Respir Crit Care Med. 2011;184(12):1400–8.
57. Ezzie ME, et al. Gene expression networks in COPD: microRNA and mRNA regulation.
Thorax. 2012;67(2):122–31.
58. Kim J, et al. An endothelial apelin-FGF link mediated by miR-424 and miR-503 is disrupted
in pulmonary arterial hypertension. Nat Med. 2013;19(1):74–82.
59. Goetze JP, et al. Apelin: a new plasma marker of cardiopulmonary disease. Regul Pept.
2006;133(1–3):134–8.
60. Drake JI, et al. Molecular signature of a right heart failure program in chronic severe pulmonary
hypertension. Am J Respir Cell Mol Biol. 2011;45(6):1239–47.
61. Rhodes CJ, et al. Reduced microRNA-150 is associated with poor survival in pulmonary
arterial hypertension. Am J Respir Crit Care Med. 2013;187(3):294–302.
62. Shen J, et al. EGFR modulates microRNA maturation in response to hypoxia through
phosphorylation of AGO2. Nature. 2013;497(7449):383–7.
63. Peng T, et al. Coordination of heart and lung co-development by a multipotent cardiopulmonary
progenitor. Nature. 2013;500(7464):589–92.
64. Shimano M, Ouchi N, Walsh K. Cardiokines: recent progress in elucidating the cardiac
secretome. Circulation. 2012;126(21):e327–32.
65. Maron BA, et al. Plasma aldosterone levels are elevated in patients with pulmonary arterial
hypertension in the absence of left ventricular heart failure: a pilot study. Eur J Heart Fail.
2013;15(3):277–83.
Chapter 15
Exercise-Induced Right Heart Disease
in Athletes
David Prior and Andre La Gerche
Effects of Athletic Training on the Right Heart
The training-related changes in cardiac structure and function enable the heart to
provide the necessary increase in cardiac output required during exercise [8–10].
In some athletes during exercise, cardiac output may increase six- to eightfold
in order to deliver more oxygen to working muscles [11, 12]. In the absence of a
significant intra- or extra-cardiac shunt, the left and right ventricles are required
to increase cardiac output by a similar amount during exercise and this occurs as a
result of an increase in both heart rate and stroke volume. Because of the architec-
ture of the circulatory system with the right ventricle, the pulmonary circulation, the
left ventricle and the systemic circulation assembled in series, the volume load on
the ventricles is essentially identical.
However, the wall stress and ventricular work of the LV and RV are dependent
not only on the volumes of the ventricles but also on the afterload; and the pulmo-
nary and systemic circulation have some distinct differences. Whilst the systemic
vascular bed has a great capacity for vasodilation due to the extensive muscle and
skin circulation which receives only a small proportion of cardiac output at rest, but
com/videos/978-1-4939-1064-9.
D. Prior, M.B.B.S., Ph.D., F.R.A.C.P., D.D.U., F.C.S.A.N.Z (*)
Department of Cardiology, St Vincent’s Hospital, University of Melbourne,
Fitzroy, VIC, Australia
e-mail: david.prior@svhm.org.au
A. La Gerche, M.B.B.S., F.R.A.C.P., Ph.D.
Department of Medicine, St Vincent’s Hospital, University of Melbourne,
Fitzroy, VIC, Australia

316 D. Prior and A. La Gerche
which receives a higher proportion during exercise, the pulmonary circulation

receives the entire cardiac output but has a pressure of approximately one fifth that
of the systemic circulation. The relationship between pressure (P), flow (F), and
resistance (R) can be simplified as: F ∝ P/R (the simplified Poiseuille’s law) and
explains how a lower resistance vascular system is associated with lower vascular
pressures. The lower resistance in the pulmonary circulation is a product of a num-
ber of unique features: firstly, there is rapid and extensive branching of vessels in the
pulmonary circulation. Total vascular resistance may be quantified as the sum of the
reciprocal of the resistance of each branch (i.e. 1/Rtotal = 1/R1 + 1/R2 + 1/R3…) such
that the greater the number of parallel branches the lower the total resistance. In
addition, the pulmonary arteries and arterioles are thinner-walled than their sys-
temic counterparts. This has a very important implication in that the thinner-walled
vessels are more compliant and this greater compliance causes a further reduction
in flow resistance and pressure. This concept is summarized in the Windkessel
model of vascular flow [13, 14]. This model predicts that compliance is inversely
proportional to resistance and thus the “stretching” of compliant vessels with pulsa-
tile flow serves to decrease the resistance and blunt pressure rises. Another potential
difference is that there is a relative independence between the arterial and venous
pressures in the systemic system whereas in the pulmonary circulation the venous
pressure has considerable influence on the pulmonary artery pressure. This may be
of particular importance during exercise. Lewis et al. recently described a strong
correlation between pulmonary artery occlusion ‘wedge’ pressure (Pcwp—a surro-
gate of pulmonary venous pressure) and cardiac output (CO) in a group of control
subjects without overt cardiac or pulmonary disease [15]. They determined the rela-
tionship Pcwp (mmHg) = 1.1 × CO (L/min) which would suggest that pulmonary
venous pressure might be expected to increase substantially as a result of the marked
increases in an athlete’s cardiac output during exercise. There have been few studies
of healthy young cohorts in which pulmonary venous or direct left atrial pressure
measurements have been obtained during exercise. Reeves et al. [16] studied healthy
young athletes and observed substantial increases in Pcwp during exercise and
Lewis et al. [15] described a linear increase in Pcwp relative to cardiac output also
implying that LV filling pressures increase significantly during high-intensity exer-
cise. The implication of this is that the RV must generate sufficient pressure to
accommodate the combined afterload of LV filling and that which is required to
augment flow through the pulmonary circulation during exercise.
In addition to a pressure increase as a result of transmitted ‘back-pressure’ from
the left atrium, pulmonary artery pressures (PAP) increase in athletes as a result of
limitations in pulmonary vascular reserve. As compared with the systemic circula-
tion which recruits and dilates the large vascular territories within the working mus-
cles, the pulmonary circulation is already mostly recruited during activities of daily
living. Therefore, the differences between the pulmonary and systemic circulations
are that the former consists of a more extensive and compliant parallel circuit which
provides minimal load for the RV at rest. However, during exercise the pulmonary
circulation has diminished capacity for further changes in resistance and compli-
ance and greater susceptibility to increases in venous pressure. PAP increases sig-
nificantly during exercise, as has now been confirmed using echocardiographic
estimates [17–20] and direct invasive measures [15, 21] (Fig. 15.1).
15 Exercise-Induced Right Heart Disease in Athletes 317
Fig. 15.1 A consistent relationship between increases in pulmonary artery pressures and cardiac
output during exercise. Echocardiographic estimates of pulmonary artery pressures (PAP)—panels
(a) and (b)—demonstrate a near-linear relationship between increases in PAP and cardiac output
(CO). These findings have been validated in untrained and trained subjects using direct invasive
pulmonary artery pressure measures (panels (a) & (c)—authors’ own unpublished data and panel
(b) adapted with permission from Argiento et al. [18])
Moreover, the increase in PAP seems disproportionate to the more moderate

increase in the systemic vascular pressure. We sought to assess this seemingly dis-
proportionate ventricular load using a combination of magnetic resonance and echo-
cardiographic imaging at rest and during exercise to quantify RV systolic wall stress,
as compared with that of the LV [19]. Using the simple construct of the LaPlace
relationship, we found that during exercise the increase in both pressure and volume
was greater for the RV, while the increase in wall thickness was relatively less than
that of the LV. As a result, the estimated RV wall stress estimates increased 125 %
during exercise as compared with a modest 14 % increase in LV wall stress [19].
Thus, it appears that the stress, work, and metabolic demands placed on the RV dur-
ing strenuous exercise are relatively greater than that of the LV. The hemodynamic
stress on the RV can be visualized during exercise using novel techniques such as
exercise cardiac magnetic resonance imaging (CMR). Video 15.1 provides a com-
parison between biventricular function in a nonathlete, an athlete, and a patient with
pulmonary hypertension. The RV dilation and septal shift during exercise can be
appreciated as can the similarities between the exercise hemodynamic stressors in
the athlete and the patient with pulmonary hypertension.
RV Structural Changes
The athlete’s heart phenotype is usually described as a symmetrical increase in the

dimensions of all four cardiac chambers. The nature and extent of cardiac remodel-
ing is defined by a number of factors, some of which remain somewhat speculative
(Fig. 15.2). It is likely that genetic and other factors modify remodeling but cer-
tainly the recurrent hemodynamic stressors imposed during regular training and
competition are a major influence. As was first documented in the seminal work by
Morganroth et al. [22] and later validated by others [23, 24], ventricular mass is
increased after both strength and endurance exercise but endurance exercise training
results in greater chamber dilation as a result of volume load. Thus, changes in ven-
tricular structure reflect the hemodynamic load imposed and this would imply that
disproportionate RV remodeling may occur as a result of the greater hemodynamic
load posed on the RV.
There are relatively few studies which have compared the extent to which exer-
cise remodeling affects the RV relative to the LV, and the available evidence is
conflicting. The structural effects of regular endurance training on the right heart are
superficially similar to the effects on the left heart with myocardial hypertrophy
resulting in increased right ventricular mass and increased right ventricular volume.
In an older adult cohort, increased right ventricular volume and mass are associated
in a fairly linear fashion with the amount of self-reported exercise performed [25],
Fig. 15.2 Training induced changes in cardiac morphology. Differences in exercise hemodynamic
stressors determine cardiac morphology in endurance and strength trained athletes with important
genetic, training-related and other modifying influences which remain imprecisely characterized
independent of other clinical variables and independent of LV mass and volumes.

In endurance athletes, the degree of left and right ventricular dilation has been
reported to be similar [26–29] reflecting the similar degrees of volume loading,
although recent work suggests that the right ventricle may enlarge to a slightly
greater extent [19]. As a result of the increased RV volume and a normal stroke
volume, a reduced resting right ventricular ejection fraction is frequently observed
in highly trained athletes.
One study in track athletes demonstrated that the right ventricular mass was
increased when compared to nonathletes in both sprinters and marathon runners
[30]. In the same cohort, in anaerobic power track athletes, more pronounced right
ventricular dilation is seen on CMR scanning than in the marathon runners.
Furthermore, some insights may be gained from animal experiments based on an
induced aortocaval fistula in pigs [31]. This intervention leads to a chronic cardiac
high-output state with an increase in volume and pressure load somewhat akin to
exercise. At 3 months after the surgery, there was a disproportionate increase in RV
stroke work index relative to that of the LV (+216 % vs. +70 %), RV fibrosis, and
the development of RV dysfunction. As compared with the more “physiological”
LV hypertrophy characterized by myocyte length increase and increased local pro-
duction of insulin-like growth factor, the RV showed more pronounced hypertrophy,
increase in both myocyte length and diameter, and associated increased collagen
deposition [31].
Thus, most forms of exercise result in increases in right ventricular mass and
volume. The degree of increase appears to relate to the amount of exercise per-
formed and has been observed both in cohorts who are already training and follow-
ing training of sedentary individuals. The degree of right ventricular remodeling in
endurance athletes appears to be slightly greater than that seen for the left ventricle.
RV Functional Changes
There are scant data to guide our understanding of RV functional changes as a result
of athletic training. Furthermore, assessment of RV function is confounded by
structural changes because the RV enlargement that constitutes part of the athlete’s
heart phenotype also affects measures of RV function. In a larger heart, variables
measuring motion tend to be larger [32] while variables measuring deformation and
ejection fraction tend to be lower [33]. Available data need to be interpreted within
this context. For example, D’Andrea et al. observed that tricuspid annular motion
was greater in athletes than in nonathletes [34] while, in contrast, Teske et al. [35]
and our own data [36] suggest that resting measured variables of strain and strain
rate tend to be lower in endurance athletes relative to controls. However, during
exercise these values tend to normalize suggesting that contractile reserve is normal
in athletes as might be expected given the remarkable cardiac outputs generated
[36]. In a relatively large magnetic resonance imaging study of over 300 sub-
jects, RV ejection fraction was lower in endurance athletes when compared
with nonathletes (50 vs. 52 % in men and 53 vs. 55 % in women) [37]. Thus, the
interpretation of many of these studies is problematic with some authors concluding
that RV function is supra-normal and others that RV function is impaired. However,
the extent to which these functional measurements represent, true changes in myo-
cardial contractility, is difficult to determine and, moreover, we would argue that it
is most important to determine myocardial function during exercise when its ability
to respond to increased demand can be appraised.
The combination of structural and functional changes in the endurance athlete’s
heart can be profound and can lead to clinical difficulties in determining whether the
extent of RV remodeling can be considered normal for an athlete or may be an indi-
cation of evolving pathology. Figure 15.3 and Video 15.2 provide examples of the
extent of RV remodeling in four elite cyclists from a single professional team.
Fig. 15.3 Examples of cardiac morphology in four elite cyclists. Refer also to Video 15.1 to
observe cardiac function in these athletes. The images exemplify the RV dilation, hypertrophy, and
hypertrabeculation which can be commonly seen amongst high-level athletes
The Importance of the RV and Pulmonary Vasculature

to Athletic Performance
Right ventricular function and the state of the pulmonary vascular bed appear to be
important determinants of exercise capacity. While this has been long appreciated in
disease states such as pulmonary arterial hypertension where right ventricular dys-
function has been shown to be a marker of both exercise capacity and poor progno-
sis [38–43], the same cannot necessarily be extrapolated to healthy athletes. Rather,
it seems that increased RV dilation is associated with improved exercise perfor-
mance in athletes.
It has been shown that RV volume is an important correlate of peak exercise
oxygen consumption (VO2peak) [12]. However, given that changes in cardiac struc-
ture are relatively balanced between the RV and LV, it is difficult to determine
whether changes in RV structure and function are any more important in predicting
exercise capacity than measures of the LV or whole heart [44]. Interestingly, the two
studies that have investigated the relationship between ventricular volumes and
VO2peak have observed a slightly stronger correlation between RV than LV vol-
umes. However, with such significant collinearity between ventricular measures, it
is most reasonable to conclude that it is the global increase in cardiac size which
best determines exercise capacity.
As has been discussed in the preceding sections, the RV and pulmonary circula-
tion are placed under disproportionate stress during exercise which raises the
intriguing hypothesis that the pre-systemic circulation may be an important deter-
minant of exercise capacity. However, assessment of the pulmonary circulation is
difficult using noninvasive measures and particularly so during exercise. A number
of studies have identified a novel noninvasive surrogate which appears to describe
pulmonary vascular physiology. Eldridge et al. [45] observed that agitated saline
contrast filled the RV, but that the bubbles were too large to pass through the pulmo-
nary circulation at rest. During exercise, however, the bubbles passed through the
pulmonary circulation and could be visualized with echocardiography passing into
the left-sided heart chambers (Fig. 15.4). The authors concluded that this repre-
sented passage through larger pulmonary vessels and hypothesized that this may be
a physiologically advantageous trait enabling higher flows at lower vascular pres-
sures. La Gerche et al. validated this theory by demonstrating that those subjects
with greater amounts of contrast in the left heart during exercise had higher cardiac
outputs, lower pulmonary artery pressures, and higher pulmonary vascular compli-
ance than did those with few bubbles passing through the pulmonary circulation
[20]. It was observed that the transit of bubbles through the pulmonary circulation
occurred to a similar extent in athletes and nonathletes, implying that it is a non-
trainable characteristic, and that it was associated with greater VO2peak and better
exercise-induced augmentation of RV function.
The exact mechanism underlying the transpulmonary passage of agitated con-
trast (PTAC) remains speculative. It has been suggested that it represents recruitable
arteriovenous shunts [46] whereas we and others have argued that it is more likely a
Fig. 15.4 Transpulmonary passage of agitated contrast. Echocardiographic apical four chamber
views at rest (left panel) and at exercise (middle and right panels) after the injection of agitated
contrast, showing appearance in the left heart chambers after 4–5 beats at moderate exercise, and
more so at intense exercise. The contrast can be seen entering the left atrium via the pulmonary
veins (arrowheads) during exercise. This phenomenon has been associated with enhanced pulmo-
nary vascular function and greater cardiac outputs during exercise
reflection of microvascular recruitment and distensibility. Using lung diffusing

capacities of carbon monoxide and nitric oxide, the group of Lalande and Naeije
demonstrated that the transpulmonary passage of agitated contrast was associated
with greater pulmonary arteriolar distensibility and capillary recruitment [47].
Furthermore, they again found an association between transpulmonary contrast and
VO2peak confirming that pulmonary vascular and RV function during exercise may
be an important constraint during exercise and that agitated contrast may be a useful
surrogate for identifying those with better pulmonary vascular reserve.
Beyond VO2peak, there are very few studies that have investigated a relationship
between exercise performance and cardiac variables. Intriguingly, Bernheim et al.
recently studied the relationship between cardiac morphology and the time taken to
complete an ultra-endurance triathlon and found a relatively strong inverse relation-
ship between time and RV volumes; that is, the larger the RV the faster the athlete
[48]. Further confirmation is required for each of these lines of inquiry, but current
evidence suggests that there may indeed be a relationship between exercise perfor-
mance and cardiovascular function and that variables pertaining to the RV and pul-
monary circulation may be most instructive.
Evidence of Adverse Effects of Endurance on Cardiac

Structure and Function
As has been detailed, exercise training is associated with changes in cardiac struc-
ture and function which tend to favor the RV and which are associated with improved
exercise performance. However, in contrast to these seemingly beneficial physio-
logical adaptations, there is evidence to suggest that some of the exercise-induced
changes may be associated with acute and chronic cardiac damage and that in a
small number of athletes this may predispose individuals to atrial and ventricular
arrhythmias. Concern regarding the potential for proarrhythmic remodeling in ath-
letes stems from the observations of cardiac damage following endurance sporting
events, an increased prevalence of some arrhythmias amongst endurance athletes
and evidence of chronic structural changes or ‘scar’ within the myocardium of some
veteran endurance athletes. Each of these factors will be discussed in detail.
Biomarkers in Endurance Exercise
Studies of endurance athletes following competitive events in different disciplines

and of different durations have shown evidence of acute myocardial injury based on
the transient elevation of biomarkers following these events. Events have included
ultra-endurance triathlon, ultra-endurance cycling events, and marathon running.
Biomarkers studied have included troponin T, troponin I and B-type natriuretic pep-
tide. The first study examining this issue in marathon runners was published in 1981
and based on monitoring of the CK-MB isoenzyme [49]. Elevated CK-MB levels
were seen following marathon running, but this work was confounded by the fact
that CK-MB may be elevated by skeletal muscle injury, an almost universal out-
come following a marathon.
The first evidence using more specific biomarkers appeared in 1999, when Rifai
and co-workers studied 23 participants competing in an ultra-endurance triathlon
and found elevated levels of cardiac troponin T and CK-MB in the athletes at the
conclusion of the event [50]. They also observed changes in left ventricular function
and concluded that ultra-endurance exercise may cause myocardial damage,
although it was unclear from this study, which did not follow up on the participants,
whether the damage was transient or permanent. Other studies also showed a similar
increase in cardiac troponin levels in cycling [51, 52], triathlon [53, 54], and mara-
thon running [55], all events with an average duration of 4 h. A meta-analysis sug-
gested that elevated cardiac troponin levels occur in approximately 50 % of
endurance exercise event participants [56]. In all studies, cardiac enzyme levels
returned to the normal range within a few days of the exercise.
The consistent finding of elevated markers of cardiac injury, but rapid normaliza-
tion prompted a debate regarding the origin, mechanisms, and significance of these
biomarkers. Neilan observed differences in the frequency of biomarker elevations in
marathon runners, with less trained individuals being more likely to have high tro-
ponin T levels [57]. In the meta-analysis of Shave et al., elevated levels were more
common after shorter events, thought to be due to the higher intensity at which the
events are performed [56]. In those competing in longer events, there does not
appear to be a clear relationship with training levels [58]. Some authors have argued
that the elevation of cardiac troponin levels, generally considered to be evidence
of cardiomyocyte necrosis, was caused by alternative mechanisms. Some have
argued that increased cardiomyocyte membrane permeability due to myocardial
stress results in diffusion of cytosolic troponin into the extracellular space [56].
Others have argued that the kinetics of troponin release with rapid normalization is
suggestive of altered myocyte metabolism rather than necrosis [59].
It appears that both exercise duration and intensity are important determinants of
the occurrence and magnitude of troponin release during exercise.
Acute Changes in RV Function with Exercise
Acute changes in cardiac function have been repeatedly demonstrated following

endurance sporting events. Evidence regarding LV function following endurance
exercise is substantive but frequently conflicting [60]. A meta-analysis of 23 studies
concluded that intense endurance exercise was associated with a modest decrease in
LV ejection fraction (–2 %) which was at least partially attributable to changes in
cardiac loading in the post-race setting. In contrast, a number of recent studies have
assessed RV function post-endurance exercise and have consistently reported decre-
ments in RV function which are far more substantive than those observed for the
LV. Relative to baseline measures, studies have reported reductions in simple geo-
metric measures of RV function such as fractional area change and tricuspid annular
displacement [57, 58, 61, 62]. Using M-mode studies two decades ago, Douglas
et al. demonstrated that the RV dilated following an ultra-endurance triathlon
whereas the LV dimensions were unchanged [63] and this observation has recently
been replicated using 2D and 3D echocardiography[58, 62]. The result of the RV
dilation combined with pericardial constraint is that the interventricular septum is
pushed toward the LV resulting in an increase in the LV eccentricity index [58, 62].
It has been hypothesized that this “squashing” of the LV during early diastole may
explain some of the observed changes in LV diastolic variables.
It may be argued that echocardiographic assessment of RV function has signifi-
cant limitations. However, studies using cardiac magnetic resonance imaging
(CMR) post-IEE have confirmed the same differential effects with no change in LV
function and a considerable reduction in RVEF [64, 65]. Finally, while multiple
studies have documented that there is no relationship between biomarkers of cardiac
injury and changes in LV function [66], two recent studies have documented mod-
erately strong inverse correlations between the decrease in measures of RV function
and the increase in release of troponin and B-type natriuretic peptide [57, 58]. Thus,
it would seem that the RV is potentially the “Achilles’ heel” of the endurance athlete
which is disproportionately fatigued or injured following endurance exercise.
Arrhythmias in Athletes
While athletes are not immune to the disturbances of cardiac rhythm seen by non-
athletes, palpitations and arrhythmias are a common problem observed in sports
cardiology practice. There is now reasonably compelling evidence that some
cardiac arrhythmias are associated with long-standing endurance training. Almost

every study conducted in endurance athletes of middle age or older athletes has
observed an increased prevalence of atrial fibrillation (AF) as compared with non-
athletic referents [67–74]. In a meta-analysis, Abdulla et al. determined a 5.3-fold
relative risk for the development of AF amongst studies matching athletes (almost
exclusively male) to nonathletic controls [6].
Evidence for an excess of other cardiac arrhythmias is less well established.
Biffi et al. reported that ventricular ectopic beats were common amongst athletes
but this was a benign and potentially reversible phenomenon as long as underlying
cardiac disease was excluded [75, 76]. In contrast, Heidbuchel et al. observed a
high incidence of major arrhythmic events (39 %) including sudden cardiac death
(20 %) amongst 46 athletes, followed for 5 years, who presented with frequent
ventricular ectopy or non/sustained ventricular tachycardia [77]. Somewhat sur-
prisingly, in 89 % of cases the arrhythmias arose from the RV and were frequently
associated with functional and/or structural changes of the RV. In a subsequent
study by the same group, the presence of right ventricular arrhythmias was associ-
ated with increased right ventricular size and decreased right ventricular systolic
function when compared to athletes without ventricular arrhythmias and nonath-
letes [78]. In these studies there was only one athlete with a family history suspi-
cious for an inherited disease process suggesting that the RV remodeling was
unlikely to be explained by arrhythmogenic right ventricular cardiomyopathy
(ARVC) (see Chap. 16). Thus this group of endurance athletes appeared to have
an unexpectedly high rate of arrhythmias arising from the right ventricle and
unexpected right ventricular dysfunction.
Evidence of Chronic Myocardial Changes Affecting the RV
An accumulating body of circumstantial evidence suggests that there may be some

overlap in the spectrum from physiological to pathological hypertrophy such that a
small amount of fibrosis may accompany more profound cardiac remodeling associ-
ated with lifelong endurance training. The concept of purely physiological remodel-
ing in response to exercise training implies that myocyte hypertrophy and hyperplasia
is stimulated in response to a hemodynamic load and is downregulated once that
stimulus is removed [79]. Thus we would expect that cardiac size would return to
normal in athletes who de-train. However, Pelliccia et al. prospectively followed 40
elite male athletes and found that while cardiac dimensions did decrease with
detraining, substantial cavity dilation persisted in nine athletes (22 %) [80] and a
number of other studies have reported enlarged cardiac dimensions amongst retired
endurance athletes and related the extent of these changes to the development of
arrhythmias [68, 72, 81, 82]. Thus, speculation has arisen that this persistent cardiac
enlargement may reflect a degree of interstitial fibrosis and this hypothesis has
recently been evaluated using CMR combined with gadolinium contrast. Cell necro-
sis and fibrosis lead to leaking of gadolinium into the extracellular space and this
Fig. 15.5 Delayed gadolinium enhancement in highly trained athletes; evidence of exercise-
induced myocardial scar? Images of five athletes in whom focal delayed gadolinium enhancement
(DGE) were identified in the interventricular septum (indicated with arrows) as compared with an
athlete with a normal study (top left). Reproduced with permission from La Gerche et al. [58]
can then be identified using gradient-echo inversion recovery imaging as a bright

signal contrasting with the normal myocardium which appears black (Fig. 15.5).
This delayed gadolinium enhancement (DGE) technique has been investigated in
small cohorts of athletes and while it appears that DGE tends to be absent in athletes
with modest training histories [64, 65, 83], four recent studies have each reported
DGE in 12–50 % of extensively trained veteran athletes [58, 84–86]. La Gerche
et al. identified DGE in 5 of 39 well-trained endurance athletes, and found that those
with DGE had a more extensive history of training and had greater cardiac dimen-
sions, particularly of the RV [58]. The patches of DGE have tended to be very small
and clustered around the septum and RV insertion points, a region which may be
subjected to local mechanical stress due to RV pressure afterload, in a manner simi-
lar to pulmonary hypertension [87, 88].
Thus, it may be concluded that the majority of evidence that raises concern of
cardiac damage secondary to extreme exercise tends to point toward the RV as the
site of greatest injury. Acute post-race changes, chronic structural changes and pro-
arrhythmic remodeling all tend to favor the RV more than the LV. Adding support to
this concept from the animal domain, Benito et al. instituted a strenuous 18-week
treadmill running regime in young rats estimating that this was the equivalent of 10
years of endurance exercise training in humans [89]. As compared with the seden-
tary control rats, there was an increase in atrial and right ventricular inflammation/
fibrosis in the “marathon rats” and, perhaps most importantly, this was associated
with a greater potential for inducible ventricular arrhythmias (42 % vs. 6 %,
p = 0.05). Once again, it is notable that just as in humans, there is a striking predilec-
tion for effects on the RV, as opposed to the LV.
Possible Mechanisms of RV injury
The available evidence supports the concept that endurance exercise may cause
acute injury to the right ventricle and in some cases there may be more permanent
changes in right ventricular structure and function. The mechanism of exercise-
induced right ventricular dysfunction is not completely understood. A number of
candidate mechanisms have been proposed and investigated to varying extents.
A prime candidate is the hemodynamic stress under which the right heart is
placed during activity. There is evidence that the increase in hemodynamic stress
on the right ventricle during exercise is significantly greater when compared to
the stress to which the left ventricle is subjected. Other possibilities which have
been proposed include myocardial ischemia, possibly mediated through the
effects of vasoconstrictor cytokines or elevated right ventricular end-diastolic
pressures, the effects of differing training regimens or possibly through genetic
susceptibility factors.
Hemodynamic Stress
As discussed in detail earlier in this chapter, evidence suggests that RV pressures,

wall stress, and work all increase disproportionately to that of the LV during intense
exercise. This is likely to manifest as greater RV injury regardless of the specific
factors which cause exercise-induced myocardial injury. There are multiple candi-
date mechanisms including substrate deficiency, ischemia, β-adrenoreceptor
desensitization, accumulation of metabolic toxins and oxidative stress. All of these
may be expected to affect the RV given the greater hemodynamic stress on the
pre-systemic circulation.
Training Regimen
It is likely that exercise intensity, exercise duration, and the degree of training are all
important in the genesis of exercise-induced right ventricular injury. Some evidence
supporting this premise comes from the studies discussed earlier which have docu-
mented changes in myocardial structure amongst highly trained veteran athletes but
not amongst younger or less-trained athletes. We have also previously promoted the
hypothesis of “over-training” of the heart (Fig. 15.6). Like over-use injuries such as
tennis elbow or Achilles’ tendinopathy, intense training and lack of adequate recov-
ery increase the risk of injury. In the heart this may manifest as small patches of
fibrosis and an increased risk of arrhythmias.
Fig. 15.6 Healthy training vs. over-training of the heart. Healthy training with balanced exercise
and recovery results in physiological remodeling in which enhanced cardiac structure and function
enable greater cardiac performance during exercise. On the other hand, we propose that excessive
exercise (training which is too intense and/or recovery that is too short) may cause cardiac injury
and proarrhythmic remodeling which predominantly affects the right ventricle. Reproduced with
permission from Heidbuchel et al. [102]
Myocardial Ischemia
Whereas ischemic injury at a microscopic and microcirculatory level cannot be

excluded as a cause of exercise-induced right ventricular injury, in most published
series of athletes with elevated cardiac biomarkers following exercise, acutely
abnormal cardiac function following exercise, chronic right ventricular abnormali-
ties or right ventricular arrhythmias, the presence of epicardial coronary artery dis-
ease has not been felt to be an important factor. The normal changes of acute
myocardial infarction have not been present on ECG following endurance events,
functional abnormalities have not been seen in a coronary artery distribution and
typical changes of myocardial infarction have not been seen on CMR [90]. It is pos-
sible that variations of other factors such as myocardial capillary density may pre-
dispose some athletes to ischemia as a result of intense exercise. Capillary density
has been shown to be an important determinant of myocardial ischemic damage in
non-ST elevation myocardial infarction [91], possibly by increasing the distance
between metabolizing myocytes and the capillaries supplying oxygen. Similar vari-
ability in right ventricular capillary density may play a role in exercise-induced
right ventricular dysfunction, but has not been systematically studied.
Genetic Predisposition
One possible influence which needs consideration in the genesis of exercise-induced

right ventricular dysfunction is genetic susceptibility. The phenotype in this condi-
tion shares similarities with arrhythmogenic right ventricular cardiomyopathy
(ARVC—see Chap. 16), a genetically mediated cardiomyopathy associated with
right ventricular enlargement, fibrosis, and susceptibility to ventricular arrhythmias,
which may be lethal in some cases. ARVC is recognized as an important cause of
sudden cardiac death during exercise, particularly in parts of Italy [92] and is
actively screened for in young athletes in that country. A number of mutations in
desmosomal components have been identified as causes of familial ARVC, although
the five most common mutations seen in desmoplakin, desmoglein, plakophilin,
plakoglobin, and desmocollin account for only 40 % of cases [93].
Amongst those with ARVC, exercise seems to accelerate phenotypic expression
of the disease. James et al. found that amongst 87 carriers of known mutations in
ARVC candidate genes, symptoms developed amongst endurance athletes at an ear-
lier age and the risk of ventricular arrhythmias was higher [94]. Similarly, La Gerche
et al. observed that in athletes with complex ventricular arrhythmias originating
from the RV, those with recognized mutations in desmosomal components were
more likely to have severe RV dysfunction with onset at lower levels of exercise
than those who did not carry the mutations [95].
Another question is whether exercise can promote an ARVC-like phenotype in the
absence of a genetic risk or in the presence of a mild genetic risk (such as multiple
uncommon polymorphisms) that are difficult to identify and quantify using current
genetic diagnostics. The findings of the study of La Gerche suggest that currently
recognized desmosomal mutations are not the major cause of exercise-induced right
ventricular dysfunction amongst endurance athletes. In a cohort of 47 athletes with
right ventricular arrhythmias, and an average age of 42 ± 11 years, having practiced
moderate to intense sports for an average of 19 years, there were desmosomal muta-
tions in six of the athletes (12.8 %). If exercise-induced right ventricular dysfunction
were simply a manifestation of inherited arrhythmogenic right ventricular cardiomy-
opathy, a positive mutation rate of around 40 % might have been expected [96–101].
This evidence suggests that the currently identified desmosomal mutations are a
contributor in only a small proportion of cases but other unrecognized mutations may
be identified which promote ARVC in the presence of considerable exercise loads.
Areas of Uncertainty and Future Research Needs
A critical clinical question is why some athletes are affected whilst others are not?
It seems that very few endurance athletes develop issues whilst the majority thrives
on massive volumes of high-intensity exercise without developing any adverse
health consequences. What explains this individual variability? There are a number
of hypotheses which are all plausible but largely unsubstantiated. It is likely that the
answers are not a result of one specific cause but rather a combination of host,
Fig. 15.7 Interaction between host and environmental factors are likely to explain an athlete’s
predisposition to arrhythmias
environmental, and disease-specific factors (Fig. 15.7) combined with an element of

chance. It may be that small patches of fibrosis are not so uncommon in athletes but
only rarely form in such a manner as to manifest arrhythmogenic potential. It is
likely that a combination of these risks may explain individual susceptibilities to
exercise-induced damage and clinical events and we have a long way to go before
we will be able to understand these in a manner sufficient to enable risk prediction
and preventative strategies.
A second important question is whether the excess of arrhythmias and potential
for exercise-induced cardiac remodeling extends beyond intense endurance sports?
The majority of the literature have focused on well-trained participants in sports
such as marathon running, cycling, triathlon, and cross-country skiing because it is
these athletes who sustain the greater exercise loads and in whom cardiac remodel-
ing is most profound. However, this pertains to a minority of the regularly exercising
public. Team sports, such as basketball and the football codes, are more popular and
there is little data on which to assess whether these athletes are placed at an excess
risk of arrhythmias and/or exercise-induced cardiac damage. Similarly, we do not
know whether the “weekend warrior” who trains only a few hours per week but then
challenges his or herself with a major endurance event, places him or herself at an
increased risk of arrhythmias. These will be important questions for the future.
Conclusions
There is accumulating evidence that extreme exercise can cause short-term injury
and chronic remodeling of the athlete’s heart. Although there is some animal and
human evidence to suggest that exercise-induced cardiac remodeling may be associ-
ated with an excess of arrhythmias, there is a clear need for large prospective studies
adequately powered to evaluate clinical end-points. These investigations should
focus specific attention on the RV because current data is consistent in identifying
the RV and pulmonary circulation as being disproportionately affected during intense
exercise, after prolonged endurance exercise and after years of habitual intense exer-
cise. The RV may be considered the “Achilles’ Heel” of the athlete’s heart.
References
1. Haskell WL, Lee IM, Pate RR, et al. Physical activity and public health—updated recom-
mendation for adults from the American college of sports medicine and the American heart
association. Circulation. 2007;116:1081–93.
2. Marijon E, Tafflet M, Antero-Jacquemin J, et al. Mortality of French participants in the Tour
de France (1947–2012). Eur Heart J. 2013;34:3145–50.
3. Kujala UM, Tikkanen HO, Sarna S, Pukkala E, Kaprio J, Koskenvuo M. Disease-specific
mortality among elite athletes. JAMA. 2001;285:44–5.
4. Sarna S, Sahi T, Koskenvuo M, Kaprio J. Increased life expectancy of world class male
athletes. Med Sci Sports Exerc. 1993;25:237–44.
5. La Gerche A. Can intense endurance exercise cause myocardial damage and fibrosis? Curr
Sports Med Rep. 2013;12:63–9.
6. Abdulla J, Nielsen JR. Is the risk of atrial fibrillation higher in athletes than in the general
population? A systematic review and meta-analysis. Europace. 2009;11:1156–9.
7. Mont L. Arrhythmias and sport practice. Heart. 2010;96:398–405.
8. Fagard R. Athlete’s heart. Heart. 2003;86:1455–61.
9. Prior DL, La Gerche A. The athlete’s heart. Heart. 2012;98:947–55.
10. Baggish AL, Wood MJ. Athlete’s heart and cardiovascular care of the athlete: scientific and
clinical update. Circulation. 2011;123:2723–35.
11. La Gerche A, Claessen G, Van de Bruaene A, et al. Cardiac MRI: a new gold standard for
ventricular volume quantification during high-intensity exercise. Circ Cardiovasc Imaging.
2013;6:329–38.
12. La Gerche A, Burns AT, Taylor AJ, Macisaac AI, Heidbuchel H, Prior DL. Maximal oxygen
consumption is best predicted by measures of cardiac size rather than function in healthy
adults. Eur J Appl Physiol. 2012;112:2139–47.
13. Lankhaar JW, Westerhof N, Faes TJ, et al. Pulmonary vascular resistance and compliance
stay inversely related during treatment of pulmonary hypertension. Eur Heart J. 2008;29:
1688–95.
14. Slife DM, Latham RD, Sipkema P, Westerhof N. Pulmonary arterial compliance at rest and
exercise in normal humans. Am J Physiol. 1990;258:H1823–8.
15. Lewis GD, Murphy RM, Shah RV, et al. Pulmonary vascular response patterns during exer-
cise in left ventricular systolic dysfunction predict exercise capacity and outcomes. Circ
Heart Fail. 2011;4:276–85.
16. Reeves JT, Groves BM, Cymerman A, et al. Operation Everest II: cardiac filling pressures
during cycle exercise at sea level. Respir Physiol. 1990;80:147–54.
17. Bidart CM, Abbas AE, Parish JM, Chaliki HP, Moreno CA, Lester SJ. The noninvasive
evaluation of exercise-induced changes in pulmonary artery pressure and pulmonary vascular
resistance. J Am Soc Echocardiogr. 2007;20:270–5.
18. Argiento P, Chesler N, Mule M, et al. Exercise stress echocardiography for the study of the
pulmonary circulation. Eur Respir J. 2010;35:1273–8.
19. La Gerche A, Heidbuchel H, Burns AT, et al. Disproportionate exercise load and remodeling
of the athlete’s right ventricle. Med Sci Sports Exerc. 2011;43:974–81.
20. La Gerche A, MacIsaac AI, Burns AT, et al. Pulmonary transit of agitated contrast is associated
with enhanced pulmonary vascular reserve and right ventricular function during exercise.
J Appl Physiol. 2010;109:1307–17.
21. Kovacs G, Berghold A, Scheidl S, Olschewski H. Pulmonary arterial pressure during rest and
exercise in healthy subjects: a systematic review. Eur Respir J. 2009;34:888–94.
22. Morganroth J, Maron BJ, Henry WL, Epstein SE. Comparative left ventricular dimensions in
trained athletes. Ann Intern Med. 1975;82:521–4.
23. Fagard RH. Athlete’s heart: a meta-analysis of the echocardiographic experience. Int J Sports
Med. 1996;17 Suppl 3:S140–4.
24. Pluim BM, Zwinderman AH, van der Laarse A, van der Wall EE. The athlete’s heart.
A meta-analysis of cardiac structure and function. Circulation. 2000;101:336–44.
25. Aaron CP, Tandri H, Barr RG, et al. Physical activity and right ventricular structure and function.
The MESA-right ventricle study. Am J Respir Crit Care Med. 2011;183:396–404.
26. Scharhag J, Schneider G, Urhausen A, Rochette V, Kramann B, Kindermann W. Athlete’s heart:
right and left ventricular mass and function in male endurance athletes and untrained individuals
determined by magnetic resonance imaging. J Am Coll Cardiol. 2002;40:1856–63.
27. Scharf M, Brem MH, Wilhelm M, Schoepf UJ, Uder M, Lell MM. Atrial and ventricular
functional and structural adaptations of the heart in elite triathletes assessed with cardiac MR
imaging. Radiology. 2010;257:71–9.
28. Scharf M, Brem MH, Wilhelm M, Schoepf UJ, Uder M, Lell MM. Cardiac magnetic
resonance assessment of left and right ventricular morphologic and functional adaptations in
professional soccer players. Am Heart J. 2010;159:911–8.
29. Spence AL, Carter HH, Murray CP, et al. Magnetic resonance imaging-derived right
ventricular adaptations to endurance versus resistance training. Med Sci Sports Exerc.
2013;45:534–41.
30. Perseghin G, De Cobelli F, Esposito A, et al. Effect of the sporting discipline on the right and
left ventricular morphology and function of elite male track runners: a magnetic resonance
imaging and phosphorus 31 spectroscopy study. Am Heart J. 2007;154:937–42.
31. Modesti PA, Vanni S, Bertolozzi I, et al. Different growth factor activation in the right and left
ventricles in experimental volume overload. Hypertension. 2004;43:101–8.
32. Oxborough D, Batterham AM, Shave R, et al. Interpretation of two-dimensional and tissue
Doppler-derived strain (epsilon) and strain rate data: is there a need to normalize for indi-
vidual variability in left ventricular morphology? Eur J Echocardiogr. 2009;10:677–82.
33. La Gerche A, Jurcut R, Voigt JU. Right ventricular function by strain echocardiography. Curr
Opin Cardiol. 2010;22:430–6.
34. D’Andrea A, Caso P, Severino S, et al. Different involvement of right ventricular myocardial
function in either physiologic or pathologic left ventricular hypertrophy: a Doppler tissue
study. J Am Soc Echocardiogr. 2003;16:154–61.
35. Teske AJ, Prakken NH, De Boeck BW, et al. Echocardiographic tissue deformation imaging
of right ventricular systolic function in endurance athletes. Eur Heart J. 2009;30:969–77.
36. La Gerche A, Burns AT, D’Hooge J, Macisaac AI, Heidbuchel H, Prior DL. Exercise strain
rate imaging demonstrates normal right ventricular contractile reserve and clarifies ambigu-
ous resting measures in endurance athletes. J Am Soc Echocardiogr. 2012;25:253–262.
37. Prakken NH, Velthuis BK, Teske AJ, Mosterd A, Mali WP, Cramer MJ. Cardiac MRI refer-
ence values for athletes and nonathletes corrected for body surface area, training hours/week
and sex. Eur J Cardiovasc Prev Rehabil. 2010;17(2):198–203.
38. D’Alonzo GE, Barst RJ, Ayres SM, et al. Survival in patients with primary pulmonary hyper-
tension. Results from a national prospective registry. Ann Intern Med. 1991;115:343–9.
39. Raymond RJ, Hinderliter AL, Willis PW, et al. Echocardiographic predictors of adverse
outcomes in primary pulmonary hypertension. J Am Coll Cardiol. 2002;39:1214–9.
40. Sun XG, Hansen JE, Oudiz RJ, Wasserman K. Exercise pathophysiology in patients with
primary pulmonary hypertension. Circulation. 2001;104:429–35.
41. Forfia PR, Fisher MR, Mathai SC, et al. Tricuspid annular displacement predicts survival in
pulmonary hypertension. Am J Respir Crit Care Med. 2006;174:1034–41.
42. Groepenhoff H, Vonk-Noordegraaf A, van de Veerdonk MC, Boonstra A, Westerhof N,
Bogaard HJ. Prognostic relevance of changes in exercise test variables in pulmonary arterial
hypertension. PLoS One. 2013;8:e72013.
43. Blumberg FC, Arzt M, Lange T, Schroll S, Pfeifer M, Wensel R. Impact of right ventricular
reserve on exercise capacity and survival in patients with pulmonary hypertension. Eur J
Heart Fail. 2013;15:771–5.
44. Steding K, Engblom H, Buhre T, et al. Relation between cardiac dimensions and peak oxygen
uptake. J Cardiovasc Magn Reson. 2010;12:8.
45. Eldridge MW, Dempsey JA, Haverkamp HC, Lovering AT, Hokanson JS. Exercise-induced
intrapulmonary arteriovenous shunting in healthy humans. J Appl Physiol. 2004;97:
797–805.
46. Stickland MK, Welsh RC, Haykowsky MJ, et al. Intra-pulmonary shunt and pulmonary gas
exchange during exercise in humans. J Physiol. 2004;561:321–9.
47. Lalande S, Yerly P, Faoro V, Naeije R. Pulmonary vascular distensibility predicts aerobic
capacity in healthy individuals. J Physiol. 2012;590:4279–88.
48. Bernheim AM, Attenhofer Jost CH, Zuber M, et al. Right ventricle best predicts the race
performance in amateur ironman athletes. Med Sci Sports Exerc. 2013;45:1593–9.
49. Siegel AJ, Silverman LM, Holman BL. Elevated creatine kinase MB isoenzyme levels in
marathon runners. Normal myocardial scintigrams suggest noncardiac source. JAMA.
1981;246:2049–51.
50. Rifai N, Douglas PS, O'Toole M, Rimm E, Ginsburg GS. Cardiac troponin T and I,
echocardiographic [correction of electrocardiographic] wall motion analyses, and ejection
fractions in athletes participating in the Hawaii Ironman Triathlon. Am J Cardiol. 1999;83:
1085–9.
51. Neumayr G, Gaenzer H, Pfister R, et al. Plasma levels of cardiac troponin I after prolonged
strenuous endurance exercise. Am J Cardiol. 2001;87:369–71, A10.
52. Neumayr G, Pfister R, Mitterbauer G, et al. Effect of the “Race Across The Alps” in elite
cyclists on plasma cardiac troponins I and T. Am J Cardiol. 2002;89:484–6.
53. La Gerche A, Boyle A, Wilson AM, Prior DL. No evidence of sustained myocardial injury
following an Ironman distance triathlon. Int J Sports Med. 2004;25:45–9.
54. La Gerche A, Taylor AJ, Prior DL. Athlete’s heart: the potential for multimodality imaging to
address the critical remaining questions. JACC Cardiovasc Imaging. 2009;2:350–63.
55. Melanson SE, Green SM, Wood MJ, Neilan TG, Lewandrowski EL. Elevation of myeloper-
oxidase in conjunction with cardiac-specific markers after marathon running. Am J Clin
Pathol. 2006;126:888–93.
56. Shave R, George KP, Atkinson G, et al. Exercise-induced cardiac troponin T release: a
meta-analysis. Med Sci Sports Exerc. 2007;39:2099–106.
57. Neilan TG, Januzzi JL, Lee-Lewandrowski E, et al. Myocardial injury and ventricular dys-
function related to training levels among nonelite participants in the Boston marathon.
Circulation. 2006;114:2325–33.
58. La Gerche A, Burns AT, Mooney DJ, et al. Exercise-induced right ventricular dysfunction and
structural remodelling in endurance athletes. Eur Heart J. 2012;33:998–1006.
59. Scherr J, Braun S, Schuster T, et al. 72-h kinetics of high-sensitive troponin T and inflamma-
tory markers after marathon. Med Sci Sports Exerc. 2011;43:1819–27.
60. Shave R, George K, Whyte G, Hart E, Middleton N. Postexercise changes in left ventricular
function: the evidence so far. Med Sci Sports Exerc. 2008;40:1393–9.
61. La Gerche A, Connelly KA, Mooney DJ, MacIsaac AI, Prior DL. Biochemical and functional
abnormalities of left and right ventricular function after ultra-endurance exercise. Heart.
2008;94:860–6.
62. Oxborough D, Shave R, Warburton D, et al. Dilatation and dysfunction of the right ventricle
immediately after ultraendurance exercise: exploratory insights from conventional two-
dimensional and speckle tracking echocardiography. Circ Cardiovasc Imaging. 2011;4:253–63.
63. Douglas PS, O’Toole ML, Hiller WD, Reichek N. Different effects of prolonged exercise on
the right and left ventricles. J Am Coll Cardiol. 1990;15:64–9.
64. Mousavi N, Czarnecki A, Kumar K, et al. Relation of biomarkers and cardiac magnetic
resonance imaging after marathon running. Am J Cardiol. 2009;103:1467–72.
65. Trivax JE, Franklin BA, Goldstein JA, et al. Acute cardiac effects of marathon running.
J Appl Physiol. 2010;108:1148–53.
66. Shave R, Baggish A, George K, et al. Exercise-induced cardiac troponin elevation: evidence,
mechanisms, and implications. J Am Coll Cardiol. 2010;56:169–76.
67. Karjalainen J, Kujala UM, Kaprio J, Sarna S, Viitasalo M. Lone atrial fibrillation in vigorously
exercising middle aged men: case-control study. BMJ. 1998;316:1784–5.
68. Grimsmo J, Grundvold I, Maehlum S, Arnesen H. High prevalence of atrial fibrillation in
long-term endurance cross-country skiers: echocardiographic findings and possible predic-
tors—a 28–30 years follow-up study. Eur J Cardiovasc Prev Rehabil. 2010;17:100–5.
69. Molina L, Mont L, Marrugat J, et al. Long-term endurance sport practice increases the inci-
dence of lone atrial fibrillation in men: a follow-up study. Europace. 2008;10:618–23.
70. Mont L, Sambola A, Brugada J, et al. Long-lasting sport practice and lone atrial fibrillation.
Eur Heart J. 2002;23:477–82.
71. Elosua R, Arquer A, Mont L, et al. Sport practice and the risk of lone atrial fibrillation:
a case-control study. Int J Cardiol. 2006;108:332–7.
72. Baldesberger S, Bauersfeld U, Candinas R, et al. Sinus node disease and arrhythmias in the
long-term follow-up of former professional cyclists. Eur Heart J. 2008;29:71–8.
73. Heidbuchel H, Anne W, Willems R, Adriaenssens B, Van de Werf F, Ector H. Endurance
sports is a risk factor for atrial fibrillation after ablation for atrial flutter. Int J Cardiol.
2006;107:67–72.
74. La Gerche A, Schmied CM. Atrial fibrillation in athletes and the interplay between exercise
and health. Eur Heart J. 2013;34(47):3599–602.
75. Biffi A, Maron BJ, Verdile L, et al. Impact of physical deconditioning on ventricular tachyar-
rhythmias in trained athletes. J Am Coll Cardiol. 2004;44:1053–8.
76. Biffi A, Pelliccia A, Verdile L, et al. Long-term clinical significance of frequent and complex
ventricular tachyarrhythmias in trained athletes. J Am Coll Cardiol. 2002;40:446–52.
77. Heidbuchel H, Hoogsteen J, Fagard R, et al. High prevalence of right ventricular involvement
in endurance athletes with ventricular arrhythmias. Role of an electrophysiologic study in
risk stratification. Eur Heart J. 2003;24:1473–80.
78. Ector J, Ganame J, van der Merwe N, et al. Reduced right ventricular ejection fraction in
endurance athletes presenting with ventricular arrhythmias: a quantitative angiographic
assessment. Eur Heart J. 2007;28:345–53.
79. Hill JA, Olson EN. Cardiac plasticity. N Engl J Med. 2008;358:1370–80.
80. Pelliccia A, Maron BJ, De Luca R, Di Paolo FM, Spataro A, Culasso F. Remodeling of left
ventricular hypertrophy in elite athletes after long-term deconditioning. Circulation. 2002;
105:944–9.
81. Luthi P, Zuber M, Ritter M, et al. Echocardiographic findings in former professional cyclists
after long-term deconditioning of more than 30 years. Eur J Echocardiogr. 2008;9:261–7.
82. Grimsmo J, Grundvold I, Maehlum S, Arnesen H. Echocardiographic evaluation of aged
male cross country skiers. Scand J Med Sci Sports. 2011;21:412–9.
83. O’Hanlon R, Wilson M, Wage R, et al. Troponin release following endurance exercise: is
inflammation the cause? A cardiovascular magnetic resonance study. J Cardiovasc Magn
Reson. 2010;12:38.
84. Breuckmann F, Mohlenkamp S, Nassenstein K, et al. Myocardial late gadolinium enhance-
ment: prevalence, pattern, and prognostic relevance in marathon runners. Radiology.
2009;251:50–7.
85. Mohlenkamp S, Lehmann N, Breuckmann F, et al. Running: the risk of coronary events:
prevalence and prognostic relevance of coronary atherosclerosis in marathon runners. Eur
Heart J. 2008;29:1903–10.
86. Wilson M, O’Hanlon R, Prasad S, et al. Diverse patterns of myocardial fibrosis in lifelong,
veteran endurance athletes. J Appl Physiol. 2011;110:1622–6.
87. Blyth KG, Groenning BA, Martin TN, et al. Contrast enhanced-cardiovascular magnetic
resonance imaging in patients with pulmonary hypertension. Eur Heart J. 2005;26:1993–9.
in pulmonary artery hypertension. AJR Am J Roentgenol. 2007;188:349–55.
89. Benito B, Gay-Jordi G, Serrano-Mollar A, et al. Cardiac arrhythmogenic remodeling in a rat
model of long-term intensive exercise training. Circulation. 2011;123:13–22.
90. Mousavi N, Czarnecki A, Kumar K, et al. Relation of biomarkers and cardiac magnetic reso-
nance imaging after marathon running. Am J Cardiol. 2009;103:1467–72.
91. Campbell DJ, Somaratne JB, Jenkins AJ, et al. Reduced microvascular density in non-
ischemic myocardium of patients with recent non-ST-segment-elevation myocardial infarc-
tion. Int J Cardiol. 2013;167:1027–37.
92. Corrado D, Basso C, Rizzoli G, Schiavon M, Thiene G. Does sports activity enhance the risk
of sudden death in adolescents and young adults? J Am Coll Cardiol. 2003;42:1959–63.
93. Sen-Chowdhry S, Syrris P, McKenna WJ. Role of genetic analysis in the management of
patients with arrhythmogenic right ventricular dysplasia/cardiomyopathy. J Am Coll Cardiol.
2007;50:1813–21.
94. James CA, Bhonsale A, Tichnell C, et al. Exercise increases age-related penetrance and
arrhythmic risk in arrhythmogenic right ventricular dysplasia/cardiomyopathy-associated
desmosomal mutation carriers. J Am Coll Cardiol. 2013;62:1290–7.
95. La Gerche A, Robberecht C, Kuiperi C, et al. Lower than expected desmosomal gene muta-
tion prevalence in endurance athletes with complex ventricular arrhythmias of right ventricu-
lar origin. Heart. 2010;96:1267–74.
96. Sen-Chowdhry S, Syrris P, Ward D, Asimaki A, Sevdalis E, McKenna WJ. Clinical and
genetic characterization of families with arrhythmogenic right ventricular dysplasia/cardio-
myopathy provides novel insights into patterns of disease expression. Circulation.
2007;115:1710–20.
97. Gerull B, Heuser A, Wichter T, et al. Mutations in the desmosomal protein plakophilin-2 are
common in arrhythmogenic right ventricular cardiomyopathy. Nat Genet. 2004;36:1162–4.
98. Pilichou K, Nava A, Basso C, et al. Mutations in desmoglein-2 gene are associated with
arrhythmogenic right ventricular cardiomyopathy. Circulation. 2006;113:1171–9.
99. van Tintelen JP, Entius MM, Bhuiyan ZA, et al. Plakophilin-2 mutations are the major deter-
minant of familial arrhythmogenic right ventricular dysplasia/cardiomyopathy. Circulation.
2006;113:1650–8.
100. Dalal D, Molin LH, Piccini J, et al. Clinical features of arrhythmogenic right ventricular
dysplasia/cardiomyopathy associated with mutations in plakophilin-2. Circulation. 2006;113:
1641–9.
101. den Haan AD, Tan BY, Zikusoka MN, et al. Comprehensive desmosome mutation analysis in
North Americans with arrhythmogenic right ventricular dysplasia/cardiomyopathy. Circ
Cardiovasc Genet. 2009;2(5):428–35. doi:10.1161/CIRCGENETICS.109.858217.
102. Heidbuchel H, Prior DL, La Gerche A. Ventricular arrhythmias associated with long-term
endurance sports: what is the evidence? Br J Sports Med. 2012;46 Suppl 1:i44–50.
Chapter 16
Arrhythmogenic Right Ventricular
Cardiomyopathy (ARVC)
Luisa Mestroni, Francesca Brun, Anita Spezzacatene,

Gianfranco Sinagra, and Matthew R.G. Taylor
Introduction
Several inherited genetic abnormalities can affect the normally constructed right
ventricle (RV), the most common of them being arrhythmogenic right ventricular
cardiomyopathy (ARVC). ARVC is an inherited heart disease characterized by
myocyte loss and fibro-fatty tissue replacement leading to life-threatening ventricu-
lar arrhythmias, progressive ventricular dysfunction of the right and the left ventri-
cle and heart failure [1]. The estimated prevalence of ARVC in the general population
ranges from 1 in 2,000 to 1 in 5,000; men are more frequently affected than women,
with an approximate ratio of 3:1 [2]. A familial history of ARVC is present in
30–50 % of cases, and the disease is usually inherited in an autosomal dominant
pattern with incomplete penetrance and variable expressivity. In rare cases, autoso-
mal recessive forms have been also reported (Naxos disease and Carvajal syn-
drome), usually associated with a cutaneous phenotype. A genetic defect can be
confirmed in approximately 40 % of cases and 12 different ARVC loci have been
reported, among which five genes (DSP, PKP2, DSG2, DSC2, and JUP) encode
proteins of the cell–cell junctions at the intercalated disc (Table 16.1). The role of
L. Mestroni, M.D. (*)

Cardiovascular Institute, University of Colorado Anschutz Medical Campus,
12700 E. 19th Avenue, F442, Auroroa, CO 80045, USA
e-mail: luisa.mestroni@ucdenver.edu
F. Brun, M.D. • A. Spezzacatene, M.D. • G. Sinagra, M.D., F.E.S.C.
Department of Cardiology, Ospedali Riuniti and University of Trieste,
Via P. Valdoni.7, Trieste 34149, Italy
e-mail: frabrun77@gmail.com; anita.spe@gmail.com; gianfranco.sinagra@aots.sanita.fvg.it
M.R.G. Taylor, M.D., Ph.D.
Department of Medicine, University of Colorado Denver,
12700 East 19th Avenue, F442, Room 8022, Aurora, CO 80045, USA
e-mail: matthew.taylor@ucdenver.edu

338 L. Mestroni et al.
Table 16.1 Different types of ARVC

Type Gene Locus Prevalence Mode of inheritance
ARVD1 TGFB3 14q23-q24 Rare AD
ARVD2 RYR2 1q42-q43 Rare AD
ARVD3 ? 14q12-q22 Unknown AD
ARVD4 ? 2q32.1-q32.3 Unknown AD
ARVD5 TMEM43 3p23 Unknown AD
ARVD6 ? 10p14-p12 Unknown AD
ARVD7 ? 10q22.3 Unknown AD
ARVD8 DSP 6p24 6–16 % AD/AR
ARVD9 PKP2 12p11 11–43 % AD
ARVD10 DSG2 18q12.1-q12 7–26 % AD
ARVD11 DSC2 18q12.1 Rare AD
ARVD12 JUP 17q21 Rare AR
Adapted from Mejia-Lopez et al. [83]
other three non-desmosomal genes has been less well established: the growth factor
TGF-β3 (TGFB3), the ion channel subunit RYR2, and the transmembrane protein 43
(TMEM43) [3]. Recently, novel variants in the giant sarcomeric protein titin (TTN)
were discovered associated with ARVC [4]. Structural impairment of titin probably
leads to proteolysis and apoptosis constitutes a novel mechanism underlying myo-
cardial remodeling and sudden death.
Definition and Epidemiology of ARVC
ARVC is a chronic, progressive, heritable myocardial disorder with a broad pheno-

typic spectrum. The disease name reflects its right ventricular (RV) preponderance,
but recognition of subtypes with early left ventricular involvement supports adop-
tion of the broader term arrhythmogenic cardiomyopathy, with redefinition accord-
ing to its distinctive natural history [5]. ARVC is a leading cause of sudden cardiac
death in people aged less than 35 years and accounts for up to 10 % of deaths from
undiagnosed cardiac disease in patients less than 65 years old [6, 7].
Clinical Features and Symptoms
The disease expression is variable and the penetrance (the proportion of carriers
manifesting the disease) appears age-related. The onset of ARVC usually occurs
after childhood, with palpitations and/or syncope. According to Dalal et al. [8], the
median age at onset is 29 years and it is rare to manifest clinical signs or symptoms
of ARVC before the age of 12 years or show onset of symptoms after the age of
16 Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) 339
60 years. The most common presenting symptoms are palpitations and syncope in
27 % and 26 % of patients, respectively. Furthermore, life-threatening ventricular
arrhythmias can be the first presentation of the disease leading to sudden cardiac
death in 23 % of cases. In young adults and athletes, ARVC has been reported as the
second most frequent cause of sudden cardiac death: in these cases, cardiac arrest
may occur in up to 50 % [9].
The natural history of ARVC, in its classic “right dominant” form, may be sepa-
rated into a number of distinct phases with progressive development of symptoms
and structural abnormalities:
• Concealed phase: a subclinical asymptomatic phase with little or no structural RV
abnormality. Sudden cardiac death may still occur in this stage of the disease [10].
• Overt electrical disorder: with palpitations, syncope, and typically with symp-
tomatic ventricular arrhythmias of RV origin usually triggered by effort.
Arrhythmias may vary from premature ventricular beats, to non-sustained ven-
tricular tachycardia with left branch block morphology up to ventricular fibrilla-
tion lading to cardiac arrest.
• RV failure: progressive loss of RV myocardium due to fibro-fatty replacement
impairs RV function and may result in severe pump failure.
• Biventricular failure: an advanced stage with involvement of the interventricular
septum and left ventricle causing congestive heart failure. Endocavitary mural
thrombosis may occur, especially within a RV aneurysm or in the left atrium if
atrial fibrillation is present. The phenotype may eventually resemble dilated car-
diomyopathy with RV involvement, making the differential diagnosis at this
stage difficult.
The diagnosis of ARVC can be often challenging, because of the heterogeneous
clinical presentation, highly variable intra- and interfamily expressivity and incom-
plete penetrance. This genotype-phenotype plasticity is largely unexplained. The
frequent involvement of the left ventricle, sometimes predominant, suggests that
ARVC is not a unique entity, but a complex disease with a spectrum of phenotypes
and three possible patterns of expression: the classic (39 % of cases), the left domi-
nant (5 %), and the biventricular (56 %) forms [5]. Consequently, in this disease it
may be more appropriate to use the term of “arrhythmogenic cardiomyopathy”
instead of the more restrictive ARVC terminology.
The “classic pattern” is characterized by an increased RV to left ventricle volume
ratio and a more severe involvement of the right ventricle, with left ventricular
involvement as a possible late complication of the disease. Conversely, the non-classic
disease subtypes of arrhythmogenic cardiomyopathy are characterized by the occur-
rence of left ventricular involvement in the setting of preserved global RV function.
Left-dominant arrhythmogenic cardiomyopathy (LDAC) is a novel entity
recently described. LDAC is characterized by fibro-adipose replacement, which pre-
dominantly involves the left ventricle and often occurs as a circumferential band in
the outer one-third of the myocardium and the right side of the interventricular septum
[11–14]. This cardiomyopathy has a predominant (but not necessarily exclusive) LV
involvement (dilation, systolic impairment, late gadolinium enhancement) exceeding
that of the right ventricle or in the presence of preserved RV function [5, 15]. Salient
features of LDAC include ventricular arrhythmia of right bundle block (RBBB) mor-
phology, isolated (infero)-lateral T-wave inversion and evidence of structural left-
dominant disease exceeding that of the RV (left ventricular dilation and systolic
impairment and extensive late gadolinium enhancement on cardiac MRI, with pre-
served RV function). LDAC can be considered one of the three possible patterns of
ARVC, together with the “classical” form and the “biventricular” form, due to the
histopathologic similarities. However, there are some relevant differences between
the two cardiomyopathies that should be mentioned. First of all, arrhythmias have
different morphology: left bundle branch block (LBBB) morphology in ARVC and
RBBB morphology in LDAC. Furthermore, while in ARVC the interventricular sep-
tum is typically spared, in LDAC many patients show its involvement with septal late
gadolinium enhancement. Moreover, in LDAC, T-wave inversion is predominantly
infero-lateral, while in ARVC it is predominantly located in right precordial leads.
Finally, isolated global RV dysfunction precedes LV involvement in ARVC, while in
LDAC, 30 % of patients have LV dilation and/or impairment in the presence of pre-
served right-sided volumes and function [15]. These inconsistencies between the two
patterns of disease may lead to a novel classification of cardiomyopathies where
LDAC is a novel distinct pathological entity.
Biventricular arrhythmogenic cardiomyopathy. The biventricular subtype of
arrhythmogenic cardiomyopathy is defined by early and parallel involvement of
the right and left ventricles [5]. Milder cases typically demonstrate localized struc-
tural abnormalities on both sides; advanced disease is characterized by biventricu-
lar dilation and/or systolic impairment. The clinical picture is generally a composite
of right-dominant and left-dominant features. Ventricular arrhythmias of both
RBBB and LBBB configuration may occur and at least 15 % of cases show
both types, underlining the presence of arrhythmogenic substrate in both ventri-
cles. The ratio of RV to left ventricular volume remains close to 1 throughout
the disease course [5].
Structural Features and Histopathology
ARVC is characterized by progressive replacement of the RV myocardium by

fibrous or fibro-fatty tissue. In the early stage of the disease, structural changes may
be absent or subtle and confined to a localized region of the RV. The most common
location for this tissue transformation is between the anterior infundibulum, right
ventricular apex, and inferior or diaphragmatic aspect of the RV, (the so-called tri-
angle of dysplasia), the hallmark of ARVC [16]. ARVC leads to RV dilatation or
aneurysms having paradoxical systolic motion (expansion with systole instead of
contraction). With disease progression, further involvement of the RV free wall, and
left ventricular involvement can occur [17].
Histological examination reveals islands of surviving myocytes interspersed
with fibrous and fatty tissue (Fig. 16.1). The replacement of the RV myocardium by
the fibrous and fibro-fatty tissue is progressive, starting from the epicardium or
Fig. 16.1 Fibro-fatty infiltration of the right ventricular wall in a patient with ARVC
Fig. 16.2 Epsilon wave. An ECG from a patient with ARVC. Arrows indicate epsilon waves
(courtesy of Prof Rossana Bussani, Dept of Morbid Anathomy, Cardiovascular Pathology,
University of Trieste; from Taylor et al. [4], with permission)
mid-myocardium and then extending to become transmural. Fatty infiltration of the

RV alone is not considered a sufficient morphological hallmark of ARVC. A certain
amount of intramyocardial fat is present in the RV anterolateral and apical regions
even in the normal heart and increases with aging and bodyweight [18]. The histo-
logical exam shows clusters of dying myocytes, providing evidence of the acquired
nature of myocardial atrophy [19]. These changes are often associated with inflam-
matory infiltrates, which probably play a major role in triggering life-threatening
arrhythmias [20–23]. The fibro-fatty replacement interferes with the electrical
impulse conduction, and is the key cause of epsilon waves (Fig. 16.2), RBBB, late
potentials, and reentrant ventricular arrhythmias. Left ventricular involvement,
usually confined to the postero-lateral subepicardium, is present in more than half

of the cases [21, 22, 24]. Predominant left ventricular fibro-fatty infiltration has also
been described [25].
Diagnosis
ARVC should be suspected in a young patient with palpitations and a personal or

family history of syncope or aborted sudden cardiac death. Ventricular tachycardia
with LBBB morphology is the classic presentation, but ventricular tachycardia with
RBBB may be present if the left ventricle is involved. Other electrocardiographic
(ECG) abnormalities such as inverted T waves in right precordial leads (V1–V3)
and frequent premature ventricular complexes (PVCs), even in asymptomatic
patients, should arouse the suspicion for this cardiomyopathy (Table 16.2) [26].
The clinical diagnosis of ARVC is often difficult because of the nonspecific
nature of the disease and the broad spectrum of phenotypic variations. ARVC is
probably underestimated as milder cases frequently go unrecognized and non-
classic subtypes have not been categorized. Left-dominant and biventricular arrhyth-
mogenic cardiomyopathy are commonly misattributed to dilated cardiomyopathy,
“hot phases” to isolated viral myocarditis, and early disease in general to idiopathic
ventricular tachycardia or benign ventricular ectopy, owing to a lack of obvious
structural abnormalities [15, 27]. That arrhythmogenic cardiomyopathy is a disease
of the young and cannot present beyond middle age is a common but erroneous
assumption, which becomes self-fulfilling as clinicians fail to consider it as a pos-
sibility in older patients. Raising clinicians’ awareness of the disease and its multi-
ple presentations is critical to timely diagnosis and prevention of sudden death.
There is no single gold-standard diagnostic test for ARVC, the diagnosis relies
on a scoring system with major and minor criteria based on the demonstration of a
combination of defects in RV morphology and function, characteristic depolariza-
tion/repolarization ECG abnormalities, characteristic tissue pathology, typical
arrhythmias, family history, and the results of genetic testing (Table 16.3). A defini-
tive diagnosis, based on the Revised 2010 Task Force Criteria [28], requires two
Table 16.2 ECG changes in ARVC/D

ECG changes Frequency
Prolonged S wave upstroke >55 ms in V1–V3 90–95 %
T waves inversions in precordial leads 82–85 %
QRS widening in V1–V3 25–70 %
Epsilon wave 30 %
Right bundle branch block (RBBB) 18–22 %
Paroxysmal episodes of ventricular tachycardia One of the most common findings
with a LBBB morphology
Modified from Mejia-Lopez et al. [83]
Table 16.3 Revised Task Force Criteria 2010
Major criteria Minor criteria
16
RV systolic By 2D echo By 2D echo

function and Regional RV akinesia, dyskinesia or aneurysm, and one of Regional RV akinesia, dyskinesia or aneurysm, and 1 of the following
structure the following (end diastole): (end diastole):
PLAT RVOT ≥ 32 mm PLAX RVOT ≥29 to <32 mm
PSAX RVOT ≥ 36 mm PSAX RVOT ≥32 to <36 mm
Or fractional area change ≤33 % Or fractional area change >33 to ≤40 %
By MRI By MRI
Regional RV akinesia, dyskinesia or aneurysm or Regional RV akinesia, dyskinesia or aneurysm or dyssynchronous RV
dyssynchronous RV contraction, and 1 of the following: contraction, and 1 of the following: Ratio of RV end-diastolic volume to
Ratio of RV end-diastolic volume to BSA ≥ 110 mL/m2 or BSA ≥100 to <110 mL/m2 (male) or ≥90 to <100 mL/m2 (female) or RV
≥100 mL/m2 (or RV EF ≤40 % >40 to ≤45 %
By RV angiography: By RV angiography:
Regional RV akinesia, dyskinesia or aneurysm Regional RV akinesia, dyskinesia or aneurysm
Tissue Residual myocytes <60 % by morphometric analysis with Residual myocytes 60–75 % (or 50–65 % if estimated), with fibrous
characterization fibrous replacement of the RV free wall myocardium in ≥1 replacement of the RV free wall myocardium in ≥1 sample, with or
sample, with or without fatty replacement of tissue on EMB without fatty replacement of tissue on EMB
Repolarization Inverted T waves in right precordial leads (V1–V3) or Inverted T waves in leads V1 and V2 in individuals >14 years of age (in
abnormality beyond in individuals >14 years of age (in the absence of the absence of complete right bundle branch block) or in V4–V6 or
complete right bundle—branch block QRS ≥120 ms inverted T waves in leads V1–V4 individuals >14 years of age in the
presence of complete right bundle branch block
Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC)
Depolarization Epsilon waves in the right precordial leads (V1–V3) Late potential by SAECG in ≥1 of 3 parameters in the absence of a QRS
abnormality duration of ≥110 ms on the standard ECG; Filtered QRS duration
≥114 ms; Duration of terminal QRS <40 μV or ≥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 QRS
Arrhythmias Non-sustained or sustained ventricular tachycardia of left Non-sustained or sustained ventricular tachycardia of RV outflow
bundle branch morphology with superior axis configuration, left bundle branch morphology with inferior axis or >500
Frequent ventricular extrasystoles (>1,000 per 24 h) (Holter) ventricular extrasystoles per 24 h (Holter)
Familial history ARVC confirmed pathologically in the first degree or History of ARVC in a first degree relative or premature sudden death
identification of a pathogenic mutation categorized as (<35 years of age) due to suspected ARVC or ARVC confirmed
343
associated or probably associated with ARVC pathologically or by current Task Force Criteria in second-degree relative
Adapted from Marcus et al. [28]
major criteria, one major criterion and two minor criteria, or four minor criteria
from different categories. Therefore, the initial evaluation of all patients suspected
of having ARVC should include physical examination, clinical history, family his-
tory of arrhythmias or sudden death, ECG, signal-averaged ECG (SAECG), 24-h
Holter monitoring, and comprehensive noninvasive imaging tests focused on both
ventricles such as echocardiography. New tools for improving diagnostic accuracy
have been introduced in the clinical practice. Among noninvasive investigations,
cardiac MRI with gadolinium late enhancement has been demonstrated to be able to
detect fibrosis in the RV and left ventricular myocardium [29].
Genetic Basis of Arrhythmogenic Cardiomyopathy
Desmosomal Genes with Autosomal Dominant Inheritance
ARVC is a genetic cardiomyopathy in which mutations of the genes encoding pro-

teins of the desmosome have been identified [2]. As discussed above, ARVC is cur-
rently considered to be a disease of myocyte adhesion caused by defects at the
intercellular junction. Cardiac myocyte-to-myocyte adhesion is maintained by des-
mosomes, adherens, and gap junctions, which together comprise the intercalated
disc [30, 31]. The desmosomes have a complex structure (Fig. 16.3) that includes
adhesion molecules of the cadherin (desmoglein-DSG and desmocollin-DSC), pla-
kin (desmoplakin-DSP), and catenin (plakophilin-PKP, and plakoglobin-JUP) fami-
lies, which link intermediate filaments of the cytoskeleton to the desmosomal
cadherins [32, 33].
Five of the known ARVC genes encode proteins of cell–cell junctions at the
intercalated disc: plakoglobin (JUP) [34], desmoplakin (DSP) [35], plakophillin-2
(PKP2) [36], desmoglein-2 (DSG2) [37], and desmocollin-2 (DSC2) [38]. Mutations
in PKP2 are the most common reported in ARVC [36]. Desmoplakin mutation car-
riers have echocardiographic, cardiac MRI, and ECG signs of a more severe involve-
ment of the left ventricle [5]. JUP gene variants in recessive families are a well
recognized cause of ARVC [34], as discussed below. Recently, a dominant mutation
of JUP has also been reported in a German family with ARVC without cutaneous
abnormalities [39].
Desmosomal Genes with Autosomal Recessive Inheritance
Naxos disease is a rare subset of ARVC notable for an autosomal recessive inheri-
tance pattern and a complex syndromic phenotype with skin (palmoplantar kerato-
derma) and hair abnormalities (woolly hair), due to homozygous mutations in the
JUP gene, encoding junctional plakoglobin [34] (Table 16.4). The syndrome takes
its name from the Greek island of Naxos, where its prevalence exceeds 1 in 1,000
Fig. 16.3 The cardiac desmosome and proposed roles of the desmosome. (a) supporting structural
stability through cell–cell adhesion, (b) regulating transcription of genes involved in adipogenesis
and apoptosis, and maintaining proper electrical conductivity through regulation of (c) gap junc-
tions and (d) calcium homeostasis. Abbreviations: Dsc2 desmocollin-2, Dsg2 desmoglein-2, Dsp
desmoplakin, Pkg plakoglobin, Pkp2 plakophilin-2, PM plasma membrane (from Awad et al., with
permission [100])
despite the autosomal recessive inheritance. The cutaneous phenotype is expressed

from infancy, facilitating recognition of affected individuals, whereas the cardiac
symptoms characteristically develop from adolescence to the fourth decade of life.
Following successful linkage mapping of the disease locus to 17q21, a homozygous
two-base-pair deletion in the plakoglobin gene (JUP) was identified as the causal
mutation [40]. Plakoglobin is a key constituent of desmosomes, the specialized
intercellular junctions of cardiac and epithelial tissue, and its isolation in Naxos
disease let to the discovery of the other desmosomal genes associated with ARVC.
Carvajal syndrome is another syndromic recessive cardiocutaneous syndrome,
described in families from India and Ecuador, caused by DSP mutations. The causal
homozygous DSP mutation results in truncation of the C terminus at the tail end of
the protein [41]. The phenotype of Carvajal syndrome consists of palmoplantar ker-
atoderma, woolly hair, and LDAC, which was initially labeled dilated cardiomyopa-
thy [41]. Clinical and pathological characterization of this entity is more limited, but
frequent and complex ventricular arrhythmias and precordial T-wave inversion have
been reported [42] along with ARVC, woolly hair, skin features localized in the
extremities, and vesicular lesions similar to pemphigus foliaceus (Table 16.4) [43].
Table 16.4 Cardiocutaneous disorders associated with ARVC

Presentation Genetics Cardiac manifestations Differences
Naxos Diffuse non- Recessive ECG is abnormal in 90 Predominant RV
disease epidermolytic mutation of of patients, RV involvement.
palmoplantar desmoplakin and structural and Fatty infiltration
keratoderma with plakoglobin, in functional is common
woolly hair and C 17 (JUP gene) abnormalities are
cardiomyopathy but there is new common. Presentation
evidence for is usually syncope and/
extensive locus or sustained
heterogeneity ventricular tachycardia
during adolescence
with a peak in young
adulthood
Carvajal Striate A recessive Abnormal myocardial Predominant LV
syndrome palmoplantar mutation of stretch, dilatation later involvement.
keratoderma with desmoplakin. fibrosis and Fatty infiltration
woolly hair and Gene map locus progressive cardiac is less common
cardiomyopathy. 6p24 failure. Common
features are: non-
compacted LV and
recurrent VT/VF with
sudden death
Extra-Desmosomal Genes
Several non-desmosomal genes have been reported as disease-causing: transforming

growth factor beta-3 (TGFB3), cardiac ryanodine receptor (RYR2), transmembrane
protein 43 (TMEM43), tumor protein p63 (TP63), desmin (DES), lamin A/C
(LMNA), alpha T-catenin (CTNNA3), and phospholamban (PLN). Thus far, more
than 800 genetic variants have been identified in 12 genes, yet only around 300 have
been classified as clearly pathogenic [3].
Concerning TGFB3 [44] and TMEM43 [45], the mechanism leading to ARVC is
still unknown, although there are some hypotheses. The TGFB3 gene encodes TGF-
β3, a cytokine that stimulates fibrosis, influences cell adhesion [46] and modulates
expression of genes for desmosomal proteins [47]. Regarding the TMEM43 gene,
this gene contains a response element for an adipogenic transcription factor, which
might correlate with the histopathology of ARVC. The S358L mutation in TMEM43,
identified in the Newfoundland founder population, causes a fully penetrant non-
classic form of the disease associated with a high incidence of premature sudden
cardiac death and heart failure in survivors [45, 48].
Other genes have been reported as possible candidates for causing ARVC:
the RYR2 gene encodes for ryanodine receptor 2, which regulates mechanisms
of calcium handling. This gene has been described as a cause of ARVC [49] and
of a distinct clinical entity, polymorphic ventricular tachycardia (ARVD2),

characterized by juvenile sudden cardiac death and effort-induced polymorphic
ventricular tachycardia [50].
Among extra-desmosomal genes, lamin A/C (LMNA) mutations are known to
cause a diverse range of clinical phenotypes, including dilated cardiomyopathy,
which may in some cases show severe skeletal muscle involvement. These patients
characteristically show atrial arrhythmias or atrioventricular blocks as the early signs
and progression to heart failure and a high incidence of sudden cardiac death later in
the disease [51, 52]. Pathological examination of hearts usually shows four-chamber
dilation, cardiomyocytes hypertrophy and fibrosis without inflammation, although
there have been reports of cases presenting with a phenotype compatible with restric-
tive cardiomyopathy, right ventricular dilation, left ventricular non-compaction and,
recently, ARVC [53]. Patients with a presumed diagnosis of ARVC but with muta-
tions in the LMNA gene were more likely to show either atrial tachycardia or conduc-
tion disease in comparison to genetically confirmed ARVC patients [54].
Finally, mutations in the TTN gene encoding for the giant sarcomeric protein titin
have been recently described in ARVC [4]. The possible mechanism, which could
explain the association between the disease and this gene, is the connection between a
structurally altered titin to the transitional junction at intercalated disks. This discovery
provides novel insights into the pathophysiology of ARVC, a complex disease with
variable expression and a variety of genes as possible candidates for its etiology.
Candidate Genes
Between 30 and 40 % of cases of ARVC harbor mutations in one of the known des-
mosomal genes, leaving more than half of patients without a known causal gene.
Therefore, further gene identification studies are ongoing. Key candidates recently
screened include components of the desmosome and PKP2 regulatory pathway,
such as pinin (PNN, NM_002687), alpha T-catenin (CTNNA3, NM_013266), cave-
olin-1 (CAV1, NM_001753), plakophilin-4 (PKP4, NM_003628), and perp (PERP,
NM_022121) [55]. However, only one rare variant in PKP4 and one in PERP poten-
tially pathogenic were found in 55 ARVC patients, these findings need further rep-
lication. Finally, a missense mutation in the tumor protein p63 gene, together with
ectodermal dysplasia (TP63) has been described [56].
Differential Diagnosis
The diagnosis of ARVC should be considered in any patient who does not have
known heart disease and who presents with frequent premature ventricular contrac-
tions or symptomatic ventricular tachycardia. The main differential diagnoses
include the following conditions discussed below.
RV Muscle Diseases with Genetic Background
Idiopathic RV outflow tract–ventricular tachycardia (RVOT-VT) is a mostly benign

condition not associated with structural heart disease. In early stage ARVC can be
difficult to distinguish from RVOT-VT in the absence of structural changes. The
differential diagnosis is based on the fact that RVOT-VT is non-familial and patients
do not have the characteristic ECG/SAECG abnormalities of ARVC (inversion T
waves in V1–V3, epsilon waves, QRS duration >110 ms) (Table 16.5).
Brugada syndrome is an inherited cardiac condition that, similarly to ARVC, is
transmitted with an autosomal dominant pattern, which can lead to sudden cardiac
death from malignant ventricular arrhythmias. This syndrome is characterized by a
distinct typical ECG pattern with a “J wave” in precordial leads, and by the absence
of morphological echocardiographic features.
Dilated cardiomyopathy can be also an inherited condition in a large proportion
of patients, and may be difficult to distinguish from ARVC when presenting with
biventricular involvement, especially in its advanced stage. In its late phase, signs
and symptoms of RV and/or LV failure are present and finally severe biventricular
congestive heart failure can occur. In the absence of classic ARVC hallmarks
(RV aneurisms, bulging), there are no other echocardiographic diagnostic features [57].
In 30 % of patients with dilated cardiomyopathy, the right ventricular function is
Table 16.5 Clinical expressions of RVOT-VT and ARVC

RVOT-VT ARVC
Age at onset Third or fifth decade of life Third or fourth decade of life
Sex Females predominantly Males predominantly
Family history − +
Reports of SCD − +
12 lead ECG Normal – T wave inversion in precordial
leads from V1 to V5
– Prolongation of QRS complex in
leads V1 or V2
– ε waves observed
SAECG Normal Late potential observed
ECHO Normal Structural and wall motion
abnormalities of RV
Arrhythmias PVCs, repetitive monomorphic PVCs, SVT, NSVT, VF
VT, induced/sustained VT
Origin of arrhythmia Septum Parietal wall
Mechanism c-AMP mediated triggered Reentrant mechanism
of arrhythmia activity
BNP levels Normal Increased
Adapted from Pamuru et al. [103]
SCD sudden cardiac death, ECG electrocardiogram, SA ECG signal-averaged ECG, ECHO echo-
cardiography, BNP brain natriuretic peptide, PVC premature ventricular complexes, NSVT non-
sustained ventricular tachycardia, VF ventricular fibrillation
significantly depressed and a biventricular dysfunction is not rare [58]. However, a

predominant RV dilation and dysfunction is rare in dilated cardiomyopathy and in
these cases, the diseases is more probably caused by ARVC with biventricular
involvement. There are two possible mechanisms underlying RV dysfunction in
dilated cardiomyopathy: intrinsic characteristics of the disease which can affect
both ventricles and/or the presence of pulmonary hypertension due to dysfunction
of the left ventricle with consequent afterload increase [59]. A severely depressed
RV ejection fraction (<35 %) and/or the presence of biventricular dysfunction have
been demonstrated to be independent predictors of more severe prognosis if com-
pared to patients with isolated LV involvement [60–62]. In patients with dilated
cardiomyopathy and biventricular dysfunction, RV function can be improved by the
use of optimized medical treatment with ACE inhibitors and beta-receptor blockers;
the persistence of RV dysfunction despite optimized treatment predicts a high risk
of death and is an indication for heart transplantation [63].
Cardiac sarcoidosis, a condition with a strong genetic component, can mimic
ARVC. Sarcoidosis is a systemic inflammatory disease with formation of noncase-
ating granulomas in the reticuloendothelial system, and skin. Approximately 5 % of
patients with sarcoidosis have clinically relevant cardiac findings. Therefore, car-
diac sarcoidosis has to be considered if conduction defects with a high-grade atrio-
ventricular block are present. A global RV hypokinesia or some regional wall motion
abnormalities can be present, due to the patchy nature of the granulomatous infiltra-
tion. The echocardiographic presentation of cardiac sarcoidosis includes normal or
dilated ventricular chambers and normal or reduced systolic function. The ventricle
may be globally hypokinetic or the patchy nature of sarcoid infiltration of the heart
may result in regional wall motion abnormalities. Segmental wall motion abnor-
malities characteristically do not conform to any particular coronary distribution
[64]. Two-dimensional echocardiographic characteristics of cardiac sarcoid vary
according to the disease activity and include wall thickening due to granulomatous
expansion and wall thinning due to fibrosis [65]. A typical but uncommon finding is
the thinning of the basal anterior septum, the appearance of which in a young patient
with a dilated cardiomyopathy is highly suggestive of sarcoidosis [66]. Scar retrac-
tion and aneurysms may develop, especially if the patient has been treated with
corticosteroids. Pulmonary involvement occurs in 90 % of patients with sarcoidosis,
thus Doppler echocardiographic examination should include the assessment of pul-
monary pressures and right ventricular function to detect early signs of pulmonary
hypertension [67]. In patients with extra cardiac sarcoidosis, advanced echocardiog-
raphy can be useful to detect, in asymptomatic patients, early alterations in strain
and rotational indices [68]. Newly diagnosed sarcoid patients appear to have lower
global longitudinal strain, despite having a well-preserved global systolic myocar-
dial function. Moreover, twist appears increased in the patient population with
respect to the control population. MRI is another imaging test used to establish the
diagnosis; both cardiac sarcoidosis and ARVC are progressive diseases and the
accuracy of cardiac MRI can vary, depending on the stage of the disease at which
the cardiac MRI data are acquired. Interestingly, myocardial fat infiltrates are absent
in cardiac MRI in patients with sarcoidosis [69].
Uhl’s Anomaly is a primary disorder of the heart, sometimes with familial

transmission, characterized by complete or partial absence of myocardium of the
right ventricle wall, first described by Henry Uhl in 1952 [70]. In the RV, there is an
apposition of epicardial and endocardial layers and no interposed adipose tissue,
while the septum, the septomarginal trabeculation, and the papillary muscles of tricus-
pid valve are spared. Uhl’s anomaly is extremely rare and it is not possible to estimate
its prevalence. Only 84 cases have been reported in a review in 1993 since the begin-
ning of the twentieth century [71]. The majority of cases are sporadic and occur more
frequently in the young: the earliest abnormality was noted in a 24-week fetus, but
no specific diagnosis was made at that time [72]. Other malformations of the heart
have been described in association with Uhl’s anomaly, in particular pulmonary atre-
sia with intact septum [73]; however, there is still doubt regarding the pathogenesis
of the right ventricular wall thinning: this abnormality could be due to a primary
myocardial dysplasia, but it could be a secondary lesion frequently encountered in
pulmonary and tricuspid atresia. Apart from this, the occurrence of other cardiac
malformations in Uhl’s anomaly is only fractionally higher than the overall incidence
of congenital cardiac malformations in live births and can be explained on the basis
of chance occurrence [71]. One hypothesis is that the absence of right ventricular
myocardium may be the result of primary non-development of myocytes or may be
due to their apoptosis [74, 75]. Another hypothesis is that overexpression of vascular
endothelial growth factor by cardiomyocytes may cause impaired development of
the ventricular myocardium [76]. The predominant mode of presentation of Uhl’s
anomaly is congestive heart failure, although arrhythmias and conduction distur-
bances may also occur. Patients may experience exercise-related palpitations, syn-
cope, or ventricular tachycardia and may benefit from ICD implantation.
In the past, Uhl’s anomaly has been considered a variant of ARVC but there are
some distinct features (Table 16.6): in Uhl’s anomaly there is no fibrous/fibro-fatty
Table 16.6 Comparison between Uhl’s anomaly and ARVC/D

Mode of Pathogenic Age at Disease’s
inheritance mechanisms presentation Presentation progression
Uhl’s Rarely Apoptotic Usually is Cyanosis, Does not
anomaly familial dysplasia diagnosed in dyspnea progress
with complete neonatal or
absence of the infant life
myocardium Male:female RV dilation and
ratio 1.27:1 heart failure
ARVC/D Most Apoptotic Usually Range from Progressive
autosomic dysplasia of the patients asymptomatic, postnatal
dominant, myocardium present palpitations, development
some variants followed by symptoms atypical chest
are inherited fibrofatty during pain to
in a recessive infiltration adolescence ventricular
pattern Male: female arrhythmias
ratio 2.28:1 and heart failure
replacement, the disease is more frequently sporadic and/or congenital, and while
ARVC is predominantly arrhythmogenic, in Uhl’s anomaly heart failure prevails.
Despite these dissimilarities, the two entities may share a common pathogenesis. In
Uhl’s anomaly, the treatment is oriented toward heart failure and prevention of
sudden death by implantable cardioverter-defibrillator (ICD). These strategies,
however, may become ineffective and surgical treatment may then be necessary.
There are three types of procedures: the most frequent approach is the exclusion of
the right ventricle by closure of the tricuspid valve orifice with atrial septectomy and
a bi-directional Glenn shunt [77]; another option is the combination of atrial septos-
tomy and bi-directional Glenn shunt with a partial right ventriculectomy (“one and
a half ventricular repair”) [78]. If there is evidence of increased filling pressures,
suggesting a Fontan-type physiology (see Chap. 9), the patient should be considered
for heart transplantation [79].
Other Non-genetic Pathologies Mimicking ARVC
Myocarditis can mimic ARVC, especially when the RV is involved. Myocarditis can
cause structural abnormalities, including microaneurysms, as well as the arrhythmic
manifestations that are typical of ARVC. Myocardial inflammatory infiltrates, myo-
cyte necrosis, and replacement fibrosis may lead to functional and structural changes
in the RV myocardium, resembling those produced by ARVC fibrofatty replace-
ment. New tools, such as three-dimensional electro-anatomic mapping, applied to
the standard endomyocardial biopsy, have been introduced to improve the diagnos-
tic accuracy in the clinical practice. Recently, Pieroni et al. found that 50 % of
patients with a noninvasive ARVC diagnosis fulfill the Dallas histological criteria of
active myocarditis [80].
Other conditions causing RV dilation and dysfunction include coronary artery
disease and myocardial infarction involving the RV, pulmonary hypertension, tri-
cuspid valvulopathy, and intracardiac shunts (e.g., atrial septal defects and anoma-
lous pulmonary venous drainage). The diagnosis can be missed on standard
echocardiogram; in these cases the cardiac MRI (that has excellent correlation with
RV angiography) can improve the diagnostic accuracy.
Prevention
Pregnancy
Most women with mild to moderate ARVD/C and no symptoms of heart failure toler-
ate pregnancy well and have uneventful deliveries [81, 82]. Close evaluation during
pregnancy is recommended, including an echocardiogram and 24-h Holter monitor-
ing at baseline (or as soon as the pregnancy is detected), at 7 months of pregnancy, and
at 3 months post-partum. Potential teratogenic effects of antiarrhythmic medications

should be considered and risks and benefits discussed with patients. Genetic counsel-
ing regarding the inheritance of ARVC should be offered [83].
Family Screening
Periodic rescreening of relatives is also recommended [84]. The appearance of

novel ECG abnormalities and progression of existing changes have been reported
over a 5-year follow-up period among patients with arrhythmogenic cardiomyopa-
thy. Age-related penetrance is also well established. Among carriers of PKP2 muta-
tions, development of symptoms, diagnosis, symptomatic ventricular tachycardia,
and death were all age-dependent phenomena [85]. In a study of the Newfoundland
founder population, the age range at clinical manifestation was 11–63 years for men
and 17–76 years for women [45]. No definitive cutoff age exists beyond which clini-
cal reassessment should be terminated. Nevertheless, although the periodicity of
evaluation for asymptomatic relatives might be on a yearly basis from adolescence
through the fourth decade of life, less frequent follow-up might be acceptable
beyond middle age provided that individuals remain vigilant for symptoms.
Physical Activity
Exercise has been related to an increased incidence of ventricular conduction disor-

ders, sudden cardiac death, worsening symptoms, and progression of the fibro-fatty
atrophy [86–89], particularly in young patients and competitive athletes. In 1996
Leclercq et al. [88] described the association between progressive sympathetic stim-
ulation present during physical activity and the onset of monomorphic sustained
ventricular tachycardia. The initiation of the ventricular tachycardia was associated
with the typical catecholamine surge observed with exercise in the setting of the
presence of arrhythmogenic substrate characteristic of these patients. For that rea-
son, high risk patients with suspected or confirmed ARVC diagnosis should avoid
vigorous physical activity including competitive sports, regular training, and strenu-
ous exertion involving abrupt physical effort, as well as any recreational activity
associated with symptoms (Level of Recommendation: IB) [89, 90].
Non-pharmacological Treatment
Prevention of sudden death is the most important management strategy of

ARVC. Retrospective analysis of clinical and pathological series identified several
risk factors such as previous cardiac arrest, syncope, young age, malignant family
history, participation in competitive sports, ventricular tachycardia, severe RV
dysfunction, left ventricular involvement, and QRS dispersion of 40 ms or more

[91–93]. However the prognostic value of these single or combined risk factors has
not been prospectively assessed. Recently, Bhonsale tried to define the incidence
and predictors of ICD therapy in patients with ARVC after placement of an ICD for
primary prevention. Nearly one-half of the ARVC patients with primary prevention
ICD implantation experienced appropriate ICD interventions [94]. Inducibility at
electrophysiologic study and non-sustained ventricular tachycardia are independent
strong predictors of appropriate ICD therapy. These markers coupled with proband
status and a high ventricular ectopy burden on 24-h Holter monitoring can be used
to risk-stratify ARVC patients before ICD implantation [94]. There is a need for
larger prospective studies of arrhythmia outcomes among ARVC patients with pro-
phylactic ICD to determine the long-term validity of these predictive markers. Left
ventricular involvement is not rare in ARVC, it may be progressive and lead to end-
stage biventricular cardiomyopathy with congestive heart failure and, sometimes,
necessity of heart transplant.
The indications of ICD for primary prevention of sudden cardiac death in ARVC
patients have not been well established. There is a consensus that high risk patients
should be considered as ICD placement candidates: consequently, patients with epi-
sodes of sustained ventricular tachycardia or ventricular fibrillation (Level of
Recommendation: IB), unexplained syncope, non-sustained ventricular tachycar-
dia, familial history of sudden death, extensive disease including those with left
ventricular involvement and good functional status (Level of Recommendation:
IIaC) [95–97] are potential candidates for ICD implantation. Additionally, patients
with genotypes of ARVC associated with a high genetic risk for sudden cardiac
death (e.g., ARVC 5) may be considered as possible candidates for ICD therapy.
It is currently recommended that asymptomatic patients should be managed on a
case-by-case basis.
The role of the electrophysiology with programmed ventricular stimulation
(PVS) remains controversial, indeed in the Darvin II study [97], PVS had poor
accuracy in predicting appropriate ICD interventions. Contrasting data came from
the study of Bhonsale et al. [94], who reported that inducibility by PVS was a strong
predictor of appropriate ICD therapy. Randomized trials have proven the efficacy of
ICD implantation in preventing sudden cardiac death in other clinical settings. The
impact of ICD implantation in ARVC has been evaluated in a recent meta-analysis
(2013): a total of 610 patients were collected from 18 cohorts with ICD for either
primary or secondary prevention (mean age 40 years, 42 % women, mean follow-up
3.8 years) and the annualized rate of appropriate ICD therapies was 9.5 % [98].
Similar to antiarrhythmic drugs, radiofrequency ablation (RFA) is not a defini-
tive therapy for ventricular arrhythmias and should not be considered an equivalent
alternative to ICD therapy in patients at high risk of sudden cardiac death. RFA can
be appropriate in selected patients who are not candidates for an ICD, or in patients
with an ICD who have frequent episodes of ventricular tachycardia (VT) and
ICD shocks despite antiarrhythmic therapy. Multiple recent studies suggest that
simultaneous epicardial and endocardial approaches for VT mapping and ablation
are feasible and might result in elimination of recurrent VT. This could be explained
by the preferential epicardial infiltration of the disease [99]. The proper role of
Catheter ablation in ARVC remains poorly defined. At the present time, it is best
used as a palliative measure for patients with refractory ventricular tachycardia.
Further research is needed to better define the role of catheter ablation in ARVC.
Cardiac transplantation is considered in patients with progressive heart failure
and intractable recurrent ventricular arrhythmias [100].
Pharmacologic Treatment
Antiarrhythmic medications have been used for symptom control in patients who
are not candidates for ICD or as an adjunct therapy to reduce frequent ICD dis-
charges due to recurrent VT. The combination of beta-receptor blockers and amio-
darone has a proven beneficial effect in suppression of non-sustained VT, in
reduction of sustained VT arrhythmias and rate, preventing syncope and favoring
anti-tachycardia pacing termination rather than shock therapy. Hence, sotalol and
amiodarone have been proposed as effective treatment of sustained VT or VF as
adjunctive therapy to ICD or in patients with ARVC that are not candidates for ICD
implantation (Class of Recommendation IIa, Level of evidence: C) [96, 101].
Furthermore, the North American ARVC Registry has demonstrated that
amiodarone alone showed the greatest efficacy of preventing sustained ventricular
tachycardia or ICD discharge [102], conversely Pinamonti et al. reported that is an
independent predictor of mortality [63].
Beta-receptor blockers and angiotensin-converting enzyme inhibitors are also
used in ARVC patients due to their proven benefit in reducing mortality and slowing
disease progression in other cardiomyopathies. There have been no studies which
have specifically assessed the response of ARVC patients to these medications.
Finally, among the genetic conditions affecting the RV, there is evidence of
genetic modifiers that provide protection or increase susceptibility, respectively, to
pulmonary hypertension. These genetic factors may alter the response of the right
ventricular wall to PAH, worsening the progression of RV dysfunction and RV fail-
ure in spite of optimal medical treatment. By contrast, the REVEAL registry sug-
gests that among 3,000 patients with PAH, approximately 8 % are in NYHA
functional class I, and therefore they may be genetically protected from the progres-
sion of the RV dysfunction. These data probably underestimate the real impact of
genetic modifiers, since a larger proportion of patient may be genetically protected
and therefore remain undetected.
Conclusions
ARVC/D is an inherited cardiomyopathy associated with malignant ventricular arrhyth-

mias and fibro-fatty replacement of the right ventricular myocardium. The diagnosis
of ARVC is based on the Task Force criteria, supported at times by genetic testing.
These criteria should be applied liberally due to the difficulty of confirming the
diagnosis of ARVC. Further research is needed to better stratify the risks of sudden
death in patients and their family members.
References
1. Corrado D, Basso C, Thiene G. Arrhythmogenic right ventricular cardiomyopathy: diagnosis,

prognosis, and treatment. Heart. 2000;83(5):588–95.
2. Corrado D, Thiene G. Arrhythmogenic right ventricular cardiomyopathy/dysplasia: clinical
impact of molecular genetic studies. Circulation. 2006;113(13):1634–7. doi:10.1161/
CIRCULATIONAHA.105.616490.
3. Campuzano O, Alcalde M, Allegue C, et al. Genetics of arrhythmogenic right ventricular
cardiomyopathy. J Med Genet. 2013;50(5):280–9. doi:10.1136/jmedgenet-2013-101523.
4. Taylor M, Graw S, Sinagra G, et al. Genetic variation in titin in arrhythmogenic right ven-
tricular cardiomyopathy-overlap syndromes. Circulation. 2011;124(8):876–85. doi:10.1161/
CIRCULATIONAHA.110.005405.
5. Sen-Chowdhry S, Syrris P, Ward D, Asimaki A, Sevdalis E, McKenna WJ. Clinical and
genetic characterization of families with arrhythmogenic right ventricular dysplasia/cardio-
myopathy provides novel insights into patterns of disease expression. Circulation.
2007;115(13):1710–20. doi:10.1161/CIRCULATIONAHA.106.660241.
6. Basso C, Corrado D, Thiene G. Cardiovascular causes of sudden death in young individuals
including athletes. Cardiol Rev. 1999;7(3):127–35.
7. Tabib A, Loire R, Chalabreysse L, et al. Circumstances of death and gross and microscopic
observations in a series of 200 cases of sudden death associated with arrhythmogenic right
ventricular cardiomyopathy and/or dysplasia. Circulation. 2003;108(24):3000–5.
doi:10.1161/01.CIR.0000108396.65446.21.
8. Dalal D, Nasir K, Bomma C, et al. Arrhythmogenic right ventricular dysplasia: a United States
experience.Circulation.2005;112(25):3823–32.doi:10.1161/CIRCULATIONAHA.105.542266.
9. Corrado D, Thiene G, Nava A, Rossi L, Pennelli N. Sudden death in young competitive ath-
letes: clinicopathologic correlations in 22 cases. Am J Med. 1990;89(5):588–96.
10. Thiene G, Nava A, Corrado D, Rossi L, Pennelli N. Right ventricular cardiomyopathy and
sudden death in young people. N Engl J Med. 1988;318(3):129–33. doi:10.1056/
NEJM198801213180301.
11. De Pasquale CG, Heddle WF. Left sided arrhythmogenic ventricular dysplasia in siblings.
Heart. 2001;86(2):128–30.
12. Collett BA, Davis GJ, Rohr WB. Extensive fibrofatty infiltration of the left ventricle in two
cases of sudden cardiac death. J Forensic Sci. 1994;39(5):1182–7.
13. Michalodimitrakis M, Papadomanolakis A, Stiakakis J, Kanaki K. Left side right ventricular
cardiomyopathy. Med Sci Law. 2002;42(4):313–7.
14. Gallo P, d’Amati G, Pelliccia F. Pathologic evidence of extensive left ventricular involvement
in arrhythmogenic right ventricular cardiomyopathy. Hum Pathol. 1992;23(8):948–52.
15. Sen-Chowdhry S, Syrris P, Prasad SK, et al. Left-dominant arrhythmogenic cardiomyopathy.
J Am Coll Cardiol. 2008;52(25):2175–87. doi:10.1016/j.jacc.2008.09.019.
16. Marcus FI, Fontaine GH, Guiraudon G, Frank R. Right ventricular dysplasia: a report of 24
adult cases. Circulation. 1982;65(2):384–98.
17. Pinamonti B, Camerini F, Fabris E, Sinagra G. The role of clinical observation: Red Flag 5 -
right ventricular involvement, arrhythmogenic right ventricular cardiomyopathy and associ-
ated phenotypes, in Genetic Cardiomyopathies, foreword by Perry Elliott, Milano, Springer,
2013, p.61–69.
18. Basso C, Thiene G. Adipositas cordis, fatty infiltration of the right ventricle, and arrhythmogenic
right ventricular cardiomyopathy. Just a matter of fat? Cardiovasc Pathol. 2005;14(1):37–41.
19. Basso C, Corrado D, Marcus FI, Nava A, Thiene G. Seminar arrhythmogenic right ventricular
cardiomyopathy. Lancet. 2009;373(9671):1289–300. doi:10.1016/S0140-6736(09)60256-7.
20. Fontaine G, Frank R, Guiraudon G, et al. [Significance of intraventricular conduction disor-
ders observed in arrhythmogenic right ventricular dysplasia]. Arch Mal Coeur Vaiss.
1984;77(8):872–9.
21. Basso C, Thiene G, Corrado D, Angelini A, Nava A, Valente M. Arrhythmogenic right ventricu-
lar cardiomyopathy. Dysplasia, dystrophy, or myocarditis? Circulation. 1996;94(5):983–91.
22. Thiene G, Basso C. Arrhythmogenic right ventricular cardiomyopathy: an update. Cardiovasc
Pathol. 2001;10(3):109–17.
23. Thiene G, Corrado D, Nava A, et al. Right ventricular cardiomyopathy: is there evidence of
an inflammatory aetiology? Eur Heart J. 1991;12(Suppl D):22–5.
24. Corrado D, Basso C, Thiene G, et al. Spectrum of clinicopathologic manifestations of
arrhythmogenic right ventricular cardiomyopathy/dysplasia: a multicenter study. J Am Coll
Cardiol. 1997;30(6):1512–20.
25. Norman M. Novel mutation in desmoplakin causes arrhythmogenic left ventricular cardio-
myopathy. Circulation. 2005;112(5):636–42. doi:10.1161/CIRCULATIONAHA.104.532234.
26. Niroomand F, Carbucicchio C, Tondo C, et al. Electrophysiological characteristics and out-
come in patients with idiopathic right ventricular arrhythmia compared with arrhythmogenic
right ventricular dysplasia. Heart. 2002;87(1):41–7.
27. Sen-Chowdhry S, Lowe MD, Sporton SC. Arrhythmogenic right ventricular cardiomyopa-
thy: clinical presentation, diagnosis, and management. Am J Med. 2004;117(9):685–95.
28. Marcus FI, McKenna WJ, Sherrill D, et al. Diagnosis of arrhythmogenic right ventricular
cardiomyopathy/dysplasia: proposed modification of the task force criteria. Circulation.
2010;121(13):1533–41. doi:10.1161/CIRCULATIONAHA.108.840827.
29. Tandri H, Saranathan M, Rodriguez ER, et al. Noninvasive detection of myocardial fibrosis
in arrhythmogenic right ventricular cardiomyopathy using delayed-enhancement magnetic
resonance imaging. J Am Coll Cardiol. 2005;45(1):98–103. doi:10.1016/j.jacc.2004.09.053.
30. Fressart V, Duthoit G, Donal E, et al. Desmosomal gene analysis in arrhythmogenic right
ventricular dysplasia/cardiomyopathy: spectrum of mutations and clinical impact in practice.
Europace. 2010;12(6):861–8. doi:10.1093/europace/euq104.
31. Sheikh F, Ross RS, Chen J. Cell-cell connection to cardiac disease. Trends Cardiovasc Med.
2009;19(6):182–90. doi:10.1016/j.tcm.2009.12.001.
32. Peters NS, Green CR, Poole-Wilson PA, Severs NJ. Reduced content of connexin43 gap
junctions in ventricular myocardium from hypertrophied and ischemic human hearts.
Circulation. 1993;88(3):864–75.
33. Smith JH, Green CR, Peters NS, Rothery S, Severs NJ. Altered patterns of gap junction dis-
tribution in ischemic heart disease. An immunohistochemical study of human myocardium
using laser scanning confocal microscopy. Am J Pathol. 1991;139(4):801–21.
34. McKoy G, Protonotarios N, Crosby A, et al. Identification of a deletion in plakoglobin in
arrhythmogenic right ventricular cardiomyopathy with palmoplantar keratoderma and woolly
hair (Naxos disease). Lancet. 2000;355(9221):2119–24. doi:10.1016/S0140-6736(00)02379-5.
35. Norgett EE, Hatsell SJ, Carvajal-Huerta L, et al. Recessive mutation in desmoplakin disrupts
desmoplakin-intermediate filament interactions and causes dilated cardiomyopathy, woolly
hair and keratoderma. Hum Mol Genet. 2000;9(18):2761–6.
36. Gerull B, Heuser A, Wichter T, et al. Mutations in the desmosomal protein plakophilin-2
are common in arrhythmogenic right ventricular cardiomyopathy. Nat Genet. 2004;
36(11):1162–4. doi:10.1038/ng1461.
37. Awad MM, Dalal D, Cho E, et al. DSG2 mutations contribute to arrhythmogenic right ven-
tricular dysplasia/cardiomyopathy. Am J Hum Genet. 2006;79(1):136–42. doi:10.1086/504393.
38. Syrris P, Ward D, Evans A, et al. Arrhythmogenic right ventricular dysplasia/cardiomyopathy
associated with mutations in the desmosomal gene desmocollin-2. Am J Hum Genet.
2006;79(5):978–84. doi:10.1086/509122.
39. Asimaki A, Syrris P, Wichter T, Matthias P, Saffitz JE, McKenna WJ. A novel dominant muta-
tion in plakoglobin causes arrhythmogenic right ventricular cardiomyopathy. Am J Hum
Genet. 2007;81(5):964–73. doi:10.1086/521633.
40. Protonotarios N, Tsatsopoulou A. Naxos disease and Carvajal syndrome: cardiocutaneous
disorders that highlight the pathogenesis and broaden the spectrum of arrhythmogenic right
ventricular cardiomyopathy. Cardiovasc Pathol. 2004;13(4):185–94. doi:10.1016/j.carpath.
2004.03.609.
41. Sen-Chowdhry S, Syrris P, McKenna WJ. Genetics of right ventricular cardiomyopathy.
J Cardiovasc Electrophysiol. 2005;16(8):927–35. doi:10.1111/j.1540-8167.2005.40842.x.
42. Durán M, Avellán F, Carvajal L. Dilated cardiomyopathy in the ectodermal dysplasia.
Electro-echocardiographic observations in palmo-plantar keratoderma with woolly hair. Rev
Esp Cardiol. 2000;53(9):1296–300.
43. Alcalai R, Metzger S, Rosenheck S, Meiner V, Chajek-Shaul T. A recessive mutation in
desmoplakin causes arrhythmogenic right ventricular dysplasia, skin disorder, and woolly
hair. J Am Coll Cardiol. 2003;42(2):319–27. doi:10.1016/S0735-1097(03)00628-4.
44. Beffagna G, Occhi G, Nava A, et al. Regulatory mutations in transforming growth factor-
beta3 gene cause arrhythmogenic right ventricular cardiomyopathy type 1. Cardiovasc Res.
2005;65(2):366–73. doi:10.1016/j.cardiores.2004.10.005.
45. Merner ND, Hodgkinson KA, Haywood AFM, et al. Arrhythmogenic right ventricular car-
diomyopathy type 5 is a fully penetrant, lethal arrhythmic disorder caused by a missense
mutation in the TMEM43 gene. Am J Hum Genet. 2008;82(4):809–21. doi:10.1016/j.
ajhg.2008.01.010.
46. Sporn MB, Roberts AB. Transforming growth factor-beta: recent progress and new
challenges. J Cell Biol. 1992;119(5):1017–21.
47. Kapoun AM, Liang F, O’Young G, et al. B-type natriuretic peptide exerts broad functional
opposition to transforming growth factor-beta in primary human cardiac fibroblasts: fibrosis,
myofibroblast conversion, proliferation, and inflammation. Circ Res. 2004;94(4):453–61.
doi:10.1161/01.RES.0000117070.86556.9F.
48. Haywood AFM, Merner ND, Hodgkinson KA, et al. Recurrent missense mutations in
TMEM43 (ARVD5) due to founder effects cause arrhythmogenic cardiomyopathies in the
UK and Canada. Eur Heart J. 2013;34(13):1002–11. doi:10.1093/eurheartj/ehs383.
49. Priori SG, Napolitano C, Tiso N, et al. Mutations in the cardiac ryanodine receptor gene
(hRyR2) underlie catecholaminergic polymorphic ventricular tachycardia. Circulation.
2001;103(2):196–200.
50. Tiso N, Stephan DA, Nava A, et al. Identification of mutations in the cardiac ryanodine recep-
tor gene in families affected with arrhythmogenic right ventricular cardiomyopathy type 2
(ARVD2). Hum Mol Genet. 2001;10(3):189–94.
51. Fatkin D, MacRae C, Sasaki T, Wolff MR. Missense mutations in the rod domain of the lamin
A/C gene as causes of dilated cardiomyopathy and conduction-system disease. N Engl J Med.
1999;341(23):1715–24.
52. Taylor MRG, Fain PR, Sinagra G, et al. Natural history of dilated cardiomyopathy due to
lamin A/C gene mutations. J Am Coll Cardiol. 2003;41(5):771–80. doi:10.1016/
S0735-1097(02)02954-6.
53. Marcus FI, McKenna WJ, Sherrill D, et al. Diagnosis of arrhythmogenic right ventricular
cardiomyopathy/dysplasia: proposed modification of the Task Force Criteria. Eur Heart
J. 2010;31:806–14. doi:10.1093/eurheartj/ehq025.
54. Quarta G, Syrris P, Ashworth M, Jenkins S. Mutations in the Lamin A/C gene mimic arrhyth-
mogenic right ventricular cardiomyopathy. Eur Heart J. 2012;33(9):1128–36.
55. Gandjbakhch E, Vite A, Gary F, et al. Screening of genes encoding junctional candidates in
arrhythmogenic right ventricular cardiomyopathy/dysplasia. Europace. 2013;15(10):1522–5.
doi:10.1093/europace/eut224.
56. Valenzise M, Arrigo T, De Luca F, et al. R298Q mutation of p63 gene in autosomal dominant
ectodermal dysplasia associated with arrhythmogenic right ventricular cardiomyopathy.
Eur J Med Genet. 2008;51(5):497–500. doi:10.1016/j.ejmg.2008.05.005.
57. Pinamonti B, Sinagra G, Salvi A, et al. Left ventricular involvement in right ventricular
dysplasia. Am Heart J. 1992;123(3):711–24.
58. Roberts WC, Siegel RJ, McManus BM. Idiopathic dilated cardiomyopathy: analysis of 152
necropsy patients. Am J Cardiol. 1987;60(16):1340–55.
59. Enriquez-Sarano M, Rossi A, Seward JB, Bailey KR, Tajik AJ. Determinants of pulmonary
hypertension in left ventricular dysfunction. J Am Coll Cardiol. 1997;29(1):153–9.
doi:10.1016/S0735-1097(96)00436-6.
60. Gavazzi A, Berzuini C, Campana C, et al. Value of right ventricular ejection fraction in pre-
dicting short-term prognosis of patients with severe chronic heart failure. J Heart Lung
Transplant. 1997;16(7):774–85.
61. Juilliere Y, Barbier G, Feldmann L. Additional predictive value of both left and right ven-
tricular ejection fractions on long-term survival in idiopathic dilated cardiomyopathy. Eur
Heart J. 1997;18(2):275.80.
62. Sun JP, James KB, Yang X, et al. Comparison of mortality rates and progression of left ven-
tricular dysfunction in patients with idiopathic dilated cardiomyopathy and dilated versus
nondilated right ventricular cavities. Am J Cardiol. 1997;80(12):1583–7.
63. Pinamonti B, Dragos AM, Pyxaras SA, et al. Prognostic predictors in arrhythmogenic right
ventricular cardiomyopathy: results from a 10-year registry. Eur Heart J.
2011;32(9):1105–13.
64. Silverman KJ, Hutchins GM, Bulkley BH. Cardiac sarcoid: a clinicopathologic study of 84
unselected patients with systemic sarcoidosis. Circulation. 1978;58(6):1204–11.
65. Seward JB, Casaclang-Verzosa G. Infiltrative cardiovascular diseases: cardiomyopathies that
look alike. J Am Coll Cardiol. 2010;55(17):1769–79. doi:10.1016/j.jacc.2009.12.040.
66. Uemura A, Morimoto S-I, Kato Y, et al. Relationship between basal thinning of the interven-
tricular septum and atrioventricular block in patients with cardiac sarcoidosis. Sarcoidosis
Vasc Diffuse Lung Dis. 2005;22(1):63–5.
67. Baughman RP. Pulmonary hypertension associated with sarcoidosis. Arthritis Res Ther.
2007;9 Suppl 2:S8. doi:10.1186/ar2192.
68. Aggeli C, Felekos I, Tousoulis D, Gialafos E, Rapti A, Stefanadis C. Myocardial mechanics
for the early detection of cardiac sarcoidosis. Int J Cardiol. 2013;168(5):4820–1. doi:10.1016/j.
ijcard.2013.07.010.
69. Steckman DA, Schneider PM, Schuller JL, et al. Utility of cardiac magnetic resonance imag-
ing to differentiate cardiac sarcoidosis from arrhythmogenic right ventricular cardiomyopa-
thy. Am J Cardiol. 2012;110(4):575–9. doi:10.1016/j.amjcard.2012.04.029.
70. Uhl HS. A previously undescribed congenital malformation of the heart: almost total absence
of the myocardium of the right ventricle. Bull Johns Hopkins Hosp. 1952;91(3):197–209.
71. Gerlis LM, Schmidt-Ott SC, Ho SY. Dysplastic conditions of the right ventricular myocardium:
Uhl’s anomaly vs arrhythmogenic right ventricular dysplasia. Br Heart J. 1993;69(2):142–50.
72. Wager GP, Couser RJ, Edwards OP. Antenatal ultrasound findings in a case of Uhl’s anomaly.
Am J Perinatol. 1988;5(2):164–7.
73. O’Connor WN, Cottrill CM, Johnson GL, Noonan JA, Todd EP. Pulmonary atresia with intact
ventricular septum and ventriculocoronary communications: surgical significance.
Circulation. 1982;65(4):805–9.
74. James TN, Nichols MM, Sapire DW, DiPatre PL, Lopez SM. Complete heart block and fatal
right ventricular failure in an infant. Circulation. 1996;93(8):1588–600.
75. Uhl H. Uhl’s anomaly revisited. Circulation. 1996;93(8):483–4.
76. Feucht M, Christ B, Wilting J. VEGF induces cardiovascular malformation and embryonic
lethality. Am J Pathol. 1997;151(5):1407–16.
77. Azhari N, Assaqqat M, Bulbul Z. Successful surgical repair of Uhl’s anomaly. Cardiol Young.
2002;12(2):192–5.
78. Yoshii S, Suzuki S, Hosaka S, Osawa H. A case of Uhl anomaly treated with one and a half
ventricle repair combined with partial right ventriculectomy in infancy. J Thorac Cardiovasc
Surg. 2001;122(5):1026–8.
79. Gilljam T, Bergh C-H. Right ventricular cardiomyopathy: timing of heart transplantation in
Uhl’s anomaly and arrhythmogenic right ventricular cardiomyopathy. Eur J Heart Fail.
2009;11(1):106–9. doi:10.1093/eurjhf/hfn014.
80. Pieroni M, Russo Dello A, Marzo F, et al. High prevalence of myocarditis mimicking arrhyth-
mogenic right ventricular cardiomyopathy differential diagnosis by electroanatomic
mapping-guided endomyocardial biopsy. J Am Coll Cardiol. 2009;53(8):681–9. doi:10.1016/j.
jacc.2008.11.017.
81. Murray B. Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C): a review
of molecular and clinical literature. J Genet Couns. 2012;21(4):494–504. doi:10.1007/
s10897-012-9497-7.
82. Bauce B, Daliento L, Frigo G, Russo G, Nava A. Pregnancy in women with arrhythmogenic
right ventricular cardiomyopathy/dysplasia. Eur J Obstet Gynecol Reprod Biol.
2006;127(2):186–9. doi:10.1016/j.ejogrb.2005.10.011.
83. Mejia-Lopez E, Romero J, Mejia-Lopez E, Manrique C, Lucariello R. Arrhythmogenic right
ventricular cardiomyopathy (ARVC/D): a systematic literature review. Clin Med Insights
Cardiol. 2013;7:97–114. doi:10.4137/CMC.S10940.
84. Hershberger RE, Lindenfeld J, Mestroni L, et al. Genetic evaluation of cardiomyopathy—a
Heart Failure Society of America practice guideline. J Card Fail. 2009;15(2):83–97.
doi:10.1016/j.cardfail.2009.01.006.
85. Dalal D, James C, Devanagondi R, et al. Penetrance of mutations in plakophilin-2 among
families with arrhythmogenic right ventricular dysplasia/cardiomyopathy. J Am Coll Cardiol.
2006;48(7):1416–24. doi:10.1016/j.jacc.2006.06.045.
86. Gemayel C, Pelliccia A, Thompson PD. Arrhythmogenic right ventricular cardiomyopathy.
J Am Coll Cardiol. 2001;38(7):1773–81.
87. Fornes P, Ratel S, Lecomte D. Pathology of arrhythmogenic right ventricular cardiomyopathy/
dysplasia—an autopsy study of 20 forensic cases. J Forensic Sci. 1998;43(4):772–83.
88. Leclercq JF, Potenza S, Maison-Blanche P, Chastang C, Coumel P. Determinants of spontane-
ous occurrence of sustained monomorphic ventricular tachycardia in right ventricular dysplasia.
J Am Coll Cardiol. 1996;28(3):720–4.
89. Maron BJ, Ackerman MJ, Nishimura RA, Pyeritz RE, Towbin JA, Udelson JE. Task Force 4:
HCM and other cardiomyopathies, mitral valve prolapse, myocarditis, and Marfan syndrome.
J Am Coll Cardiol. 2005;45:1340–5. doi:10.1016/j.jacc.2005.02.011.
90. Furlanello F, Bertoldi A, Dallago M, et al. Cardiac arrest and sudden death in competitive
athletes with arrhythmogenic right ventricular dysplasia. Pacing Clin Electrophysiol.
1998;21(1 Pt 2):331–5.
91. Turrini P, Corrado D, Basso C, Nava A, Bauce B. Dispersion of ventricular depolarization-
repolarization a noninvasive marker for risk stratification in arrhythmogenic right ventricular
cardiomyopathy. Circulation. 2001;103(25):3075–80.
92. Corrado D, Leoni L, Link MS, et al. Implantable cardioverter-defibrillator therapy for pre-
vention of sudden death in patients with arrhythmogenic right ventricular cardiomyopathy/
dysplasia. Circulation. 2003;108(25):3084–91. doi:10.1161/01.CIR.0000103130.33451.D2.
93. Silvano M, Corrado D, Köbe J, et al. Risk stratification in arrhythmogenic right ventricular
cardiomyopathy. Herzschrittmacherther Elektrophysiol. 2013;24(4):202–8. doi:10.1007/
s00399-013-0291-5.
94. Bhonsale A, James CA, Tichnell C, et al. Incidence and predictors of implantable cardioverter-
defibrillator therapy in patients with arrhythmogenic right ventricular dysplasia/cardiomy-
opathy undergoing implantable cardioverter-defibrillator implantation for primary prevention.
J Am Coll Cardiol. 2011;58(14):1485–96. doi:10.1016/j.jacc.2011.06.043.
95. Epstein AE, DiMarco JP, Ellenbogen KA, et al. ACC/AHA/HRS 2008 guidelines for device-
based therapy of cardiac rhythm abnormalities: executive summary a report of the American
College of Cardiology/American Heart Association Task Force on Practice Guidelines
(Writing Committee to Revise the ACC/AHA/NASPE 2002 Guideline Update for
Implantation of Cardiac Pacemakers and Antiarrhythmia Devices): developed in collabora-
tion with the American Association for Thoracic Surgery and Society of Thoracic Surgeons.
Circulation. 2008;117(21):2820–40. doi:10.1161/CIRCUALTIONAHA.108.189742.
96. Zipes DP, Camm AJ, Borggrefe M, et al. ACC/AHA/ESC 2006 guidelines for management
of patients with ventricular arrhythmias and the prevention of sudden cardiac death: a report
of the American College of Cardiology/American Heart Association Task Force and the
European Society of Cardiology Committee for Practice Guidelines (Writing Committee to
Develop Guidelines for Management of Patients With Ventricular Arrhythmias and the
Prevention of Sudden Cardiac Death). J Am Coll Cardiol. 2006;48(5):e247–346.
97. Corrado D, Calkins H, Link MS, Leoni L, et al. Prophylactic implantable defibrillator in
patients with arrhythmogenic right ventricular cardiomyopathy/dysplasia and no prior ven-
tricular fibrillation or sustained ventricular tachycardia. Circulation. 2010;122(12):1144–52.
98. Schinkel AFL. Implantable cardioverter defibrillators in arrhythmogenic right ventricu-
lar dysplasia/cardiomyopathy: patient outcomes, incidence of appropriate and inappropriate
interventions, and complications. Circ Arrhythm Electrophysiol. 2013;6(3):562–8.
doi:10.1161/CIRCEP.113.000392.
99. Garcia FC, Bazan V, Zado ES, Ren J-F, Marchlinski FE. Epicardial substrate and outcome with
epicardial ablation of ventricular tachycardia in arrhythmogenic right ventricular cardiomyopa-
thy/dysplasia.Circulation.2009;120(5):366–75.doi:10.1161/CIRCULATIONAHA.108.834903.
100. Awad MM, Calkins H, Judge DP. Mechanisms of disease: molecular genetics of arrhythmo-
genic right ventricular dysplasia/cardiomyopathy. Nat Clin Pract Cardiovasc Med.
2008;5(5):258–67. doi:10.1038/ncpcardio1182.
101. Wichter T, Borggrefe M, Haverkamp W, Chen X, Breithardt G. Efficacy of antiarrhythmic
drugs in patients with arrhythmogenic right ventricular disease. Results in patients with
inducible and noninducible ventricular tachycardia. Circulation. 1992;86(1):29–37.
102. Marcus GM, Glidden DV, Polonsky B. Efficacy of antiarrhythmic drugs in arrhythmogenic
right ventricular cardiomyopathya report from the North American ARVC Registry. J Am
Coll Cardiol. 2009;54(7):609–15.
103. Pamuru PR, Dokuparthi M, Remersu S, Calambur N. Comparison of Uhl’s anomaly, right
ventricular outflow tract ventricular tachycardia (RVOT VT) & arrhythmogenic right ven-
tricular dysplasia/cardiomyopathy (ARVD/C) with an insight into genetics of ARVD/C. Indian
J Med Res. 2010;131:35–45.
Chapter 17
The Right Ventricle in Left Heart Failure
Louis J. Dell’Italia
Introduction
The right ventricle (RV), because of its low pressure working conditions and its
complex geometry, stands in stark contrast to the left ventricle (LV). Thus, under
normal baseline conditions the RV’s unique anatomy, myocardial ultrastructure, and
coronary physiology reflect a high volume low pressure pump. Early work by Starr
[1] and others [2–4] described the RV as a passive conduit with minimal pumping
capability. Despite the marked differences in loading conditions and geometry in
the normal state, RV myocardial and chamber dynamics respond in a manner simi-
lar to the LV pump mechanics. It is now well appreciated that through its own
unique properties and a mechanism of ventricular interdependence, RV systolic
function and diastolic load contribute importantly to the prognosis and treatment of
patients with congestive heart failure (CHF).
With the advent of imaging modalities for the assessment of right ventricular
(RV) function, it has been well appreciated for the past 30 years that RV function is
one of the best independent predictors of functional status [5] and survival of
patients with CHF [6–11]. In particular, over the past 20 years there have been many
investigations demonstrating a strong correlation between RV function and heart
failure mortality, in both ischemic and nonischemic cardiomyopathies (Fig. 17.1)
[6–11]. In several studies, a reduction of RV systolic function more closely predicts
impaired exercise capacity and poor survival than does LV systolic function [5, 6,
11]. However, the degree of pulmonary hypertension, in the presence of either a
normal LVEF or a reduced LVEF, also correlates with mortality, presumably because
of the effect of an increased afterload on RV function [12, 13]. In a study of patients
with chronic heart failure, patients who had both RV dysfunction and pulmonary
L.J. Dell’Italia, M.D. (*)

Department of Medicine, University of Alabama and Birmingham Medical Center,
Birmingham, AL, USA
e-mail: loudell@uab.edu

362 L.J. Dell’Italia
Fig. 17.1 Kaplan–Meier plots for all-cause mortality (a) and HF hospitalization (b) by RV ejec-
tion fraction categories [11]. (with permission Meyer P, Filippatos GS, Ahmed MI, et al. Effects of
right ventricular ejection fraction on outcomes in chronic systolic heart failure. Circulation.
2010;121:252–258.)
hypertension had worse outcomes than patients with either of these findings alone,
suggesting that RV dysfunction and PH have an additive effect in their contribution
to mortality [9]. All of these previously mentioned studies included heart failure
patients of mixed etiology. The potential prognostic impact of RV systolic dysfunc-
tion in patients with nonischemic dilated cardiomyopathy has been reported in
small studies and these suggest RV systolic dysfunction as an independent predictor
of survival [7, 14]. Most recently in 2013, a study of 250 consecutive patients with
dilated cardiomyopathy showed that a decreased RV ejection fraction of ≤45 %
assessed by magnetic resonance imaging, was a powerful, independent predictor of
transplant-free survival and worse heart failure prognosis [15]. Finally, cardiac
resynchronization therapy has been shown to reduce the risk of death and heart
failure events in patients with heart failure, low ejection fraction, and a wide
QRS. Recent evaluations of large scale clinical trials of the Multicenter Automatic
Defibrillator Implantation Trial with Cardiac Resynchronization Therapy (MADIT-
CRT) Trial, the REsyncronization re-VErses Remodeling in Systolic left vEntricu-
lar dysfunction (REVERSE) Trial, and the Cardiac Resynchronization-Heart Failure
(CARE-HF) Trial have provided insights into the critically important role of RV
function in predicting functional outcome and mortality in patients receiving resyn-
chronization therapy for CHF [16–19].
Early Studies Demonstrating the Importance

of RV Function in Left Heart Failure
Left ventricular failure or left-sided overload of systolic or diastolic nature repre-

sents the most common cause of RV dysfunction resulting from the passive eleva-
tion of pulmonary pressures. The mechanism of hemodynamic compromise results
17 The Right Ventricle in Left Heart Failure 363
Fig. 17.2 Four chamber views of a patient with heart failure before and after insertion of LV assist
device demonstrating the increase in RV dimensions and decrease in LV dimensions due to the
unloading effect of the LV assist device [22]. (with permission Dell’Italia LJ. Anatomy and physi-
ology of the right ventricle. Cardiol Clin 2012;30:167–187.)
from an increased RV afterload and subsequent decreased stroke volume. However,

in contrast to the primary pressure overload of the RV, this situation is accompanied
by systolic dysfunction and chamber enlargement of the LV and, therefore, there is
no dramatic evidence of underfilling of the LV via the mechanism of leftward shift
of the interventricular septum as in the setting of an acute pulmonary embolus or RV
myocardial infarction. Nonetheless, ventricular interactions may explain the
improvement in hemodynamics after treatment with drugs having a beneficial effect
on RV afterload in patients with severe CHF, since there is a well-documented inter-
action of RV and LV systolic contraction [20–22]. The decision to use univentricu-
lar versus biventricular support is one of the key problems in the successful
application of mechanical circulatory support for the treatment of patients with
heart failure. Figure 17.2 demonstrates a four chamber apical echocardiographic
view of a patient with heart failure before and after insertion of a LV assist device
demonstrating the increase in RV dimensions and decrease in LV dimensions due to
the unloading effect of the LV assist device [22]. The mechanisms of diastolic and
systolic ventricular interaction weigh heavily in this decision and it would appear
that the decision will depend upon the pulmonary vascular resistance and the status
of RV function in each individual case.
The physiologic effects on RV function may have important consequences
because of the very compelling evidence that RV function is an important determi-
nant of the hemodynamic response, and the prognosis and exercise capacity in
patients with CHF. As early as 1983, Polak and coworkers emphasized the
importance of RV function in the prognosis of 34 patients with LV failure secondary

to atherosclerotic coronary disease [6]. Only 16 patients were alive after a 2-year
follow-up and these patients had a higher RV ejection fraction and less LV dysfunc-
tion. When a RV ejection fraction of less than 35 % was used as a cut off, mortality
was significantly greater among the 21 patients with depressed RV ejection (71 vs.
23 %). Although patients with depressed RV ejection fraction had a greater preva-
lence of chronic obstructive lung disease and previous inferior myocardial infarc-
tion, the differences between the groups were not statistically significant. These
underlying problems must be taken into consideration because they are a cause of
RV dysfunction independent of left heart failure. Nevertheless, RV ejection fraction
has also been identified as an important predictor of outcome after mitral valve sur-
gery in patients with isolated mitral regurgitation in the absence of coronary artery
disease [23–28].
Hochreiter and coworkers studied 53 patients with chronic severe mitral regurgi-
tation using right heart catheterization, radionuclide angiography, exercise testing,
and ambulatory electrocardiography [23]. Stepwise multiple logistic regression
analysis demonstrated only resting RV ejection fraction and left atrial size to be
independently associated with exercise capacity, and RV ejection fraction
was inversely proportional to the pulmonary arterial systolic pressure (r = −0.67,
p < 0.001) and pulmonary capillary wedge pressure (r = −0.68, p < 0.001). Of interest,
RV ejection fraction was the only variable significantly related to the presence or
absence of complex arrhythmias. Finally, all deaths among medically treated patients
are clustered among those with RV ejection fraction <30 % (p < 0.0001 vs. patients
with RV ejection fraction >30 %) and LV ejection fraction <45 %. Subsequent stud-
ies in small numbers of patients have demonstrated that the failure of the RV ejection
fraction to rise despite absence of symptoms and well-preserved LV ejection fraction
indicates an almost 50 % likelihood of HF during the succeeding 3 years, which is
fourfold greater than for patients with preserved exercise RVEF [23–26]. Most
recently in 2012 and 2013, the results from a follow-up of large numbers of patients
demonstrate the prognostic importance of the pulmonary systolic pressure [27, 28]
or RV ejection fraction measured by radionuclide angiography (Fig. 17.3) [29] in
patients with degenerative isolated mitral regurgitation. Figure 17.3 demonstrates
the dramatic decrease in 10-year cardiovascular survival in patients with RV and LV
ejection fraction impairment [29]. These studies demonstrate the critical importance
of RV performance in determining the functional severity of mitral regurgitation and
in predicting its important effect on survival that is most likely related to the severity
of chronic afterload excess. Indeed, an estimated pulmonary systolic pressure of
50 mmHg is an indication for consideration for mitral valve surgery in the absence
of symptoms and a LV ejection fraction >60 % [30, 31].
Also starting in the early 1980s, several studies demonstrated that the exercise
capacity of heart failure patients is also dependent on RV function. Baker and
coworkers studied 25 patients with chronic LV failure due to coronary artery disease
(n = 12) and idiopathic dilated cardiomyopathy (n = 13) [32]. Maximum upright
bicycle exercise testing was performed to determine maximum oxygen consump-
tion (MVO2) which averaged only 13 + 4 mL/min/kg in this group of patients.
Fig. 17.3 (a) Ten-year cardiovascular survival rate after mitral valve surgery in patients with pre-
served (>35 %) versus depressed (≤35 %) RV EF (p = 0.037). (b) Ten-year cardiovascular survival
rate after mitral valve surgery in patients with various combinations of RV and LV ejection fraction
measured by radionuclide angiography. Importantly, there is a dramatic decrease in 10-year cardio-
vascular survival in patients with RV and LV ejection fraction impairment compared to the remaining
patients (p < 0.0001) [29]. (with permission Le Tourneau T, Deswarte G, Lamblin N, Foucher-Hossein
C, Fayad G, Richardson M, Polge AS, Vannesson C, Topilsky Y, Juthier F, Trochu JN, Enriquez-
Sarano M, Bauters C. Right Ventricular Systolic Function in Organic Mitral Regurgitation: Impact of
Biventricular Impairment. Circulation. 2013;127(15):1597–608.)
Resting LV ejection fraction did not correlate with MVO2 (r = 0.08). However, resting
RV ejection fraction did correlate with MVO2 (r = 0.70, p < 0.001) in the 25 patients,
even when these patients were separated into ischemic (r = 0.88, p < 0.001) and
nonischemic (r = 0.60, p < 0.01) causes of cardiomyopathy. Leier and coworkers
demonstrated significantly improved clinical status and exercise capacity during
treatment with isosorbide dinitrate in 30 patients with moderate to severe CHF [33].
This improvement in exercise capacity may have been attributed to afterload reduction
of the RV resulting in an augmented RV stroke output and improved LV filling; in
addition, Franciosa and Baker demonstrated that indices of pulmonary vascular
resistance afterload are better indicators of exercise capacity than previously studied
markers of LV systolic dysfunction [34]. In 41 patients with chronic LV failure,
exercise MVO2 correlated with the resting pulmonary artery wedge pressure
(r = −0.54, y = 32.8−0.8x, p < 0.001) and mean pulmonary artery pressure (r = −0.54,
y = 44.9−1.0x, p < 0.001) but not systemic vascular resistance (r = −0.20). It is
therefore tempting to speculate that in the pre-captopril era of heart failure therapy,
improved survival in the VA Cooperative Study achieved with combined hydrala-
zine and nitrate therapy may have been to a large part due to a drug related decrease
of the pulmonary vascular resistance [35].
To determine the relative efficacy of right versus left-sided afterload reduction on
the hemodynamic response to nitroprusside infusion, Yin and coworkers measured
both pulmonary and systemic vascular impedance in seven patients with severe
CHF [36]. Left ventricular unloading was manifested by a fall in systemic vascular
resistance, whereas significant unloading of the RV was manifested by a similar
decrease in pulmonary vascular resistance but also by a direct decrease in pulmo-
nary artery compliance by simultaneously measuring pressure and flow in the main
pulmonary artery. Thus measuring pulmonary vascular impedance (see also Chap. 2)
reveals hemodynamic alterations in the compliance of the central pulmonary vessels
that are not reflected in the standard pulmonary vascular resistance and suggest a
direct, active effect of nitroprusside on the pulmonary vasculature rather than a
passive decrease in pulmonary venous pressures. These data suggest that both LV
hemodynamics and cardiac output benefit in an additive fashion from a primary
afterload reduction of the RV during nitroprusside infusion. The value of pulmonary
vascular impedance measurement in the determination of RV afterload will be fur-
ther discussed in this chapter.
In 1985 Packer and coworkers compared the effects of captopril and isosorbide
dinitrate, drugs with known effects on pulmonary arteriolar resistance, in patients
with severe left ventricular failure [37]. Left ventricular filling pressures declined
similarly with both captopril and isosorbide dinitrate; however, the mean right
atrial pressure decreased to a greater extent with nitrates than with captopril.
Although systemic resistance declined similarly with both drugs, the cardiac index
increased to a greater extent with nitrate therapy than during converting-enzyme
inhibition (+0.47 vs. +0.23 L/min/m2, p < 0.01). The authors speculated that an
inappropriately high pulmonary afterload limits the degree to which the RV output
can increase during converting-enzyme inhibition; this may explain why patients
with poor RV function not respond to converting-enzyme inhibitors. Furthermore,

preliminary data from early work by Packer and coworkers suggested that RV func-
tion appears to be the principle determinant of long-term survival in patients treated
with captopril [38]. In summary, these and other early studies [39–42] demonstrate
the importance of both pulmonary and systemic arterial afterload reduction not
only in the treatment of patients with CHF but also in patients with mitral valvular
heart disease.
Most recently, it was reported that in patients presenting with acute decompen-
sated left heart failure, improvement in RV mechanics in response to intensive med-
ical therapy was associated with a lower rate of long-term adverse events when
compared to patients not showing improvement of RV function [43]. It is important
to note that in this study the presence of tricuspid regurgitation was significantly
worse in patients with adverse events. This study utilized two-dimensional echocar-
diographic strain imaging to quantify regional myocardial function. This fairly
simple technique can provide a more direct assessment of RV mechanics and RV
strain imaging (see also Chap. 10). These results suggest that medical therapy tar-
geted to improve RV function in heart failure will improve functional capacity and
outcomes. At this point it is important to address the assessment of RV function,
which will be more completely addressed in Chaps. 2, 11, and 12.
The RV forms a crescent-shaped structure with a very flat main chamber having
a heavily trabeculated but thin free wall. It is bounded by the thicker interventricular
septum medially and the cylindrical outflow tract superiorly, and in contrast to the
ellipsoidal LV, the RV chamber defies measurements based on an appropriate geo-
metric model. To further complicate matters, the ejection of blood from the RV
chamber emanates from an interaction of three different sources: free wall, inter-
ventricular septum, and conus. The conus, with its circumferentially arranged mus-
cle fibers [44], contracts 30–50 ms after the base and apex of the free wall; [45–47]
this can be exaggerated by vagal stimulation or abolished by sympathetic stimula-
tion [48, 49]. The free wall contracts in a peristalsis wave-like fashion starting at the
base and progressing to the apex (see also Chap. 11). In the normal RV, because of
the highly compliant lung circulation, RV free wall and outflow tract segments
cease shortening, and even lengthen, as the ejection continues and RV pressure rap-
idly fall during relaxation [50]. Thus, it has been proposed that RV systolic ejection
dynamics are dependent on early active shortening of the free wall surface area and
septal to free wall distance and later, when the column of blood located in the out-
flow tract continues to flow into the pulmonary artery, due to the momentum of the
expelled blood and the normally highly compliant pulmonary vascular bed [51].
Figure 17.4 demonstrates these important features of RV contraction using mag-
netic resonance imaging in a patient with a previous left anterior descending coro-
nary artery occlusion with LV apical thinning but well preserved RV systolic
function. As described above, there is a very impressive RV free wall shortening
with marked translation of the tricuspid annulus and decrease in RV area from end-
diastole to end-systole, which is evident in the normal hearts, in hearts of marathon
runners, and in patients with well-preserved RV and LV function with isolated
Fig. 17.4 Magnetic resonance imaging in a patient with a previous left anterior descending artery
occlusion with LV apical thinning but well preserve RV systolic function. There is very impressive
RV free wall thickening with marked translation of the tricuspid annulus that is greater than that
of the LV
mitral regurgitation (Fig. 17.5). However, this RV free wall thickening and tricuspid
annular excursion is markedly reduced in a diffuse ischemic cardiomyopathy
(Fig. 17.6). These anatomic and functional features of RV ejection dynamics dem-
onstrate the utility of the echo/Doppler equivalents of RV function measured by RV
free wall area, tricuspid annular plane systolic excursion, and RV free wall strain
imaging which have been used in large scale studies to determine the prognostic
importance of RV function in left heart failure.
Even with the most advanced imaging techniques, the complex anatomy of the
RV still poses challenges that are not encountered when imaging the more sym-
metrical LV. It must be emphasized that multiple techniques have been utilized to
assess the impact of RV function on prognosis in left heart failure including echo-
cardiographic RV fractional area [19], tricuspid annular displacement [9, 17], and
RV free wall strain [43] and radionuclide RV ejection fraction [5, 11]. The nuclear
imaging technique is the method that has been widely utilized in many of the pub-
lished studies demonstrating the importance of RV function in left heart failure [5,
11]. The advantage of radionuclide angiographic techniques used to measure RV
ejection fraction is its geometry independence, but the weakness of this technique is
the right atrial overlap. However, it is important to appreciate the differences in RV
ejection fraction that can occur with various radionuclide imaging techniques.
Figure 17.7 demonstrates the inherent problems associated with the gated equilib-
rium and the first pass techniques with regard to the problem of anatomical right
atrial overlap with the RV chamber in the right anterior oblique and left anterior
Fig. 17.5 End diastolic imaged from the short axis and end-diastolic and end-systolic images from
four chamber below of normal, marathon runner, and mitral regurgitation subjects demonstrating
the differences in LV and RV remodeling in the marathon runner and mitral regurgitation subjects.
Note the elongation of the heart in the marathon runner and the sphericalization of the LV in the
mitral regurgitation LV. The RV function is well preserved with increased end-diastolic volume in
the marathon runner and RV free wall thickening and marked translation of the tricuspid annular
plane [159]. (with permission Schiros CG, Ahmed MI, Sanagala T, et al. Ventricular structural
remodeling in endurance athletes compared to patients with mitral regurgitation using magnetic
resonance imaging with three-dimensional analysis. Am J Cardiol. 2013;111(7):1067–1072.)
oblique projections (Fig. 17.7) [52]. Marving and coworkers compared RV ejection
fractions calculated from three approaches: (1) gated first pass fixed region of inter-
est, (2) gated first pass variable region of interest, and (3) gated equilibrium method
[52]. Methods 1 and 3 had a tendency to underestimate the RV ejection fraction,
probably resulting from inclusion of right atrial activity into the RV region of inter-
est at end-systole. However, LV ejection fraction is unaltered by any of the tech-
niques. Using cine-magnetic resonance imaging as the gold standard for RV ejection
fraction, we showed that a first pass 2-region of interest method or the first pass right
atrial subtracted single region of interest method are the most accurate methods for
assessing RV ejection fraction [53].
Fig. 17.6 Ischemic cardiomyopathy demonstrating inferior wall thinning and akinesis in the two
chamber image (far left). In the four chamber image (middle) there is lateral wall akinesis with RV
dilatation and markedly reduced RV free wall shortening and minimal tricuspid annular movement
from end-diastole to end-systole. In the short axis images there is RV dilatation with reduced free
wall thickening and severe LV systolic dysfunction. The LV inferior wall akinesis is also present
in the inferior portion of the interventricular septum
Fig. 17.7 First pass end-diastolic (a) and end-systolic (b) frames and gated equilibrium radionu-
clide angiographic images from end-diastole to end-systole (1–8) demonstrating the problem of
right atrial overlap with the RV chamber in each of the techniques. The fixed region technique with
first pass (white dots) and overlap with the equilibrium technique (arrows) demonstrate the contri-
bution of right atrial counts to end-systolic RV counts [52]. (with permission Marving J, Hoilund-
Carlsen PF, Chræmmer-jorgensen B, Gadsboll N. Are right and left ventricular ejection fractions
equal? Ejection fractions in normal subjects and in patients with first acute myocardial infarction.
Circulation. 1985;72(3):502–514.)
Right Ventricular Anatomy and Physiology
The reason for the important predictive capacity of RV function in the setting of left
heart failure may be obvious because the failure of both ventricles not surprisingly
results in a greater overall loss of function and decreased survival. However, at this
point it is important to review the great capability of the RV to maintain function in the
setting of ischemic heart disease. Protection from ischemic damage may also explain
the importance of the RV in predicting not only morbidity and mortality, but also
exercise capacity and response to biventricular pacing in LV systolic heart failure.
A description of the anatomy of the RV emphasizes the importance of the conus
in support of RV function. The muscle mass of the low pressure RV is approximately
one-sixth that of the high pressure LV. The thin-walled RV forms a crescent-shaped
chamber comprised of a sinus (body) and outflow tract which stand in stark contrast
to the ellipsoidal, concentric left ventricle. Both ventricles are bound together by
spiraling muscle bundles encircling both ventricles in a complex interlacing fashion
forming a functionally single unit. Of particular interest is the RV conus or outflow
tract, because of its mechanical advantage of circumferentially organized fibers and
its protection from ischemic injury due to the unique anatomy of the right coronary
circulation.
Already in 1924 the RV conus was recognized as being anatomically distinct
from the main portion of the RV [54]. In all developing vertebrate embryos, the
bulbus cordis is present as a separate chamber distal to the common ventricle but
disappears in the LV as development proceeds, whereas in the RV it remains to form
the infundibulum or outflow tract (see also Chap. 1). The muscle fibers of the conus
run in a parallel alignment from epicardium to endocardium in nine different mam-
malian species including man; while muscle fibers of the sinus or body of the RV
undergo a slow right angular directional change from epicardium to endocardium
and this fiber orientation is similar to that of the LV [44]. Both sinus and conus have
a similar wall thickness; however, the conus has a mechanical advantage over the
sinus because it has a smaller radius of curvature. Armour and coworkers have also
demonstrated that there exists an appreciable pressure drop from the sinus to the
conus portion during stellate stimulation in the anesthetized dog and that the lower
pressure in the conus section is transmitted to the pulmonary artery [44]. The ability
of the conus to function as a resistive element preventing the high sinus pressure
from reaching the pulmonary artery is easily appreciated given its anatomy. This
cylindrical structure is composed of parallel circumoral fibers resulting in a much
smaller radius of curvature and a greater wall thickness to radius when compared to
the thin-walled sinus. Consequently, the conus region has a lower wall stress for any
given pressure and is capably suited for absorbing and dissipating the high pressure
generated by the sinus. Therefore, there exists an architectural and functional sepa-
ration of the inflow and outflow tracts of the RV.
It is of interest that Schlesinger and coworkers reported a lower incidence of
occlusion of the conus artery than any other artery directly connected to the aorta
[55]. This feature, coupled with its location between the main left anterior descending
and right coronary arteries, explains its functional importance in supplying collateral
blood flow to these vessels with a much higher incidence of occlusion [56, 57].
In addition, the unique anatomic position of the conus artery arising close to the
ostium or as a separate ostium artery generally results in preservation of systolic
function of the RV outflow tract in patients with acute RV myocardial infarction,
because ostial occlusions of the right coronary artery are an infrequent occurrence.
In the setting of left heart failure it is tempting to speculate that the conus shortening
is important for the preservation of RV systolic function independent of the body of
the RV. In support of this hypothesis, RV outflow tract shortening by M-mode echo-
cardiography from the parasternal short axis view was shown to accurately separate
patients with normal and reduced RV function [58].
One of the more remarkable capacities of the RV is the well-documented recovery
of RV ejection fraction after RV myocardial infarction [59–61]. This unique feature
of the RV is even more impressive when taking into consideration that these studies
were performed before the widespread use of coronary reperfusion with either
thrombolytic therapy and percutaneous transluminal coronary angioplasty. In the
pig, the RV has a lower mitochondrial density and ratio of mitochondria:myofibrils
than that of the LV, which has a higher workload and greater myocardial oxygen
consumption (MVO2) [62]. RV oxygen extraction is difficult to measure in vivo
because the RV venous drainage is accomplished through a complex network of
Thebesian veins and five to seven anterior cardiac veins [63]; this complicates the
accurate assessment of the venous efflux from the RV. Nevertheless, cannulation of
the anterior cardiac veins and the coronary sinus in open-chest dogs showed that RV
myocardial oxygen consumption (MVO2) was approximately one-half that of the LV
and right coronary artery blood flow was lower than coronary blood flow in the left
anterior descending artery under baseline conditions [64]. Pacing, isoproterenol, and
methoxamine stress, resulted in an increase in the left anterior descending artery
flow with no increase in MVO2 in the LV; while in the RV these stresses resulted in
an increase in both right coronary artery blood flow as well as oxygen extraction.
Cardiac volume loading induced by creation of an arterio-venous shunt increased
RV MVO2 and augmented oxygen extraction in addition to a rise in right coronary
artery blood flow; while the increment in LV oxygen extraction was less than that in
the RV (31 vs. 54 %, p < 0.01) [65]. Other studies also demonstrate that RV oxygen
demand, blood flow rate and oxygen extraction are approximately one-half that of
the LV [66, 67]. These properties, combined with a higher coronary vasomotor tone
at baseline, explain the RV’s unique ability to increase oxygen extraction in response
to afterload and inotropic stress. These properties, however, are abolished in dogs
with RV hypertrophy caused by pulmonary artery banding (PAB) resulting in
responses which were indistinguishable from those of the LV [68].
The RV with its thinner wall and lower operating pressures offers other interest-
ing contrasts regarding coronary flow dynamics throughout the cardiac cycle, result-
ing in a systolic-diastolic flow ratio that is much greater in the coronary vessels that
perfuse the RV when compared to those that perfuse the LV [69–75]. Normal phasic
flow in the right and left coronary arteries has been extensively studied in the dog
using electromagnetic flow probes. This is a unique preparation because the canine
right coronary artery is a nondominant vessel which only supplies the RV free wall.
Systolic coronary artery flow commences rapidly in both arteries after opening of the
aortic valve producing an early peak which declines immediately to a higher plateau
throughout systole in the right coronary artery compared to the left coronary artery.
Subsequently, the level of flow in the right coronary artery during diastole remains
relatively constant in contrast to the rapidly declining diastolic flow in the left coro-
nary circulation. However, systolic flow was markedly reduced and was inversely
related to peak RV systolic pressure in dogs with congenital pulmonic stenosis.
In summary, low oxygen demands, the ability to extract more oxygen during
times of stress, and both systolic and diastolic coronary flow provide a greater
reserve of nutrients and oxygen during ischemia. These mechanisms may work in
concert to prevent irreversible ischemic damage to the RV in the setting of heart
failure due to ischemic heart disease. However, RV necrosis was markedly increased
in pigs after right coronary occlusion with a preexisting RV hypertrophy induced by
PAB [76]. This inherent protection from ischemic RV damage may be offset in
patients by any condition that causes RV hypertrophy due to chronic pulmonary
hypertension or results in a greater extent of coronary artery disease. It is of interest
that in a recent report, a reduction in RV ejection fraction to less than 40 % beyond
the first 30 days after an acute myocardial infarct predicted a three times higher
long-term mortality risk independent of other variables [77]. In another recent study
cMRI evidence of RV infarction after primary percutaneous coronary intervention
indicates a 16-fold higher risk of major adverse cardiac events and even more so in
patients with an anterior myocardial infarct [78]. Thus, the presence of more exten-
sive coronary artery disease may explain why there are some studies where RV
function is not predictive of exercise capacity in heart failure patients [79, 80]. It is
of further interest that in a large cohort of subjects in the Multi-Ethnic Study of
Atherosclerosis (MESA) study, RV hypertrophy measured by cMRI was associated
with the risk of heart failure or death in a multi-ethnic population free of clinical
cardiovascular disease at baseline [81]. It is tempting to speculate that RV hypertro-
phy may be an early indicator of increased LV end-diastolic pressure resulting from
LV systolic or diastolic dysfunction, which in turn increases RV pressure and wall
stress. This study underscores the importance of RV morphology as well as RV
ejection fraction in the complete assessment of the patient with heart failure.
There is mounting evidence for the importance of LV diastolic dysfunction in the
development of pulmonary hypertension in patients with heart failure and preserved
LV ejection fraction [12, 82, 83], which not surprisingly is exacerbated by the coex-
istence of mitral regurgitation [84]. Recent studies reinforce the concept that a com-
bined noninvasive echo-derived assessment of RV systolic function using tricuspid
annular plane systolic excursion and Doppler pulmonary systolic pressure is the
most sensitive and predictive index for prognosis of both patients presenting with
either reduced or preserved LV systolic function [85–87]. Figure 17.8 demonstrates
that the tricuspid annular plane systolic excursion vs. pulmonary artery systolic
pressure relationship shows a downshift of the regression line for non-survivors vs.
survivors. Further, the tricuspid annular plane systolic excursion vs. pulmonary
artery systolic pressure relationship quartiles distribution shows that this relation-
ship is shifted downward in non-survivors with a similar distribution in heart failure
Fig. 17.8 TAPSE vs. PASP

relationship and shows a
downshift of the regression
line for non-survivors vs.
survivors (a). Non-survivors
exhibited a more unfavorable
relationship having higher
PASP and lower TAPSE
values, respectively. HFrEF
and HFpEF (b) were
significantly different
(p = 0.009) despite a similar
distribution across the
respective TAPSE and
PASP. When patients were
separated according to
TAPSE </≥16 mm, a
downward shift occurred for
TAPSE <16 mm 184 group
with slope of the regression
significantly different
(p = 0.048) (c). No correlation
was found between TAPSE
and LV ejection fraction [87].
(with permission Guazzi M,
Bandera F, Pelissero G,
Castelvecchio S, Menicanti
L, Ghio S, Temporelli P,
Arena R. Tricuspid Annular
Systolic Excursion and
Pulmonary Systolic Pressure
Relationship in Heart Failure:
an Index of Right Ventricular
Contractility and Prognosis.
Am J Physiol. 2013 Aug 30.)
patients with reduced or preserved LV systolic function (Fig. 17.8). Taken together,
these recent studies emphasize that reduced RV function alone is not the crucial fac-
tor for the patient’s prognosis, but rather the coexistence with elevated pulmonary
systolic pressure is crucial for prognosis and survival in left heart failure. This infor-
mation now adds to the previous data demonstrating the independent prognostic
importance of both pulmonary systolic pressure and RV systolic function in left
heart failure and opens the question of how the low pressure RV pump responds to
increasing afterload at the level of the myocardium.
Characteristics of RV as a Pump
The thinner RV free wall and conus comprise a markedly different chamber geom-
etry that has one-sixth the mass and operates at volumes slightly greater than the
LV. At the chamber level, pressure–volume relationships from isolated hearts dem-
onstrate that the RV has greater chamber distensibility than the LV (see also Chap. 2)
[88, 89]. Since the right and left ventricles are comprised of the same interlacing
muscle fibers that encircle the heart, the greater distensibility reflects a necessary
functional difference of two pumps in series having equal stroke outputs but cou-
pled to markedly different vascular loads. Diastolic ventricular interaction is present
on a moment to moment and beat to beat basis especially during respiration; how-
ever, ventricular interaction is most apparent with acute changes in ventricular volume,
in particular, in the setting of an acute pulmonary embolus and after implantation of
an LV assist device, as demonstrated in Fig. 17.2 (see also Chap. 9).
The force opposing the shortening of muscle fibers, or afterload, is a major deter-
minant of myocardial performance in isolated muscle preparations and in the intact
heart. Pulmonary Impedance is a measure of the opposition to pulmonary artery
flow. Pulmonary input impedance measurements in normal animals [90–93] and
man [94–97] have consistently demonstrated a pulse wave velocity that was approx-
imately one-half that of the normal systemic circulation. This causes reflected pres-
sure waves to return later, after the pulmonic valve closure, and appears to offset the
shorter distances to reflecting sites in the pulmonary arteries so that the right and left
ventricles are optimally matched at physiologic heart rates. Figure 17.9 demonstrates
simultaneous tracings of the electrocardiogram, the first derivative of RV pressure
development (dP/dt), pulmonary artery flow velocity, and high-fidelity right ven-
tricular and pulmonary artery pressures in a normal subject [98]. The normal RV
pressure wave form has a low peak pressure which occurs early in systole and sub-
sequently drops off rapidly. The pre-ejection period (PEP) and RV ejection time
(RVET) aid in demonstrating minimal isovolumic contraction due to the low pul-
monary artery diastolic pressure and ejection of blood as the RV pressure is rapidly
declining. The observation of continued forward flow in the presence of, not only a
declining pressure, but also a negative pressure gradient, emphasizes the inability of
pressure measurements alone to define the mechanisms of RV-pulmonary artery
coupling because total RV afterload is comprised of resistive, capacitative, inertial,
Fig. 17.9 Simultaneously

recorded electrocardiogram
(ECG), RV analog signal of
pressure development (dP/
dt), phasic pulmonary artery
flow, pulmonary artery
pressure (PAP), and RV
pressure (RVP) in a human.
Vertical lines demonstrate the
PEP and RVET. The hangout
interval (HOI) represents the
time interval between the
pulmonary incisura and the
RV pressure wave form, due
to ejection into the very
compliant pulmonary
vasculature (see also Chap. 2)
[22]. (with permission
Dell’Italia LJ. Anatomy and
physiology of the right
ventricle. Cardiol Clin
2012;30:167–187.)
and pulse wave reflection properties of the pulmonary vasculature (see also Chap. 2).
In contrast, Fig. 17.10 demonstrates the response to acute pressure loading with
phenylephrine in humans without cardiovascular disease; RV pressure and flow
dynamics generate a longer period of isovolumic pressure which in part accounts
for a higher dP/dtmax. In addition, the earlier reflection of pressure waves produces a
more rounded RV pressure wave form with cessation of forward flow soon after the
peak pressure. Indeed, chronic [99, 100] RV hypertension in humans demonstrates
pressure and flow characteristics similar to those of the LV and aorta. In normal
subjects and in patients with chronic pulmonary hypertension, there is a linear
relationship between pulmonary artery pressure and peak + dP/dtmax [99].
Furthermore, high + RV dP/dtmax values have been noted in patients with pulmonary
hypertension despite clinical evidence of RV failure manifested by markedly ele-
vated right heart filling pressures, ascites, and peripheral edema [100]. Therefore,
values in the normal RV are low (100–250 mmHg/s) and do not provide a reliable
index of contractility because of the load dependency of peak + dP/dtmax.
As demonstrated above, the continuation of forward blood flow during a phase
of a rapidly declining pressure characterizes RV ejection dynamics in the presence
of a normal pulmonary circulation. The role of RV unloading in CHF remains
largely unexplored, despite the recognition that RV performance has both great
functional and prognostic importance in heart failure. As mentioned, early studies
demonstrated that the cardiac index increased to a greater extent with nitrate therapy
than during converting-enzyme inhibition, raising the question whether renin-
angiotensin system blockade has any direct effect on pulmonary vascular resistance
other than its unloading of the LV [37]. In contrast nitroprusside produced a balanced
Fig. 17.10 Simultaneous electrocardiogram (ECG), RV dP/dt, phasic pulmonary artery (PA) flow
velocity, and PA and RV pressure at low, medium, and high loading conditions produced by nitro-
prusside and phenylephrine infusion. The increase in RV pressure is accompanied by a higher dP/
dt, greater wave reflection, and increased isovolumic contraction time [22]. (with permission
Dell’Italia LJ. Anatomy and physiology of the right ventricle. Cardiol Clin 2012;30:167–187.)
unloading effect on the systemic circulation and the RV, manifested by a decrease in
pulmonary vascular resistance and a decrease in pulmonary artery compliance in
heart failure patients [36]. In addition, the amplitude of impedance oscillations was
less at higher nitrate doses, suggesting less wave reflection [101]. A recent study of
dogs with pacing-induced heart failure produced a profound increase of the RV
afterload (measured by pulmonary impedance) and RV systolic dysfunction that
was out of proportion to the estimated pulmonary vascular resistance or pulmonary
artery pressure [102]. This study underscores the potential effects of a subclinical
afterload on the RV that may not be apparent by standard hemodynamic monitoring
of pressures.
RV Diastolic Function in Heart Failure
All of the foregoing discussion supports the notion that the prognosis in heart failure
patients is heavily dependent on the adaptation of RV function to an increased after-
load. There are now numerous reports from clinical registries documenting the
importance of an increased right atrial pressure/pulmonary capillary wedge pres-
sure ratio for predicting an increased risk of adverse outcomes in patients with
advanced heart failure [103–105]. Some of the studies demonstrate further associa-
tions between higher pulmonary vascular resistance and reduced RV function mani-
fested by an enlarged right atrium and ventricle and a lower RV stroke work index
[105]. In the more extreme example of RV dysfunction in acute RV myocardial
infarction, an increase of the right atrial pressure/pulmonary capillary wedge pres-
sure ratio >0.8 is coincident with low cardiac output and RV systolic and diastolic
dysfunction (see also Chap. 9) [60, 106–109]. In a systematic and prospective study
of 53 patients with inferior myocardial infarction, the findings of both an elevated
jugular venous pressure (>8 cm H2O) and Kussmaul’s sign on physical examination
were the most sensitive (88 %) and specific (100 %) markers for hemodynamically
important RVMI by invasive hemodynamic recordings [110]. Taken together, a
simple physical examination that demonstrates an unequivocally normal or only
slightly elevated jugular venous pressure should suggest well-preserved RV systolic
function and a better prognosis in patients with CHF. Indeed, of the 7,788 partici-
pants in the Digitalis Investigation Group trial, 1,020 (13 %) had an elevated JVP at
baseline and in these patients the JVP was a marker of a higher burden of sickness
and poor outcomes [111].
Functionally, the RV is coupled to a highly compliant pulmonary vasculature and
the LV matched to a less compliant systemic circulation, encased within the pericar-
dium which does not expand significantly in response to sudden stresses. Because of
its greater distensibility, the RV can affect LV filling and chamber size with an acute
or chronic hemodynamic load as occurs in pulmonary embolus or chronic primary
pulmonary hypertension or in an acute RV myocardial infarction. However, the
effect of left heart failure on the diastolic interaction of the RV is less well defined.
Here again the biventricular effects of nitroglycerin and nitropusside are under-
scored in elegant studies of the right and left ventricular pressure–volume relation-
ship in humans. Several studies have demonstrated parallel downward shifts of the
LV diastolic pressure–volume relation in humans during nitroglycerin [112] or
nitroprusside [113, 114] infusions. However, amyl nitrite caused no downward dis-
placement of the LV diastolic pressure–volume relation when compared with nitro-
glycerin, which produced a similar reduction in mean arterial pressure but shifted
the pressure–volume relation downward [115]. This result was attributed to the fail-
ure of amyl nitrate to decrease RV diastolic pressure in contrast to the significant
decrease in RV filling pressure resulting from nitroglycerin infusion. On the other
hand, an increase in total systemic peripheral resistance has been shown to impose
an acute increase in afterload on the LV and RV and, through a mechanism of ven-
tricular interaction, resulting in a parallel upward shift of the RV diastolic pressure–
volume relationship [116]. In the intact circulation when acute alterations in arterial
and venous pressures affect all four heart chambers simultaneously and total cardiac
volume is varied, pericardial restraint is a mechanism mediating these changes in
passive diastolic properties of the ventricles. What cannot be gleaned from these
studies is the differential effect of these drugs on the pulmonary vascular load,
which in turn can affect RV diastolic filling pressures. There is now mounting inter-
est in drugs such as sildenafil in the treatment of left heart failure with the expressed
purpose of having a more direct effect on the pulmonary vascular afterload.
Therapy Targeted at Pulmonary Vascular Afterload

in Left Heart Failure
The importance of pulmonary artery hypertension was underscored by the findings

from a study that combined invasive hemodynamic monitoring with the assessment
of RV systolic function [9]. Despite optimal medical therapy, increased pulmonary
artery pressure and decreased RV systolic function portends a poor prognosis,
whereas a preserved RVEF implies a prognosis that is very similar to that of patients
with normal pulmonary artery pressure in patients with left heart failure. If the
assumption is that the RVEF can be improved with optimal afterload reduction, then
long-term prognosis and freedom from transplantation should be improved with
drugs more directly targeting the pulmonary vasculature [117, 118]. In fact, the
response of the RV to acute pulmonary vasodilation predicted the outcome in
patients with advanced heart failure and pulmonary hypertension [119]. In a recent
evaluation of patients enrolled in the Vasodilation in the Management of Acute
Congestive Heart Failure (VMAC) trial, the presence of reactive pulmonary hyper-
tension after maximal medical therapy with diuretics and vasodilators was associ-
ated with the most severe mortality rates (Fig. 17.11) [120]. Moreover, data from the
CHAMPION study recently showed that a therapeutic strategy based on the preven-
tion of a rising mean pulmonary artery pressure monitored by daily data capture of
an implanted device proved most successful to reduce HF hospitalizations [121].
Taken together, these studies underscore the importance of reactive pulmonary
hypertension, and the need to utilize drug therapy that specifically targets the pul-
monary vasculature [122].
Initial studies utilizing epoprostenol [123] and selective or dual endothelin recep-
tor antagonists [124] added to standard heart failure medical regimens failed to
change outcomes in patients with left heart failure. Phosphodiesterase 5 (PDE5) is
highly expressed in the lung, and this expression rises further in patients with pul-
monary vascular disease. Sildenafil induces vasorelaxation by blocking PDE5-
cGMP hydrolysis, raising cGMP levels in smooth muscle cells to activate protein
Fig. 17.11 Kaplan–Meier

survival curves according to
post-treatment pulmonary
hypertension categories
(comparison by log-rank test)
[120]. (with permission
Aronson D, Amon E, Dragu
R, Burger A. Relationship
between reactive pulmonary
hypertension and mortality in
patients with acute
decompensated heart failure.
Circ Heart Fail 2011;
4:644–650.)
kinase G. Thus, the first studies focused on the positive effects of acute and chronic
PDE5 inhibition on functional capacity and exercise capacity and quality of life
[125–128]. Guazzi and coworkers added significantly to these observations—
providing evidence that sildenafil also improves both LV systolic and diastolic func-
tion and reverses remodeling in patients with left heart failure when followed over
1 year (Fig. 17.8) [129]. As Kass points out in an editorial to this study, PDE5 was
thought to be largely expressed in selective vascular beds, in particular in the lung
vessels [130]. However, the improvement in LV remodeling and function is consis-
tent with emerging evidence that sildenafil reversed maladaptive cardiac remodeling
induced by sustained pressure overload in the mouse [131] and by chronic volume
overload of mitral regurgitation in the rat [132]. These studies suggest a direct effect
on the heart because there were minimal effects on ventricular loading.
The aforementioned studies have emphasized selective vasodilatory and perhaps
antiproliferative effects in regards the pulmonary vasculature, because of the lack of
significant PDE5 expression in the normal heart. However, data from the Michelakis
laboratory has demonstrated a marked increase in PDE5 mRNA and protein expres-
sion in the RV tissue from patients with RV hypertrophy due to a variety of clinical
conditions [133]. They further showed that PDE5 inhibition significantly increased
contractility, when measured in the perfused heart and in isolated cardiomyocytes
taken from monocrotaline induced hypertrophied RVs but not normal RVs. Taken
together, sildenafil may target both pulmonary vascular as well as right and left
ventricular remodeling and contractility in patients with left heart failure.
One proposed mechanism of increased contractility after PDE5 inhibition relates
to increased cyclic AMP [134]. Increased myocardial cAMP levels have been asso-
ciated with increased mortality, presumably due to ventricular arrhythmias [134].
However, PDE5 inhibitors have now been used for a number of years for the treat-
ment of pulmonary hypertension patients and there have been no reports of increased
mortality, ventricular arrhythmias, or cardiac-related deaths. The study to test the
effects of riociguat in patients with pulmonary hypertension associated with LV
systolic dysfunction (LEPHT) trial is a phase IIb, double-blind placebo controlled
trial enrolling patients with a LVEF ≤40 % and a mPAP ≥25 mm Hg at rest [135].
Although there was no significant reduction in the mean pulmonary artery pressure
with any of the three doses tested, the cardiac index increased without changes in
heart rate or systemic blood pressure, as there was a parallel decrease in systemic
and systemic vascular resistance in addition to an improvement in the quality of life
with the soluble guanylate cyclase inhibitor riociguat. The NIH-funded
(1U01HL105562-01A1) PITCH-HF (Phosphodiesterase Type 5 Inhibition with
Tadalafil Changes Outcomes in Heart Failure) trial will be the first clinical trial
powered to determine the effect of PDE5 inhibition on mortality and hospitaliza-
tions and on clinical outcomes in heart failure patients [136].
In the early 1990s, Bristow and coworkers reported β1-receptor down-regulation,
depletion of tissue norepinephrine, decreased adenylate cyclase basal activity, and a
decrease in the isoproterenol and forskolin stimulation of adenylate cyclase in both
RVs from patients with primary pulmonary hypertension and left heart failure [137].
Thus, β-adrenergic blockade would be expected to have the same beneficial effects
on the failing RV as in the LV in left heart failure. However, Simpson and Jensen
have reported a potentially interesting difference between the RV and LV that may
have clinical relevance for a targeted medical therapy. The normal RV inotropic
response to α-1 adrenergic receptors is switched from negative to positive in heart
failure RVs, via a pathway that leads to increased myofilament Ca2+ sensitivity [138,
139]. It is of interest that α1-ARs mediate a positive inotropic response in the neo-
natal mouse RV myocardium, in contrast to a negative inotropic response in the
nonfailing adult RV myocardium [140]. In addition, α1A- and α1b-AR density is not
downregulated in the failing LV and the α1A-AR demonstrate a similar distribution
and function in the human and mouse heart [141]. An increased α−1 AR inotropic
responses in the RV myocardium may be an adaptive response to increased pulmo-
nary pressures. Taken together, the RV α receptor may represent an important phar-
macological target in the treatment of right heart failure. More importantly, these
studies may explain why the nonselective beta-receptor blocker bucindolol had a
deleterious effect on outcomes in patients enrolled in the BEST trial who had an
RVEF less than 20 % [142, 143]. Possibly bucindolol’s α-receptor blocking—
combined with central sympatholytic properties may have removed the adrenergic
support necessary for patients with advanced heart failure.
Right Ventricular Adaptation to Altered Load
As demonstrated by the acute response to pressure overload in Fig. 17.10, the

marked differences in loading conditions and geometry in the normal state do not
prevent the RV chamber dynamics to respond in a manner similar to the LV pump
mechanics. In addition, studies in the isolated heart [144] and in humans [145, 146]
have demonstrated that the RV follows the construct of time-varying elastance,
thereby suggesting that the right and left ventricles behave as hydraulic pumps opti-
mally matched to their respective arterial loads. Recently, Borgdorff and coworkers
compared hemodynamics, exercise, and hypertrophy in rat models of pressure over-
load due to PAB, pressure overload due to PH, combined pressure and volume over-
load, and isolated volume load [147]. Figure 17.12 demonstrates that the adaptive
RV response depends on loading conditions and that the pressure–volume response
is similar to that of the LV to similar chronic loads; the RV demonstrates the con-
tractile properties of the end-systolic pressure–volume relationship and preload
recruitable stroke work [147]. Many of the early studies of pressure overload
induced cardiac hypertrophy were performed using a model of PAB in the cat in the
1960s and early 1970s (see also Chap. 22) [148–154]. As opposed to aortic generat-
ing LV pressure overload, the RV pressure overload of PAB does not change coro-
nary perfusion dynamics, thereby negating this important factor and allowing for
examination of the effects of pressure loading alone on the myocardium. The results
of these studies demonstrate that contractile performance of a unit mass of pressure
hypertrophied RV myocardium decreases before evidence of CHF. Future studies
must be performed to determine whether the molecular mechanisms involved in the
response to a chronic increase in afterload or preload are unique to the RV and
require novel treatment targets [155, 156].
Fig. 17.12 (a) Representative

RV pressure–volume loops
during vena cava occlusion
from controls (Con),
pulmonary hypertension (PH
from monocrotaline), PAB
and (b) from control, PH,
PH + aortocaval shunt, and
aortocaval shunt alone [147].
(with permission Borgdorff
MA, Bartelds B, Dickinson
MG, Steendijk P, de Vroomen
M, Berger RM. Distinct
loading conditions reveal
various patterns of right
ventricular adaptation. Am J
Physiol. 2013;305(3):
H354–H364.)
Summary
Normal RV myocardial and chamber dynamics respond in a manner similar to the

LV pump mechanics in response to acute and chronic load, despite the marked dif-
ferences in loading conditions and geometry. The independent prognostic impor-
tance of pulmonary hypertension and RV function in left heart failure has now been
well established and more recent data have demonstrated the added prognostic value
of both RV shortening matched to pulmonary artery systolic pressure in patients with
heart failure with decreased as well as preserved LV ejection fraction [157]. Future
evaluations of heart failure patients should include combined pulmonary artery pres-
sure and RV functional analysis with therapy targeting the pulmonary vasculature, in
addition to the conventional neurohormonal blockade. This is the logical next step
because the beneficial therapeutic effect of complete renin-angiotensin system com-
bined with beta-receptor blockade has reached a plateau and calls for new targets
[158]. The clinical trials targeting cyclic GMP are of great interest because of their
primary effect on the pulmonary vasculature as well as providing inotropic support
of the RV, which may also have a beneficial direct effect on LV function either
directly or through the mechanism of ventricular interaction. Taken further, RV mor-
phology and RV ejection fraction in addition to pulmonary artery pressure should be
evaluated early in the course of LV dysfunction. If the results of clinical trials with
cyclic GMP inhibitors prove positive, it is tempting to speculate that their implemen-
tation should not be reserved for late LV failure but that they rather should be
employed at an earlier time point to preserve a more normal RV-pulmonary vascular
coupling and to prevent adverse RV remodeling and failure.
References
after severe damage to the right ventricle of the dog, with a discussion of the relation between
clinical congestive failure and heart disease. Am Heart J. 1943;26:291–301.
2. Bakos AC. The question of the function of the right ventricular myocardium: an experimental
study. Circulation. 1950;1:724–31.
3. Kagan A. Dynamic responses of the right ventricle following extensive damage by cauteriza-
tion. Circulation. 1952;5:816–23.
4. Donald DE, Essex HE. Pressure studies after inactivation of the major portion of the canine
right ventricle. Am J Physiol. 1954;176:155–61.
5. Di Salvo TG, Mathier M, Semigran MJ, Dec GW. Preserved right ventricular ejection frac-
tion predicts exercise capacity and survival in advanced heart failure. J Am Coll Cardiol.
1995;25:1143–53.
6. Polak JF, Holman BL, Wynne J, Colucci WS. Right ventricular ejection fraction: an indicator
of increased mortality in patients with congestive heart failure associated with coronary
artery disease. J Am Coll Cardiol. 1983;2:217–24.
7. Juilliere Y, Barbier G, Feldmann L, et al. Additional predictive value of both left and right
ventricular ejection fractions on long-term survival in idiopathic dilated cardiomyopathy. Eur
Heart J. 1997;18:276–80.
8. de Groote P, Millaire A, Foucher-Hossein C, et al. Right ventricular ejection fraction is an
independent predictor of survival in patients with moderate heart failure. J Am Coll Cardiol.
1998;32:948–54.
9. Ghio S, Gavazzi A, Campana C, et al. Independent and additive prognostic value of right
ventricular systolic function and pulmonary artery pressure in patients with chronic heart
failure. J Am Coll Cardiol. 2001;37:183–8.
10. Gavazzi A, Berzuini C, Campana C, et al. Value of right ventricular ejection fraction in pre-
dicting short term prognosis of patients with severe chronic heart failure. J Heart Lung
Transplant. 1997;16:774–85.
11. Meyer P, Filippatos GS, Ahmed MI, et al. Effects of right ventricular ejection fraction on
outcomes in chronic systolic heart failure. Circulation. 2010;121:252–8.
12. Bursi F, McNallan SM, Redfield MM, et al. Pulmonary pressures and death in heart failure.
13. Desai RV, Meyer P, Ahmed MI, et al. Relationship between left and right ventricular ejection
fractions in chronic advanced systolic heart failure: insights from the BEST trial. Eur J Heart
Fail. 2011;13:392–7.
14. La Vecchia L, Paccanaro M, Bonanno C, Varotto L, Ometto R, Vincenzi M. Left ventricular
versus biventricular dysfunction in idiopathic dilated cardiomyopathy. Am J Cardiol. 1999;
83:120–2.
15. Gulati A, Ismail TF, Jabbour A, et al. The prevalence and prognostic significance of right
ventricular systolic dysfunction in non-ischemic dilated cardiomyopathy. Circulation. 2013;
128:1623–33.
16. Damy T, Ghio S, Rigby AS, Hittinger L, Jacobs S, Leyva F, Delgado JF, Daubert JC, Gras D,
Tavazzi L, Cleland JG. Interplay between right ventricular function and cardiac
resynchronization therapy: an analysis of the CARE-HF trial (Cardiac Resynchronization-
Heart Failure). J Am Coll Cardiol. 2013;61(21):2153–6.
17. Kjaergaard J, Ghio S, St. John Sutton M, Hassager C. Tricuspid annular plane systolic excur-
sion and response to cardiac resynchronization therapy: results from the REVERSE trial.
J Card Fail. 2011;17:100–7.
18. Lumens J, Ploux S, Strik M, Gorcsan 3rd J, Cochet H, Derval N, Strom M, Ramanathan C,
Ritter P, Haïssaguerre M, Jaïs P, Arts T, Delhaas T, Prinzen FW, Bordachar P. Comparative
electromechanical and hemodynamic effects of left ventricular and biventricular pacing in
dyssynchronous heart failure: electrical resynchronization versus left-right ventricular inter-
action. J Am Coll Cardiol. 2013;62:2395–403.
19. Campbell P, Takeuchi M, Bourgoun M, Shah A, Foster E, Brown MW, Goldenberg I, Huang
DT, McNitt S, Hall WJ, Moss A, Pfeffer MA, Solomon SD. Multicenter automatic defibrilla-
tor implantation trial with cardiac resynchronization therapy (MADIT-CRT) investigators.
Right ventricular function, pulmonary pressure estimation, and clinical outcomes in cardiac
resynchronization therapy. Circ Heart Fail. 2013;6(3):435–42.
20. Dell’Italia LJ, Santamore WP. Can indices of left ventricular function be applied to the right
ventricle? Prog Cardiovasc Dis. 1998;40:309–24.
butions to right ventricular systolic function. Prog Cardiovasc Dis. 1998;40:289–308.
22. Dell’Italia LJ. Anatomy and physiology of the right ventricle. Cardiol Clin. 2012;30:
167–87.
23. Hochreiter C, Niles N, Devereux RB, et al. Mitral regurgitation: relationship of noninvasive
descriptors of right and left ventricular performance to clinical and hemodynamic findings
and to prognosis in medically and surgically treated patients. Circulation. 1986;73(5):
900–12.
24. Borer JS, Hochreiter CA, Supino PG, Herrold EM, Krieger KH, Isom OW. Importance of
right ventricular performance measurement in selecting asymptomatic patients with mitral
regurgitation for valve surgery. Adv Cardiol. 2002;39:144–552.
25. Rosen SE, Borer JS, Hochreiter C, Supino P, Roman MJ, Devereux RB, Kligfield P, Bucek
J. Natural history of the asymptomatic/minimally symptomatic patient with severe mitral
regurgitation secondary to mitral valve prolapse and normal right and left ventricular perfor-
mance. Am J Cardiol. 1994;74(4):374–80.
26. Wencker D, Borer JS, Hochreiter C, et al. Preoperative predictors of late postoperative out-
come among patients with nonischemic mitral regurgitation with ‘high risk’ descriptors and
comparison with unoperated patients. Cardiology. 2000;93:37–42.
27. Barbieri A, Bursi F, Grigioni F, Tribouilloy C, Avierinos JF, Michelena HI, Rusinaru D,
Szymansky C, Russo A, Suri R, Bacchi Reggiani ML, Branzi A, Modena MG, Enriquez-
Sarano M. Mitral Regurgitation International DAtabase (MIDA) Investigators. Prognostic
and therapeutic implications of pulmonary hypertension complicating degenerative mitral
regurgitation due to flail leaflet: a multicenter long-term international study. Eur Heart
J. 2011;32(6):751–9.
28. Le Tourneau T, Richardson M, Juthier F, Modine T, Fayad G, Polge AS, Ennezat PV, Bauters
C, Vincentelli A, Deklunder G. Echocardiography predictors and prognostic value of pulmo-
nary artery systolic pressure in chronic organic mitral regurgitation. Heart. 2010;96(16):
1311–7.
29. Le Tourneau T, Deswarte G, Lamblin N, Foucher-Hossein C, Fayad G, Richardson M, Polge
AS, Vannesson C, Topilsky Y, Juthier F, Trochu JN, Enriquez-Sarano M, Bauters C. Right
ventricular systolic function in organic mitral regurgitation: impact of biventricular impair-
ment. Circulation. 2013;127(15):1597–608.
30. Bonow RO, Carabello BA, Chatterjee K, de Leon AC, Faxon Jr DP, Freed MD, Gaasch WH,
Lytle BW, Nishimura RA, O’Gara PT, O’Rourke RA, Otto CM, Shah PM, Shanewise JS.
2008 focused update incorporated into the ACC/AHA 2006 guidelines for the management
of patients with valvular heart disease: a report of the American College of Cardiology/
American Heart Association Task Force on Practice Guidelines (Writing Committee to revise
the 1998 guidelines for the management of patients with valvular heart disease). Endorsed by
the Society of Cardiovascular Anaesthesiologists, Society for Cardiovascular Angiography
and Interventions, and Society of Thoracic Surgeons. J Am Coll Cardiol. 2008;52:e1–142.
31. Joint Task Force on the Management of Valvular Heart Disease of the European Society of
Cardiology (ESC), European Association for Cardio-Thoracic Surgery (EACTS), Vahanian
A, Alfieri O, Andreotti F, Antunes MJ, Barón-Esquivias G, Baumgartner H, Borger MA,
Carrel TP, De Bonis M, Evangelista A, Falk V, Iung B, Lancellotti P, Pierard L, Price S,
Schäfers HJ, Schuler G, Stepinska J, Swedberg K, Takkenberg J, Von Oppell UO, Windecker
S, Zamorano JL, Zembala M. Guidelines on the management of valvular heart disease (ver-
sion 2012). Eur Heart J. 2012;33(19):2451–96.
32. Baker BJ, Wilen MM, Boyd CM, et al. Relation of right ventricular ejection fraction to exer-
cise capacity in chronic left ventricular failure. Am J Cardiol. 1984;54:596–9.
33. Leier CV, Huss P, Magorien RD, Unverferth DV. Improved exercise capacity and differing
arterial and venous tolerance during chronic isosorbide dinitrate therapy for congestive heart
failure. Circulation. 1983;67:817–22.
34. Franciosa JA, Baker BJ, Seth L. Pulmonary versus systemic hemodynamics in determining
exercise capacity of patients with chronic left ventricular failure. Am Heart J. 1985;110:
807–13.
35. Cohn JN, Archibald DG, Phil M, et al. Effect of vasodilator therapy on mortality in chronic
congestive heart failure. N Engl J Med. 1986;314:1547–52.
36. Yin FCP, Guzman PA, Brin KP, et al. Effect of nitroprusside on hydraulic vascular loads on
the right and left ventricle of patients with heart failure. Circulation. 1983;67:1330–9.
37. Packer M, Medina N, Yushak M, Lee WH. Comparative effects of captopril and isosorbide
dinitrate on pulmonary arteriolar resistance and right ventricular function in patients with
severe left ventricular failure: results of a randomized crossover study. Am Heart J. 1985;109:
1293–9.
38. Packer M, Lee WH, Medina N, Yushak M. Hemodynamic and clinical significance of the
pulmonary vascular response to long-term captopril therapy in patients with severe chronic
heart failure. J Am Coll Cardiol. 1985;6(3):635–45.
39. Colucci WS, Holman BL, Wynne J, et al. Improved right ventricular function and reduced
pulmonary vascular resistance during prazosin therapy of congestive heart failure. Am J Med.
1981;71:75–80.
40. Massie B, Kramer BL, Topic N, Henderson SG. Hemodynamic and radionuclide effects of
acute captopril therapy for heart failure: changes in left and right ventricular volumes and
function at rest and during exercise. Circulation. 1982;65(7):1374–81.
41. Konstam MA, Salem DN, Isner JM, et al. Vasodilator effect on right ventricular function in
congestive heart failure and pulmonary hypertension: end-systolic pressure-volume relation.
Am J Cardiol. 1984;54:132.
42. Konstam MA, Cohen SR, Salem DN, et al. Comparison of left and right ventricular end-
systolic pressure-volume relations in congestive heart failure. J Am Coll Cardiol. 1985;5:1326.
43. David Verhaert D, Mullens W, Borowski A, et al. Right ventricular response to intensive
medical therapy in advanced decompensated heart failure. Circ Heart Fail. 2012;3:340–6.
44. Armour JA, Randall WC. Structural basis for cardiac function. Am J Physiol. 1970;
218(6):1517–23.
45. Santamore WP, Meier GD, Bove AA. Effects of hemodynamic alterations on wall motion in
the canine right ventricle. Am J Physiol. 1979;236(2):H254–62.
46. Meier GD, Bove AA, Santamore WP, Lynch PR. Contractile function in canine right ventri-
cle. Am J Physiol. 1980;239:H794–804.
47. Raines RA, LeWinter MM, Covell JW. Regional shortening patterns in canine right ventricle.
Am J Physiol. 1976;231(5):1395–400.
48. Armour JA, Pace JB, Randall WC. Interrelationship of architecture and function of the right
ventricle. Am J Physiol. 1970;218(1):174–9.
49. Pace JB, Keefe WF, Armour JA, Randall WC. Influence of sympathetic nerve stimulation on
right ventricular outflow-tract pressures in anesthetized dogs. Circ Res. 1969;24:397–407.
50. Pouleur H, Lefèvre J, Mechelen HV, Charlier AA. Free-wall shortening and relaxation during
ejection in the canine right ventricle. Am J Physiol. 1980;239:H601–13.
51. Raizada V, Sahn DJ, Covell JW. Factors influencing late right ventricular ejection. Cardiovasc
Res. 1988;22:244–8.
52. Marving J, Hoilund-Carlsen PF, Chræmmer-jorgensen B, Gadsboll N. Are right and left ven-
tricular ejection fractions equal? Ejection fractions in normal subjects and in patients with
first acute myocardial infarction. Circulation. 1985;72(3):502–14.
53. Johnson LL, Lawson MA, Blackwell GG, Tauxe EL, Russell K, Dell’Italia LJ. Optimizing
the method to calculate RV ejection fraction from first pass data acquired using a multicrystal
camera. J Nucl Cardiol. 1995;2:372–9.
54. Keith A. Fate of the bulbus cordis in the human heart. Lancet. 1924;2:1267–73.
55. Schlesinger MJ, Zoll PN, Wessler S. The conus artery: a third coronary artery. Am Heart
J. 1949;38:823–36.
56. Levin DC, Beckmann CF, Garnic JD, et al. Frequency and clinical significance of failure to
visualize the conus artery during coronary arteriography. Circulation. 1981;63(4):833–7.
57. Adams J, Treasure T. Variable anatomy of the right coronary artery supply to the left ventri-
cle. Thorax. 1985;40:618–20.
58. Asmer I, Adawi S, Ganaeem M, Shehadeh J, Shiran A. Right ventricular outflow tract systolic
excursion: a novel echocardiographic parameter of right ventricular function. Eur Heart J
Cardiovasc Imaging. 2012;13:871–7.
59. Dell’Italia LJ, Lembo NJ, Starling MR, et al. Hemodynamically important right ventricular
infarction: follow-up evaluation of right ventricular systolic function at rest and during exercise
with radionuclide ventriculography and respiratory gas exchange. Circulation. 1987;75:996.
60. Dell’Italia LJ, Starling MR, Crawford MH, et al. Right ventricular infarction: identification
by hemodynamic measurements before and after volume loading and correlation with nonin-
vasive techniques. J Am Coll Cardiol. 1984;4:931.
61. Steele P, Kirch D, Ellis J, et al. Prompt return to normal of depressed right ventricular ejection
fraction in acute inferior infarction. Br Heart J. 1977;39:1319.
62. Singh SF, White FC, Bloor CM. Myocardial morphometric characteristics in swine. Circ Res.
1981;49:434–41.
63. Marchetti G, Merlo L, Noseda V. Coronary sinus outflow and O2 content in anterior cardiac
vein blood at different levels of right ventricle performance. Pflugers Arch. 1969;310:116–27.
64. Kusachi S, Nishiyama O, Yasuhara K, et al. Right and left ventricular oxygen metabolism in
open-chest dogs. Am J Physiol. 1982;243:H761–6.
65. Takeda K, Haraoka S, Nagashima H. Myocardial oxygen metabolism of the right ventricle
with volume loading and hypoperfusion. Jpn Circ J. 1987;51:563–72.
66. Saito D, Yamada N, Kusachi S, et al. Coronary flow reserve and oxygen metabolism of the
right ventricle. Jpn Circ J. 1989;53:1310–6.
67. Zong P, Tune JD, Downey HF. Mechanisms of oxygen demand/supply balance in the right
ventricle. Exp Biol Med (Maywood). 2005;230(8):507–19.
68. Saito D, Tani H, Kusachi S, et al. Oxygen metabolism of the hypertrophic right ventricle in
open chest dogs. Cardiovasc Res. 1991;25(9):731–9.
69. Kolin A, Ross G, Gaal P, et al. Simultaneous electromagnetic measurement of blood flow in
the major coronary arteries. Nature. 1964;203(4941):148–50.
70. Ross G. Blood flow in the right coronary artery of the dog. Cardiovasc Res. 1967;1:138–44.
71. Aukland K, Kiil F, Kjekshus J. Relationship between ventricular pressures and right and left
myocardial blood flow. Acta Physiol Scand. 1967;70:116–26.
72. Bellamy RF, Lowensohn HS. Effect of systole on coronary pressure-flow relations in the right
ventricle of the dog. Am J Physiol. 1980;238:H481–6.
73. Cross CE. Right ventricular pressure and coronary flow. Am J Physiol. 1962;202(1):12–6.
74. Hess DS, Bache RJ. Transmural right ventricular myocardial blood flow during systole in the
awake dog. Circ Res. 1979;45(1):88–94.
75. Lowensohn HS, Khouri EM, Gregg DE, et al. Phasic right coronary artery blood flow in con-
scious dogs with normal and elevated right ventricular pressures. Circ Res. 1976;39(6):760–6.
76. Peter RH, Ramo BW, Ratliff N, et al. Collateral vessel development after right ventricular
infarction in the pig. Am J Cardiol. 1972;29:56–60.
77. Larose E, Ganz P, Reynolds HG, Dorbala S, Di Carli MF, Brown KA, et al. Right ventricular
dysfunction assessed by cardiovascular magnetic resonance imaging predicts poor prognosis
late after myocardial infarction. J Am Coll Cardiol. 2007;49:855–62.
78. Jensen CJ, Jochims M, Hunold P, Sabin GV, Schlosser T, Bruder O. Right ventricular involve-
ment in acute left ventricular myocardial infarction: prognostic implications of MRI findings.
Am J Roentgenol. 2010;194:592–8.
79. Rubis P, Podolec P, Kopec G, et al. The dynamic assessment of right-ventricular function and
its relation to exercise capacity in heart failure. Eur J Heart Fail. 2010;12:260–7.
80. Clark AL, Swan JW, Laney R, et al. The role of right and left ventricular function in the ven-
tilator response to exercise in chronic heart failure. Circulation. 1994;89:2062–9.
81. Kawut SM, Barr RG, Lima JA, Praestgaard A, Johnson WC, Chahal H, Ogunyankin KO,
Bristow MR, Kizer JR, Tandri H, Bluemke DA. Right ventricular structure is associated with
the risk of heart failure and cardiovascular death: the Multi-Ethnic Study of Atherosclerosis
(MESA)-right ventricle study. Circulation. 2012;126:1681–8.
82. Lam CS, Roger VL, Rodeheffer RJ, Borlaug BA, Enders FT, Redfield MM. Pulmonary
hypertension in heart failure with preserved ejection fraction: a community-based study. J
Am Coll Cardiol. 2009;53:1119–26.
83. Leung CC, Moondra V, Catherwood E, Andrus BW. Prevalence and risk factors of pulmonary
hypertension in patients with elevated pulmonary venous pressure and preserved ejection
fraction. Am J Cardiol. 2010;106:284–6.
84. Maréchaux S, Neicu DV, Braun S, Richardson M, Delsart P, Bouabdallaoui N, Banfi C,
Gautier C, Graux P, Asseman P, Pibarot P, Le Jemtel TH, Ennezat PV, HFpEF Study Group.
Functional mitral regurgitation: a link to pulmonary hypertension in heart failure with pre-
served ejection fraction. J Card Fail. 2011;17:806–12.
85. Ghio S, Temporelli PL, Klersy C, Simioniuc A, Girardi B, Scelsi L, Rossi A, Cicoira M, Tarro
Genta F, Dini FL. Prognostic relevance of a non-invasive evaluation of right ventricular func-
tion and pulmonary artery pressure in patients with chronic heart failure. Eur J Heart Fail.
2013;15:408–14.
86. Damy T, Kallvikbacka-Bennett A, Goode K, Khaleva O, Lewinter C, Hobkirk J, Nikitin NP,
Dubois- Rande JL, Hittinger L, Clark AL, Cleland JG. Prevalence of, associations with, and
prognostic value of tricuspid annular plane systolic excursion (TAPSE) among out-patients
referred for the evaluation of heart failure. J Card Fail. 2012;18:216–25.
87. Guazzi M, Bandera F, Pelissero G, Castelvecchio S, Menicanti L, Ghio S, Temporelli P,
Arena R. Tricuspid annular systolic excursion and pulmonary systolic pressure relationship
in heart failure: an index of right ventricular contractility and prognosis. Am J Physiol.
2013;305:H1373–81.
88. Laks MM, Garner D, Swan HJC. Volumes and compliances measured simultaneously in the
right and left ventricles of the dog. Circ Res. 1967;20:565–9.
89. Taylor RR, Covell JW, Sonnenblick EH, Ross Jr J. Dependence of ventricular distensibility
on filling of the opposite ventricle. Am J Physiol. 1967;213:711–8.
90. Piene H. Pulmonary arterial impedance and right ventricular function. Physiol Rev.
1986;66(3):606–52.
91. van den Bos GC, Westerhof N, Randall OS. Pulse wave reflection: can it explain the differ-
ences between systemic and pulmonary pressure and flow waves? A study in dogs. Circ Res.
1982;51:479–85.
92. Bargainer JD. Pulse wave velocity in the main pulmonary artery of the dog. Circ Res.
1967;20:630–7.
93. Bergel DH, Milnor WR. Pulmonary vascular impedance in the dog. Circ Res. 1965;16(5):401–15.
94. Milnor WR, Conti CR, Lewis KB, O’Rourke MF. Pulmonary arterial pulse wave velocity and
impedance in man. Circ Res. 1969;25(6):637–49.
95. Murgo JP, Westerhof N. Input impedance of the pulmonary arterial system in normal man.
Effects of respiration and comparison to systemic impedance. Circ Res. 1984;54:666–73.
96. Caro CG, Harrison GK, Mognoni P. Pressure wave transmission in the human pulmonary
circulation. Cardiovasc Res. 1967;1:91–100.
97. Reuben SR. Wave transmission in the pulmonary arterial system in disease in man. Circ Res.
1970;27:523–9.
98. Dell’Italia LJ, Walsh RA. Acute determinants of the hangout interval in the pulmonary circu-
lation. Am Heart J. 1988;116:1289–97.
99. Gleason WL, Braunwald E. Studies on the first derivative of the ventricular pressure pulse in
man. J Clin Invest. 1962;41(1):80–91.
100. Stein PD, Sabbah HN, Anbe DT, et al. Performance of the failing and nonfailing right
ventricle of patients with pulmonary hypertension. Am J Cardiol. 1979;44:1050–5.
101. Kussmaul WG, Altschuler WH, Mathai WK, Laskey WK. Right ventricular-vascular interac-
tion in congestive heart failure. Importance of low-frequency impedance. Circulation.
1993;88:1010–5.
102. Pagnamenta A, Dewachter C, McEntee K, Fesler P, Brimioulle S, Naeije R. Early right
ventriculo-arterial uncoupling in borderline pulmonary hypertension on experimental heart
failure. J Appl Physiol. 2010;109:1080–5.
103. Drazner MH, Brown RN, Kaiser PA, Cabuay B, Lewis NP, Semigran MJ, Torre-Amione G,
Naftel DC, Kirklin JK. Relationship of right- and left-sided filling pressures in patients with
advanced heart failure: a 14-year multi-institutional analysis. J Heart Lung Transplant.
2012;31:67–72.
104. Campbell P, Drazner MH, Kato M, Lakdawala N, Palardy M, Nohria A, Stevenson
LW. Mismatch of right- and left-sided filling pressures in chronic heart failure. J Card Fail.
2011;17:561–8.
105. Drazner MH, Velez-Martinez M, Ayers CR, Reimold SC, Thibodeau JT, Mishkin JD,
Mammen PP, Markham DW, Patel CB. Relationship of right- to left-sided ventricular filling
pressures in advanced heart failure: insights from the ESCAPE trial. Circ Heart Fail.
2013;6:264–70.
106. Coma-Canella I, Lopez-Sendon J, Gamallo C. Low output syndrome in right ventricular
infarction. Am Heart J. 1979;98:613–20.
107. Lloyd EA, Gersh BJ, Kennelly BM. Hemodynamic spectrum of “dominant” right ventricular
infarction in 19 patients. Am J Cardiol. 1981;48:1016–22.
108. Jensen DP, Goolsby JP, Oliva PB. Hemodynamic pattern resembling pericardial construction
after acute inferior myocardial infarction with right ventricular infarction. Am J Cardiol.
1978;42:858–61.
109. Lopez-Sendon J, Coma-Cannella I, Gamallo C. Sensitivity and specificity of hemodynamic
criteria in the diagnosis of acute right ventricular infarction. Circulation. 1981;64:515–25.
110. Dell’Italia LJ, Starling MR, O’Rourke RA. Physical examination for exclusion of hemody-
namically important right ventricular infarction. Ann Intern Med. 1983;99:608–11.
111. Meyer P, Ekundayo OJ, Adamopoulos C, Mujib M, Aban I, White M, Aronow WS, Ahmed
A. A propensity-matched study of elevated jugular venous pressure and outcomes in chronic
heart failure. Am J Cardiol. 2009;103(6):839–44.
112. Ludbrook PA, Byrne JD, Kurnik PB, McKnight RC. Influence of reduction of preload and
afterload by nitroglycerin on left ventricular diastolic pressure-volume relations and relax-
ation in man. Circulation. 1977;56:937–43.
113. Alderman EL, Glantz SA. Acute hemodynamic interventions shift the diastolic
pressure-volume curve in man. Circulation. 1976;54:662–71.
114. Brodie BR, Grossman W, Mann R, McLaurin LP. Effects of sodium nitroprusside on left
ventricular diastolic pressure-volume relations. J Clin Invest. 1977;59:59–68.
115. Ludbrook PA, Byrne JD, Kurnik PB, et al. Influence of right ventricular hemodynamics on
left ventricular diastolic pressure-volume relations in man. Circulation. 1979;59:21–31.
116. Dell’Italia LJ, Walsh RA. Right ventricular diastolic pressure-volume relations and regional
dimensions during acute alterations in loading conditions. Circulation. 1988;77:1276–82.
117. DiSalvo TG. Pulmonary hypertension and right ventricular failure in left ventricular systolic
dysfunction. Curr Opin Cardiol. 2012;27:262–72.
118. Schmeisser A, Schroetter H, Vraun-Dulleaus RC. Management of pulmonary hypertension in
left heart disease. Ther Adv Cardiovasc Dis. 2013;7(3):131–51.
119. Gavazzi A, Ghio S, Scelsi L, Campana C, Klersy C, Serio A, Raineri C, Tavazzi L. Response
of the right ventricle to acute pulmonary vasodilation predicts the outcome in patients with
advanced heart failure and pulmonary hypertension. Am Heart J. 2003;145(2):310–6.
120. Aronson D, Amon E, Dragu R, Burger A. Relationship between reactive pulmonary hyper-
tension and mortality in patients with acute decompensated heart failure. Circ Heart Fail.
2011;4:644–50.
121. Abraham WT, Adamson PB, Bourge RC, et al. Wireless pulmonary artery haemodynamic
monitoring in chronic heart failure: a randomised controlled trial. Lancet. 2011;377:658–66.
122. Chatterjee NA, Lewis GD. What is the prognostic significance of pulmonary hypertension in
heart failure? Circ Heart Fail. 2011;4:541–5.
123. Califf RM, Adams KF, McKenna WJ, et al. A randomized controlled trial of epoprostenol
therapy for severe congestive heart failure: the Flolan International Randomized Survival
Trial (FIRST). Am Heart J. 1997;134:44–54.
124. Kalra PR, Moon JC, Coats AJ. Do results of the ENABLE (Endothelin Antagonist Bosentan
for Lowering Cardiac Events in Heart Failure) study spell the end for non-selective endothe-
lin antagonism in heart failure? Int J Cardiol. 2002;85:195–7.
125. Lewis GD, Lachmann J, Camuso J, et al. Sildenafil improves exercise hemodynamics and
oxygen uptake in patients with systolic heart failure. Circulation. 2007;115(1):59–66.
126. Guazzi M, Tumminello G, Di Marco F, Fiorentini C, Guazzi MD. The effects of phosphodi-
esterase-5 inhibition with sildenafil on pulmonary hemodynamics and diffusion capacity,
exercise ventilatory efficiency, and oxygen uptake kinetics in chronic heart failure. J Am Coll
Cardiol. 2004;44:2339–48.
127. Lewis GD, Shah R, Shahzad K. Sildenafil improves exercise capacity and quality of life in
patients with systolic heart failure and secondary pulmonary hypertension. Circulation.
2007;116(14):1555–62.
128. Guazzi M, Samaja M, Arena R, et al. Long-term use of sildenafil in the therapeutic manage-
ment of heart failure. J Am Coll Cardiol. 2007;50:2136–44.
129. Guazzi M, Vincenzi M, Arena R, Guazzi MD. PDE5-inhibition with sildenafil improves left
ventricular diastolic function, cardiac geometry, and clinical status in patients with stable
systolic heart failure: results of a 1-year prospective, randomized, placebo-controlled study.
Circ Heart Fail. 2011;4:8–17.
130. Kass DA. Res-erection of Viagra as a heart drug. Circ Heart Fail. 2011;4:2–4.
131. Takimoto E, Champion HC, Li M, Belardi D, Ren S, Rodriguez ER, Bedja D, Gabrielson KL,
Wang Y, Kass DA. Chronic inhibition of cyclic GMP phosphodiesterase 5A prevents and
reverses cardiac hypertrophy. Nat Med. 2005;11:214–22.
132. Kim KH, Kim YJ, Ohn JH, Yang J, Lee SE, Lee SW, Kim HK, Seo JW, Sohn DW. Long-term
effects of sildenafil in a rat model of chronic mitral regurgitation. Benefits of ventricular
remodeling and exercise capacity. Circulation. 2012;125(11):1390–401.
133. Nagendran J, Archer SL, Soliman D, Gurtu V, Moudgil R, Haromy A, St Aubin C, Webster L,
Rebeyka IM, Ross DB, Light PE, Dyck JR, Michelakis ED. Phosphodiesterase type 5 is
highly expressed in the hypertrophied human right ventricle, and acute inhibition of
phosphodiesterase type 5 improves contractility. Circulation. 2007;116(3):238–48.
134. DiBianco R, Shabetai R, Kostuk W, Moran J, Schlant RC, Wright R. A comparison of oral
milrinone, digoxin, and their combination in the treatment of patients with chronic heart
failure. N Engl J Med. 1989;320:677–83.
135. Ghio S, Bonderman D, Felix SB, et al. Left ventricular systolic dysfunction associated with
pulmonary hypertension riociguat trial (LEPHT): rationale and design. Eur J Heart Fail.
2012;14:946–53.
136. Late-Breaking Clinical Trial Abstracts. Circulation. 2012;126:2776–99.
137. Bristow MR, Minobe W, Rasmussen R, et al. Beta-adrenergic neuroeffector abnormalities in
the failing human heart are produced by local rather than systemic mechanisms. J Clin Invest.
1992;89(3):803–15.
138. Wang GY, McCloskey DT, Turcato S, et al. Contrasting inotropic responses to alpha1-
adrenergic receptor stimulation in left versus right ventricular myocardium. Am J Physiol.
2006;291:H2013–7.
139. Wang G-Y, Yeh C-C, Hensen BC, et al. Heart failure switches the RV α1-adrenergic inotropic
response from negative to positive. Am J Physiol. 2010;298:H213–20.
140. Tanaka H, Manita S, Matsuda T, et al. Sustained negative inotropism mediated by alpha-
adrenoceptors in adult mouse myocardia: developmental conversion from positive response
in the neonate. Br J Pharmacol. 1995;114:673–7.
141. Jensen BC, Swigart PM, De Marco T, et al. Alpha-1-adrenergic receptor subtypes in nonfail-
ing and failing human myocardium. Circ Heart Fail. 2009;2:654–63.
142. White M, Desai RV, Guichard JL, Mujib M, Aban IB, Ahmed MI, Feller MA, de Denus S,
Ahmed A. Bucindolol, systolic blood pressure, and outcomes in systolic heart failure: a pre-
specified post hoc analysis of BEST. Can J Cardiol. 2012;28(3):354–9.
143. Desai RV, Guichard JL, Mujib M, Ahmed MI, Feller MA, Fonarow GC, Meyer P, Iskandrian
AE, Bogaard HJ, White M, Aban IB, Aronow WS, Deedwania P, Waagstein F, Ahmed
A. Reduced right ventricular ejection fraction and increased mortality in chronic systolic
heart failure patients receiving beta-blockers: insights from the BEST trial. Int J Cardiol.
2013;163(1):61–7.
144. Maughan WL, Shoukas AA, Sagawa K, Weisfeldt ML. Instantaneous pressure-volume rela-
tionship of the canine right ventricle. Circ Res. 1979;44:309–15.
145. Dell’Italia LJ, Walsh RA. Application of a time varying elastance model to right ventricular
performance in man. Cardiovasc Res. 1988;22:864–74.
146. Brown KA, Ditchey RV. Human right ventricular end-systolic pressure-volume relation
defined by maximal elastance. Circulation. 1988;78:81–91.
147. Borgdorff MA, Bartelds B, Dickinson MG, Steendijk P, de Vroomen M, Berger RM. Distinct
loading conditions reveal various patterns of right ventricular adaptation. Am J Physiol.
2013;305(3):H354–64.
148. Spann Jr JF, Buccino RA, Sonnenblick EH, Braunwald E. Contractile state of cardiac muscle
obtained from cats with experimentally produced ventricular hypertrophy and heart failure.
Circ Res. 1967;21:341–54.
149. Cooper IV G, Satava Jr RM, Harrison CE, Coleman III HN. Mechanism for the abnormal
energetics of pressure-induced hypertrophy of cat myocardium. Circ Res. 1973;33:213–23.
150. Cooper IV G, Satava RM, Harrison CE, Coleman III HN. Normal myocardial function and
energetics after reversing pressure-overload hypertrophy. Am J Physiol. 1974;226(5):1158–65.
151. Gunning JF, Coleman III HN. Myocardial oxygen consumption during experimental hyper-
trophy and congestive heart failure. J Mol Cell Cardiol. 1973;5:25–38.
152. Bishop SP, Melsen LR. Myocardial necrosis, fibrosis, and DNA synthesis in experimental
cardiac hypertrophy induced by sudden pressure overload. Clin Res. 1976;39(2):238–45.
153. Cooper IV G, Tomanek RJ, Ehrhardt JC, Marcus ML. Chronic progressive pressure overload
of the cat right ventricle. Circ Res. 1981;48(4):488–97.
154. Cooper IV G, Marino TA. Complete reversibility of cat right ventricular chronic progressive
pressure overload. Circ Res. 1984;54:323–31.
155. Drake JI, Gomez-Arroyo J, Dumur CI, Kraskauskas D, Natarajan R, Bogaard HJ, Fawcett P,
Voelkel NF. Chronic carvedilol treatment partially reverses the right ventricular failure tran-
scriptional profile in experimental pulmonary hypertension. Physiol Genomics.
2013;45(12):449–61.
156. Bogaard HJ, Natarajan R, Mizuno S, Abbate A, Chang PJ, Chau VQ, Hoke NN, Kraskauskas
D, Kasper M, Salloum FN, Voelkel NF. Adrenergic receptor blockade reverses right heart
remodeling and dysfunction in pulmonary hypertensive rats. Am J Respir Crit Care Med.
2010;182(5):652–60.
157. Kalogeropoulos AP, Georgiopoulou VV, Borlaug BA, Gheorghiade M, Butler J. Left ven-
tricular dysfunction with pulmonary hypertension: part 2: prognosis, noninvasive evaluation,
treatment, and future research. Circ Heart Fail. 2013;6:584–93.
158. Dell’Italia LJ. Translational success stories: angiotensin II receptor blockers in CHF. Circ
Res. 2011;109:437–52.
159. Schiros CG, Ahmed MI, Sanagala T, et al. Ventricular structural remodeling in endurance
athletes compared to patients with mitral regurgitation using magnetic resonance imaging
with 3-dimensional analysis. Am J Cardiol. 2013;111(7):1067–72.
Chapter 18
The Right Ventricle in Chronic Lung Diseases
Norbert F. Voelkel and Otto C. Burghuber
COPD/Emphysema
Ever since the description of the lung vessel pathology in COPD/emphysema

patients by Averill Liebow [1] and the characterization of the hemodynamic
response of COPD patients to exercise by Burrows et al. [2], the overall importance
of pulmonary hypertension and the structural pulmonary vascular abnormalities for
the prognosis and outcome of COPD patients has been discussed [3–8]. Whereas in
these early years pulmonary hypertension had been identified as a consequence of
hypoxic vasoconstriction and impaired cardiac function as a consequence of lung
hyperinflation (the causes of “cor pulmonale” have been scholarly reviewed in [9]),
more recently, pulmonary vascular remodeling and lung vessel endothelial cell dys-
function have been documented in non-hypoxemic smokers [10] and right ventricu-
lar dysfunction in COPD patients that have had no resting pulmonary hypertension
[11]. MacNee in his two part review [3] concluded that “cor pulmonale” was a
complex syndrome of many causes. Barr et al. [12] in their large MESA cohort
showed that the percent of emphysematous lung tissue destruction correlated with
smaller LV volumes (LVEDV, LVESV, SV), less CO and LV mass but preserved left
ventricular ejection fraction (EF%) and Grau et al. [13] found that the percent of
emphysema was associated with smaller RV volumes and a lower RV mass—both,
likely as an effect of pulmonary hyperinflation. In contrast, Hilde and the group
N.F. Voelkel, M.D. (*)

O.C. Burghuber, M.D.
Department of Respiratory and Critical Care Medicine, Otto Wagner Hospital,
Bastiengasse 78, Vienna 1180, Austria
e-mail: burghuber@me.com

392 N.F. Voelkel and O.C. Burghuber
Fig. 18.1 Right ventricular

isovolumetric acceleration
(RVIVA), right ventricular
basal strain, and right
ventricular myocardial
performance index (RVMPI)
are increased in COPD
patients without pulmonary
hypertension as assessed
during right heart
catheterization at rest
(reproduced with permission
from Hilde et al. [11])
from the University Hospital in Oslo, Norway [11], found an increase in RV wall
thickness and increased RV basal strain in their cohort of COPD patients that had a
significant smoking history, and air trapping but no PAH at rest [14] (Fig. 18.1).
Many of these patients also had a reduced pulmonary artery compliance. These
authors suggest that RV functional changes start early in the course of chronic pul-
monary obstructive disease and occur with relatively low levels of pulmonary artery
pressures but reduced pulmonary artery compliance. The same group of investiga-
tors also examined the hemodynamic response of a group of COPD patients (n = 98)
to exercise, and they concluded that the majority of patients without PAH at rest
showed a significant increase in the pulmonary artery pressure during exercise [15]
18 The Right Ventricle in Chronic Lung Diseases 393
Fig. 18.2 Schematic illustration of the effect of similar intrathoracic pressures (blue arrows) on
right atrial (RA) filling, RV filling, and the pulmonary artery pressure in a situation of either a low
(a) or high (b) right atrial pressure. When RAP is low, the positive intrathoracic pressure during
expiration leads to an impaired venous return and a variation in RV filling and stroke volume dur-
ing the respiratory cycle. When RAP pressure is high, the right atrium acts as a reservoir which
maintains RV filling and ensures a stable pulmonary artery pulse pressure and RV stroke volume
during expiration
confirming Burrows’ findings [2]. Thus, it continues to be difficult to prove that RV

impairment in these COPD patients is afterload independent, and the take home
message ever since Burrows studies [2] remains that most COPD patients develop
symptoms during mild to moderate exercise and that the hemodynamic impairment
and dyspnea, as part of the CODP syndrome, cannot be fully understood, unless the
cardiovascular response of any given patient is assessed during exercise [16, 17].
The exercise limitation introduced by severe air trapping (auto-PEEP or dynamic
hyperinflation) is most intuitive [18] (Fig. 18.2), yet preload and afterload indepen-
dent mechanisms of RV dysfunction are largely unexplored. The effect of exercise
on pulmonary artery compliance has recently been evaluated [17], and we have
postulated that “bad humor” released from the sick lung circulation, and mediators
of systemic inflammation may also contribute to the impaired RV and LV dysfunc-
tion in patients with COPD/emphysema [19]. The “sick lung circulation” concept,
as it may apply to patients with severe COPD/emphysema, posits that cell fragments
(RNA containing microparticles) and mediators of inflammation are released from
activated and injured cells of the lung circulation. These biologically active compo-
nents impact the myocardial microcirculation, and damage the endothelium of the
heart (Fig. 18.3) (see also Chap. 14). Such a mechanism would provide a new mech-
anistic explanation of the pathobiology of “cor pulmonale.” Unfortunately there are
Fig. 18.3 This concept

illustrates in the form of a
flow diagram how circulating
factors, “bad humors,” can
affect the microcirculation of
the heart and contribute to the
pathobiology of cor
pulmonale (reproduced with
permission from Voelkel et al.
[19])
no published data in support of this concept. A histological examination and the

application of modern immunohistochemistry technique are presently lacking.
However this novel hypothesis is now discussed in the context of heart failure with
preserved ejection fraction (HFPEF) and in this setting coronary microvascular
endothelial cell inflammation has been proposed [20]. The heart of patients with
COPD/emphysema has so far escaped the probing interest of the pathologist, while
there is little doubt that both RV and LV function are impaired in severe COPD
patients [21–25].
Pulmonary Fibrosis
Echocardiographic and hemodynamic studies have recently been conducted to assess

the RV function in idiopathic pulmonary fibrosis [26]. In a retrospective cohort study
of 135 IPF patients (FVC 51 % of predicted and DLCO 39 % of predicted), the
RVSP for the cohort was 47 ± 18 mmHg and the CI 2.9 ± 0.5; 13 % of the patients had
a moderately or severely dilated right atrium and 11 % a moderate to severe degree
of RV dysfunction. Patients with a TAPSE < 1.6 cm had a worse survival (Fig. 18.4).
The authors concluded that right-sided heart dysfunction was more strongly associ-
ated with outcome than the Pa pressure [26]. A study of 25 IFP patients with associ-
ated PAH from the Cleveland clinic concluded that noninvasive tests such as
Fig. 18.4 The survival of

patients with idiopathic
pulmonary fibrosis (IPF) is
determined by the right heart
function as
echocardiographically
assessed. TAPSE tricuspid
annular plane systolic
excursion (reproduced with
permission from Rivera-
Lebron et al. [26])
echocardiography and the 6 MW distance performed poorly in detecting PAH in IPF

patients. Right heart catheterization revealed that their patients had a mean Pap of
33 ± 8 mmHg and, unfortunately, parameters of right or left heart function were not
evaluated [27].
Little information of cardiac MRI studies in patients with pulmonary fibrosis
exists, with the exception of studies that have examined patients with systemic
sclerosis [28–33] many of which have a pulmonary fibrosis disease component. In
scleroderma patients with and without interstitial lung disease, with and without
pulmonary vascular involvement, fibrosis and microvessel disease of the heart can
be present. In patients with sarcoidosis pulmonary vascular disease and pulmonary
hypertension can affect the performance of the RV and cardiac MRI is useful to
assess or rule out cardiac sarcoidosis as another cause of RVF [34].
The recently described entity of upper lobe emphysema, lower lobe fibrosis,
hypoxemia, dyspnea, and highly prevalent pulmonary hypertension (“The syn-
drome of combined pulmonary fibrosis and emphysema”; [35–37]) is receiving
more and more attention because of its poor prognosis. A low value for TAPSE of
11 mm has been reported in a 76-year-old man who hemodynamically improved
after treatment with an endothelin receptor blocker plus a PDE 5 inhibitor [38]; a
systematic evaluation of RV function in these patients is still lacking.
Cystic Fibrosis
Right ventricular function in patients with cystic fibrosis with and without PAH has
been examined repeatedly by measuring RVEF [38, 39] or echocardiography vari-
ables [40, 41] The consensus of these studies appears to be that there is an impairment
of RV function (a decreased RVEF) in patients with significant PAH; a recent study
from Spain of 37 cystic fibrosis patients concluded that RV functional abnormalities

may already be present at early stages of the disease [41], a similar conclusion as the
one reached by Hilde et al. [11] after investigating RF function in COPD patients
without resting PAH.
Many clinicians over the years had conceptual difficulties to explain for them-
selves and to their students “cor pulmonale” as a consequence of pulmonary
hypertension alone [9], in part because of the frequently acknowledged associated
LV dysfunction. COPD, cystic fibrosis, and interstitial fibrosis have as one com-
mon denominator lung inflammation and a “sick lung circulation,” thus an inflam-
mation concept of “cor pulmonale” appears now more attractive than an RV
afterload hypothesis. An inflammation-related hypothesis [42] of RV dysfunction
could even accommodate the results of a single center study of 51 children with
asthma; these investigators used tissue Doppler echocardiography to demonstrate
subclinical RV dysfunction [43]. Lastly, we would predict that radiation therapy,
resulting in lung and heart tissue irradiation [44, 45] causing profound oxidative
stress and inflammation (pneumonitis and myocardial injury) would impact not
only LV but also RV function.
Treatment
Every so often the question is raised whether patients with cor pulmonale should
receive therapy that targets pulmonary hypertension [46–49]. The opinions vary
from nihilism to individualized treatment strategies. The late David Flenley had
famously quipped: “patients with COPD die with cor pulmonale, not from it.”
A recent meta-analysis of COPD patients treated with pulmonary hypertension tar-
geting therapy concluded that pulmonary hypertension directed treatments have a
significant effect in improving exercise capacity in COPD patients with pulmonary
hypertension [50]. Yet whether or not pulmonary hypertension targeting therapy is
efficacious in patients with COPD remains controversial [51, 52] and the therapy of
the underlying disease is still the only recommended option as outlined in the man-
agement guidelines of COPD [53]; generally evidence of improved RV function
after vasodilator therapy has been lacking.
References
1. Liebow AA. Pulmonary emphysema with special reference to vascular changes. Am Rev
Respir Dis. 1959;80(1 Pt 2):67–93.
2. Burrows B, Kettel LJ, Niden AH, Rabinowitz M, Diener CF. Patterns of cardiovascular dys-
function in chronic obstructive lung disease. N Engl J Med. 1972;286(17):912–8.
3. MacNee W. Pathophysiology of cor pulmonale in chronic obstructive pulmonary disease. Part
one. Am J Respir Crit Care Med. 1994;150(3):833–52.
4. Kubo K, Ge RL, Koizumi T, Fujimoto K, Yamanda T, Haniuda M, et al. Pulmonary artery
remodeling modifies pulmonary hypertension during exercise in severe emphysema. Respir
Physiol. 2000;120(1):71–9.
5. Naeije R. Pulmonary hypertension and right heart failure in chronic obstructive pulmonary
disease. Proc Am Thorac Soc. 2005;2(1):20–2.
6. Falk JA, Kadiev S, Criner GJ, Scharf SM, Minai OA, Diaz P. Cardiac disease in chronic
obstructive pulmonary disease. Proc Am Thorac Soc. 2008;5(4):543–8.
7. Chaouat A, Naeije R, Weitzenblum E. Pulmonary hypertension in COPD. Eur Respir
J. 2008;32(5):1371–85.
8. Minai OA, Chaouat A, Adnot S. Pulmonary hypertension in COPD: epidemiology, signifi-
cance, and management: pulmonary vascular disease: the global perspective. Chest. 2010;137
(6 Suppl):39S–51.
9. Voelkel NF, Cool CD. Pulmonary vascular involvement in chronic obstructive pulmonary dis-
ease. Eur Respir J Suppl. 2003;46:28s–32.
10. Barbera JA. Mechanisms of development of chronic obstructive pulmonary disease-associated
pulmonary hypertension. Pulm Circ. 2013;3(1):160–4.
11. Hilde JM, Skjorten I, Grotta OJ, Hansteen V, Melsom MN, Hisdal J, et al. Right ventricular
dysfunction and remodeling in chronic obstructive pulmonary disease without pulmonary
12. Barr RG, Bluemke DA, Ahmed FS, Carr JJ, Enright PL, Hoffman EA, et al. Percent emphysema,
airflow obstruction, and impaired left ventricular filling. N Engl J Med. 2010;362(3):217–27.
13. Grau M, Barr RG, Lima JA, Hoffman EA, Bluemke DA, Carr JJ, et al. Percent emphysema and
right ventricular structure and function: the Multi-Ethnic Study of Atherosclerosis-Lung and
Multi-Ethnic Study of Atherosclerosis-Right Ventricle Studies. Chest. 2013;144(1):136–44.
14. Liu C, Jiang R, Dashnaw S, et al. Pulmonary artery stiffness in chronic obstructive pulmonary
disease (COPD)—the MESA COPD study. J Cardiovasc Magn Reson. 2011;13 Suppl 1:73.
15. Hilde JM, Skjorten I, Hansteen V, Melsom MN, Hisdal J, Humerfelt S, et al. Haemodynamic
responses to exercise in patients with COPD. Eur Respir J. 2013;41(5):1031–41.
16. Hickam JB, Cargill WH. Effect of exercise on cardiac output and pulmonary arterial pressure
in normal persons and in patients with cardiovascular disease and pulmonary emphysema. J
Clin Invest. 1948;27(1):10–23.
17. Lewis GD, Bossone E, Naeije R, Grunig E, Saggar R, Lancellotti P, et al. Pulmonary vascular
hemodynamic response to exercise in cardiopulmonary diseases. Circulation.
2013;128(13):1470–9.
18. Boerrigter B, Trip P, Bogaard HJ, Groepenhoff H, Oosterveer F, Westerhof N, et al. Right atrial
pressure affects the interaction between lung mechanics and right ventricular function in spon-
taneously breathing COPD patients. PLoS One. 2012;7(1):e30208.
19. Voelkel NF, Natarajan R, Drake JI, Bogaard HJ. Right ventricle in pulmonary hypertension.
Compr Physiol. 2011;1:595–610.
20. Paulus WJ, Tschope C. A novel paradigm for heart failure with preserved ejection fraction:
comorbidities drive myocardial dysfunction and remodeling through coronary microvascular
endothelial inflammation. J Am Coll Cardiol. 2013;62(4):263–71.
21. Mahler DA, Brent BN, Loke J, Zaret BL, Matthay RA. Right ventricular performance and
central circulatory hemodynamics during upright exercise in patients with chronic obstructive
pulmonary disease. Am Rev Respir Dis. 1984;130(5):722–9.
22. Render ML, Weinstein AS, Blaustein AS. Left ventricular dysfunction in deteriorating patients
with chronic obstructive pulmonary disease. Chest. 1995;107(1):162–8.
23. Funk GC, Lang I, Schenk P, Valipour A, Hartl S, Burghuber OC. Left ventricular diastolic
dysfunction in patients with COPD in the presence and absence of elevated pulmonary arterial
pressure. Chest. 2008;133(6):1354–9.
24. Agarwal SK, Heiss G, Barr RG, Chang PP, Loehr LR, Chambless LE, et al. Airflow obstruc-
tion, lung function, and risk of incident heart failure: the Atherosclerosis Risk in Communities
(ARIC) study. Eur J Heart Fail. 2012;14(4):414–22.
25. Watz H, Waschki B, Meyer T, Kretschmar G, Kirsten A, Claussen M, et al. Decreasing cardiac
chamber sizes and associated heart dysfunction in COPD: role of hyperinflation. Chest.
2010;138(1):32–8.
26. Rivera-Lebron BN, Forfia PR, Kreider M, Lee JC, Holmes JH, Kawut SM. Echocardiographic
and hemodynamic predictors of mortality in idiopathic pulmonary fibrosis. Chest.
2013;144(2):564–70.
27. Modrykamien AM, Gudavalli R, McCarthy K, Parambil J. Echocardiography, 6-minute walk
distance, and distance-saturation product as predictors of pulmonary arterial hypertension in
idiopathic pulmonary fibrosis. Respir Care. 2010;55(5):584–8.
28. Garau P, Vacca A, Calvisi S, Matta G, De Candia G, Cauli A, et al. The growing role of cardiac
magnetic resonance imaging in assessment and follow-up of pulmonary arterial hypertension
associated with systemic sclerosis. Semin Arthritis Rheum. 2012;41(4):e7–8.
29. Skrok J, Shehata ML, Mathai S, Girgis RE, Zaiman A, Mudd JO, et al. Pulmonary arterial
hypertension: MR imaging-derived first-pass bolus kinetic parameters are biomarkers for pul-
monary hemodynamics, cardiac function, and ventricular remodeling. Radiology.
2012;263(3):678–87.
30. Dinser R, Frerix M, Meier FM, Klingel K, Rolf A. Endocardial and myocardial involvement
in systemic sclerosis—is there a relevant inflammatory component? Joint Bone Spine.
2013;80(3):320–3.
31. Tzelepis GE, Kelekis NL, Plastiras SC, Mitseas P, Economopoulos N, Kampolis C, et al.
Pattern and distribution of myocardial fibrosis in systemic sclerosis: a delayed enhanced mag-
netic resonance imaging study. Arthritis Rheum. 2007;56(11):3827–36.
32. Di Cesare E, Battisti S, Di Sibio A, Cipriani P, Giacomelli R, Liakouli V, et al. Early assess-
ment of sub-clinical cardiac involvement in systemic sclerosis (SSc) using delayed enhance-
ment cardiac magnetic resonance (CE-MRI). Eur J Radiol. 2013;82(6):e268–73.
33. Vogel-Claussen J, Skrok J, Shehata ML, Singh S, Sibley CT, Boyce DM, et al. Right and left
ventricular myocardial perfusion reserves correlate with right ventricular function and pulmo-
nary hemodynamics in patients with pulmonary arterial hypertension. Radiology.
2011;258(1):119–27.
34. Lonborg J, Ward M, Gill A, Grieve SM, Figtree GA. Utility of cardiac magnetic resonance in
assessing right-sided heart failure in sarcoidosis. BMC Med Imaging. 2013;13:2.
35. Cottin V, Cordier JF. The syndrome of combined pulmonary fibrosis and emphysema. Chest.
2009;136(1):1–2.
36. Cottin V, Nunes H, Brillet PY, Delaval P, Devouassoux G, Tillie-Leblond I, et al. Combined
pulmonary fibrosis and emphysema: a distinct underrecognised entity. Eur Respir
J. 2005;26(4):586–93.
37. Kitaguchi Y, Fujimoto K, Hanaoka M, Kawakami S, Honda T, Kubo K. Clinical characteristics
of combined pulmonary fibrosis and emphysema. Respirology. 2010;15(2):265–71.
38. Mercurio V, Carlomagno G, Fazio S. Response to pulmonary vasodilator treatment in a former
smoker with combined interstitial lung disease complicated by pulmonary hypertension: case
report and review of the literature. Heart Lung. 2011;45(5):512–7.
39. Burghuber OC, Salzer-Muhar U, Bergmann H, Gotz M. Right ventricular performance and
pulmonary haemodynamics in adolescent and adult patients with cystic fibrosis. Eur J Pediatr.
1988;148(3):187–92.
40. Hirschfeld SS, Fleming DG, Doershuk C, Liebman J. Echocardiographic abnormalities in
patients with cystic fibrosis. Chest. 1979;75(3):351–5.
41. Bano-Rodrigo A, Salcedo-Posadas A, Villa-Asensi JR, Tamariz-Martel A, Lopez-Neyra A,
Blanco-Iglesias E. Right ventricular dysfunction in adolescents with mild cystic fibrosis.
J Cyst Fibros. 2012;11(4):274–80.
42. Gonzalez A, Ravassa S, Beaumont J, Lopez B, Diez J. New targets to treat the structural
remodeling of the myocardium. J Am Coll Cardiol. 2011;58(18):1833–43.
43. Ozdemir O, Ceylan Y, Razi CH, Ceylan O, Andiran N. Assessment of ventricular functions by
tissue Doppler echocardiography in children with asthma. Pediatr Cardiol.
2013;34(3):553–9.
44. Ghobadi G, van der Veen S, Bartelds B, de Boer RA, Dickinson MG, de Jong JR, et al.
Physiological interaction of heart and lung in thoracic irradiation. Int J Radiat Oncol Biol
Phys. 2012;84(5):e639–46.
45. Bradley J, Graham MV, Winter K, Purdy JA, Komaki R, Roa WH, et al. Toxicity and outcome
results of RTOG 9311: a phase I-II dose-escalation study using three-dimensional conformal
radiotherapy in patients with inoperable non-small-cell lung carcinoma. Int J Radiat Oncol
Biol Phys. 2005;61(2):318–28.
46. Ferrer MI, Harvey RM, et al. Some effects of digoxin upon the heart and circulation in man;
digoxin in chronic cor pulmonale. Circulation. 1950;1(2):161–86.
47. Barbera JA, Roger N, Roca J, Rovira I, Higenbottam TW, Rodriguez-Roisin R. Worsening of
pulmonary gas exchange with nitric oxide inhalation in chronic obstructive pulmonary disease.
Lancet. 1996;347(8999):436–40.
48. Stolz D, Rasch H, Linka A, Di Valentino M, Meyer A, Brutsche M, et al. A randomised, con-
trolled trial of bosentan in severe COPD. Eur Respir J. 2008;32(3):619–28.
49. Blanco I, Gimeno E, Munoz PA, Pizarro S, Gistau C, Rodriguez-Roisin R, et al. Hemodynamic
and gas exchange effects of sildenafil in patients with chronic obstructive pulmonary disease
and pulmonary hypertension. Am J Respir Crit Care Med. 2010;181(3):270–8.
50. Park J, Song JH, Park DA, Lee JS, Lee SD, Oh YM. Systematic review and meta-analysis of
pulmonary hypertension specific therapy for exercise capacity in chronic obstructive pulmo-
nary disease. J Korean Med Sci. 2013;28(8):1200–6.
51. Blanco I, Santos S, Gea J, Guell R, Torres F, Gimeno-Santos E, et al. Sildenafil to improve
respiratory rehabilitation outcomes in COPD: a controlled trial. Eur Respir J. 2013;42(4):
982–92.
52. Vonk-Noordegraaf A, Boerrigter BG. Sildenafil: a definitive NO in COPD. Eur Respir
J. 2013;42(4):893–4.
53. Vestbo J, Hurd S, Agusti A, Jones P, Vogelmeier C, Anzieto A, Barnes P, Fabbri L, Martinez
F, Nishimura M, Stockley R, Sin D. Rodriguez-Roisin Global strategy for the diagnosis,
management, and prevention of chronic obstructive pulmonary disease (GOLD executive
summary). Am J Respir Crit Care Med. 2013;187(4):347–65.
Chapter 19
Treatment of Chronic Right Heart Failure
Jasmijn S.J.A. van Campen and Harm J. Bogaard
In this chapter current and experimental treatment options in chronic RHF are
discussed, which aim to reduce right ventricular afterload, to optimize right ventricu-
lar preload, or to improve intrinsic right ventricular function. We artificially divided
treatment options into these three main categories for the sake of clarity, but many
drugs influence multiple conditions simultaneously. Scheme 1 provides an overview.
Despite the recognition of its prognostic significance in pulmonary hypertension
(PH), RV failure is not yet a direct pharmaceutical target in PH treatment. PAH-
specific drugs affect RV function by reducing RV after load, but they also have
direct effects on the heart. Future therapies may specifically target mechanisms con-
tributing to RV maladaptation.
Since right ventricular failure (RVF) is a progressive and ultimately fatal syn-
drome, appropriate palliative care should be given in the terminal phase of the dis-
ease to improve patients’ quality of life.
This chapter provides an overview of the current and possible future treatment
possibilities for patients with chronic right ventricular failure.
In Chap. 10, which dealt with acute RVF, right heart failure (RHF) was defined
as a complex clinical syndrome that results from any structural or functional impair-
ment of right ventricular filling or ejection of blood [1, 2]. In contrast to acute RVF,
chronic RVF is characterized by a gradually increasing inability of the heart to ade-
quately pump blood. This causes complaints of dyspnea and fatigue which may
limit exercise tolerance and can lead to fluid retention. Chronic RV failure is a
progressive syndrome and is ultimately fatal.
J.S.J.A.van Campen, M.D.

Department of pulmonary Medicine,
MC Haaglanden, Lijnbaan 32, 2512 VA Den Haag, The Netherlands
H.J. Bogaard, M.D., Ph.D. (*)
e-mail: hj.bogaard@vumc.nl

402 J.S.J.A. van Campen and H.J. Bogaard
The most common cause of RVF is chronic left-sided heart failure (HF, see
Chap. 17). Generally speaking, RHF is provoked by various forms of pressure- or
volume-overload, or by ischemia, intrinsic myocardial disease, congenital heart
defects, or pericardial constraint [1]. The adaptive response of the right ventricle
(RV) to an increased afterload, which is the focus of this chapter, is complex and
varies from compensated hypertrophy to progressive dilatation and failure, and
determines the degree of symptoms and survival of patients [3, 4]. Despite the rec-
ognition of its prognostic significance in pulmonary hypertension (PH), RV failure
is not a direct pharmaceutical target in PH treatment. PAH-specific drugs affect RV
function by reducing RV after load, but they also have direct effects on the heart.
Future therapies may specifically target mechanisms contributing to RV maladapta-
tion, including neurohormonal activation, apoptotic loss of cardiomyocytes, meta-
bolic remodeling, mitochondrial dysfunction and myocardial ischemia, and their
underlying altered gene expression [5].
Pharmacological Treatment
In this chapter we will discuss current and experimental treatment options in RHF,
which aim to reduce right ventricular afterload, to optimize right ventricular pre-
load, or to improve intrinsic right ventricular function. For the sake of clarity, we
artificially divided treatment options into these three main categories, but many
drugs influence multiple conditions simultaneously. Since RVF is a progressive and
ultimately fatal syndrome, we will also discuss appropriate palliative care which
should be provided in the terminal phase of the disease (Fig. 19.1).
Reducing Afterload
Increased RV afterload often leads to RV dilation and the resulting increase in wall
stress can cause RV ischemia and further aggravates ventricular dysfunction. This is
extensively discussed in Chap. 10. The potential reversibility of RV failure is best
illustrated by the restoration of RV function after normalization of the afterload
after surgical thromboendarterectomy in CTEPH patients [6] or lung transplanta-
tion for PAH [7]. Such profound effects on pulmonary vascular resistance are only
rarely achieved by the vasodilator drugs currently used to treat PAH. The indirect,
after load-dependent, effects of these drugs on RV function are not the topic of this
chapter. Here, it suffices to say that the effects on RV function of modest decreases
in RV after load are unpredictable [4]. In this section we will summarize the limited
body of evidence which has accumulated recently suggesting that these drugs also
have direct, afterload-independent, effects on intrinsic RV function.
19 Treatment of Chronic Right Heart Failure 403
Fig. 19.1 This block diagram organizes the different treatment modalities utilized in patients with
chronic right heart failure. An attempt is made to list the effects on preload, contractility, and RV
afterload. The (+) sign denotes a positive effect, the (−) sign a negative effect, and the (?) symbol
indicates that the effect is uncertain or unknown
Oxygen
Hypoxic pulmonary vasoconstriction can be mitigated by administering supple-

mental oxygen to patients with hypoxemia. This is associated with a modest
decrease in the pulmonary artery pressure and pulmonary vascular resistance.
In hypoxemic patients with PH related to either COPD or ILD this is the treatment
of choice. A target oxygen saturation of 90 % has been proposed [8]. Although
supplemental oxygen can offer support to an RV prone to ischemia [9], theoretical
negative effects on the RV, including formation of reactive oxygen species (ROS)
and suppression of angiogenesis, have not been studied.
Calcium Channel Blockers
Calcium channel blockers are used in the small minority of patients with significant
pulmonary vascular reactivity. Notwithstanding the negative inotropic effect of cal-
cium channel blockers, their use in this group of patients is associated with a sur-
vival benefit [10] and with an improvement of the cardiac index in patients with a
long-term favorable response to this drug [11]. Direct consequences for the RV have
not been investigated, but it can be postulated that the negative inotropic effects of
these drugs may be harmful, at least in the short term.
Anticoagulation
The risk of thromboembolic events in patients with chronic RV failure has not been
well established. Although clinical practice varies, anticoagulation usually is rec-
ommended in patients with evidence of intracardiac thrombus, documented throm-
boembolic events and PAH (indirect evidence for idiopathic PAH and expert opinion
for PH associated with scleroderma and CHD) [1, 10]. Anticoagulation is also
advised for patients with paroxysmal or persistent atrial flutter or fibrillation, in
combination with significant RV dysfunction or previous thromboembolic events
[12, 13]. Direct effects of anticoagulation on the RV are not known, but there is no
suggestion of harmfulness.
Prostacyclin Analogues
For more than two decades, intravenous Epoprostenol has played an important role
in the treatment of PAH. The therapeutic effects of prostacyclin analogues are
thought to be due to a combination of vasodilation and inhibition of platelet aggre-
gation and vascular remodeling [14]. However, there is no proof that long-term
prostacyclin treatment prevents or reverses lung vessel remodeling in PAH [15, 16].
At least part of the therapeutic effects of prostacyclin analogues has been attributed
to improvement of RV function [17, 18]. In patients with severe heart failure pros-
tacyclin treatment results in an immediate and substantial increase in cardiac output
and a reduction in cardiac filling pressures [19]. Reflex tachycardia and pulmonary
vasodilation seem to contribute to the increase in cardiac output, but a direct effect
on the RV by improvement of contractility, reduction of fibrosis, and increase of

capillary-to-myocyte ratio was also seen in several animal studies [20, 21].
Furthermore, prostacyclin analogues suppress pressure overload-induced cardiac
hypertrophy via the inhibition of both cardiomyocyte hypertrophy and cardiac
fibrosis [22, 23]. On the other hand, the increase in cardiac output that initially
improves exercise capacity comes at the costs of higher myocardial oxygen con-
sumption, which could be detrimental in the long run. This could be an explanation
for the increased mortality which was seen after long-term Epoprostenol treatment
in patients with severe left heart failure (LHF) [24, 25] and the negative results in
PAH patients of the Beraprost Study Group [26]. The latter study is the only ran-
domized clinical trial with a follow-up time of 1 year with specific PAH-therapy. In
this study the initial increase in exercise capacity was transient and disappeared
after 1 year. Taking all of the above into consideration, the direct effects of prosta-
cyclin on the RV are still poorly understood.
Endothelin Receptor Blockers
Due to a number of different stimuli (vasoactive hormones, growth factors, shear

stress, hypoxia, ROS), cardiomyocytes and endothelial cells produce more ET-1 in
heart failure [27, 28]. ET-1 increases pulmonary vascular tone, enhances cardio-
myocyte contractility, and has a role in the development of pressure overload-
induced cardiac hypertrophy [27, 29]. These effects have also been shown to occur
in the pressure-overloaded RV [30]. As such, treatment with ET-receptor antago-
nists could theoretically act as a double-edged sword in RVF: while RV after load
can decrease via a reduction in pulmonary vascular tone, inotropic effects of ET-1
are nullified. Furthermore, cardiomyocyte apoptosis may be induced by treatment
with ET-receptor blockers, which is potentially harmful. Galiè et al. have shown that
in PAH patients, Bosentan improves RV systolic function and LV early diastolic
filling and leads to a decrease of RV dilation and an increase in LV size is measured
with echocardiography [31]. Whether these effects occur because of or despite of
direct Endothelin-1 receptor antagonism in the heart remains to be determined.
In LHF clinical trials which assessed direct effects of ET-receptor antagonists on
the heart, the results were not favorable [32–34]. It can be postulated that by increas-
ing pulmonary vascular tone, ET-1 contributes to optimization of preload for the
failing left ventricle, which when prevented would translate into another potentially
harmful effect of ET-receptor antagonists in LVF.
Phosphodiesterase Inhibitors
cGMP is a ubiquitous intracellular secondary messenger and its action provides

pulmonary vasodilation and suppression of cell proliferation. cGMP/PKG signaling
protects the heart from apoptosis [35, 36], may decrease myocardial oxygen
consumption [37], and blunts the hypertrophic response to pressure overload, with
an associated enhanced systolic function [38, 39].
Type 5 phosphodiesterase (PDE5) degrades cGMP and an increase in cGMP avail-
ability in the lung (and subsequent vasodilation) explains the benefits of the PDE5
inhibitor Sildenafil in PAH [40]. PDE5 is expressed in the hypertrophic RV and not in
the normal RV, and preclinical studies have shown that suppression of PDE5 activity
is associated with a direct increase in right ventricular contractility [41].
In patients with PAH, Sildenafil reduces RV mass, improves the cardiac index
and exercise capacity [42], and improves RV diastolic function [43]. The first clini-
cal trials of PDE5 inhibition in patients with non-PAH heart failure with decreased
[44, 45] and preserved ejection fraction [46] have shown positive results, but larger
randomized controlled trials are necessary. It remains undetermined whether the
benefit of PDE5 inhibitors in PAH is predominantly mediated through effects in the
pulmonary vasculature or heart.
Possible Future Therapies in PAH
A new concept of a quasi-malignant behavior of endothelial cells in the PAH lung

vasculature has fueled the investigation into a number of new targets for drug devel-
opment [47]. These drugs are designed to interfere with increased cell proliferation,
angiogenesis, and apoptosis resistance. The potential danger of these drugs lies in
the fact that the failing RV may suffer from ischemia, capillary rarefaction, and
cardiomyocyte apoptosis. These are mechanisms, which may be aggravated by the
newer therapies with possible detrimental effects on RV function.
One of these potential new drugs is Imatinib, a kinase inhibitor affecting the
Tyrosine domain of the platelet-derived growth factor (PDGF) receptor. PDGF sig-
naling has many positive effects on the heart after myocardial infarction [48–50]
and is an important element of adaptive remodeling of the pressure-overloaded LV
[51]. Inhibition of PDGF-R by Imatinib could therefore negatively influence adap-
tive cardiac remodeling in PAH, regardless of its effects as a vasodilator of the pul-
monary vasculature. Although Imatinib was beneficial in isolated PAH cases
[52–55], a recent phase II study was negative in regard to its primary end point [56].
Studies of Imatinib treatment in selected groups of patients will follow. Another
tyrosine kinase inhibitor that is currently tested in PAH is Nilotinib (ClinicalTrials.
gov Identifier NCT01320865). It is hypothesized that Nilotinib provides clinical
benefit to patients with PAH through inhibition of mast cell progenitor proliferation,
mobilization, and differentiation. A possible cardiotoxicity of Nilotinib is not cur-
rently considered.
In PAH, positive effects of epidermal growth factor (EGF) receptor blockers can
be anticipated on the pulmonary vasculature and the pressure-overloaded RV. MCT-
induced PH in rats was improved by EGF receptor blockers [57]. Further research
is needed to know whether EGF receptor blockers will have a role in PAH treatment.
The same is true for Rho kinase inhibitors, which have beneficial effects on the
pulmonary vasculature but as yet undetermined direct effects on the RV. HMG-CoA
reductase inhibitors (statins) have been shown to effectively reverse pulmonary vas-
cular remodeling and RV hypertrophy in a rat model [58], but the results of a recent
trial in PAH patients were disappointing [59].
Optimization of Preload
In general, the RV adapts better to volume overload than to pressure overload. A rise
in preload increases the stretching of the muscle fibers, causing the cardiac muscle
to contract more forcefully according to the Frank–Starling mechanism. This allows
the cardiac output to be synchronized with venous return. Overstretching of muscle
fibers in severely volume-overloaded patients further increases RV dilation and wall
stress, thereby impairing filling of the left ventricle. In these patients diuretic treat-
ment leads to a decrease of preload and improvement of the Frank–Starling relation-
ship, resulting in a relief of symptoms. However, this observation [56] is rather more
based on clinical experience than on empirical evidence. In patients with severe
RVF, an improvement in left ventricular function can be attained with a reduction in
RV end diastolic volume, a diminution of the leftward interventricular septum shift
and thereby improvement of left ventricular diastolic function.
Treatment with diuretics is not without risks (see also Chap. 9, The diabolical
effects of preload reduction). Patients with RV failure are highly preload dependent
and too rapid diuresis may result in a decline in stroke volume. Diuretic therapy
with loop diuretics also predisposes patients to metabolic alkalosis and arrhythmias
due to hypokalemia. The aldosterone-antagonist spironolactone has many poten-
tially beneficial effects which are not mediated through effects on volume status.
Spironolactone prevents hypokalemia and arrhythmias and is also associated with
other beneficial effects, such as immune modulation and reversal of maladaptive
remodeling [60]. Although its use has not yet been investigated in detail, spirono-
lactone is recommended by the current treatment guidelines of heart failure and
PAH [2, 61, 62]. In addition to diuretic therapy, PAH patients are advised to restrict
their daily fluid and salt intake to optimize preload [61].
Improving Intrinsic RV Function
While the goal of PAH-specific treatment is to reduce pulmonary vascular resis-

tance, patients die of RHF (see Chap. 13). The recognition of a key role of RV func-
tion in patient survival [4] has not yet resulted in a treatment to directly improve RV
function. Mechanisms of RV failure are still not fully understood and often extrapo-
lated from studies of chronic LHF, despite increasing evidence that mechanisms of
left and right heart failure are not identical. Some LHF treatments were successfully
applied in models of experimental PAH, but others have shown adverse effects.
Perhaps the only uniformly accepted form of RV-directed therapy in PAH is aimed
at the maintenance of sinus rhythm [63–65].
In LHF, a close correlation has been demonstrated between an increase in heart
rate and progression of HF and mortality [66]. When atrial fibrillation develops,
there is no active atrial contraction to force an additional volume of blood into the
ventricles (“atrial kick”) resulting in a 20–30 % decline in stroke output and a
decrease in cardiac output [67, 68].
Patients with RV failure are at risk for atrial tachyarrhythmias, mostly atrial flut-
ter and atrial fibrillation. These arrhythmias, as well as tachycardia, cause impair-
ment of the ventricular function, can lead to hemodynamic instability, and are
associated with an increased morbidity and mortality [12, 69–72]. In addition to its
hemodynamic consequences, a rise in heart rate is also associated with increased
myocardial oxygen consumption [73], which could also partially explain the detri-
mental effects of tachycardia in the long run. In the aggregate, maintenance of sinus
rhythm and heart rate control are essential in RVF treatment.
Digoxin
Digoxin is an oral cardiac glucoside with a positive inotrope and negative chrono-
trope effect. In patients with left ventricular systolic dysfunction, digoxin provides
symptomatic benefits, but in RHF digoxin is only indicated for rate control in
patients with atrial tachyarrhythmias [61]. Rich et al. showed that digoxin improved
cardiac output in patients with idiopathic PAH, but the efficacy of chronic digoxin
treatment remains unknown [64]. Detrimental effects are suggested, including pul-
monary vasoconstriction [74, 75]. Additionally, digoxin toxicity may occur, partic-
ularly in patients with hypokalemia induced by diuretics and hypoxemia—both
conditions which are common in RVF.
Beta-Blockers
In analogy to the treatment of LHF, the increased activity of the neurohormonal axis
in PAH is a potential treatment target [76]. Although it is uncertain whether increased
sympathetic activation is a cause or a consequence of right heart failure, sympa-
thetic overdrive is clearly associated with a poor prognosis of PAH patients [77].
Increased sympathetic activity is an acute compensatory mechanism to maintain
cardiac function by increasing contractility and heart rate, but in the long run chronic
adrenergic overactivity has detrimental effects on cardiac function. This is the fun-
damental basis for beta-adrenergic receptor blockade in current LHF management,
which has been demonstrated to reduce LV remodeling and mortality by about 30 %
[2]. Heart rate reduction is thought to be one of the main factors contributing to the
beneficial effects of beta-blockers on survival in patients with LVF [78].
Notwithstanding the substantial evidence for their beneficial effects in LHF, the
use of beta-blockers in patients with PAH has been considered contraindicated [61].
This recommendation is based on the fear of systemic hypotension due to acute
negative inotropic effects and a decreased heart rate. Provencher [79] and Peacock
[80] described the improvement of exercise capacity after withdrawal of a nonselec-
tive beta-blocker in patients with portopulmonary hypertension and negative effects
of beta-blocker therapy in one unstable patient with portopulmonary hypertension.
In contrast, three preclinical studies were performed that assessed the long-term
effects of AR-blockers in rats with PAH. The studies of Bogaard et al. and De Man
and Handoko et al. both show several beneficial hemodynamic and morphological
effects in experimental PAH in rats and it has been demonstrated that Carvedilol and
Bisoprolol delayed the progression towards right heart failure in experimental PAH
[81, 82]; these findings are associated with specific changes in gene expression [83].
Despite the fact that current guidelines prohibit the use of beta-blocker therapy in
PAH [61], So et al. reported a prevalence of beta-blocker use of 28 % in a Canadian
PAH cohort. At follow-up, no detrimental effects on clinical, functional, and hemo-
dynamic outcomes have been observed in this group compared to PAH patients not
treated with beta-blockers [84].
These findings are the foundation of a phase I–II study assessing the safety and
efficacy of Bisoprolol treatment in patients with PAH, which will report its results
in 2014 (Clinicaltrials.gov identifier NCT01246037).
Ace Inhibitors and AT1R Antagonist
Along with the sympathetic nerve system, the renin-angiotensin-aldosterone-system

(RAAS) is activated in PAH [85]. Although an early increase in cardiac output can
result from RAAS activation, the long-term effects of an overactive RAAS are
assumed to be harmful for the RV. Nevertheless, the use of ACE inhibitors and
AT1R antagonists in PAH is controversial. This is due to the systemic vasodilatation
that these drugs can induce, which can be life threatening. Conclusions from animal
studies are discrepant: in rabbits with PH due to pulmonary artery banding (PAB)
an improvement in systolic function was seen [86], but in the SU5416/hypoxia rat
model of severe PAH no effects on RV hypertrophy were found [87]. Whether ACE
inhibitors or ATIR antagonists have additional effects in patients already taking
aldosterone-antagonists is doubtful.
Inotropic Agents
As discussed extensively in Chap. 9, intravenous inotropic agents including dobuta-

mine (a beta-adrenergic receptor agonist), Milrinone (a selective phosphodiester-
ase-3 inhibitor), Norepinephrine (an α1/β1-receptor agonist), and Levosimendan
(a calcium-sensitizing agent) may help to stabilize patients with acute RVF. All of
these agents increase right ventricular contractility, as well as decrease afterload by
inducing pulmonary vasodilatation and their primary side effect is systemic
hypotension.
In chronic left ventricular failure, inotropic drugs are considered to be harmful
long term and there is no reason to believe that it would have substantially different
effects in patients with right ventricular dysfunction. However, these days a more
prolonged infusion of dopamine may be useful as a bridge to lung transplantation in
patients with refractory right heart failure in PAH [88].
Exercise
Exercise training (or regular physical activity) is recommended as safe and effective
for patients with LHF who are able to participate in exercise programs in order to
improve their functional status [2, 62]. After Hambrecht et al. proved that exercise
training corrected endothelial dysfunction and improved exercise capacity in
chronic heart failure [89], the first randomized control trial on the effects of exercise
rehabilitation in PAH was conducted [90]. After a 4-month training program, the
mean difference in 6 min walking distance between intervention and control groups
was 111 m. This is a considerably larger effect than the observed improvement in
most PAH medication trials. In other recent studies in PAH patients, 10 weeks of
exercise training was associated with increased physical activity and decreased
fatigue [91], and 10 weeks of brisk treadmill walking improved 6MWT distance,
cardiorespiratory function, and patient-reported quality of life [92]. These data
strongly suggest that exercise is beneficial for patients with PAH, but whether the
results can be extrapolated to other forms of RVF has not been tested.
Iron and Anemia
Ruiter et al. have shown that iron deficiency is frequently present in patients with
IPAH and associated with a lower exercise capacity. The small response to oral iron
in 44 % of the treated patients suggests impaired iron absorption in these patients
[93]. Intravenous treatment of iron deficiency in patients with chronic LHF reduces
the risk of hospitalizations without increasing adverse events [94]. This suggests
that intravenous iron treatment could have a place in the iron-deficient patient with
RVF. Whether iron supplementation leads to improvements in cardiac function or
skeletal muscle function remains to be determined.
As in acute RVF, anemia in chronic HF is associated with an increased risk of
mortality, and therefore treatment should be considered [95].
Other Possible Future Therapies
A wide range of possible therapies is in more or less advanced stages of clinical and
preclinical testing with the aim to improve RV function. Among these strategies are
neutral endopeptidase (NEP) inhibitors [96, 97], i.v. recombinant human BNP
(Nesiritide) [98], adrenomedullin [99–102], growth hormone substitution [103–107],
antioxidants [108, 109], cyclosporin [110], and immune-modulating therapy [111,
112]. Perhaps attempts to control of gene expression by histone deacetylase inhibi-
tors [113] or antagonists of microRNAs [114] and the targeting of myocardial energy
metabolism by dichloroacetate [115] may be added to the RVF treatment arsenal.
Palliative Care
RVF is a chronic and progressive disease that is eventually fatal if organ transplanta-
tion is not possible. In their final year of life, patients often have many complaints
despite maximal medical therapy. In this terminal stage, symptoms of dyspnea and
fatigue are followed by pain, nausea, constipation, a dry mouth, cough, cachexia,
depression, and anxiety [116]. These symptoms have profound effects on patients’
quality of life and need to be addressed. In addition to symptomatic treatment,
effective communication with the patient and family are of greatest importance, and
coordination of care can alleviate complaints and improve patients’ satisfaction
with the received care [117].
In patients with terminal HF, there is a delicate balance between volume over-
and under filling. An elevated preload can give complaints of congestion, while a
reduced preload can cause hypo-perfusion of the brain and the kidneys, which can
lead to renal insufficiency and somnolence. The latter is generally preferred in end-
stage disease [118]. The therapeutic options suggested below are mostly based on
research in left HF, but it can be argued that these measures can also bring relief to
patients with terminal RVF.
Dyspnea is one of the main complaints of patients with terminal HF. When a
patient remains symptomatic despite maximal treatment of all possible causes,
treatment with morphine could be considered to numb the sensation of dyspnea
[119, 120]. A fan to stimulate the flow receptors in the face of patients is thought to
bring relief of breathlessness; however, the evidence is weak [121]. Often, dyspnoea
is accompanied by anxiety for which benzodiazepines could bring relief. Treatment
needs to be tailored to the individual [122].
Constipation is a problem in 37 % of the patients with chronic LHF and is often
caused by a combination of opioid treatment, immobility, and decreased motility of
the bowel by edema [122]. For this reason, laxatives should be started. In our clini-
cal experience, PAH patients suffer far more often from diarrhea. This can be caused
by PAH-specific medications, as ERAs, PDE5 inhibitors, and prostacyclins all have
diarrhea as a side effect. It is unknown whether bowel edema contributes to this
problem as well. In case of diarrhea loperamide can be considered.
Pain in terminal PAH patients is frequently abdominal pain and can be due to
liver congestion, bowel ischemia, ascites, or constipation. Leg pain can be caused
by edema, muscle cramps, or gout. Aminocetophen (paracetamol) is the painkiller
of first choice and when insufficient, opioids can be added. NSAIDs are contraindi-
cated as they can aggravate fluid retention and can precipitate kidney failure. In
patients with gout, colchicine or prednisolone should be considered [122]. Some
patients may benefit from relaxation techniques for the relief of chronic pain [123].
Fatigue is a major symptom of heart failure, with 69 % of the patients in the last
year of life and 78 % of the patients in the last 2 weeks of life feeling very tired
[122]. There is no other treatment than maximal heart failure treatment and limita-
tion of exertion. Methylphenidate is contraindicated as it increases sympathetic
nerve activity and could thereby worsen HF.
Digoxin and spironolactone can cause symptoms of nausea, as do constipation
and ascites. Use of medication should be reevaluated and laxatives should be pre-
scribed. Ascites drainage can be considered, but has only temporal effects: in 90 %
of patients ascites reoccurs within 2 weeks. Symptomatic treatment with metoclo-
pramide can be considered [122].
Malnutrition is a problem in 35–50 % of CHF patients. Due to edema, weight
loss is sometimes hard to determine. There is cachexia when a patient loses >7.5 %
of his weight in 6 months. Patients should be advised to eat several small portions
during the day and patients can be referred to a dietician. Whether feeding interven-
tions and drug therapy with progestativa or corticosteroids to stimulate appetite are
effective has not been well examined [122].
Dry mouth and thirst are hard to fight. Extra fluid intake makes patients more
dyspneic. Ice cubes sometimes give a relief of symptoms and may help to limit fluid
intake. Furthermore, anticholinergic drugs and opioids can cause complaints of a
dry mouth and should be reconsidered in these patients [122].
A dry cough can be fought with noscapine, dextromethorphan, or codeine. In
patients in whom codeine does not alleviate cough, morphine can still offer relief.
In patients already taking opioids increasing the dosage by 25–50 % may some-
times help [122]. Anticholinergic drugs, such as promethazine or tiotropium, are
relatively contraindicated because of a possible induction of tachycardia.
Twenty-three percent of chronic heart failure patients have depressive symptoms,
ranging from a gloomy mood to major depression [122]. Depending on the severity
of symptoms, referral to a psychiatrist or psychologist with experience with termi-
nal patients should be considered. If drug treatment is needed, SSRIs are the first
choice, because tricyclic antidepressants can provoke arrhythmias [122].
Conclusion
Chronic RV failure is a progressive and ultimately fatal syndrome that results from
a gradually increasing inability of the heart to adequately pump blood. This causes
symptoms of dyspnea and fatigue which may limit exercise tolerance and can lead
to fluid retention.
In this chapter current and experimental treatment options in chronic RHF are
discussed, which aim to reduce right ventricular afterload, to optimize right ven-
tricular preload, or to improve intrinsic right ventricular function. Despite the rec-
ognition of its prognostic significance in pulmonary hypertension (PH), RV failure
is not yet a direct pharmaceutical target in PH treatment. One or more of the many
therapeutic strategies currently studied will hopefully change this.
Since RVF is a progressive and ultimately fatal syndrome, appropriate palliative
care should be given in the terminal phase of the disease to improve patients’ quality
of life.
References
1. Haddad F, Doyle R, Murphy DJ, Hunt SA. Right ventricular function in cardiovascular
disease, part II: pathophysiology, clinical importance, and management of right ventricular
failure. Circulation. 2008;117:1717–31.
2. Yancy CW, et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of
the American College of Cardiology Foundation/American Heart Association Task Force on
Practice Guidelines. J Am Coll Cardiol. 2013;62:e147–239. doi:10.1016/j.jacc.2013.05.019.
3. Chin KM, Kim NHS, Rubin LJ. The right ventricle in pulmonary hypertension. Coron Artery
Dis. 2005;16:13–8.
4. Van de Veerdonk MC, et al. Progressive right ventricular dysfunction in patients with pulmo-
nary arterial hypertension responding to therapy. J Am Coll Cardiol. 2011;58:2511–9.
2009;135:794–804.
6. Corsico AG, et al. Long-term outcome after pulmonary endarterectomy. Am J Respir Crit
Care Med. 2008;178:419–24.
7. Olland A, Falcoz P-E, Canuet M, Massard G. Should we perform bilateral-lung or heart–lung
transplantation for patients with pulmonary hypertension? Interact Cardiovasc Thorac Surg.
2013;17:166–70.
8. Lee SH, Rubin LJ. Current treatment strategies for pulmonary arterial hypertension. J Intern
Med. 2005;258:199–215.
9. Gómez A, et al. Right ventricular ischemia in patients with primary pulmonary hypertension.
10. Rich S, Kaufmann E, Levy PS. The effect of high doses of calcium-channel blockers on sur-
vival in primary pulmonary hypertension. N Engl J Med. 1992;327:76–81.
11. Sitbon O, et al. Long-term response to calcium channel blockers in idiopathic pulmonary
arterial hypertension. Circulation. 2005;111:3105–11.
12. Walsh EP, Cecchin F. Arrhythmias in adult patients with congenital heart disease. Circulation.
2007;115:534–45.
13. McLaughlin VV, Rich S. Pulmonary hypertension. Curr Probl Cardiol. 2004;29:575–634.
14. Olschewski H, et al. Prostacyclin and its analogues in the treatment of pulmonary hyperten-
sion. Pharmacol Ther. 2004;102:139–53.
15. Achcar ROD, et al. Morphologic changes in explanted lungs after prostacyclin therapy for
pulmonary hypertension. Eur J Med Res. 2006;11:203–7.
16. Rich S. Right ventricular adaptation and maladaptation in chronic pulmonary arterial hyper-
tension. Cardiol Clin. 2012;30:257–69.
17. Montalescot G, et al. Effects of prostacyclin on the pulmonary vascular tone and cardiac
contractility of patients with pulmonary hypertension secondary to end-stage heart failure.
Am J Cardiol. 1998;82:749–55.
18. Kisch-Wedel H, et al. The prostaglandins epoprostenol and iloprost increase left ventricular
contractility in vivo. Intensive Care Med. 2003;29:1574–83.
19. Yui Y, Nakajima H, Kawai C, Murakami T. Prostacyclin therapy in patients with congestive
heart failure. Am J Cardiol. 1982;50:320–4.
20. Gomez-Arroyo JG, et al. Inhaled iloprost reverses established fibrosis and improves right
ventricular dysfunction by reducing connective tissue growth factor expression and collagen
synthesis. Am J Respir Crit Care Med. 2013;187:A3984.
21. Van Albada ME, et al. Prostacyclin therapy increases right ventricular capillarisation in a
model for flow-associated pulmonary hypertension. Eur J Pharmacol. 2006;549:107–16.
22. Hara A, et al. Augmented cardiac hypertrophy in response to pressure overload in mice lack-
ing the prostaglandin I2 receptor. Circulation. 2005;112:84–92.
23. Francois H, et al. Prostacyclin protects against elevated blood pressure and cardiac fibrosis.
Cell Metab. 2005;2:201–7.
24. Sueta CA, et al. Safety and efficacy of epoprostenol in patients with severe congestive heart
failure. Epoprostenol Multicenter Research Group. Am J Cardiol. 1995;75:34A–43A.
25. Califf RM, et al. A randomized controlled trial of epoprostenol therapy for severe congestive
heart failure: The Flolan International Randomized Survival Trial (FIRST). Am Heart
J. 1997;134:44–54.
26. Barst RJ, et al. Beraprost therapy for pulmonary arterial hypertension. J Am Coll Cardiol.
2003;41:2119–25.
27. Giannessi D, Del Ry S, Vitale RL. The role of endothelins and their receptors in heart failure.
Pharmacol Res. 2001;43:111–26.
28. Sakai S, et al. Endogenous endothelin-1 participates in the maintenance of cardiac function
in rats with congestive heart failure. Marked increase in endothelin-1 production in the failing
heart. Circulation. 1996;93:1214–22.
29. Sugden PH. An overview of endothelin signaling in the cardiac myocyte. J Mol Cell Cardiol.
2003;35:871–86.
30. Nagendran J, et al. Endothelin axis is upregulated in human and rat right ventricular hyper-
trophy. Circ Res. 2013;112:347–54.
31. Galiè N, et al. Effects of the oral endothelin-receptor antagonist bosentan on echocardio-
graphic and doppler measures in patients with pulmonary arterial hypertension. J Am Coll
Cardiol. 2003;41:1380–6.
32. Anand I, et al. Long-term effects of darusentan on left-ventricular remodelling and clinical
outcomes in the EndothelinA Receptor Antagonist Trial in Heart Failure (EARTH): ran-
domised, double-blind, placebo-controlled trial. Lancet. 2004;364:347–54.
33. Kalra PR, Moon JCC, Coats AJS. Do results of the ENABLE (endothelin antagonist bosentan
for lowering cardiac events in heart failure) study spell the end for non-selective endothelin
antagonism in heart failure? Int J Cardiol. 2002;85:195–7.
34. Kaluski E, et al. Clinical and hemodynamic effects of bosentan dose optimization in symp-
tomatic heart failure patients with severe systolic dysfunction, associated with secondary
pulmonary hypertension—a multi-center randomized study. Cardiology. 2008;109:273–80.
35. Das A, Xi L, Kukreja RC. Phosphodiesterase-5 inhibitor sildenafil preconditions adult car-
diac myocytes against necrosis and apoptosis. Essential role of nitric oxide signaling. J Biol
Chem. 2005;280:12944–55.
36. Fisher PW, Salloum F, Das A, Hyder H, Kukreja RC. Phosphodiesterase-5 inhibition with
sildenafil attenuates cardiomyocyte apoptosis and left ventricular dysfunction in a chronic
model of doxorubicin cardiotoxicity. Circulation. 2005;111:1601–10.
37. Zaccolo M, Movsesian MA. cAMP and cGMP signaling cross-talk: role of phosphodiester-
ases and implications for cardiac pathophysiology. Circ Res. 2007;100:1569–78.
38. Fiedler B, et al. Inhibition of calcineurin-NFAT hypertrophy signaling by cGMP-dependent
protein kinase type I in cardiac myocytes. Proc Natl Acad Sci U S A. 2002;99:11363–8.
39. Takimoto E, et al. Chronic inhibition of cyclic GMP phosphodiesterase 5A prevents and
reverses cardiac hypertrophy. Nat Med. 2005;11:214–22.
40. Galiè N, et al. Sildenafil citrate therapy for pulmonary arterial hypertension. N Engl J Med.
2005;353:2148–57.
41. Nagendran J, et al. Phosphodiesterase type 5 is highly expressed in the hypertrophied human
right ventricle, and acute inhibition of phosphodiesterase type 5 improves contractility.
Circulation. 2007;116:238–48.
42. Wilkins MR, et al. Sildenafil versus endothelin receptor antagonist for pulmonary hyperten-
sion (SERAPH) study. Am J Respir Crit Care Med. 2005;171:1292–7.
43. Gan CT-J, et al. Right ventricular diastolic dysfunction and the acute effects of sildenafil in
pulmonary hypertension patients. Chest. 2007;132:11–7.
44. Lewis GD, et al. Sildenafil improves exercise hemodynamics and oxygen uptake in patients
with systolic heart failure. Circulation. 2007;115:59–66.
45. Guazzi M, Vicenzi M, Arena R, Guazzi MD. PDE5 inhibition with sildenafil improves left
ventricular diastolic function, cardiac geometry, and clinical status in patients with stable
systolic heart failure: results of a 1-year, prospective, randomized, placebo-controlled study.
Circ Heart Fail. 2011;4:8–17.
46. Guazzi M, Vicenzi M, Arena R, Guazzi MD. Pulmonary hypertension in heart failure with
preserved ejection fraction: a target of phosphodiesterase-5 inhibition in a 1-year study.
Circulation. 2011;124:164–74.
47. Voelkel NF, Gomez-Arroyo J, Abbate A, Bogaard HJ, Nicolls MR. Pathobiology of
pulmonary arterial hypertension and right ventricular failure. Eur Respir J. 2012;40:
1555–65.
48. Tang J, et al. The absence of platelet-derived growth factor-B in circulating cells promotes
immune and inflammatory responses in atherosclerosis-prone ApoE-/- mice. Am J Pathol.
2005;167:901–12.
49. Xaymardan M, et al. Platelet-derived growth factor-AB promotes the generation of adult
bone marrow-derived cardiac myocytes. Circ Res. 2004;94:E39–45.
50. Beltrami AP, et al. Adult cardiac stem cells are multipotent and support myocardial regenera-
tion. Cell. 2003;114:763–76.
51. Chintalgattu V, et al. Cardiomyocyte PDGFR-beta signaling is an essential component of the
mouse cardiac response to load-induced stress. J Clin Invest. 2010;120:472–84.
52. Ghofrani HA, Seeger W, Grimminger F. Imatinib for the treatment of pulmonary arterial
hypertension. N Engl J Med. 2005;353:1412–3.
53. Overbeek MJ, van Nieuw Amerongen GP, Boonstra A, Smit EF, Vonk-Noordegraaf
A. Possible role of imatinib in clinical pulmonary veno-occlusive disease. Eur Respir
J. 2008;32:232–5.
54. Patterson KC, Weissmann A, Ahmadi T, Farber HW. Imatinib mesylate in the treatment of
refractory idiopathic pulmonary arterial hypertension. Ann Intern Med. 2006;145:152–3.
55. Souza R, Sitbon O, Parent F, Simonneau G, Humbert M. Long term imatinib treatment in
pulmonary arterial hypertension. Thorax. 2006;61:736.
56. Ghofrani HA, et al. Imatinib in pulmonary arterial hypertension patients with inadequate
response to established therapy. Am J Respir Crit Care Med. 2010;182:1171–7.
57. Merklinger SL, Jones PL, Martinez EC, Rabinovitch M. Epidermal growth factor receptor
blockade mediates smooth muscle cell apoptosis and improves survival in rats with pulmo-
nary hypertension. Circulation. 2005;112:423–31.
58. Taraseviciene-Stewart L, et al. Simvastatin causes endothelial cell apoptosis and attenuates
severe pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol. 2006;291:L668–76.
59. Kawut SM, et al. Randomized clinical trial of aspirin and simvastatin for pulmonary arterial
hypertension: ASA-STAT. Circulation. 2011;123:2985–93.
60. Tang WHW, Parameswaran AC, Maroo AP, Francis GS. Aldosterone receptor antagonists in
the medical management of chronic heart failure. Mayo Clin Proc. 2005;80:1623–30.
61. Galiè N, et al. Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur
Respir J. 2009;34:1219–63.
62. Dickstein K, et al. ESC guidelines for the diagnosis and treatment of acute and chronic heart
failure 2008: the Task Force for the diagnosis and treatment of acute and chronic heart failure
2008 of the European Society of Cardiology. Developed in collaboration with the Heart
Failure Association of the ESC (HFA) and endorsed by the European Society of Intensive
Care Medicine (ESICM). Eur J Heart Fail. 2008;10:933–89.
63. Hori M, Okamoto H. Heart rate as a target of treatment of chronic heart failure. J Cardiol.
2012;60:86–90.
64. Rich S, et al. The short-term effects of digoxin in patients with right ventricular dysfunction
from pulmonary hypertension. Chest. 1998;114:787–92.
65. Olsson KM, Nickel NP, Tongers J, Hoeper MM. Atrial flutter and fibrillation in patients with
pulmonary hypertension. Int J Cardiol. 2013;167:2300–5.
66. Fox K, et al. Heart rate as a prognostic risk factor in patients with coronary artery disease and
left-ventricular systolic dysfunction (BEAUTIFUL): a subgroup analysis of a randomised
controlled trial. Lancet. 2008;372:817–21.
67. Alpert JS, Petersen P, Godtfredsen J. Atrial fibrillation: natural history, complications, and
management. Annu Rev Med. 1988;39:41–52.
Circulation. 2008;117:1436–48.
69. O’Rourke RA, Dell’Italia LJ. Diagnosis and management of right ventricular myocardial
infarction. Curr Probl Cardiol. 2004;29:6–47.
70. Goldstein S. Toward a new understanding of the mechanism and prevention of sudden death
in coronary heart disease. Circulation. 1990;82:284–8.
71. Tongers J, et al. Incidence and clinical relevance of supraventricular tachyarrhythmias in
pulmonary hypertension. Am Heart J. 2007;153:127–32.
72. Swedberg K, et al. Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised
placebo-controlled study. Lancet. 2010;376:875–85.
73. Wong YY, et al. Systolic pulmonary artery pressure and heart rate are main determinants of
oxygen consumption in the right ventricular myocardium of patients with idiopathic pulmo-
nary arterial hypertension. Eur J Heart Fail. 2011;13:1290–5.
74. Polić S, et al. Role of digoxin in right ventricular failure due to chronic cor pulmonale. Int J
Clin Pharmacol Res. 1990;10:153–62.
75. Mathur PN, Powles P, Pugsley SO, McEwan MP, Campbell EJ. Effect of digoxin on right
ventricular function in severe chronic airflow obstruction. A controlled clinical trial. Ann
Intern Med. 1981;95:283–8.
76. De Man FS, Handoko ML, Guignabert C, Bogaard HJ, Vonk-Noordegraaf A. Neurohormonal
axis in patients with pulmonary arterial hypertension: friend or foe? Am J Respir Crit Care
Med. 2013;187:14–9.
77. Ciarka A, Doan V, Velez-Roa S, Naeije R, van de Borne P. Prognostic significance of sympa-
thetic nervous system activation in pulmonary arterial hypertension. Am J Respir Crit Care
Med. 2010;181:1269–75.
78. McAlister FA, Wiebe N, Ezekowitz JA, Leung AA, Armstrong PW. Meta-analysis: beta-
blocker dose, heart rate reduction, and death in patients with heart failure. Ann Intern Med.
2009;150:784–94.
79. Provencher S, et al. Deleterious effects of beta-blockers on exercise capacity and hemody-
namics in patients with portopulmonary hypertension. Gastroenterology. 2006;130:120–6.
80. Peacock A, Ross K. Pulmonary hypertension: a contraindication to the use of {beta}-adreno-
ceptor blocking agents. Thorax. 2010;65:454–5.
tion in pulmonary hypertensive rats. Am J Respir Crit Care Med. 2010;182:652–60.
82. De Man FS, et al. Bisoprolol delays progression towards right heart failure in experimental
pulmonary hypertension. Circ Heart Fail. 2012;5:97–105.
transcriptional profile in experimental pulmonary hypertension. Physiol Genomics.
2013;45:449–61.
84. So PP-S, et al. Usefulness of beta-blocker therapy and outcomes in patients with pulmonary
arterial hypertension. Am J Cardiol. 2012;109:1504–9.
85. De Man FS, et al. Dysregulated renin-angiotensin-aldosterone system contributes to pulmo-
nary arterial hypertension. Am J Respir Crit Care Med. 2012;186:780–9.
86. Rouleau JL, et al. Cardioprotective effects of ramipril and losartan in right ventricular pres-
sure overload in the rabbit: importance of kinins and influence on angiotensin II type 1 recep-
tor signaling pathway. Circulation. 2001;104:939–44.
87. Braun MU, Szalai P, Strasser RH, Borst MM. Right ventricular hypertrophy and apoptosis
after pulmonary artery banding: regulation of PKC isozymes. Cardiovasc Res. 2003;59:
658–67.
88. Peacock AJ, Naeije R, Rubin LJ. Pulmonary circulation: diseases and their treatment.
London: Hodder Arnold; 2011. ISBN 9780340981924 034098192X.
89. Hambrecht R, et al. Regular physical exercise corrects endothelial dysfunction and improves
exercise capacity in patients with chronic heart failure. Circulation. 1998;98:2709–15.
90. Mereles D, et al. Exercise and respiratory training improve exercise capacity and quality of
life in patients with severe chronic pulmonary hypertension. Circulation. 2006;114:1482–9.
91. Weinstein AA, et al. Effect of aerobic exercise training on fatigue and physical activity in
patients with pulmonary arterial hypertension. Respir Med. 2013;107:778–84.
92. Chan L, et al. Benefits of intensive treadmill exercise training on cardiorespiratory function
and quality of life in patients with pulmonary hypertension. Chest. 2013;143:333–43.
93. Ruiter G, et al. Iron deficiency is common in idiopathic pulmonary arterial hypertension. Eur
Respir J. 2011;37:1386–91.
94. Kapoor M, Schleinitz MD, Gemignani A, Wu W-C. Outcomes of patients with chronic heart
failure and iron deficiency treated with intravenous iron: a meta-analysis. Cardiovasc Hematol
Disord Drug Targets. 2013;13:35–44.
95. Groenveld HF, et al. Anemia and mortality in heart failure patients a systematic review and
meta-analysis. J Am Coll Cardiol. 2008;52:818–27.
96. Yap LB, Ashrafian H, Mukerjee D, Coghlan JG, Timms PM. The natriuretic peptides and
their role in disorders of right heart dysfunction and pulmonary hypertension. Clin Biochem.
2004;37:847–56.
97. Tamura N, et al. Cardiac fibrosis in mice lacking brain natriuretic peptide. Proc Natl Acad Sci
U S A. 2000;97:4239–44.
98. O’Connor CM, et al. Effect of nesiritide in patients with acute decompensated heart failure.
N Engl J Med. 2011;365:32–43.
99. Nishikimi T, et al. Increased plasma levels of adrenomedullin in patients with heart failure.
100. Kakishita M, et al. Increased plasma levels of adrenomedullin in patients with pulmonary
hypertension. Clin Sci (Lond). 1999;1979(96):33–9.
101. Ishimitsu T, Ono H, Minami J, Matsuoka H. Pathophysiologic and therapeutic implications
of adrenomedullin in cardiovascular disorders. Pharmacol Ther. 2006;111:909–27.
102. Nagaya N, Kangawa K. Adrenomedullin in the treatment of pulmonary hypertension.
Peptides. 2004;25:2013–8.
103. Maison P, Chanson P. Cardiac effects of growth hormone in adults with growth hormone
deficiency: a meta-analysis. Circulation. 2003;108:2648–52.
104. Ito H, et al. Insulin-like growth factor-I induces hypertrophy with enhanced expression of
muscle specific genes in cultured rat cardiomyocytes. Circulation. 1993;87:1715–21.
105. Cittadini A, et al. Insulin-like growth factor-1 but not growth hormone augments mammalian
myocardial contractility by sensitizing the myofilament to Ca2+ through a wortmannin-
sensitive pathway: studies in rat and ferret isolated muscles. Circ Res. 1998;83:50–9.
106. Anker SD, et al. Acquired growth hormone resistance in patients with chronic heart failure:
implications for therapy with growth hormone. J Am Coll Cardiol. 2001;38:443–52.
107. Osterziel KJ, Blum WF, Strohm O, Dietz R. The severity of chronic heart failure due to coro-
nary artery disease predicts the endocrine effects of short-term growth hormone administra-
tion. J Clin Endocrinol Metab. 2000;85:1533–9.
108. Hoshikawa Y, et al. Generation of oxidative stress contributes to the development of pulmo-
nary hypertension induced by hypoxia. J Appl Physiol. 2001;1985(90):1299–306.
109. Takimoto E, et al. Oxidant stress from nitric oxide synthase-3 uncoupling stimulates cardiac
pathologic remodeling from chronic pressure load. J Clin Invest. 2005;115:1221–31.
110. Leinwand LA. Calcineurin inhibition and cardiac hypertrophy: a matter of balance. Proc Natl
Acad Sci U S A. 2001;98:2947–9.
111. Sun M, et al. Tumor necrosis factor-alpha mediates cardiac remodeling and ventricular dys-
function after pressure overload state. Circulation. 2007;115:1398–407.
112. Abbate A, et al. Interleukin-1 blockade with anakinra to prevent adverse cardiac remodeling
after acute myocardial infarction (Virginia Commonwealth University Anakinra Remodeling
Trial [VCU-ART] Pilot study). Am J Cardiol. 2010;105:1371–77.e1.
113. Bogaard HJ, et al. Suppression of histone deacetylases worsens right ventricular dysfunction
after pulmonary artery banding in rats. Am J Respir Crit Care Med. 2011;183:1402–10.
114. Pullamsetti SS, et al. Inhibition of microRNA-17 improves lung and heart function in
experimental pulmonary hypertension. Am J Respir Crit Care Med. 2012;185:409–19.
115. Ashrafian H, Frenneaux MP, Opie LH. Metabolic mechanisms in heart failure. Circulation.
2007;116:434–48.
116. de Hosson SM. Probleemgeoriënteerd denken in de palliatieve zorg: een praktijkboek voor de
opleiding en de kliniek. (De Tijdstroom; 2012).
117. Shah AB, et al. Failing the failing heart: a review of palliative care in heart failure. Rev
Cardiovasc Med. 2013;14:41–8.
118. CBO. Multi disciplinaire richtlijn hartfalen 2010. 2010.
119. Johnson MJ, McDonagh TA, Harkness A, McKay SE, Dargie HJ. Morphine for the relief of
breathlessness in patients with chronic heart failure—a pilot study. Eur J Heart Fail.
2002;4:753–6.
120. Oxberry SG, Johnson MJ. Review of the evidence for the management of dyspnoea in people
with chronic heart failure. Curr Opin Support Palliat Care. 2008;2:84–8.
121. Bausewein C, Booth S, Gysels M, Higginson I. Non-pharmacological interventions for
breathlessness in advanced stages of malignant and non-malignant diseases. Cochrane
Database Syst Rev 2008:CD005623. doi:10.1002/14651858.CD005623.pub2.
122. de Graeff A. Palliatieve zorg: richtlijnen voor de praktijk. ISBN:9789072175397 9072175395
(Vereniging van Integrale Kankercentra, 2010).
123. Carroll D, Seers K. Relaxation for the relief of chronic pain: a systematic review. J Adv Nurs.
1998;27:476–87.
Chapter 20
Atrial Septostomy
Julio Sandoval and Adam Torbicki
Introduction
Survival in pulmonary arterial hypertension (PAH) is clearly associated with right

ventricular function or dysfunction. In the 1980s, the registry from the National
Institutes of Health showed that patients with a cardiac index (CI) lower than
2.0 L min m2, and in particular patients with a mean right atrial pressure (RAP)
>20 mmHg had a very poor survival expectancy [1]. Without treatment, the natural
history of PAH is characterized by a progressive increase in pulmonary artery
pressure (PAP), development of right ventricular failure (RVF), and death.
Without question our management and treatment of PAH now has improved. The
current PAH-targeting drugs have improved the quality of life as well as the life
span of these patients [2]. However, it is also true that these pharmacologic interven-
tions are not always readily available and, most importantly, that not all patients
respond to these drugs. Many patients still deteriorate in spite of medical treatment
and will require alternative treatment strategies such as balloon atrial septostomy
(BAS) and transplantation.
J. Sandoval, M.D. (*)

Division of Research, National Institute of Cardiology of Mexico,
Juan Badiano # 1, Colonia Sección XVI, Tlalpan, Mexico City, DF 14090, Mexico
e-mail: sandovalzarate@prodigy.net.mx
A. Torbicki, M.D., Ph.D.
Department of Pulmonary Circulation and Thromboembolic Diseases, Center Postgraduate
Medical Education, ECZ-Otwock, Borowa 14/18, Otwock 05-400, Poland
e-mail: adam.torbicki@ecz-otwock.pl

420 J. Sandoval and A. Torbicki
Rationale for BAS
There is experimental and clinical evidence suggesting that a veno-arterial shunt

may be of benefit in the setting of PAH. From an experimental point of view, Austen
and coworkers demonstrated many years ago that an atrial septal defect improved
exercise performance and the survival of dogs with RV hypertension [3]. Using a
similar experimental approach, other authors have also shown beneficial effects on
right heart mechanics [4, 5] (see below). From the clinical point of view, we know
that Eisenmenger patients with a comparable degree of pulmonary hypertension live
longer and that their RV is more resilient and protected against RV failure when
compared to patients with PAH due, at least in part, to the existence of a veno-
arterial shunt that allows CI preservation [6].
The rationale for an atrial septostomy is based on the fact that clinical deteriora-
tion and death in PAH are associated with obstruction of pulmonary blood flow and
dilation and failure of the right ventricle. The creation of an atrial septal defect in
this setting allows a right-to-left shunt to increase systemic blood flow to allow
decompression of the right heart chambers alleviating right heart failure.
Procedure
The technique of atrial septostomy has been modified between centers and it has
evolved over time, at present, balloon dilation atrial septostomy (BDAS) in the pre-
ferred technique [7] (Fig. 20.1). Briefly, baseline right and left heart pressures are
Fig. 20.1 Balloon dilation atrial septostomy. After perforation of the septum with the
Brockenbrough needle, a circular-end guidewire is positioned in the left atrium (left panel). An
initial dilation of the atrial septum is done with the Inoue dilator, and concluded with balloons of
different sizes (right panel) in a step-by-step manner
20 Atrial Septostomy 421
recorded simultaneously and cardiac output is calculated by the Fick method.

Following transseptal puncture using standard technique, the septostomy orifice is
balloon-dilated in a carefully graded step-by-step approach, beginning at a diameter
of 4 mm, and followed by dilation to 8-, 12-, and 16-mm. Between each step and
after a 3-min waiting period allowing for the assessment of hemodynamic stability,
recording of left ventricular end-diastolic pressure (LVEDP) and of arterial oxygen
saturation (SaO2) are obtained. The final size of the atrial septal defect is individual-
ized in each patient and limited by the time at which any of the following first
occurred: (1) an LVEDP increase of 18 mmHg; (2) a SaO2 reduction to 80 %; or (3)
a 10 % SaO2 decrease from baseline. Follow-up of the patients is done in the inten-
sive care unit for the first 48 h after BAS, where continuous supplementary oxygen
is administrated and appropriate anticoagulation is started. All patients are followed
at our outpatient clinic with particular care to maintain effective oral anticoagula-
tion and appropriate hemoglobin levels [7].
Current Worldwide Experience for AS
Atrial septostomy as a palliative intervention for the treatment of PAH has been
performed for almost 30 years since the initial report by Rich and Lam in 1983 [8].
However, the proper appreciation of its role in the management of PAH has been
limited mainly by the lack of a controlled clinical trial demonstrating its efficacy
and safety. Most of our knowledge regarding the procedure has been derived from
small series or case reports. In addition, the relative success of the current pharma-
cologic treatment regimens as well as the fear of a previously reported high
procedure-related mortality [9] have limited a more widespread use of this valuable
intervention.
Here we review the worldwide literature regarding the use of BAS in the setting
of severe PAH. There have been approximately about 352 procedures performed in
304 patients reported as series [10–32], and 20 additional procedures have been
published as single case reports [33–52] (Table 20.1). Atrial septostomy has been
performed in young patients (~30 years), mostly women (72 %), and most of them
at an advanced stage of the disease (functional classes III and IV). Regarding the
etiology of pulmonary hypertension, the procedure has been performed mostly in
patients with idiopathic PAH (77 %), however, it has also been performed in patients
with PAH associated with collagen vascular disease (15 %) or with corrected con-
genital heart disease (9 %), and in a few cases of distal chronic thromboembolic
pulmonary hypertension (5 %). RVF alone (50 %) or combined with syncope
(19.8 %) have been the main indications for the procedure. In many of these patients
atrial septostomy had been performed after the failure of pharmacologic treatment.
As shown in Table 20.2, BDAS has been by far the preferred technique for the
procedure [7]. BDAS has the advantage of a better control of the desired size of the
defect which is not easily obtained with a blade septostomy. The final size of the
defect has varied in the different series but there is a tendency to create small defects
Table 20.1 Clinical, demographic, and functional characteristics of PAH patients undergoing atrial septostomy
Author n Age Female IPAH CTD CHD CTEPH Other NYHA 6MWT Syncope CHF Both
Nihill (1991) 14 20.5 ± 12.1 78.6 % 6 1 6 1 3.8 ± 0.4 NA 5 6 3
Sobrino 3 36.0 ± 5.0 33 % 2 1 4.0 ± 0 NA 3
(1993)
Kerstein 15 24.9 ± 11.3 86.6 % 15 3.53 ± 0.52 305 ± 116 7 8
(1995)
Rich (1997) 6 38.8 ± 7.7 83.3 % 6 3.7 ± 0.5 NA 6
Thanapoulos 6 6.1 ± 2.6 NA 6 3±0 NA 3 3
(1996)
Hayden 6 35a 83.3 % 6 4.0 ± 0 NA 1 5
(1997)
Sandoval 15 33 ± 9 87 % 13 1 1 3.6 ± 0.6 107 ± 127 4 8 3
(1998)
Rothman 12 37 ± 12 83.3 % 9 1 1 1 3.6 ± 0.5 NA 6 5 1
(1999)
Kothari 11 16.2 ± 8.9 36 % 7 4 3.62 ± 0.69 NA 1 8 2
(2002)
Reichenberger 17 35.9 ± 14.2 70.6 % 13 2 1 1 3.7 ± 0.5 NA 4 10 3
(2003)
Kurzyna 2 26.5 ± 6.4 100 % 2 4.0 ± 0 NA 2
(2003)
Allcock 9 56.4 ± 22.4 100 % 6 3 3.7 ± 0.5 ~206 ± 120 9
(2003)
Vachiery 16 NA NA 16 3.6 ± 0.4 235 ± 139
(2003)
Micheletti 20 8.4 ± 5.6 55 % 19 1 3.5 ± 0.5 NA 12 7 1
(2006)
Kurzyna 11 33.0 ± 12 54.5 % 9 1 1 3.3 ± 0.5 NA 11
(2007)
Ciarka (2007) 11 48.0 ± 5 54.5 % 6 1 4 3.5 ± 0.5 376 ± 29 1 8 2
Law (2007) 43 12.5b 81 % 29 2 10 2 3–4 NA 18 22 3
O’Byrne 5 29.4 ± 10.5 60 % 5 3–4 NA 2 2 1
(2007)
Lammers 7 8.9 ± 5.4 57 % 7 3.1 ± 0.4 NA 3 4
(2007)
Els Troost 15 48.2 ± 20.5 80 % 5 3 1 3 3 4.0 ± 0 322 ± 87 15
(2009)
Fenstad (2011) 8 40.0 ± 13 89 % 8 3–4 311 ± 131 8
Sandoval 34 35.0 ± 10 85 % 29 1 1 3 3.5 ± 0.6 100 ± 114 9 14 11
(2011)
Velázquez 7 NA 71 % 2 1 4 3–4 NA 2 5
(2012)
Baglini (2013) 11 45.5 ± 12 45.5 % 8 2 1 3.6 ± 0.5 NA 11
Total in series 304 30.7 ya 201/282 234/304 15/304 28/304 10/304 17/304 3.9 ± 0.3 – 86/288 145/288 57/288
(71.6 %) (77 %) (4.9 %) (9.2 %) (3.3 %) (5.6 %) (29.8 %) (50.3 %) (19.8 %)
Case reports 20 30 ± 13.5 13 (68.5 %) 14 (70 %) 3 (15 %) 2 (10 %) 1 (5 %) – 3.9 ± 0.3 NA 2 (20 %) 10 (50 %) 8 (40 %)
references
[33–52]
IPAH idiopathic pulmonary arterial hypertension, CTD PAH associated to collagen tissue disease, CHD PAH associated to previously corrected congenital heart disease,
CTEPH distal chronic thromboembolic pulmonary hypertension, 6MWT 6-min walk test, CHF Congestive heart failure, NA non-available
a
Mean value
b
Median
Table 20.2 Septostomy characteristics and outcome
Immediate Mortality Late Total
Author n Proc Blade BDAS Combined Size, mm death (24 h) 1-month deaths deaths Transplanted FW-up months
Nihill (1991) 14 14 4 10 8–20 2 1 2 5 1 31.5 (0–96)
Sobrino (1993) 3 3 3 16 ± 6 1 1 0–13 Mo
Kerstein (1995) 15 16 4 12 4–18 2 4 6 2 0–45 Mo
Rich (1997) 6 6 4 2 NA 2 1 3 NA
Thanapoulos (1996) 6 6 6 8.7 ± 1.2 0 0 22 Mo (4–48)
Hayden (1997) 6 6 6 NA 2 2 4 NA
Sandoval (1998) 15 22 22 10 ± 3 1 1 2 5 16 Mo (0–36)
Rothman (1999) 12 13 13 10.2 ± 1.3 2 1 2 5 5 0–18 Mo
Kothari (2002) 11 11 11 4–15 2 1 1 4 20 Mo (0–60)
Reichenberger 17 20 20 10.6 ± 1.6 4 1 5 5 0–18 Mo
(2003)
Kurzyna (2003) 2 2 2 7 ± 1.4 1 0–5 Mo
Allcock (2003) 9 12 12 15,3 ± 2.8 0 2 2 1 0–30 Mo
Vachiery (2003) 16 18 18 NA 1 1 1 3 NA
Micheletti (2006) 20 22 2 17 3 6.9 ± 2.4 0 2 2 2 2.1 y (1
Mo–6.7 y)
Kurzyna (2007) 11 14 14 6.6 ± 1.6 0 1 6 7 2 8.1 Mo
(0.8–20.2)
Ciarka (2007) 11 11 11 15,2 ± 2.7 0 NA
Law (2007) 43 46 30 5 11 12.2 ± 2.9 2 8 9 19 3 1981–2005
O’Byrne (2007) 5 5 4 1 NA 0 4–216 days
Lammers (2007) 7 7 7 11.7 ± 2.2 0 25.7 Mo
(18–31)
Els Troost (2009) 15 17 17 4 (3–5) 1 2 3 6 4 0.7 y (0–5.9)
Fenstad (2011) 8 11 11 NA 0 1 1 2 1 243 ± 183 days
Sandoval (2011) 34 50 50 8.5 ± 2.5 1 21 22 58.5 ± 38 Mo
(3–138)
Velázquez (2012) 7 9 9 Mean 11 0 4 4 1 18 Mo (0–67)
Baglini (2013) 11 11 11 NA 2 2 4 8.2 ± 3.8 Mo
Series 304 352 40 273 39 (11 %) Mean 10.8 24 (6.8 %) 17 (4.8 %) 62 102 35
(11.4 %) (77.5 %)
Case reports 20 20 14 6 8–18 mm 3 (15 %) 2 (10 %) 1 5 1 0–60 Mo
references [33–52]
Total 324 372 40 287 45 (27/372) 7.2 % (19/372
5.1 %
Proc procedures, BDAS balloon dilation atrial septostomy, FW-up follow-up, Mo Months, y years, NA non-available
Table 20.3 Variables associated with immediate (24 h) mortality, Univariate analysis
Hazard ratio (95 %
Variable confidence interval) p Value
Age, yrs 1.01 (0.990–1.037) 0.263
NYHA 2.82 (1.02–7.81) 0.045
Syncope 0.17 (0.04–0.75) 0.019
Right heart failure 3.09 (1.24–7.66) 0.015
Type, BDAS 1.51 (0.641–3.58) 0.343
Size, mm 0.97 (0.797–1.24) 0.973
Baseline RAP, mmHg 1.13 (1.07–1.19) 0.000
Baseline RAP > 20 mmHg 11.4 (3.75–34.7) 0.000
RAP after, mmHg 1.18 (1.07–1.31) 0.001
Baseline PAP, mmHg 1.03 (1.01–1.05) 0.001
Baseline LAP, mmHg 1.07 (0.93–1.2) 0.331
LAP after, mmHg 1.26 (1.07–1.48) 0.005
Baseline R-L atrial pressure, mmHg 1.12 (1.04–1.21) 0.002
R-L atrial pressure after, mmHg 1.03 (0.91–1.17) 0.557
Baseline SaO2% 0.99 (0.88–1.11) 0.944
SaO2% after 0.91 (0.87–0.95) 0.000
Delta (decrease) SaO2% 1.09 (1.05–1.13) 0.000
Baseline Cardiac Index, L min m2 0.32 (0.12–0.85) 0.022
Cardiac Index after, L min m2 0.46 (0.64–1.32) 0.154
Delta Cardiac Index (%) 1.01 (1.006–1.03) 0.003
(~10 mm) in a step-by-step fashion, rather than large orifices, which probably
accounts for the reduction in procedure-related deaths noticed in the last few years.
In this global experience analysis there have been 27 immediate (first 24 h)
procedure-related deaths (~7 %), most of them related to acute and refractory
hypoxemia. If we also take into account the deaths occurring within 1-month
(although not necessarily related to the procedure itself) the global procedure mor-
tality for atrial septostomy is about 12 %.
Variables associated with immediate, procedure-related mortality are shown in
Table 20.3. The baseline RAP, in particular a RAP greater than 20 mmHg is the
most significant risk factor for death due to the procedure. A decrease (delta) in the
arterial oxygen saturation after the procedure, perhaps as a result of the creation of
a “too large” septostomy is also associated with the risk of death. Refractory hypox-
emia is indeed a feared complication. In this regard, the use of inhaled Iloprost for
the treatment of severe refractory hypoxemia post septostomy, proposed by Kurzyna
et al. [23], is a useful recommendation and an important contribution.
In patients surviving the procedure, symptoms and signs of RVF are improved
after AS (i.e., syncope and systemic venous congestion either disappear or decrease
in frequency or intensity) and, as seen in Table 20.1, about 10 % have received a
lung transplant.
20.0
10.0
0.0
Delta SaO2%
−10.0
−20.0
−30.0
−40.0
−50.0
0.0 50.0 100.0 150.0
Delta CI %
Fig. 20.2 Correlation between the change in cardiac index (Delta CI%) and the change in arterial
oxygen saturation (Delta SaO2%); r = −0.49; p ≤ 0.001
Regarding the immediate hemodynamic effects after septostomy in this

worldwide experience, there is a modest but significant decrease in RAP (from
14.8 ± 8 to 11.8; p < 0.001) which is similar to the increase in left atrial pressure
(from 5.9 ± 3.3 to 8.3 ± 4; p < 0.00). As a result of the decrease in RAP and the
increase in left atrial pressure, the interatrial gradient of pressure (R-L atrial pres-
sure) decreased significantly (from 8.4 ± 7 to 3.0 ± 5.7; p < 0.001). Due to the shunt-
ing of blood after septostomy, there is a significant increase in the cardiac index
(from 2.0 ± 0.68 to 2.61 ± 0.80; p < 0.001) and, as expected, also a significant
decrease in arterial oxygen saturation (from 93.1 ± 3.9 to 83.0 ± 8.4; p < 0.001).
Figure 20.2 demonstrates the significant inverse correlation between the increase in
CI and the decrease in SaO2%. Pulmonary and systemic pressures did not signifi-
cantly change after septostomy.
The hemodynamic effects after septostomy depend on the level of baseline RAP
(Table 20.4). The higher the baseline RAP the more pronounced the hemodynamic
effects, especially in the group with RAP > 20 mmHg. These patients, however,
have a significant risk of death during the procedure as a result of refractory hypox-
emia. The indications for the procedure varied among the groups. Although syncope
was the main indication for the procedure in patients with baseline a RAP < 10 mmHg,
there was also some improvement in CI in this group. Based on this simple analysis,
the best risk/hemodynamic benefit ratio is for the group with a RAP between 10 and
20 mmHg.
It is important to stress that most of the hemodynamic changes reported until
now are during rest and the situation might be quite different during exercise when
428
Table 20.4 Hemodynamic effects of atrial septostomy according to baseline right atrial pressure
Baseline RAP < 10 mmHg Baseline RAP 10–20 mmHg Baseline RAP > 20 mmHg
(N = 27) (N = 51) (N = 26)
Variable Before After p Value Before After p Value Before After p Value
Age, years 23 ± 14 28 ± 14 27.5 ± 12
Syncope (%) 65.2 % 26.2 % 12 %
RVF (%) 26 % 33.3 % 64 %
Both (RVF + syncope) 8.7 % 40.5 % 24 %
RAP, mmHg 5.8 ± 1.96 5.48 ± 3.1 0.622 14.1 ± 3.2 11.4 ± 3.8 0.001 25.8 ± 4.9 19.2 ± 4.4 0.001
LAP, mmHg 4.9 ± 2.47 6.5 ± 2.5 0.050 5.3 ± 3.6 7.9 ± 4.2 0.001 7.9 ± 3 10.4 ± 3.7 0.024
R-L atrial pressure, 1.17 ± 3.2 −1.32 ± 3.2 0.023 8.4 ± 4.1 3.3 ± 5.5 0.001 17.3 ± 5 7.7 ± 5.3 0.001
mmHg
Mean PAP, mmHg 62.8 ± 17 64 ± 19.6 0.588 64.9 ± 16.7 65.6 ± 16.7 0.617 64.8 ± 23 69.9 ± 24.7 0.185
Cardiac Index, 2.37 ± 0.61 2.80 ± 0.7 0.001 2.10 ± 0.70 2.7 ± 0.9 0.001 1.6 ± 0.5 2.2 ± 0.6 0.001
L min m2
SaO2% 93.5 ± 4.1 87.2 ± 7.4 0.001 92.9 ± 4.1 82.8 ± 7.4 0.001 92.2 ± 4.5 78.3 ± 9.7 0.001
Procedure-related 0/27 (0 %) 2/51 (4 %) 11/26 (42.3 %)
mortality 1-month
RVF right ventricular failure; rest of abbreviations as in Table 20.3
J. Sandoval and A. Torbicki
450
Before After
400
350
300
250
200
150
100
50
0
Sandoval 98 Vachiery 2003 Allcock 2003 Els Troost 2009
Fig. 20.3 Effect of atrial septostomy on exercise capacity as assessed by 6-min walk test (6MWT),
in four of the reported series [15, 20, 21, 28]
the septostomy should be functioning as a safety valve. The greater role of septos-
tomy during exercise has been demonstrated by Austen many years ago [3] and this
may explain the improvement in exercise endurance reported in some series [15, 20,
21, 28] (Fig. 20.3).
The impact of septostomy on the long-term survival of the patients is difficult to
establish as there are no controlled studies (incidentally this applies also to all of our
pharmacologic interventions). However, most of the data on survival [12, 15, 25,
28] have shown a short-term beneficial effect when the Kaplan Meier survival esti-
mates for patients who survived septostomy are compared with those of predicted
survival based on the NIH equation or with historic controls. When examining these
survival curves, however, it becomes clear that the intervention provides only a
short-term survival benefit, indicating that AS is only a palliative procedure that
alleviates acute on chronic RV failure and provides valuable time for the application
of other interventions (i.e., PAH-specific drugs and/or transplantation).
Effects of Septostomy on Right Ventricular Function
With regard to the long-term effects of septostomy on RV function, information is

scarce but there appears to be a long-term improvement in RV function. Kerstein
[12] and Law [25] have shown an improvement in long-term hemodynamics; about
2 years after septostomy, RAP was lower and CI was higher than the values obtained
immediately after the procedure. Likewise, Espínola-Zavaleta [53] showed that
after 3–6 months after septostomy there was a reduction in right atrial and also in
both end-systolic and end-diastolic right ventricular areas, a finding that is compat-
ible with a decompression of the right heart chambers. In agreement with the
decompression phenomenon and the relief of failure is the report from O’Byrne
et al., demonstrating a significant decrease in BNP after septostomy [26].
Atrial septostomy may also have additional beneficial effects on RV function.
Ciarka and coworkers, showed a significant decrease in muscle sympathetic nerve
activity after the procedure despite the decrease in SaO2% [24], this is important as
it has been demonstrated that sympathetic overdrive in PAH may be one mechanism
involved in RV failure ([54], see Chap. 19). The decrease in sympathetic activity
after septostomy also likely reflects the decompression of the heart mediated by the
procedure as the drop in sympathetic activity correlated with the decrease in RAP.
An increase in systemic oxygen transport (SOT) resulting from the increase in CI
despite the drop in SaO2% has been suggested in some clinical studies as a potential
mechanism to explain the benefit of atrial septostomy in the setting of PAH [55].
The importance of this mechanism, however, has been recently questioned by inves-
tigators using computational models [56, 57] (see below).
Information Derived from Experimental

and or Computational Models
In a recent article by Zierer and coworkers [4], the effect of an interatrial shunt on
right atrial and right ventricular mechanics was addressed. The authors used a
canine model of right ventricular pressure overload produced by pulmonary artery
banding (PAB), similar to that used by Austen many years ago [3]. They used an
8 mm cannula connecting the two atria so that this interatrial shunt could be open or
closed to assess the hemodynamic effects. The effects of shunting on the mechanics
of the right heart chamber were assessed by the analysis of instantaneous pressure/
volume curves. Two levels of shunting were explored; low flow, equivalent to 15 %
of the total cardiac output, and high flow representing almost 30 % of the total out-
put, which was manipulated by controlling the venous return. The authors found
that the slope of Emax in both chambers, that is RV or RA contractility, does not
change. However the compliance changes, in particular the compliance of the right
atrium increases, especially during the low-flow maneuver. Apart from the improved
compliance of the right atrium, there was also a significant shift from the reservoir
to the conduit function ratio in this chamber. In addition, as a result of the increase
in LV preload due to the shunt, cardiac output and systemic oxygen delivery also
increased. However, and importantly, at high-flow shunt (30 % increase in output)
all of these beneficial effects on RA compliance and on systemic oxygen delivery
were reversed. Therefore, the lesson and conclusion from this work is that, when
performing the septostomy, one should try to keep the shunt at 15–20 % of the base-
line cardiac output.
In a dog model of acutely increased (moderate and severe) RV afterload pro-
duced by PAB designed to indentify the ideal right-to left shunt-fraction during
septostomy, Weimar et al. [5], recently arrived at a similar conclusion; in severe RV

hypertension (RVH), a shunt flow of 11 % of baseline CO represented the ideal
shunt-fraction. The authors also showed that in the setting of moderate RV stress,
atrial septostomy is a less promising intervention.
The increase in systemic oxygen delivery as a potential explanation for the clini-
cal benefit after atrial septostomy for PAH has been questioned upon the findings
derived from computer modelling on the effects of AS on tissue oxygenation. In one
of these studies, Diller and coworkers [56] showed that the clinically observed ben-
eficial effects of atrial septostomy are the result of improved blood flow rather than
augmented tissue oxygenation, provided that right ventricular function is adequate.
In another recent study by Koeken et al. [57], using a multiscale computational
model of the cardiovascular system, it was shown that AS only improves symptoms
of right heart failure in patients with severe PH if a net right-to-left shunt flow
occurs during exercise. The computational modeling also demonstrated that this
right–left flow enhances left ventricular filling and allows blood pressure mainte-
nance, but does not increase the oxygen availability of peripheral tissue.
Summary and Conclusions
Based on our review of this the available published data, some final conclusions can
be drawn: (1) In the majority of the patients AS has been performed in an advanced
stage of disease, when there is a significant risk of death. Yet, even in these very sick
patients, atrial septostomy may produce clinical as well as hemodynamic improve-
ment. The beneficial impact is on two of the prognostic variables which are associ-
ated with RV dysfunction in the setting of PAH: namely, RA pressure and cardiac
index, (2) The beneficial effect on these two variables appears to be the result of
both, an increase in left ventricular preload, and a decompression effect of the right
heart chambers, (3) At present the procedure-related mortality is still high but it
appears to be decreasing as the recommendations to minimize the risk are being
implemented [58]. The following guidelines are important: (a) Not to perform sep-
tostomy in moribund patients (RAP > 20 mmHg); (b) always attempt BDAS in a
step-by-step fashion; (c) monitor the important variables RAP, LVEDP, CI, and
SaO2%; (4) limit the size of the defect to a decrease in baseline SaO2% of no more
than 10 % and an increase in baseline cardiac index of no more than 15–20 % (see
also the data derived from the experimental models).
Figure 20.4 summarizes what we believe are the acute physiologic effects of an
atrial septostomy. First, as a result of the right-to-left shunt, there is an increase in
left ventricular preload and therefore an increase in cardiac output. Secondly, there
occurs a decompression of the right heart which decreases RV wall stress and oxy-
gen demand and possibly produces an improvement in RV performance, according
to the law of Laplace (As is an afterload reducing intervention), and this might also
contribute to the increase in cardiac output.
Chronic Pressure Overload
RV Hypertrophy
RV Dysfunction
↓ RH R-to-L
Dilation Shunt
↓ RV Wall
Stress &
O2 demand
Atrial Septostomy
↑ Cardiac
Output
↑ LV Preload
Fig. 20.4 Potential physiologic effects of BDAS. First, as a result of the right-to-left shunt, there
is an increase in left ventricular preload and therefore an increase in cardiac output. Secondly, there
is decompression of the right heart which decreases RV wall stress; improving RV performance
may also contribute to the increase in cardiac output
Future Perspectives
Timing
Based on the results obtained with atrial septostomy in patients with only mild-to-
moderate right ventricular dysfunction (i.e., patients with RAP lower than 10 mmHg)
in whom there appears to be a hemodynamic benefit and a very low procedure-
related mortality, it would appear appropriate to recommend the early employment
of the procedure in this population. Early intervention combined with PAH-specific
drug therapy has been recently suggested based on a retrospective clinical study
[30]. This recommendation, however, should be tested in a proper prospective man-
ner as there is experimental evidence that in the setting of moderate right ventricular
hypertension, atrial septostomy is a less promising intervention [5].
Closure of Septostomy
Spontaneous closure of the septostomy is not an infrequent finding when follow-

ing up on patients after septostomy, a problem that can be solved by repeating
the procedure. In this regard, however, other approaches have been undertaken.
Micheletti and coworkers in England proposed the use of a custom-designed

fenestrated Amplatzer device in children [22]. This approach has been used by
others [44, 46]. Another approach is the use of a butterfly Stent as reported by
Prieto [45] and others [52]. We do not know whether the introduction of an
Amplatzer device or a Stent will indeed prevent spontaneous closure. In a publi-
cation from the group that initially proposed the use of the Amplatzer device
[27], the authors reported on the occlusion of this device in four out of nine
patients despite the use of warfarin or aspirin. Very recently, the use of cryoabla-
tion of the septostomy borders has been described [59]. The safety as well as the
long-term efficacy of these additional interventions remains to be investigated.
Our personal point of view is that the septostomy closes either because the cre-
ated defect was too small (to avoid refractory hypoxemia in a given patient) or
because the gradient of pressure between the atria decreases and thus, closure
may signal a favorable long-term response to the hemodynamic changes after
septostomy.
Potts’ Procedure
The creation of a post-tricuspid shunt instead of an interatrial shunt might be another

approach to manage refractory RV dysfunction in the setting of PAH. The procedure
attempts to reproduce the Eisenmenger physiology in the setting of a patent ductus
arteriosus [6]. The Potts procedure, which basically consists of a side-by-side anas-
tomosis between the left pulmonary artery and the descending aorta, was proposed
for the management of PAH by Blanc and coworkers [60]. The authors initially
report on the outcome of this operation in 2 boys with supra-systemic pulmonary
hypertension. After the operation the patients improved rapidly; there was no fur-
ther syncope and the patients remained in functional class II at 6 and 18 months
after surgery.
In more recent communications of the same group of investigators, Serraf and
coworkers [61], and more recently Baruteau et al. [62] described the long-term
experience with this procedure. The procedures were performed between 2003 and
2010 in eight children (mean age: 110.4 ± 56.3 months). All of the children had
severe PAH and were refractory to medical PAH treatment. The baseline 6-min
walk distance (available for six of the patients) was 302 ± 95 m and all were in
WHO/NYHA class IV. The procedure was performed via a left thoracotomy with-
out cardiopulmonary bypass and the mean size of the shunt was 9 ± 3 mmHg. There
were two procedure-related deaths (postoperative days 11 and 13) due to a low
cardiac output which was attributed to stopping medical treatment preoperatively
[62] or to a restrictive anastomosis [61]. Although the Potts procedure is also a pal-
liative intervention, the long-term evolution of the 6 survivors was excellent. After
a follow-up of 63.7 ± 16.1 months all patients are alive, in NYHA/WHO functional
class I. The 6 min walk distance improved from 302 ± 95 to 456 ± 91 m. The marked
improvement of RV function, as assessed by BNP levels and echocardiography
findings was also documented.
So far, the procedure has been performed exclusively in children with PAH
where the Potts anastomosis may be a life-saving procedure and an alternative for
the treatment of children with severe PAH and RVF despite optimal medical treat-
ment. Although from a physiologic point of view it makes sense to perform a post-
tricuspid valve intervention that creates a PDA-Eisenmenger physiology, rather than
an interatrial shunt such as atrial septostomy, it is difficult to establish the superior-
ity of one procedure over the other because head-to-head comparisons are not avail-
able. We want to point out that children with PAH undergoing atrial septostomy in
the worldwide experience have been at an earlier stage of disease (i.e., lower RAP
and higher CI) when compared to adults, and the procedure-related mortality has
been relatively low in this pediatric population (~6 %) [63]. By reviewing the pre-
operative values of RAP and CI in Baruteau’s report a similar hemodynamic situa-
tion is found, syncope rather than end-stage RVF are the main indications for the
procedure in children. Intriguing is the long-term survival of those children who
survived after the Potts’ procedure.
At present, it is difficult to draw a firm conclusion regarding the general applica-
bility of the Potts shunt. Adults with advanced RVF from PAH undergoing Potts’
operation might have very significant perioperative mortality. A too narrow anasto-
mosis and other complications [64] may affect the postoperative course of these
patients. Accordingly, more experience and longer follow-up are necessary to con-
firm the initial and encouraging observations of this novel approach. The potential
usefulness of a unidirectional valved Potts anastomosis is now being tested in an
animal model of acute exercise-induced pulmonary hypertension [65].
References
1. D’Alonso GE, Barst RJ, Ayres SM, et al. Survival in patients with primary pulmonary hyper-
tension. Results of a national prospective study. Ann Intern Med. 1991;115:343–9.
2. Humbert M, Sitbon O, Chaouat A, et al. Survival in patients with idiopathic, familial, and
anorexigen-associated pulmonary arterial hypertension in the modern management era.
Circulation. 2010;122:156–63.
3. Austen WG, Morrow AG, Berry WB. Experimental studies of the surgical treatment of pri-
mary pulmonary hypertension. J Thorac Cardiovasc Surg. 1964;48:448–55.
4. Zierer A, Melby SJ, Voeller RK, Moon MR. Interatrial shunt for chronic pulmonary hyperten-
sion: differential impact of low-flow vs. high-flow shunting. Am J Physiol Heart Circ Physiol.
2009;296:H639–44.
5. Weimar T, Watanabe Y, Kazui T, et al. Impact of differential right-to-left shunting on systemic
perfusion in pulmonary arterial hypertension. Catheter Cardiovasc Interv. 2013;81:888–95.
6. Hopkins WE, Ochoa LL, Richardson GW, et al. Comparison of the hemodynamics and
survival of adults with severe primary pulmonary hypertension or Eisenmenger syndrome.
J Heart Lung Transplant. 1996;15:100–5.
7. Sandoval J, Gaspar J. Atrial septostomy and other interventional procedures. In: Peacock AJ,
Naeije R, Rubin LJ, editors. Pulmonary circulation. Diseases and their treatment. 3rd ed.
London: Hodder Arnold Ltd; 2011. p. 391–404. ISBN 978-0340981924.
8. Rich S, Lam W. Atrial septostomy as palliative therapy for refractory primary pulmonary
hypertension. Am J Cardiol. 1983;51:1560–1.
9. Rich S, Dodin E, McLaughlin VV. Usefulness of atrial septostomy as a treatment for primary
pulmonary hypertension and guidelines for its application. Am J Cardiol. 1997;80:369–71.
10. Nihill MR, O’Laughlin MP, Mullins CE. Effects of atrial septostomy in patients with terminal
cor pulmonale due to pulmonary vascular disease. Cathet Cardiovasc Diagn. 1991;24:
166–72.
11. Sobrino N, Frutos A, Calvo L, Casamayor LM, Arcas R. Palliative interatrial septostomy in
severe pulmonary hypertension. Rev Esp Cardiol. 1993;46:125–8.
12. Kerstein D, Levy PS, Hsu DT, et al. Blade balloon atrial septostomy in patients with severe
primary pulmonary hypertension. Circulation. 1995;91:2028–35.
13. Thanopoulos BD, Georgakopoulos D, Tsaousis GS, Simeunovic S. Percutaneous balloon
dilatation of the atrial septum: immediate and midterm results. Heart. 1996;76:502–6.
14. Hayden AM. Balloon atrial septostomy increases cardiac index and may reduce mortality
among pulmonary hypertension patients awaiting lung transplantation. J Transpl Coord. 1997;
7:131–3.
15. Sandoval J, Gaspar J, Pulido T, et al. Graded balloon dilation atrial septostomy in severe pri-
mary pulmonary hypertension. A therapeutic alternative for patients non-responsive to vasodi-
lator treatment. J Am Coll Cardiol. 1998;32:297–304.
16. Rothman A, Slansky MS, Lucas VW, et al. Atrial septostomy as a bridge to lung transplanta-
tion in patients with severe pulmonary hypertension. Am J Cardiol. 1999;84:682–6.
17. Kothari SS, Yusuf A, Juneja R, et al. Graded balloon atrial septostomy in severe pulmonary
hypertension. Indian Heart J. 2002;54:164–9.
18. Reichenberger F, Pepke-Zaba J, McNeil K, et al. Atrial septostomy in the treatment of severe
pulmonary arterial hypertension. Thorax. 2003;58:797–800.
19. Kurzyna M, Dabrowsky M, Torbicki A, et al. Atrial septostomy for severe primary pulmonary
hypertension. Report of two cases. Kardiol Pol. 2003;58:27–33.
20. Allcock RJ, O’Sullivan JJ, Corris PA. Atrial septostomy for pulmonary hypertension. Heart.
2003;89:1344–7.
21. Vachiery JL, Stoupel E, Boonstra A, Naeije R. Balloon atrial septostomy for pulmonary hyper-
tension in the prostacyclin era. Am J Respir Crit Care Med. 2003;167:A692.
22. Micheletti A, Hislop A, Lammers A, et al. Role of atrial septostomy in the treatment of
children with pulmonary arterial hypertension. Heart. 2006;92:969–72.
23. Kurzyna M, Dabrowski M, Bielecki D, et al. Atrial septostomy in treatment of end-stage right
heart failure in patients with pulmonary hypertension. Chest. 2007;131:947–8.
24. Ciarka A, Vachiery JL, Houssiere A, et al. Atrial septostomy decreases sympathetic overactiv-
ity in pulmonary arterial hypertension. Chest. 2007;131:1831–7.
25. Law MA, Grifka RG, Mullins CE, Nihill MR. Atrial septostomy improves survival in select
patients with pulmonary hypertension. Am Heart J. 2007;153:779–84.
26. O’Byrne ML, Berman-Rosenzweig ES, Barst RJ. The effect of atrial septostomy on the con-
centration of brain-type natriuretic peptide in patients with idiopathic pulmonary arterial
hypertension. Cardiol Young. 2007;17:557–9.
27. Lammers AE, Derrick G, Haworth SG, et al. Efficacy and long-term patency of fenestrated
Amplatzer devices in children. Catheter Cardiovasc Interv. 2007;70:578–84.
28. Troost E, Delcroix M, Gewillig M, Van Deyk K, Budts W. A modified technique of stent fen-
estration of the interatrial septum improves patients with pulmonary hypertension. Catheter
Cardiovasc Interv. 2009;73:173–9.
29. Fenstad ER, Le RJ, McGoon MD, et al. Atrial septostomy in patients with pulmonary arterial
hypertension. Circulation. 2011;124:A9476.
30. Sandoval J, Gaspar J, Peña H, et al. Effect of atrial septostomy on the survival of patients with
severe pulmonary arterial hypertension. Eur Respir J. 2011;38:1343–8.
31. Velázquez Martin M, Albarrán González-Trevilla A, Garcia Tejada J, et al. Utilidad de la sep-
tostomía auricular como tratamiento paliativo en pacientes con hipertensión pulmonar grave y
disfunción ventricular. Rev Esp Cardiol. 2012;65 Suppl 3:253.
32. Baglini R. Atrial septostomy in patients with end-stage pulmonary hypertension. No more
needles but wires, energy and close anatomical definition. J Interv Cardiol. 2013;26:62–8.
33. Collins TJ, Moore JW, Kirby WC. Atrial septostomy for pulmonary hypertension. Am Heart
J. 1988;116:873–4.
34. Hausknecht MJ, Sims RE, Nihill MR, et al. Successful palliation of primary pulmonary hyper-
tension by atrial septostomy. Am J Cardiol. 1990;65:1045–6.
35. Rothman A, Beltran D, Kriett JM, et al. Graded balloon dilation atrial septostomy as a bridge
to transplantation in primary pulmonary hypertension. Am Heart J. 1993;125:1763–6.
36. Unger P, Stoupel E, Vachiery JL, De Backer D. Atrial septostomy under transesophageal guid-
ance in a patient with primary pulmonary hypertension and absent right superior vena cava.
Intensive Care Med. 1996;22:1410–1.
37. Fulwani M, Nabar A, Iyer R, Lokhandwala Y. Palliative blade-balloon atrial septostomy in
primary pulmonary hypertension. Indian Heart J. 1997;49:185–6.
38. Takigiku K, Shibata T, Yasui K, Iwamoto M. Successful blade atrial septostomy in a patient
with severe primary pulmonary hypertension–a case report. Jpn Circ J. 1997;61:877–81.
39. Allcock RJ, O’Sullivan JJ, Corris PA. Palliation of systemic sclerosis-associated pulmonary
hypertension by atrial septostomy. Arthritis Rheum. 2001;44:1660–2.
40. Chau EMC, Fan KYY, Chow WH. Combined atrial septostomy and oral sildenafil for severe
right ventricular failure due to primary pulmonary hypertension. Hong Kong Med
J. 2004;10:281–4.
41. Moscussi M, Dairywala IT, Chetcuti S, et al. Balloon atrial septostomy in end-stage pulmonary
hypertension guided a novel intracardiac echocardiographic transducer. Catheter Cardiovasc
Interv. 2001;52:530–4.
42. Wawrzynska L, Remiszewski P, Kurzyna M, et al. A case of a patient with idiopathic pulmo-
nary arterial hypertension treated with lung transplantation: a bumpy road to success. Pol Arch
Med Wewn. 2006;115:565–71.
43. Rogan MP, Walsh KP, Gaine SP. Migraine with aura following atrial septostomy for pulmo-
nary arterial hypertension. Nat Clin Pract Cardiovasc Med. 2007;4:55–8.
44. Fraisse A, Chetaille P, Amin Z, et al. Use of Amplatzer fenestrated atrial septal defect device
in a child with familial pulmonary hypertension. Pediatr Cardiol. 2006;27:759–62.
45. Prieto LR, Latson LA, Jennings C. Atrial septostomy using a butterfly stent in a patient with
severe pulmonary arterial hypertension. Catheter Cardiovasc Interv. 2006;68:642–7.
46. O’loughlin AJ, Keogh A, Muller DW. Insertion of a fenestrated Amplatzer atrial septostomy
device for severe pulmonary hypertension. Heart Lung Circ. 2006;15:275–7.
47. Lagioia A, Atamañuk N, Bortman G. Tratamiento intervencionista de la hipertensión pulmo-
nar. Rev Insuf Cardíaca. 2007;2:137–40.
48. Althoff TF, Knebel F, Panda A, McArdle J, Gliech V, Franke I, Witt C, Baumann G, Borges
AC. Long-term follow-up of a fenestrated Amplatzer atrial septal occluder in pulmonary arte-
rial hypertension. Chest. 2008;133:283–5.
49. Baglini R, Scardulla C. Reduction of a previous atrial septostomy in a patient with end-stage
pulmonary hypertension by a manually fenestrated device. Cardiovasc Revasc Med. 2010;
11(4):264.e9–11.
50. Demerouti E, Manginas A, Rammos S, Athanassopoulos G, Karatasakis G, Pavlides
G. Postpartum pulmonary arterial hypertension: two cases covering a wide spectrum of pre-
sentations. Hellenic J Cardiol. 2012;53:472–5.
51. Kapoor A, Khanna R, Batra A, Kumar S. Inoue balloon atrial septostomy in severe persistent
pulmonary hypertension following surgical ASD closure. J Cardiol Cases. 2012;6:e1–3.
52. Roy AK, Gaine SP, Walsh KP. Percutaneous atrial septostomy with modified butterfly stent and
intracardiac echocardiographic guidance in a patient with syncope and refractory pulmonary
arterial hypertension. Heart Lung Circ. 2013;22(8):668–71. pii: S1443-9506(13)00025-5. doi:
10.1016/j.hlc.2013.01.005.
53. Espínola-Zavaleta N, Vargas-Barrón J, Tazar JI, et al. Echocardiographic evaluation of patients
with pulmonary hypertension before and after atrial septostomy. Echocardiography. 1999;
16:625.
54. Velez Roa S, Ciarka A, Najem B, et al. Increased sympathetic nerve activity in pulmonary
artery hypertension. Circulation. 2004;110:1308–12.
55. Sandoval J, Rothman A, Pulido T. Atrial septostomy for pulmonary hypertension. Clin Chest
Med. 2001;22:547–60.
56. Diller GP, Lammers AE, Haworth SG, et al. A modeling study of atrial septostomy for pulmo-
nary arterial hypertension, and its effect on the state of tissue oxygenation and systemic blood
flow. Cardiol Young. 2010;20(1):25–32. doi:10.1017/S1047951109991855.
57. Koeken Y, Kuijpers NHL, Lumens J, Arts T, Delhass T. Atrial septostomy benefits severe pul-
monary hypertension patients by increase of left ventricular preload reserve. Am J Physiol
58. Keogh A, Mayer E, Benza R, Corris P, Dartavelle P, Frost A, Kim N, Lang I, Pepke-Zaba J,
Sandoval J. Interventional and surgical modalities of treatment in PAH. J Am Coll Cardiol.
2009;54:S67–77.
59. Guerrero M, Cajigas H, Awdish R, Greebaum A, Khandelwal A, Sandoval J. First-in-man expe-
rience with cryoplasty during graded balloon atrial septostomy to reduce spontaneous closure in
a patient with severe pulmonary arterial hypertension. EuroIntervention. 2014;9(10):1235–6.
60. Blanc J, Vouhé P, Bonnet D. Potts shunt in patients with pulmonary hypertension. N Engl J
Med. 2004;350:623.
61. Serraf A, Petit J, Belli E, et al. Potts anastomosis for severe pulmonary arterial hypertension in
children. ATS International Conference, May 2007.
62. Baruteau AE, Serraf A, Lèvy M, et al. Potts shunt in children with idiopathic pulmonary arte-
rial hypertension: long-term results. Ann Thorac Surg. 2012;94:817–24.
63. Sandoval J, Pulido T, Gaspar J. Surgical interventional therapy using balloon atrial septostomy
and Potts’ procedure. In: Beghetti M, editor. Pediatric pulmonary hypertension. Munich:
Elsevier GmbH; 2011. p. 341–52.
64. Lakhani ZM, McGarry KM, Taylor RF, Fortune RL, Jugdutt BI. Two-dimensional echocardio-
graphic detection of left pulmonary artery aneurysm following Potts´s anastomosis. Chest.
1983;84:782–3.
65. Bui MT, Grollmus O, Ly M, Mandache A, Fadel E, Decante B, Serraf A. Surgical palliation of
primary pulmonary arterial hypertension by a unidirectional valved Potts anastomosis in an
animal model. J Thorac Cardiovasc Surg. 2011;142:1223–8.
Chapter 21
Right Ventricular Assist Devices
Lynn R. Punnoose, Marc A. Simon, Daniel Burkhoff, and Evelyn M. Horn
Introduction
Acute decompensated right heart failure (ADRFH) often proves refractory to medi-
cal therapy that includes measures such as pulmonary vasodilators, systemic vaso-
pressors, and inotropes (see also Chap. 10) oxygen therapy and (where appropriate)
balloon atrial septostomy. In this chapter, we will discuss the use of mechanical
circulatory support devices (MCSD) to sustain the failing right ventricle (RV). We
will focus in particular on the role of extracorporeal life support (ECLS) and inno-
vative device therapies in patients with pulmonary hypertension (PH), most of
whom are candidates for bridge to transplant (and occasionally bridge to recovery)
strategies.
L.R. Punnoose, M.D. (*)

Department of Cardiology, University of Pittsburgh Medical Center,
200 Lothrop Street, Scaife Hall, Pittsburgh, PA 15213, USA
e-mail: punnoosl@alum.mit.edu; punnoosel2@upmc.edu
M.A. Simon, M.D., M.S.
Heart and Vascular Institute, University of Pittsburgh Medical Center,
200 Lothrop Street, Scaife Hall, Pittsburgh, PA 15213, USA
e-mail: simonma@upmc.edu
D. Burkhoff, M.D., Ph.D.
Department of Medicine, Columbia University,
177 Fort Washington Avenue, New York, NY 10032, USA
e-mail: db59@columbia.edu
E.M. Horn, M.D.
Department of Medicine/Division of Cardiology, Weill Cornell Medical College of Cornell
University, 520 East 70th Street, ST-443, New York, NY 10021, USA
e-mail: horneve@med.cornell.edu

440 L.R. Punnoose et al.
Mechanical Circulatory Support Options for the Failing Right

Ventricle Vary by Clinical Scenario
Broadly defined as impaired RV filling or emptying in the absence of overt heart

failure (HF) symptoms [1], RV dysfunction arises in the setting of concomitant left
ventricular (LV) dysfunction, cardiomyopathies, lung disease, congenital heart dis-
ease, PH, and hepatic failure [2, 3]. RV failure is typically characterized by a com-
bination of low cardiac output and elevated central venous pressures (CVP) [4], and
elevated RV end diastolic pressure (EDP) [3], underfilling of the LV and variable
LVEDP, which clinically can manifest with systemic hypotension, fatigue, organ
hypoperfusion, peripheral edema, and ascites [5]. If left untreated, RV failure can
lead to end-organ damage, including renal and/or hepatic failure and death.
The initial goals of management of the patient with RV failure are to optimize RV
preload, contractility, and afterload [6]. Both hypervolemia and hypovolemia can
challenge RV function and reduce cardiac output [6, 7]. Volume removal strategies
include diuresis and ultrafiltration [3, 6]. Vasopressors such as norepinephrine and
vasopressin can be used to maintain systemic pressures above pulmonary arterial pres-
sures [6, 7]. Intravenous prostacyclins such as epoprostenol and treprostinil, as well as
inhaled therapies such as nitric oxide (iNO), iloprost, treprostinil, and even inhaled
milrinone can reduce pulmonary vascular resistance (PVR) and RV afterload [7].
For RV dysfunction refractory to medical therapy including inotropes, RV assist
devices (RVADs) may be considered [6]. RVADs have traditionally been used to
support the RV after acute myocardial infarction (MI), myocarditis, or in the setting
of post-cardiac surgery RV failure, such as after cardiotomy, in acute or chronic
rejection after heart transplant, or after left ventricular assist device implantation
(LVAD) [5–7]. Adverse events include thromboembolism, bleeding, and infection
[3]. In select cases with appropriate therapy and support, RV dysfunction tends to
be more reversible than left sided failure [2], permitting shorter duration of support.
But while RV failure remains a long-term sequela of device therapy in a subset of
patients with LVADs as “destination therapy,” there are currently no devices in the
United States approved for long-term support for persistent RV failure [8].
In patients with fulminant myocarditis, or after cardiotomy and LVAD implanta-
tion, biventricular support is associated with worse outcomes, in part related to
increased severity of disease with manifestations of multiorgan system dysfunction
[3]. In particular, the prevalence of RV failure after LVAD implantation is estimated
at greater than 40 % [8, 9] and mortality is greater than 70 % [9]. RV volume and
wall stress increase postoperatively, as the LV is decompressed and the septum
shifts leftward [4, 8]. In select patients, preemptive RVAD at the time of LVAD
implantation has been shown to lead to better outcomes in terms of survival to dis-
charge and 1 year survival [10].
In general, although virtually all patients have echocardiographic manifestations
of RV dysfunction after LVAD implantation, the incidence of frank acute RV failure
requiring device therapy has diminished with increasing use of continuous-flow
devices as compared to pulsatile devices and with more aggressive medical therapy.
21 Right Ventricular Assist Devices 441
While there are a multitude of risk profiles to predict the need for RVADs, some of
the simplest preoperative characteristics include signs of hepatic congestion (aspar-
tate aminotransferase AST > 80 U/L and bilirubin > 2 mg/dL) creatinine > 2.3 mg/dL
[11], blood urea nitrogen (BUN) > 39 [12], and a CVP/pulmonary capillary wedge
pressure (PCWP) ratio > 0.63 [12].
In those patients with PH and medically refractory RV failure, RVADs should be
cautiously considered as there is at least a theoretical risk that the high flow and
pressure generated in a remodeled pulmonary vascular bed may damage the pulmo-
nary microcirculation [6] and lead to pulmonary hemorrhage [13]. Newer
continuous-flow pumps may be safer in this regard. ECLS, which incorporates an
oxygenator blood pump, provides an alternative route to maintain cardiac output in
a patient with a failing RV [7] while minimizing this risk [6]. This will be addressed
in the ECLS section. Thus, approaches to device therapy in the setting of chronic
RV failure need to be distinct from those in the biventricular heart failure population
and must be individualized based on the pathology.
RVAD Design Innovations Focus on Miniaturization

and Blood Compatibility
Compared to LVADs, RVADs face much lower hydraulic loads and require lower
power [8]. On average, the devices must generate between 2 and 6 L/min of flow,
with a pump pressure between 20 and 50 mmHg [8]. To meet these requirements,
modifications to LVADs include outlet banding that increases resistance to flow [8],
constrictors [14], lower pump speed [9], and the use of spacers to shorten inflow
cannulas that are placed in the RV [14]. Such adaptations minimize the risk of pul-
monary overcirculation, ventricular suction events, and thrombosis [8].
Inflow cannulas can be placed in either the right atrium (RA) or RV. RV cannula-
tion maximizes RV unloading and reduces thrombus risk in severe dysfunction
when there is little expectation of recovery [15]. However, it has been associated
with higher scar formation and suction events compared to LV cannulation [8]. If
temporary support is required, RA cannulation [8] might allow for higher rates of
pulmonary valve opening, lower RV stroke work, and eventual RV recovery [15].
However, RA cannulation has also been used in pulsatile devices for longer support
as a bridge to transplantation [8].
Both pulsatile and continuous-flow devices are currently used for RV support.
Unlike pulsatile devices, continuous-flow assist devices empty the ventricle in both
systolic and diastole [8]. They are smaller and contain fewer moving parts compared
to pulsatile devices, with improved durability [8]. However, with decreased sensitiv-
ity to preload, continuous-flow devices are more susceptible to suction events [8].
Concerns about infection risk, quality of life, hemolysis, and thrombosis have
traditionally caused delays in referral for RV support [9] and are being addressed in
more recent device designs. Solutions currently under evaluation include miniatur-
ization, percutaneous approaches, and contactless suspension that reduce the surface
area exposed to blood and a control system then enables long-term support and
ambulation [9].
RVADs Vary in Terms of Implantation Technique,

Flow Rates, and Complications
MCSD are available in configurations ranging from extracorporeal, in which the

pumps are external to the body and connected via cannulas that are tunneled out of
the body, to implantable, in which the pumps are internal with only a control cable
tunneled out of the body. Technologies have evolved from pulsatile pumps that are
either electrically or pneumatically driven to continuous-flow pumps that work via
an inline turbine or a centrifugally oriented rotor. For support of the left ventricle,
most pumps utilized today are continuous-flow pumps due to the smaller size and
greater device longevity. However, many of these newer devices are not yet approved
for RV or biventricular support.
Extracorporeal Support
Extracorporeal pumps are designed for short-term mechanical support. They have
typically been used in critically ill patients who have developed RV failure after
cardiac surgery (cardiotomy, transplantation, and/or LVAD). Outcomes are gener-
ally poor but better than would otherwise be expected in such cases of multiorgan
failure and reflects the inherent high risk in this population [16–19].
Surgically Implanted Extracorporeal Devices
The centrifugal continuous-flow pump Centrimag® (Levitronix LLC, Waltham, MA,

USA) is the only FDA-approved extracorporeal device for RV support [3]. It uses a
magnetic suspended impeller [3, 9] (Fig. 21.1a) and can be used for up to 30 days of
support [3]. The lack of bearings and seals minimizes friction and wear over time, thus
reducing thermal damage to blood cells and lowering rates of hemolysis and thrombo-
sis [16]. In a retrospective review of 29 patients, this pump was used for the treatment
of RV failure after cardiotomy, transplantation, and LVAD implantation. The mean
duration of support was 8.8 days, with 70 % of the transplant and 58 % of the LVAD
patients successfully weaned off support. The 30-day mortality was 48 % [16].
By contrast, the Biomedicus® (Medtronic Inc., Minneapolis, MN, USA)
continuous-flow pump [9] (Fig. 21.1b) has higher rates of hemolysis [4] and platelet
damage [16]. Other adverse events include bleeding and thromboembolism [4].
In a retrospective review of 141 patients who required RV support after valve
surgery, coronary artery bypass grafting (CABG) or aortic surgeries, the Biomedicus®
pump was used in eight patients for isolated RV support and 23 for biventricular
support [17]. The duration of support ranged from 1 to 7 days for patients with
Fig. 21.1 Extracorporeal RV assist devices. (a) Centrimag impeller and pump (video by Thoratec
Corp.). (b) BioMedicus pump and circuits for RV support alone (left) and biventricular support
(right). Adapted with permission from Noon et al. [17]. (c) Abiomed BVS 5000 (video by Abiomed
Inc.). (d) TandemHeart circuit. Two configurations, one with outflow cannula in jugular vein (left)
and the other with cannulae in the right heart and PA (right). Adapted with permission from
CardiacAssist Inc. (e) Impella RP (video by Abiomed Inc.)
RVAD alone, and from 1 to 22 days for biventricular support. Only one RVAD
patient was successfully weaned off support, and eight off biventricular support [17].
A pulsatile device, the BVS 5000® (Abiomed, Inc.) requires a sternotomy as
the outflow graft must be anastamosed end to side to the main PA (Fig. 21.1c) [9].
It is a large device that significantly restricts mobility and requires re-operation to
remove [9]. A retrospective review [18] of 71 patients who received this pump
showed that 22 received it for biventricular support and 30 for RVAD alone. Cases
included RV failure after CABG and valve surgery, transplantation, LVAD implan-
tation, acute MI, myocarditis, and refractory ventricular arrhythmia. The mean
duration of support was 5.3 ± 4.2 days for RVADs and 5.1 ± 44 days for biVADs.
Fifty percent of patients receiving an RVAD and 36.4 % of those who received a
biVAD died [18].
Percutaneously Implanted Extracorporeal Devices
Both devices that are currently available for percutaneous implantation are indi-
cated for short-term use, only. The TandemHeart™ (CardiacAssist Inc., Pittsburgh,
PA, USA) percutaneous ventricular assist device (pVAD) is a centrifugal continuous-
flow pump which can be adapted to provide RV support [2, 3]. The RA and pulmo-
nary artery (PA) [2] are cannulated (Fig. 21.1d), with percutaneous access obtained
via the femoral vein. A recent review [19] included 46 patients in whom the pVAD
(percutaneous and surgical approach) was used for isolated RV as well as biven-
tricular support. Cases included acute MI, myocarditis, chronic LV dysfunction, and
patients post valve and CABG surgery. The mean duration of support was 4.8 ± 6.1
days for the percutaneous approach, and 6.5 ± 6.2 days for the surgical approach.
Mean flow provided was 4.2 ± 1.3 L/min. Overall in-hospital mortality was 57 %,
with cause of death being multiorgan failure [19].
An axial continuous-flow pump, the Impella RP can also provide RV support [3]
with flows up to 4.8 L/min [2]. It is a small device, with a diameter of 6.4 mm and
weight of 17 g, which permits both percutaneous and central approaches for implan-
tation (Fig. 21.1e) [9]. The inlet cannula is placed in the inferior vena cava (IVC)
and outflow in the PA [2]. Advantages over the Centrimag and AB5000 include a
much smaller surface area exposed to blood [2], but the device relies on mechanical
bearings which increase the risk of hemolysis and thrombosis [9]. As a result, it is
presently approved for only 10 days of support [9]. In first-in-man trials in Canada
and Europe, the device has been used in patients with RV failure after cardiac sur-
gery and after LVAD implantation. The duration of support has ranged from 1 to 7
days, with >60 % of patients being supported for more than 4 days and having the
device explanted upon recovery of the RV [2, 20].
Paracorporeal Support
The options for paracorporeal support are comprised of pneumatic pulsatile devices.
Of these, only the Thoratec PVAD (Thoratec Corp., Pleasanton, CA, USA) has been
approved by the FDA for RV support [3]. As a bridge to transplantation and recov-
ery [3, 9], it has been used for univentricular or biventricular support in over 4,000
patients since 2010 (Fig. 21.2a) [4]. In general, biventricular support has worse
outcomes than LV support alone [21] and planned biventricular support is
Fig. 21.2 Paracorporeal RV assist devices. (a) Thoratec PVAD, biventricular support model
(video by Thoratec Corp.). (b) Abiomed AB5000 ventricle (video by Abiomed Inc.). (c)
BerlinHeart Excor in biventricular configuration with driver allowing ambulatory support (video
by BerlinHeart GmbH)
associated with better outcomes than LVAD implantation followed by RV failure

requiring a second operation for RVAD implantation [10]. Single center experience
with biventricular support using the Thoratec PVAD has reported survival rates of
75 % when excluding those supported for postcardiotomy or post-infarct shock
which is known to have very poor outcomes [22].
The AB5000 (Abiomed Inc.) requires a sternotomy to cannulate the RA and PA
[16], but the device can be exchanged at the bedside without a re-operation [9].
Duration of support can last up to months [16]. It can generate flows of up to
5–6.5 L/min, and has a fixed drive pressure of 300 mmHg (Fig. 21.2b) [4]. Introduced
in 1988 [23], the BerlinHeart Excor (Berlin Heart GmbH) device can be used as a
bridge to recovery or transplantation [4]. It can provide ambulatory support for up

to 10 h [9], and has been demonstrated to provide biventricular support for up to 575
days (Fig. 21.2c) [23].
Implantable Devices
The pulsatile Thoratec IVAD™ (Thoratec Corp., Pleasanton, CA, USA) [3] can
provide intermediate to long-term support and is indicated for biventricular support
as a bridge to transplant or recovery (Fig. 21.3a) [9]. In a multicenter clinical trial of
29 patients, 15 received biventricular support using the IVAD. Of the 14 bridge to
transplant candidates, eight patients survived: one was weaned off support, and the
other seven were transplanted [24].
Continuous-flow devices such as the HVAD® (HeartWare International Inc., MA,
USA) and HeartMate II® (Thoratec Corp., Pleasanton, CA, USA) have been used to
provide biventricular support [9] in cases such as giant cell myocarditis [25] and
after cardiac arrest during non-cardiac surgery [26]. With dual controllers, the
Heartware system has been increasingly used as an alternative to the total artificial
heart. Such dual support can provide successful physiologic levels of support and
can alter flows to respond to changes in preload and afterload [26]. The duration of
support has ranged from 7 days [26] to 4 months [25]. Complications include suc-
tion events causing RA collapse [26]. Although these devices are not approved by
the FDA for RV support, they have been used for RV support in Europe and in the
United States (via individual appeals to the FDA for Humanitarian Device
Exemption), utilizing separate controllers and certain adaptations by some centers.
With such biventricular support, RVAD flows have been set lower than systemic
output, to avoid overloading the LV [8].
However, some investigators point out that adapting LVADs for RV support—
specifically by reducing pump speeds beyond design specifications—increases
thrombosis risk [8]. A continuous-flow pump designed specifically for the RV, the
Cleveland Clinic’s DexAide RVAD has been successfully implanted in calves and
averaged 24 ± 21days of support, generating flows of 5.4 ± 1 L/min [8, 9]. In animal
models of biventricular support using continuous-flow devices, these investigators
have found that the circulatory loop is most stable when RVAD flows are lower than
the LVAD’s [8]. Specifically, in a biventricular support model, RVAD speeds must
ideally (1) adjust so that flows match 50–75 % of the LVAD output at any point in
time and (2) have a maximum threshold so that, in the event of hypovolemia or LV
failure, the system can avoid suction events and overdriving [8].
The Circulite® Synergy® micropump has similarly been used for biventricular
support in fibrillating sheep hearts [14]. This miniature pump, which weighs 25 g,
has a pressure gradient of 70–80 mmHg and can generate flows up to 4.25 L/min.
Lower flow rates of 3 L/min can be generated at the lowest speed of 20,000 rpm and
a pressure gradient of 30 mmHg, which make it ideal for RV support (Fig. 21.3b)
[14]. In the fibrillating heart model, right and left sided flows always equilibrated,
Fig. 21.3 Implantable RV

assist devices. (a) Thoratec
IVAD (video by Thoratec
Corp). (b) Circulite device
configured for RV support
(video by Daniel Bukhoff)
with a proportional decrease in left atrial (LA)-aorta pressure gradient if the RA-PA
gradient were increased with increasing RVAD speeds [14]. The Circulite system is
currently undergoing revision.
Low Flow RVAD in PH Disease Models
There is potentially a great need for RV support in pulmonary arterial hypertension

(PAH), as many patients die from RV failure (see Chap. 14). RV dysfunction in the
setting of PAH or pulmonary veno-occlusive disease poses a significant challenge
Fig. 21.4 Simulated case of severe pulmonary arterial hypertension with incorporation of right
sided mechanical support device. (a) Total output compared to RV and device flows. (b) PA sys-
tolic, diastolic, and mean pressures. (c) Aortic systolic, diastolic, and mean pressures. (d) Wedge
and central venous pressures. (video by Punnoose et al. [27])
for mechanical support, as the RV pump failure is also accompanied by significant

LV diastolic dysfunction [27]. Case reports of patients in florid cardiogenic shock
have also described significantly elevated pulmonary pressures with and without
associated pulmonary hemorrhage after RVAD implantation [13, 28]. Indeed, a
computer simulation of the cardiovascular system in PAH and RV dysfunction
incorporating a continuous-flow micropump showed that, while left sided filling
and cardiac output improved with mechanical support, pulmonary arterial pressures
and PCWP rose significantly [27]. However, the increase in pulmonary arterial pres-
sures could be mitigated by setting lower RVAD flow rates with continued improve-
ment of the systemic hemodynamics (Fig. 21.4) [27].
Such a system has been shown to be feasible in animal models. One such device
is the OxyRVAD, which generates flows of up to 3 L/min through the pulmonary
vascular bed [29]. It includes both an axial flow pump and a low resistance gas
exchanger, with the VAD cannula placed in the RA appendage and the outflow graft
anastamosed to the PA. The device successfully provided hemodynamic support for
14 days in healthy sheep [29]. The MC3 BioLung is a thoracic artificial lung (TAL)
that has been studied in sheep models with chronic PH [30]. The circuit connects the
PA and LA, and it does not (yet) incorporate a blood pump. The total impedance of
the TAL in parallel with the native pulmonary circulation is less than the native
system alone, thus decreasing pulmonary resistance and RV afterload. More blood
can be diverted to the TAL when the PA is banded, but this is at the expense of
increased overall impedance and afterload. The systemic output drops when >75 %
of blood flow is diverted to the TAL [30].
More recently, the successful use of a paracorporeal artificial lung (PAL) has
been described in patients with PH and RV failure [31, 32]. The Novalung, which
does not incorporate a blood pump, connects the PA and LA and has been
demonstrated to generate flows of 3.5 L/min, reduce PA pressures, and improve
systemic hemodynamics [31]. In a retrospective review of patients with PAH who
were listed for lung transplantation, the incorporation of ECLS strategy with select
patients receiving the Novalung, was shown to reduce mortality and time on the
waiting list for transplantation [33].
Extracorporeal Life Support (ECLS)
Similar to the initiation of support for the left heart as a bridge to transplant in
INTERMACS 1 and/or 2 patients [34], several institutions have utilized the mark-
edly improved technology of ECLS in the PH patient population awaiting lung
transplant as a bridge to transplant or less commonly, as a bridge to recovery as the
best means of support for the ultimate failing RV [33, 35–37]. In a newer paradigm
of RV support, whereas the RVAD may ultimately be considered in the chronically
failing patient (Fig. 21.4), extracorporeal membrane oxygenation (ECMO) support
is the choice for the “crash and burn” viable, transplantable, “PH INTERMAS 1 and
2” equivalent in the setting of PH and RV failure. Timing is crucial—to intervene in
the patient with imminent but not end-organ injury generally characterized by ino-
trope dependence or resistance, diuretic resistance, systemic hypotension with renal
insufficiency and/or abnormal liver function tests. In particular, transfer of patients
to centers where cardiac support device therapies have been established in a timely
fashion is advisable. ECLS may include traditional femoral [38] vs. upper torso
ambulatory “Sport Model” configurations [39] for VA or VAV ECMO circuits, sin-
gle catheter VV configurations across existing intracardiac shunts [39] for effective
VA support, attempts at VV with larger natural or created PFO configurations and
PA-LA Novalung configurations [33].
Novalung
Extracorporeal AV removal of CO2 can be accomplished with newer generations of

low resistance membrane oxygenators (Avecor, Quadrox-D, Novalung) and smaller
canulas [40]. The pumpless interventional lung assist Novalung has been used in this
setting most frequently in Hannover, Germany and Toronto, Canada. It is a low resis-
tance device which can be connected as an AV circuit and perfused by approximately
20 % of the cardiac output [41]. Developments of the low resistance exchange mem-
brane and a biocompatible heparin/albumin coating has permitted prolonged pump-
less lung support which is driven by the patient’s cardiac output with maintained
pulsatile flow. While the Novalung does not require a pump for CO2 removal, a
centrifugal pump is added into the circuit in hypoxic patients. In some a VV circuit
with left atrial decompression (LAD) and centrifugal pump has been used to support
BTT patients for several weeks. Support for PAH patients who are dying from RV
failure necessitates both support of the heart and gas exchange with effective RV
unloading. Furthermore, the Novalung pulmonary artery to left atrium pumpless
configuration effectively unloads the RV, bypasses the venous occlusion and may be
the most effective support for the patient with PVOD. The underlying pulmonary
hypertension allows for sufficient generated force in the pulmonary artery to func-
tion as the driving force for the system [41] along with a canula size which is a
determining factor of flow. The oxygenator circuit is placed in parallel to the native
pulmonary circuit and overall PVR is thus decreased. There are institutions that pre-
fer this mechanical support to that of long-term ECMO configurations although
most often a temporary peripheral ECMO is placed for hemodynamic stabilization
prior to LAD central implantation. Earlier reports included parallel circuits to be
assured of patency but device exchanges have been performed without problems for
patients who are awaiting transplant for weeks.
Extracorporeal Cardiopulmonary Support (ECMO)
Traditional ECMO support began as early as 1930 with a roller pump in the setting
of massive pulmonary embolic events. Countless contributions and collaborative
efforts to deal with issues such as massive hemolysis, plasma leakage, artificial lung
technology, membrane oxygenators, prolonged bypass support, and silicone mem-
brane oxygenator have paved the wave to our modern use of it. Dr. Robert Bartlett
is responsible for bringing this technology to the neonates [42] and the onset of its
burgeoning success in the neonatal ICU. The introduction of ECMO in adult patients
has been much slower. Not until the CESAR UK trial as a regionalized ECMO
approach and one that utilized a VV approach, was there any success in adult respi-
ratory failure patients. Coincident with its development was the worldwide H1N1
pandemic and need for specialized centers which could provide ECMO support for
primary respiratory failure in previously healthy patients. In the current era, innova-
tions in cannula design, next generation centrifugal pump technology, membrane
construction, and now anticoagulation protocols have demonstrated the feasibility
of prolonged support with a durable device. It was essential to eliminate the massive
transfusion requirements and risks of hemorrhage previously inherent in adult
ECMO support. Further developments of upper body ECMO, extubation, and phys-
ical therapy on support have markedly changed the outcomes of patients awaiting
lung transplantation on ECMO support [43]. ECMO may, in fact, improve the pre-
transplant patient’s status by allowing physical therapy, conditioning, nutrition,
improvement of end-organ perfusion to allow for better post transplant outcomes.
Cannulation techniques and ECMO configurations may vary with either peripheral
or central cannulation, ECMO configurations with may be VV, VA, VAV, or pulmo-
nary artery to left atrium. Traditional concerns of femoral cannulation include both
a decreased upper extremity and importantly cerebral oxygenation, for which we
require monitoring of upper extremity arterial saturation and the need for antegrade
superficial femoral perfusion catheter due to risk of limb ischemia and lack of mobi-
lization. Introduction of a Dacron graft as an end to side anastomosis into the distal
subclavian artery and placement of a tunneled cannula into the graft protects the
upper limb and avoids direct cannulation of the subclavian artery coupled with a
right internal jugular venous drainage “Sport model” catheter allows for early
ambulation on ECMO [43]. Unique configurations of the VV EMCO for congenital
heart disease allow a bicaval dual lumen catheter to be placed under echocardio-
graphic guidance at the atrial septal defect level allowing oxygenated blood to be
shunted to the left atrium, and allowing for an oxygenated right to left shunt.
Overall, there has been significant progress in use of the mechanical support as a
bridge to lung transplant with >80 % successful bridging and outcomes post lung
transplant [36] making this now a viable option for a select number of patients
already listed for lung transplant. Attempts at extending this approach to “bridge to
recovery,” carrying patients over a period of RV pump failure to initiate more
aggressive PH therapy have on occasion been successful.
Summary
RV failure arises in a variety of clinical scenarios, ranging from primary RV dys-

function after an acute MI to failure in the setting of endstage severe pulmonary
hypertension. Rescue ECLS is a feasible option for bridging PH patients to lung
transplant with ECMO or pumpless PA to LA support (Novalung). Options for
RVAD mechanical support vary significantly in terms of invasiveness, duration of
support, complication profile and durability, and include extracorporeal, paracorpo-
real, and implantable devices. Efforts at design improvement are now focused on
device miniaturization, improved blood compatibility and combination with gas
exchange devices for longer periods of time. More recent applications which have
not yet been evaluated in larger trials include continuous-flow LVADs used in a
biventricular configuration, and low flow devices that combine a blood pump and
oxygenator to treat patients with RV failure and pulmonary hypertension. New
applications of mechanical devices to provide respiratory support, overcome hemo-
dynamic instability and acute on chronic right ventricular failure, and devices
which provide chronic right ventricular support and combined cardiopulmonary
support will lead to a new era of support for the patient with the failing RV
(Fig. 21.5) [44, 45].
Fig. 21.5 Algorithm for selecting the appropriate RVAD in patients with cardiogenic shock.
Image reprinted with permission from Medscape Reference (http://emedicine.medscape.com/)
2013 [44] and Kar et al. [45]
Disclosure Daniel Burkhoff is an employee of Heartware Inc., manufacturer of the Synergy

micropump.
References
1. Haddad F, Ashley E, Michelakis ED. New insights for the diagnosis and management of right
ventricular failure, from molecular imaging to target right ventricular therapy. Curr Opin
Cardiol. 2010;25:131–40.
2. Goldstein JA, Kern MJ. Percutaneous mechanical support for the failing right heart. Cardiol
Clin. 2012;30:303–10.
3. Simon MA. Assessment and treatment of right ventricular failure. Nat Rev Cardiol.
2013;10:204–18.
4. Hsu P, Parker J, Egger C, et al. Mechanical circulatory support for right heart failure: current
technology and future outlook. J Artif Organs. 2012;36(4):332–47.
5. Haddad F, Skhiri M, Michelakis E. Right ventricular dysfunction in pulmonary hypertension.
In: Yuan et al., editors. Textbook of pulmonary vascular disease. New York: Springer; 2011.
6. Price LC, Wort SJ, Finney SJ, Marino PS, Brett SJ. Pulmonary vascular and right ventricular
dysfunction in adult critical care: current and emerging options for management: a systematic
literature review. Crit Care. 2010;14:R169.
hypertension and right heart failure. Am J Respir Crit Care Med. 2011;184:1114–24.
8. Fukamachi K, Shiose A, Massiello AL, et al. Implantable continuous-flow right ventricular
assist device: lessons learned in development of a Cleveland Clinic device. Ann Thorac Surg.
2012;93(5):1746–52.
9. Hsu P, Parker J, Egger C et al. Mechanical right ventricular assistance—past, present and
future. In: World Congress on Medical Physics and Biomedical Engineering, IFMBE
Proceedings. 2013; vol 39. p. 1365–8.
10. Fitzpatrick 3rd JR, Frederick JR, Hieseinger W, et al. Early planned institution of biventricular
mechanical circulatory support results in improved outcomes compared with delayed conver-
sion of a left ventricular assist device to a biventricular assist device. J Thorac Cardiovasc
Surg. 2009;137(4):971–7.
11. Matthews JC, Koelling TM, Pagani FD, et al. The right ventricular failure risk score a
preoperative tool for assessing the risk of right ventricular failure in left ventricular assist
device candidates. J Am Coll Cardiol. 2008;51(22):2163–72.
12. Kormos RL, Teuteberg JJ, Pagani FD, et al. Right ventricular failure in patients with the
HeartMate II continuous-flow left ventricular assist device: incidence, risk factors and effects
on outcomes. J Thorac Cardiovasc Surg. 2010;139:1316–24.
13. Gregoric ID, Chandra D, Myers TJ, Scheinin SA, Loyalka P, Kar B. Extracorporeal membrane
oxygenation as a bridge to emergency heart-lung transplantation in a patient with idiopathic
pulmonary arterial hypertension. J Heart Lung Transplant. 2008;27:466–8.
14. Schmitto JD, Burkhoff D, Avsar M, et al. Two axial-flow synergy micro-pumps as a biventricular
assist device in an ovine animal model. J Heart Lung Transplant. 2012;31:1223–9.
15. Gregory SD, Pearcy MJ, Fraser J, et al. Evaluation of inflow cannulation site for implantation
of right-sided rotary ventricular assist device. Artif Organs. 2013;37(8):704–11.
16. Bhama JK, Kormos RL, Toyoda Y, et al. Clinical experience using the Levitronix Centrimag
system for temporary right ventricular mechanical circulatory support. J Heart Lung Transplant.
2009;29:971–6.
17. Noon GP, Lafuente JA, Irwin S. Acute and temporary ventricular support with BioMedicus
centrifugal pump. Ann Thorac Surg. 1999;68:650–4.
18. Morgan JA, Stewart AS, Lee BJ, et al. Role of the Abiomed BVS 5000 device for short-term
support and bridge to transplantation. ASAIO J. 2004;50:360–3.
19. Kapur NK, Paruchuri V, Jagannathan A. Mechanical circulatory support for right ventricular
failure. JACC: Heart Failure. 2013;1(2):127–34.
20. Cheung A, Leprince P, Freed D. First clinical evaluation of a novel percutaneous right ven-
tricular assist device: Impella RP. J Am Coll Cardiol. 2012;59(13):E872.
21. Kirklin JK, Naftel DC, Kormos RL, et al. Fifth INTERMACS annual report: risk factor analy-
sis from more than 6,000 mechanical circulatory support patients. J Heart Lung Transplant.
2013;32(2):141–56.
22. Tsukui H, Teuteberg JJ, Murali S, et al. Biventricular assist device utilization for patients with
morbid congestive heart failure: a justifiable strategy. Circulation. 2005;112(9 Suppl):I65–72.
23. Drews T, Loebe M, Hennig E, et al. The ‘Berlin Heart’ assist device. Perfusion.
2000;15:387–96.
24. Slaughter MS, Tsui SS, El-Banayosy A, et al. Results of a multicenter clinical trial with the tho-
ratec implantable ventricular assist device. J Thorac Cardiovasc Surg. 2007;133(6):1573–80.
25. McGee EC, Ahmad U, Tamez D, et al. Biventricular continuous flow VADs demonstrate diur-
nal flow variation and lead to end-organ recovery. Ann Thorac Surg. 2011;92:e1–3.
26. Loebe M, Bruckner B, Reardon MJ, et al. Initial clinical experience of total cardiac replace-
ment with dual Heartmate II axial flow pumps for severe biventricular heart failure. Methodist
Debakey Cardiovasc J. 2011;7:40–4.
27. Punnoose L, Burkhoff D, Rich S, Horn EM. Right ventricular assist device in end-stage pul-
monary arterial hypertension: insights from a computational model of the cardiovascular sys-
tem. Prog Cardiovasc Dis. 2012;55(2):234–43.
28. Rajdev S, Benza R, Misra V. Use of Tandem Heart as a temporary hemodynamic support
option for severe pulmonary artery hypertension complicated by cardiogenic shock. J Invasive
Cardiol. 2007;19:E226–9.
29. Wang D, Lick SD, Zhou X, et al. Ambulatory oxygenator right ventricular assist device for
total right heart and respiratory support. Ann Thorac Surg. 2007;84(5):1699–703.
30. Akay B, Reoma JL, Camboni D, et al. In-parallel artificial lung attachment at high flows in
normal and pulmonary hypertension models. Ann Thorac Surg. 2010;90(1):259–65.
31. Camboni D, Philipp A, Arlt M, et al. First experience with a paracorporeal artificial lung in
humans. ASAIO J. 2009;55(3):304–6.
32. Schmid C, Philipp A, Hilker M, et al. Bridge to lung transplantation through a pulmonary
artery to left atrial oxygenator circuit. Ann Thorac Surg. 2008;85(4):1202–5.
33. De Perrot M, Granton JT, McRae K, et al. Impact of extracorporeal life support on outcome in
patients with idiopathic pulmonary arterial hypertension awaiting lung transplantion. J Heart
Lung Transplant. 2011;30(9):997–1002.
34. Kirklin JK, Naftel DC, Kormos RL, Stevenson LW, et al. The fourth INTERMACS annual
report: 4000 implants and counting. J Heart Lung Transplant. 2012;31:117–26.
35. Olsson KM, Simon A, Strueber M, Hadem J, et al. Extracorporeal membrane oxygenation in
nonintubated patients as bridge to lung transplantation. Am J Transplant. 2010;10(9):2173–8.
36. Javidfar J, Brodie D, Iribarne A, et al. Extracorporeal membrane oxygenation as a bridge to
lung transplantation and recovery. J Thorac Cardiovasc Surg. 2012;144:716–21.
37. Toyoda Y, Bhama JK, Shigemura N, Zaldonis D, Pilewski J, Crespo M, Bermudez C. Efficacy
of extracorporeal membrane oxygenation as a bridge to lung transplantation. J Thorac
Cardiovasc Surg. 2013;145(4):1065–70.
38. Shafii AE, Mason DP, Brown CR, Vakil N, Johnston DR, McCurry KR, et al. Growing experi-
ence with extracorporeal membrane oxygenation as a bridge to lung transplantation. ASAIO
J. 2012;58:526–9.
39. Javidfar J, Brodie D, Wang D, et al. Use of bicaval dual-lumen catheter for adult venovenous
extracorporeal membrane oxygenation. Ann Thorac Surg. 2011;91:1763–9.
40. Lynch WR. Artifical lung. In: Annich GM, Lynch WR, MacLaren G, Wilson JM, Bartless RH,
editors. ECMO extracorporeal cardiopulmonary support in critical care. 4th ed. Ann Arbor,
MI: Extracorporeal Life Support Organization; 2012.
41. Strueber M, Hoeper MM, Fischer S, Cypel M, et al. Bridge to thoracic organ transplantation in
patients with pulmonary arterial hypertension using a pumpless lung assist device. Am J
Transplant. 2009;9:853–7.
42. Fortenberry J. The history and development of extracorporeal support. In: Annich GM, Lynch
WR, MacLaren G, Wilson JM, Bartless RH, editors. ECMO extracorporeal cardiopulmonary
support in critical care. 4th ed. Ann Arbor, MI: Extracorporeal Life Support Organization; 2012.
43. Javidfar J, Bacchetta M. Bridge to lung transplantation with extracorporeal membrane oxygen-
ation support. Curr Opin Organ Transplant. 2012;17:496–502.
44. Brittain EL, Maltais S. Extracorporeal tight ventricular assist devices. In: Peter K, editor.
Medscape. http://emedicine.medscape.com/article/2052470-overview. Accessed 22 Sept 2013.
45. Kar J, Gregoric ID, Basra SS, et al. The percutaneous ventricular assist device in severe refrac-
tory cardiogenic shock. J Am Coll Cardiol. 2011;57(6):688–96.
Chapter 22
Animal Models of Chronic Right Ventricular
Stress and Failure
Jose Gomez-Arroyo, Michiel Alexander de Raaf, Harm Jan Bogaard,

and Norbert F. Voelkel
Introduction
Animal models studies of disease are of pivotal importance for the investigation of
normal organ function, the pathobiology of frequent and rare disorders as well as for
preclinical proof of principle treatment studies. It has been increasingly noticed that
there is a substantial gap between our knowledge of left ventricular and right ven-
tricular failure (RVF) mechanisms and that the concepts of RVF mechanisms have
been mainly adapted from models of left ventricle failure or extrapolated from mod-
els of acute RVF [1]. Still today many of the heart failure studies that utilize geneti-
cally engineered mice focus their interest on the performance of the LV (the limitations
of mouse models of pulmonary hypertension have been recently reviewed [2]).
Experimental pulmonary hypertension research began with the discovery of
hypoxic pulmonary vasoconstriction by Euler and Liljestrand [3] and the pioneering
studies by Grover and Reeves [4, 5] and the Cardiovascular Pulmonary Research
Laboratory in Denver, Colorado. In the early days the main interest was the charac-
terization of the pulmonary hemodynamics and the associated remodeling of the
lung vessels upon exposure to chronic hypoxia. Certainly, the Fulton index, the ratio
J. Gomez-Arroyo, M.D., Ph.D. (*)

Department of Immunology, University of Pittsburgh,
3002 E. Broad Street, APT B, Richmond, VA 23223, USA
e-mail: jgomezarroyo@vcu.edu
M.A. de Raaf, M.Sc., B.A.Sc. • H.J. Bogaard, M.D., Ph.D.
De Boelelaan 1117, Amsterdam, The Netherlands
e-mail: m.deraaf@vumc.nl; hj.bogaard@vumc.nl
N.F. Voelkel, M.D.
1220 E. Brodd Street, Richmond, VA 23298, USA

456 J. Gomez-Arroyo et al.
between right ventricular/left ventricular weights, was always measured in all of the
animal studies and cardiac output was often measured using the green dye dilution
method. At the time tools were limited and cardiac function was difficult to assess;
echocardiography had not yet discovered the right ventricle. Furthermore, right ven-
tricular hypertrophy (RVH) was not determined as a study endpoint or had been the
endpoint of mechanistic investigations. Indeed, although in most circumstances
RVH was linearly related to the mean pulmonary artery pressure and right ventricu-
lar systolic pressure, a rationale to explain why some animals, within the same spe-
cies, exposed to the same conditions and duration of the experimental stimulus or
challenge, developed more or less RVH, was and remains a mystery.
Today, several models of pulmonary hypertension are used by investigators and there-
fore, the aim of this chapter is to briefly describe the current models of adaptive and mal-
adaptive RV hypertrophy in small and large animals. We seek to discuss the pros and cons
of each model depending on what aspect of the disease the researcher is trying to repro-
duce. Lastly, we make case for the development of new animal models of chronic RVF.
Large Animal Models of Right Heart Stress
Early investigators of large animal models performed main pulmonary arterial

banding (PAB) in dogs and cats to generate RV hypertrophy and to examine the
relationship between RV mass and stroke work [6] and then evaluated RV contrac-
tility after RV hypertrophied had been established [7, 8]. Geha et al. [6] were able
to generate an RV/LV ratio of 0.93 and an RV mass increase of 40 % in dogs 6
weeks after PAB surgery. In cats, Spann et al. [7] studied isolated papillary RV
muscle strips to measure contractility. Interestingly, when they constricted the pul-
monary artery to 20 % of the normal lumen, the animals developed RVH without
failure, but when they constricted the vessel lumen to 10 % of normal the animals
developed heart failure, which they defined both clinically (by the presence of pleu-
ral fluid and ascites) and hemodynamically (RV end-diastolic pressure 13 mmHg).
A major finding of their investigation was “an extreme depression of the intrinsic
contractile state with overt congestive heart failure” [7], while the active tension
produced by the muscle from RV hypertrophied hearts without failure was compa-
rable with the tension generated by normal RV muscle strips. Indeed, 6 weeks after
PAB the cardiac output was still comparable to that of unbanded cats [8]. Murray
et al. characterized RV myocardial perfusion 4 months after PAB and they demon-
strated no significant change in the ratio of the capillary to muscle fiber number,
suggesting sustained RV perfusion [9]. A more recent study collected morphometric
data of the RV coronary circulation in pigs following PAB. The authors found that,
5 weeks after PAB, the number of vessel segments is approximately four times
larger, in particular, the number of small arterioles and capillaries [10].
Kurt Stenmark’s group continues to investigate the pulmonary circulation in the
newborn calf, a model originally characterized by Reeves and Leathers [11]. In this
model, Holstein calves are exposed to chronic hypoxia inside a hypobaric chamber
in Fort Collins, Colorado, for 14 days, in order to simulate an altitude of 4,570 m
22 Animal Models of Chronic Right Ventricular Stress and Failure 457
above sea level (barometric pressure: 430 mmHg). Chronic hypoxia exposure not
only prevents the normal evolution of the fetal lung vessels but generates pulmonary
vasoconstriction and lung vessel remodeling resulting in a mean pulmonary arterial
pressure approaching 100 mmHg, while the RV/LV + S is approximately 0.85. Some
of the animals develop RVF as shown by an elevated right atrial pressure and RV
dilatation by echocardiography [12]. The right ventricles from these calves demon-
strate a disruption of the myocardial cytoskeleton as evidenced by altered expres-
sion of vinculin, metavinculin, desmin, and vimentin. Whether there is an increased
number of cardiomyocytes undergoing apoptosis in the right ventricles of this neo-
natal right heart failure model has not been investigated. However, the decreased
contractility of the RV was confirmed by decreased sarcomeric Ca++-sensitivity and
a decreased degree of protein phosphorylation [13].
Taken together, it is clear that a high-grade stenosis of the main pulmonary artery
and a relatively short exposure of neonatal calves to chronic hypoxia can cause RVF,
however, moderate stenosis will lead to adaptive RV hypertrophy. In PAB models of
right heart stress, the initiating event is the RV afterload, however, whether the tran-
sition from compensatory RVH to RVF is a direct consequence of pressure overload
or accompanied or caused by other factors such as neuroendocrine systems activa-
tion or systemic inflammation remains unknown.
Small Animal Models of Right Heart Stress and Failure
Because studies of large animals are expensive and increasingly difficult to do in a

highly developed system of regulatory agencies and because mice and rats can be
genetically modified, small animals are now preferred by many research groups. For
the past three decades, two rodent models have been central to the investigation of
human pulmonary hypertension: The chronic hypoxia exposure model and the
monocrotaline (MCT) lung injury model. Although the mechanisms whereby
hypoxia induces vascular remodeling are understood to some degree, complex oblit-
erative lesions such as those found in human patients with severe PAH do not develop
in the chronic hypoxia model. The MCT rat model continues to be a frequently
investigated model of PAH as it offers technical simplicity, reproducibility, and low
cost compared to other models of PAH. However, other rat models based on vascular
endothelial growth factor receptor blockade-based models have been introduced in
the last decade and continue to be characterized. Pulmonary artery banding (PAB)
can also be performed in mice and rats and allows the study of adaptive RV hyper-
trophy as well as interventional studies designed to “push the RV into failure.”
Pulmonary Artery Banding
Here we review the methods used to perform PAB in rats and mice and then survey
the published data in order to obtain a perspective of the strength and weaknesses of
PAB models of RVH and RVF. Similarly to the procedure in larger animals, a
stressor of the pulmonary artery is achieved with a suture or a clip. Briefly, after a
left thoracotomy, the pulmonary artery is dissected free from the aorta, as shown in
Fig. 22.1a. To fix the diameter of the suture, a silk thread is positioned behind the
pulmonary artery, Fig. 22.1b, c, and an 18-gauge needle is placed alongside the
pulmonary artery, as shown in Fig. 22.1d. A suture is tied tightly around the needle,
and the needle is rapidly removed to produce a fixed constricted opening in the
lumen equal to the diameter of the needle. One needs to make sure that the gradient
between the RV outflow tract and the pulmonary artery is close to 50 mmHg.
A gradient higher than 50 mmHg could lead to acute RV failure [9, 11, 14]. Banding
of the pulmonary artery can also be performed using a clip (Pulmonary Trunk
Banding, PTB) as described by Andersen et al. [15]. The remodeling of the RV
secondary to PAB is closely associated with the body weight gain. In fact, the band-
ing surgery should be performed in young animals (120 g) to allow for sufficient
hypertrophy to develop.
Many researchers have utilized the PAB model to study the effects of mechani-
cally induced pressure overload of RV. Olivetti and coworkers [16] performed PAB
in male Wistar rats, reducing the pulmonary arterial luminal diameter by 35 %
which caused a 70 % increase in the mass of the RV free wall (1.43 mm versus
0.8 in the sham-operated rats). The focus of their investigation was the RV capillary
luminal volume and the number of RV mast cells. Their rationale for counting the
Fig. 22.1 Surgical procedure to place pulmonary artery banding. Pulmonary artery is dissected
free from the aorta (a) white arrow and then a silk thread is positioned behind the pulmonary artery
(b-c) white arrow marks pulmonary artery. An 18-gauge needle is placed alongside the pulmonary
artery to set the degree of constriction (d) white arrow marks needle. The suture should be tied
tightly around the needle, and the needle rapidly removed to produce a fixed constricted opening
in the lumen equal to the diameter of the needle. Banding of the pulmonary artery can also be
performed using a clip (f and g) white arrow marks pulmonary artery
Table 22.1 Changes in right ventricular myocardium produced by pulmonary artery banding:
absolute component volumes, length, and surface area
Parameter SO rats PAB rats % difference p<
Volume, mm3
Ventricular wall 281 ± 36 426 ± 82 52 0.001
Myocytes 216 ± 30 338 ± 73 56 0.005
Cytoplasm 213 ± 30 334 ± 73 57 0.005
Mitochondria 73 ± 15 114 ± 27 56 0.005
Myofibrils 119 ± 18 197 ± 45 66 0.001
Matrix 22 ± 5 23 ± 10 5 NS
Interstitium 64 ± 9 88 ± 14 38 0.005
Myocyte length (m) 1,228 ± 296 1,252 ± 233 2 NS
Myocyte surface (mm2) 73,743 ± 17,409 72,647 ± 22,870 1 NS
Sarcomere length (μm) 2.15 ± 0.14 2.16 ± 0.09 1 NS
SO sham-operated rats, PAB pulmonary artery–banded rats. Results are presented as mean ± SD.
NS not significant (p > 0.05)
mast cells is interesting. They were motivated by their knowledge that mast cells
were implicated in tumor angiogenesis and they wondered whether the adaptive
capillary response to RV pressure overload could be explained by mast cell-
dependent release of heparin and subsequent heparin-mediated angiogenesis. They
found a twofold increase in the RV mast cell number. Prior to these studies, the
group of Anversa had characterized the changes in the RV myocardium 150 days
after the banding procedure and part of the data are summarized in Table 22.1 [17].
Faber et al. [18] evaluated right and left ventricular function in PAB rats (see also
Chap. 16) and found that 6 weeks of pressure overload resulted in enhanced base-
line RV contractility while LV baseline contractility remained unaffected. These
data are different from the data published by Piao et al. [19]. Piao, Archer, and col-
laborators showed that 4 weeks after PAB, the CO and treadmill distance were sig-
nificantly reduced in the PAB versus control animals. Possible explanations for this
discrepancy are the difference in pulmonary artery lumen reduction and the time
allowed for RV adaptation, as it has been illustrated by the different degrees of RV
expressed cytoplasmic proteins [20]. Bogaard et al. [14] revisited the rat PAB model
and compared the measurements obtained with the SU5416/hypoxia model, a model
of severe pulmonary hypertension and RVF (see below). The PAB rats were able to
tolerate high RV systolic pressures for a remarkably long time and TAPSE (tricus-
pid annular plannar systolic excursion), a heart-rate-independent measurement of
RV longitudinal contractility commonly used to evaluate RV function in patients
with PAH, was similar to that of control rat RVs (3.25 mm in PAB versus 3.46 in
controls). In order to explain why the RV of PAB rats was more “resilient,”
microarray-based gene expression analysis of the compensated rat RVH was per-
formed. This analysis allowed the characterization of a “RV failure transcriptional
signature” [21]. Following PAB surgery, rats showed an increased expression
of IGF-1 (insulin-like growth factor-1) mRNA, normal levels of phosphorylated
Akt and VEGF protein levels, as well as and an increased amount of apelin (another
pro-angiogenic factor) when compared to control RV tissues [21]. Another interest-

ing feature of the expression of RV in PAB rats are the changes in the gene expres-
sion as they relate to cardiac metabolism. PAB induces an increase in the expression
of genes encoding enzymes which control fatty acid oxidation and glycolysis [22].
In a recent study, it was found that the gene expression of acyl-coenzyme A dehy-
drogenases, a group of enzymes required for fatty acid β-oxidation, was increased
in the RV from PAB versus control rats. This change in the expression of genes
encoding enzymes required for fatty acid metabolism was associated with preserved
citrate synthase activity and respiration of mitochondria isolated from the RV when
tested for oxidative phosphorylation in vitro [23].
The differences between RV and LV subjected to pressure overload have also
been addressed in rodents. The Stanford pediatric cardiology group performed PAB
in mice and subjected RV and LV tissues to microarray gene expression analysis.
Animals with moderate pulmonary stenosis had a 50 % survival of >50 days.
Importantly, the right ventricular end-diastolic pressure increased 6 h postopera-
tively in mice with severe stenosis, but remained within the normal range in the
animals with moderate outflow tract stenosis. Furthermore, the authors demonstrated
a differential expression of genes between the pressure overloaded right ventricles
when compared to the left counterparts. In particular, the expression of periostin
was significantly different between the two models [24]. Altogether, the data sug-
gest that PAB can be used as a model of RV pressure overload with associated adap-
tive hypertrophy.
Chronic Hypoxia Exposure
Similarly to PAB, chronic hypoxia alone induces significant RV hypertrophy in rats

(and to a lesser degree in mice) but not RVF [2, 25]. As such, under physiological
conditions, chronic hypoxia could be used to generate a model of adaptive RV
hypertrophy, however if additional stressors are added or if essential genes required
for RV adaptation are genetically ablated, chronic hypoxia might be sufficient to
drive RV into failure. For example, Gautier et al. [26] demonstrated that inhaled
carbon monoxide during hypoxic exposure is associated with fibrosis and necrosis
of the RV, while carbon monoxide alone does not affect the RV tissue (Fig. 22.2).
Few investigators have examined the effects of gene deletion on RV function in
chronic PH. An early example was the study of heme oxygenase-1 (HO-1) knockout
mice, which is, perhaps, the first study to show that there are genes which are
required for the establishment of compensatory RV hypertrophy. HO-1 regulates the
response to reactive oxygen species in the cell and, upon exposure to chronic
hypoxia, HO-1−/− mice develop severe RV dilatation [27] (Fig. 22.3). More recently,
Cruz et al. examined the effect of RV pressure overload in caveolin-1 KO mice.
Caveolin-1 plays important roles in angiogenesis and cardiac hypertrophy. Similarly
to the HO-1 KO mice, Cav-1−/− mice developed signs of RVF after 3 weeks of chronic
hypoxia exposure [28]. The RV systolic pressure dropped (likely as the result of a
reduction in cardiac output) and RV contractility was also decreased (Fig. 22.4).
More importantly, the development of RVF was prevented by expressing an
Fig. 22.2 Carbon monoxide (50 ppm) alters the adaptive response of the RV to chronic hypoxia and
induced ischemic lesions when carbon monoxide was applied during 3 weeks of hypoxia. Normal RV
wall (a), RV necrosis indicated by the arrow (b), RV fibrosis (c), and RV tissue necrosis (d) occurring
in the hypoxic plus carbon monoxide-treated group [reproduced from Gautier et al. with permission]
Fig. 22.3 Right ventricular dilatation and wall-adherent thrombus in hemeoxygenase-1 knockout (b)
mice following 7 weeks of chronic hypoxia shown in comparison with the wild-type mouse RV (a).
Chronic hypoxia generated a modest increase in the RV afterload in the mice. The degree of RV pres-
sure increase was lower in the HO-1 knockout mice (c) [reproduced from Yet et al. with permission]
Fig. 22.4 The right ventricular pressure (RVSP) elevation is not maintained after 3 weeks of
hypoxic exposure in caveolin-1 (Cav-1) knockout mice when compared to wild type (a) and cave-
olin-1 reconstituted mice. The cardiac output dropped during chronic hypoxia exposure in the
caveolin knockout (Cav-1−/−) mice as well as the RV contractility index (b and c) [reproduced from
Cruz et al. with permission]
endothelial-specific Cav-1 transgene or by treating Cav-1−/− mice with a nitric oxide

synthase inhibitor. These data suggest that, at least in Cav-1−/− mice, increased
oxidative/nitrosative stress impairs the adaptive response of the RV to pressure over-
load, contributing to the transition from adaptive RV hypertrophy to RV failure.
Monocrotaline-Mediated Lung Injury
MCT is a macrocyclic pyrrolizidine alkaloid derived from the seeds of the Crotalaria
spectabilis plant. The MCT alkaloid is metabolized in the liver to the active metabo-
lite dehydromonocrotaline pyrrole (MCTP), a reaction that is highly dependent on
CYP3A4 (cytochrome p450) [29, 30]. When administered in a dose of 60 mg/kg
(usually subcutaneously), MCT induces a syndrome characterized—among other
manifestations—by lethal pulmonary hypertension and RVH [31, 32]. Importantly,
it has been recently reported that when administered in a dose of 40 mg/kg, which is
frequently used to induce “moderate” pulmonary hypertension, the MCT syndrome

is spontaneously reversible [30] MCT-induced pulmonary hypertension is one of the
standard models of PAH, however, the model is problematic because liver damage
and pulmonary fibrosis could contribute to the high animal mortality [29]. Indeed,
rats treated with 60 mg/kg of MCT exhibit an unusually high mortality in relation to
the function of the right ventricle, when compared to other models of PAH [29]. It
has been demonstrated that, along with pathological vascular remodeling, MCT-
treated rats exhibit a significant leukocyte infiltration of the myocardium in both left
and right ventricles, a feature that is uncommon in the human pulmonary vascular
diseases [29]. Furthermore, MCT-treated rats are highly prone to fatal arrhythmias
[33, 34]. All together these findings have raised the question of whether the rats, in
this particular model, die from pulmonary hypertension or with pulmonary hyper-
tension. Other variations of the MCT model have been described. When combined
with pneumonectomy, MCT (60 mg) causes severe PAH associated with dramatic
obliteration of the pulmonary arterioles, a finding that is not normally observed with
MCT alone. In this protocol rats develop substantial RVH (RV/LV + S: 0.08), but
because the animals only survive for approximately 5 weeks, this short-survival lim-
its the use of this model for preclinical studies. Furthermore, whether animals with
pneumonectomy plus MCT (60 mg) develop RVF is unknown [35].
Several groups of investigators have made use of the MCT rat model of PH to
assess RV function and a selection of these publications is listed in Table 22.2.
However, many of the drugs that have been shown to prevent or reverse RV failure
Table 22.2 The investigation of right ventricular function in the monocrotaline rat model
RVH, CHF Cardiac autonomic nerve abnormalities Sanyal et al. [44]
presynaptic vagal nerve degeneration
RVH ↑ plasma BNP and plasma norepinephrine Usui et al. [45]
↑ RV tissue BNP and ANP
RVH, RVF ↓ TAPSE (1.3 mm) ↑ RV end-diastolic Hardziyenka et al. [46]
(6.4 mm) diameter
RVH ↑ wall stress Borgdorff et al. [47]
RVF RV gene expression ↓ S1Rt1, PGC-1α, Enache et al. [48]
TFAM skeletal muscle mitochondrial
dysfunction precedes RV impairment
RVF ↓ IN β1 adrenergic receptor density Piao et al. [19]
Treatment of RV dysfunction
Simvastatin No mortality, ↓ mPAP, ↓RVH Nishimura et al. [49]
Bisoprolol Delay of time to RVF, no effect on RVSP de Man et al. [37]
Dehydroepiandrosterone ↓ mPAP, ↓ RVH Paulin et al. [50]
[DHEA]
Sildenafil Prevention of PH and RV dysfunction Jasinska-Stroschein
Fasudil Prevention of PH and RV dysfunction et al. [51]
Chloroquine Prevents progression of PH Long et al. [52]
Exercise Exercise ↑ RV capillarization, no change in Colombo et al. [53]
RVSP when compared with “sedentary”
MCT rats; unchanged pulmonary congestion
Further ↓ of CO in progressive PH Handoko et al. [54]
have also reduced RV afterload by affecting lung vascular remodeling. In this par-
ticular scenario, it is impossible to separate a potential direct myocardial drug effect
from the effects secondary to afterload reduction. Recently researchers have dem-
onstrated the beneficial effects of drugs on the RV without affecting the remodeled
lung circulation. Bogaard et al. [36], as well as de Man et al. [37], have demonstrated
that adrenergic receptor blockade with carvedilol or bisoprolol, respectively,
improve RV function and delay the progression to RV failure.
Whereas the MCT rat model of pulmonary hypertension remains a model favored
by many investigators. It is difficult to separate the effects of afterload reduction
from direct cardiac effects.
VEGF Receptor Blockade-Based Models

of Severe Pulmonary Hypertension
The VEGF receptor 1 (Flt) and 2 (KDR) blocker, SU5416, was one of the first small
molecule tyrosine kinase inhibitors discovered by screening for growth inhibitory
activity of cultured endothelial cells incubated with the potent angiogenic VEGF
ligand [38]. SU5416 when combined with a “second hit” such as chronic hypoxia,
ovalbumin treatment, or the immune insufficiency of the athymic rat (reviewed in
[31]), causes severe angioobliterative PAH. The SU5416/hypoxia model is charac-
terized by severe PH, it exhibits plexiform-like lesions and the model is largely
refractory to treatment. Furthermore, this model is attractive because RV dysfunc-
tion and failure occur in tandem with the severe lung vascular disease. Hemodynamic
measurements show that the cardiac output is severely reduced [39], (Fig. 22.5)
(see also Chap. 16).
This rat model has served as a model for preclinical drug studies designed
to examine whether the pulmonary vascular disease could be reversed once
established, and indeed, a wide range of drugs have been tested. Whereas simvas-
tatin (an HMG-CoA reductase inhibitor) and a bradykinin agonist had a small
effect on established PH and RVH, a Ca++ channel blocker (nifedipine), angiotensin
converting enzyme inhibitor (lisinopril), angiotensin receptor blocker (ibersartan)
and bosentan (a nonselective endothelin receptor blocker) were all not effective
[40, 41].
The RV from SU5416/hypoxia rats has been examined. Confocal microscopy of
the RV, after in vivo labeling of the endothelial cells of the cardiac microcirculation
with a texas red® conjugated tomato lectin (lycopersicon esculentum lectin) has
revealed that RV failure tissue is characterized by significant loss of capillaries (cap-
illary rarefaction) [42]. A microarray-based gene expression analysis has identified
a molecular signature in the failing RVs characterized by changes in angiogenesis,
metabolic remodeling, mitochondrial dysfunction, and fibrosis, etc. [21].
Other groups utilizing this SM5416/hypoxia model of RV failure have provided
important insights into the pathobiology of RVF. Stephen Archer’s group has
demonstrated a G-protein-coupled receptor kinase 2 (GRK2)-mediated uncoupling
Fig. 22.5 Right ventricular pressure increase (RVSP) and cardiac output (CO) decrease early and
late during the development of angioobliterative pulmonary hypertension (a, b); the dotted line
indicates the normal values. The right ventricular pressure and RV hypertrophy (RV/LV + S) are
related to the % number of obliterated pulmonary arterioles. (c, d) Reduction in cardiac output
early and late during the disease development is associated with an increase in the right ventricular
systolic pressure (a, b). Relationships between percentage of closed vessels (CV) and RVSP and
RV/LV + S weight ratio (c, d) [from Oka et al. [39] with permission]
of cardiac β-adrenergic receptor signaling [19] and in a different study, SU5416/

hypoxia rats treated with adenovirus-delivered mitofusion-2 exhibited decreased
pulmonary vascular resistance and improved the treadmill walking distance [43].
As stated, the SU5416/hypoxia rat animal model is a highly reproducible, which
reproduces multiple features of human PAH and RVF and is relatively refractory to
medical treatment; thus this model is well suited for preclinical proof of principle
studies. As a cautionary note, SU5416 affects the immune system and endothelial
cell differentiation, while treatment of rats with SU5416 alone is not sufficient to
induce RV dysfunction.
Experiments Designed to Push the RV into Failure
To begin investigating the molecular mechanisms underlying RVF we suggest two

different strategies: (1) Evaluate the effects of a drug that improves RV function
without affecting the lung vascular tone or remodeling, or (2) Induce failure in a
model of established adaptive RV hypertrophy. Because PAB and chronic hypoxia
usually result in RVH without failure, by adding one or several challenges one can
attempt to drive the RV into failure. One example of this strategy is treatment of rats
with stable PAB-induced compensated RVH with the histone deacetylase inhibitor
(HDACi) trichostatin A (TSA). Unlike the experimental improvement of LV hyper-
trophy observed after HDCA inhibition treatments, PAB rats treated with TSA, 4
weeks after the pulmonary artery had been ligated, develop severe RV failure. These
experiments suggest that the maintenance of a compensated overloaded RV requires
HDAC activity and that epigenetic modifications resulting from abnormal HDCA
activity/expression can influence the behavior of the stressed RV. As mentioned [27,
28], chronic hypoxia can be employed as a second hit to push the RV into failure,
however, prolonged hypoxia exposure periods may be necessary to generate overt
RVF. This particular strategy is useful when evaluating potentially cardiotoxic
effects of drug treatments designed to de-remodel the lung circulation.
Conclusions
Animal models serve as powerful tools in the evaluation of human diseases, but it is
clear that there are few perfect animal models and each of the models presented in
this chapter offers unique, and perhaps, complementary features for the researcher
invested in the exploration of the RV. The PAB model, as well as chronic hypoxia-
induced pulmonary hypertension, in rats and mice offer opportunities to study genes
and proteins required for the adaptation of the RV to chronic pressure overload.
Conversely, models of established RV failure such as MCT or SU5416/hypoxia can
be used to analyze the mechanisms involved in the transition from adaptive to mal-
adaptive RV hypertrophy and can therefore serve to identify the key molecular
mechanisms of reversal of RV failure. Although genetic mouse models of pulmo-
nary hypertension present multiple disadvantages, a systematic research program
utilizing transgenic mice engineered to evaluate the effects of loss or gain of func-
tion in the stressed RV will be of great benefit and advance our understanding of the
mechanisms of chronic RVF.
Summary for the Investigator
• There are large and small animal models of right ventricular strain and right heart
failure.
• There is not a single perfect animal model but each model offers unique, and
perhaps, complementary features.
• PAB causes RV hypertrophy with or without RVF depending on the degree of the
pulmonary outflow stenosis.
• RVF can be documented by echocardiography and hemodynamic assessment
(decrease in RVSP and decreased CO).
• There is a molecular signature pattern which distinguishes RVH and RVF.
• The SU5416/hypoxia rat model manifests signs of RVF characterized by apoptosis,
fibrosis, capillary rarefaction, and mitochondrial dysfunction.
References
1. Voelkel NF, et al. Mechanisms of right heart failure—a work in progress and a plea for failure
prevention. Pulm Circ. 2013;3(1):137–43.
2. Gomez-Arroyo JG, et al. A brief overview of mouse models of pulmonary arterial hyperten-
sion: problems and prospects. Am J Physiol Lung Cell Mol Physiol. 2012;302(10):L977–91.
3. Euler V, Liljestrand G. Observations on the pulmonary arterial blood pressure in the cat. Acta
Physiol Scand. 1946;12:301–20.
4. Will DH, et al. High altitude-induced pulmonary hypertension in normal cattle. Circ Res.
1962;10:172–7.
5. Reeves JT, Leathers JE. Hypoxic pulmonary hypertension of the calf with denervation of the
lungs. J Appl Physiol. 1964;19:976–80.
6. Geha AS, Duffy JP, Swan HJ. Relation of increase in muscle mass to performance of hypertro-
phied right ventricle in the dog. Circ Res. 1966;19(2):255–9.
7. Spann Jr JF, et al. Contractile state of cardiac muscle obtained from cats with experimentally
produced ventricular hypertrophy and heart failure. Circ Res. 1967;21(3):341–54.
8. Williams Jr JF, Potter RD. Normal contractile state of hypertrophied myocardium after
pulmonary artery constriction in the cat. J Clin Invest. 1974;54(6):1266–72.
9. Murray PA, et al. Effects of experimental right ventricular hypertrophy on myocardial
blood-flow in conscious dogs. J Clin Invest. 1979;64(2):421–7.
10. Huo Y, Linares CO, Kassab GS. Capillary perfusion and wall shear stress are restored in the
coronary circulation of hypertrophic right ventricle. Circ Res. 2007;100(2):273–83.
11. Reeves JT, Leathers JE. Circulatory changes following birth of the calf and the effect of
hypoxia. Circ Res. 1964;15:343–54.
12. Lemler MS, et al. Myocyte cytoskeletal disorganization and right heart failure in hypoxia-induced
neonatal pulmonary hypertension. Am J Physiol Heart Circ Physiol. 2000;279(3):H1365–76.
13. Walker LA, et al. Biochemical and myofilament responses of the right ventricle to severe
pulmonary hypertension. Am J Physiol Heart Circ Physiol. 2011;301(3):H832–40.
15. Andersen A, et al. Effects of phosphodiesterase-5 inhibition by sildenafil in the pressure
overloaded right heart. Eur J Heart Fail. 2008;10(12):1158–65.
16. Olivetti G, et al. Long-term pressure-induced cardiac hypertrophy: capillary and mast cell
proliferation. Am J Physiol. 1989;257(6 Pt 2):H1766–72.
17. Olivetti G, et al. Cellular basis of wall remodeling in long-term pressure overload-induced
right ventricular hypertrophy in rats. Circ Res. 1988;63(3):648–57.
18. Faber MJ, et al. Right and left ventricular function after chronic pulmonary artery banding in
rats assessed with biventricular pressure-volume loops. Am J Physiol Heart Circ Physiol.
2006;291(4):H1580–6.
19. Piao L, et al. GRK2-mediated inhibition of adrenergic and dopaminergic signaling in right
ventricular hypertrophy: therapeutic implications in pulmonary hypertension. Circulation.
2012;126(24):2859–69.
20. Faber MJ, et al. Time dependent changes in cytoplasmic proteins of the right ventricle during
prolonged pressure overload. J Mol Cell Cardiol. 2007;43(2):197–209.
21. Drake JI, et al. Molecular signature of a right heart failure program in chronic severe pulmonary
hypertension. Am J Respir Cell Mol Biol. 2011;45(6):1239–47.
22. Fang YH, et al. Therapeutic inhibition of fatty acid oxidation in right ventricular hypertrophy:
exploiting Randle’s cycle. J Mol Med (Berl). 2012;90(1):31–43.
23. Gomez-Arroyo J, et al. Metabolic gene remodeling and mitochondrial dysfunction in failing
right ventricular hypertrophy secondary to pulmonary arterial hypertension. Circ Heart Fail.
2013;6(1):136–44.
24. Urashima T, et al. Molecular and physiological characterization of RV remodeling in a murine
model of pulmonary stenosis. Am J Physiol Heart Circ Physiol. 2008;295(3):H1351–68.
25. Brown RD, et al. MAP kinase kinase kinase-2 (MEKK2) regulates hypertrophic remodeling of
the right ventricle in hypoxia-induced pulmonary hypertension. Am J Physiol Heart Circ
Physiol. 2013;304(2):H269–81.
26. Gautier M, et al. Continuous inhalation of carbon monoxide induces right ventricle ischemia
and dysfunction in rats with hypoxic pulmonary hypertension. Am J Physiol Heart Circ
Physiol. 2007;293(2):H1046–52.
27. Yet S-F, et al. Hypoxia induces severe right ventricular dilatation and infarction in heme
oxygenase-1 null mice. J Clin Invest. 1999;103:R23–9.
28. Cruz JA, et al. Chronic hypoxia induces right heart failure in caveolin-1-/- mice. Am J Physiol
29. Gomez-Arroyo JG, et al. The monocrotaline model of pulmonary hypertension in perspective.
Am J Physiol Lung Cell Mol Physiol. 2012;302(4):L363–9.
30. Ruiter G, et al. Reversibility of the monocrotaline pulmonary hypertension rat model.
Eur Respir J. 2013;42(2):553–6.
31. Nicolls MR, et al. New models of pulmonary hypertension based on VEGF receptor blockade-
induced endothelial cell apoptosis. Pulm Circ. 2012;2:434–42.
transcriptional profile in experimental pulmonary hypertension. Physiol Genomics. 2013;
45(12):449–61.
33. Benoist D, et al. Arrhythmogenic substrate in hearts of rats with monocrotaline-induced
pulmonary hypertension and right ventricular hypertrophy. Am J Physiol Heart Circ Physiol.
2011;300(6):H2230–7.
34. Mitani Y, Maruyama K, Sakurai M. Prolonged administration of L-arginine ameliorates
chronic pulmonary hypertension and pulmonary vascular remodeling in rats. Circulation.
1997;96(2):689–97.
35. Okada K, et al. Pulmonary hemodynamics modify the rat pulmonary artery response to injury.
A neointimal model of pulmonary hypertension. Am J Pathol. 1997;151(4):1019–25.
doi:10.1164/rccm.201003-0335OC.
37. de Man FS, et al. Bisoprolol delays progression towards right heart failure in experimental
pulmonary hypertension. Circ Heart Fail. 2012;5(1):97–105.
38. Fong TA, et al. SU5416 is a potent and selective inhibitor of the vascular endothelial growth
factor receptor (Flk-1/KDR) that inhibits tyrosine kinase catalysis, tumor vascularization, and
growth of multiple tumor types. Cancer Res. 1999;59(1):99–106.
39. Oka M, et al. Rho kinase-mediated vasoconstriction is important in severe occlusive pulmonary
arterial hypertension in rats. Circ Res. 2007;100(6):923–9.
40. Taraseviciene-Stewart L, et al. Simvastatin causes endothelial cell apoptosis and attenuates
severe pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol. 2006;291(4):L668–76.
41. Taraseviciene-Stewart L, et al. Bosentan fails to prevent right ventricular hypertrophy and
heart failure in immune impaired animals exposed to chronic hypoxia. Am J Respir Crit Care
Med. 2009;179:A1822.
43. Ryan JJ, et al. PGC1alpha-mediated mitofusin-2 deficiency in female rats and humans with
pulmonary arterial hypertension. Am J Respir Crit Care Med. 2013;187(8):865–78.
44. Sanyal SN, et al. Cardiac autonomic nerve abnormalities in chronic heart failure are associated
with presynaptic vagal nerve degeneration. Pathophysiology. 2012;19(4):253–60.
45. Usui S, et al. Upregulated neurohumoral factors are associated with left ventricular remodeling
and poor prognosis in rats with monocrotaline-induced pulmonary arterial hypertension. Circ
J. 2006;70(9):1208–15.
46. Hardziyenka M, et al. Right ventricular failure following chronic pressure overload is associ-
ated with reduction in left ventricular mass evidence for atrophic remodeling. J Am Coll
Cardiol. 2011;57(8):921–8.
47. Borgdorff MA, et al. Distinct loading conditions reveal various patterns of right ventricular
adaptation. Am J Physiol Heart Circ Physiol. 2013;305(3):H354–64.
48. Enache I, et al. Skeletal muscle mitochondrial dysfunction precedes right ventricular impair-
ment in experimental pulmonary hypertension. Mol Cell Biochem. 2013;373(1–2):161–70.
49. Nishimura T, et al. Simvastatin rescues rats from fatal pulmonary hypertension by inducing
apoptosis of neointimal smooth muscle cells. Circulation. 2003;108(13):1640–5.
50. Paulin R, et al. Dehydroepiandrosterone inhibits the Src/STAT3 constitutive activation in pul-
monary arterial hypertension. Am J Physiol Heart Circ Physiol. 2011;301(5):H1798–809.
51. Jasinska-Stroschein M, et al. The beneficial impact of fasudil and sildenafil on monocrotaline-
induced pulmonary hypertension in rats: a hemodynamic and biochemical study. Pharmacology.
2013;91(3–4):178–84.
52. Long L, et al. Chloroquine prevents progression of experimental pulmonary hypertension via
inhibition of autophagy and lysosomal bone morphogenetic protein type II receptor degrada-
tion. Circ Res. 2013;112(8):1159–70.
53. Colombo R, et al. Effects of exercise on monocrotaline-induced changes in right heart function
and pulmonary artery remodeling in rats. Can J Physiol Pharmacol. 2013;91(1):38–44.
54. Handoko ML, et al. Opposite effects of training in rats with stable and progressive pulmonary
hypertension. Circulation. 2009;120(1):42–9.
Epilogue
Norbert F. Voelkel and Dietmar Schranz
It is ok to be on the right track, but you must also move!

Will Rogers.
We are moving. The right ventricle is receiving attention: for the first time at the
World Symposium on Pulmonary Hypertension in 2013 a new working group deal-
ing with right heart failure had been established [1]. The causes and circumstances
of death in pulmonary hypertension are being assessed [2, 3]. The cardiac auto-
nomic nervous system in RVH and RVF is being investigated [4] and the first clini-
cal study has explored the effects of central pulmonary artery denervation in 13
patients with severe PAH [5]. We are moving forward with new surgical approaches
for the correction of congenital heart diseases. However, we need to ask new ques-
tions which are based on clinical observations, for example: the role of RV in chil-
dren and adults with Eisenmenger syndrome caused by differently located shunt
lesions; what is the role of a total body cyanosis based on a right-to-left shunt at the
ventricular level versus a “Harlequin-like” cyanosis caused by a right–left shunting
ductus arteriosus; what detrimental or beneficial role plays the ventriculo-ventricular
interaction and what is the nature of RV dysfunction in patients with cystic fibrosis
[6]? What are the mechanisms of right heart dysfunction in patients with end-stage
kidney disease [7]; to name just a few questions. We have noted that a paradigm
shift has occurred with a lesser focus on pulmonary vasodilation and a greater focus
on the functional stability of the subpulmonary positioned RV. While any lasting
decrease in the RV-systolic pressure unloads the RV, achieved with the help of a
mechanical device or by pulmonary arterial denervation, the goal is improved out-
come. As our understanding of the cellular and molecular mechanisms of RVF
deepens [8], we are alerted to the potential of the impaired metabolism of a subpul-
monary or sub-aortic positioned RV and we are watchful to detect cardiotoxicities
of present and future drug treatment strategies.
We may be moving forward even more rapidly if we combine images, mechan-
ics, and molecules and not only focus on the affected target, but also by considering
the role of the not—or only “passively” involved part of the heart and the circula-
tion. Yet many challenges still remain, both conceptually when it comes to the

Respiratory Medicine, DOI 10.1007/978-1-4939-1065-6
472 Epilogue
understanding of mechanisms of RV dysfunction and when it comes to the treat-

ment of RV dysfunction.
It has been our goal to make this relationship between knowledge and improved
therapy a bit more transparent by highlighting the work of the involved disciplines.
Having sufficiently moved on the right track, we can see the product: an improved
patient’s life-span and the improved quality of life of the patients.
As editors we wish to express our gratitude to all of “the Friends of the
Right Ventricle.”
References
1. Haddad F, Chin KM, Forfia PR, Kawut SM, Lumens J, Naeije R, et al. Right ventricular adapta-
tion to pulmonary arterial hypertension: physiology and pathobiology. World Health
Organization conference, Nice; 2014.
2. Tonelli AR, Arelli V, Minai OA, Newman J, Bair N, Heresi GA, et al. Causes and circum-
stances of death in pulmonary arterial hypertension. Am J Respir Crit Care Med.
2013;188(3):365–9.
3. Oudiz RJ. Death in pulmonary arterial hypertension. Am J Respir Crit Care Med.
2013;188(3):269–70.
4. Sanyal SN, Wada T, Yamabe M, Anai H, Miyamoto S, Shimada T, et al. Cardiac autonomic
nerve abnormalities in chronic heart failure are associated with presynaptic vagal nerve degen-
eration. Pathophysiology. 2012;19(4):253–60.
5. Chen SL, Zhang FF, Xu J, Xie DJ, Zhou L, Nguyen T, et al. Pulmonary artery denervation to
treat pulmonary arterial hypertension: the single-center, prospective, First-in-Man PADN-1
Study (first-in-man pulmonary artery denervation for treatment of pulmonary artery hyperten-
sion). J Am Coll Cardiol. 2013;62(12):1092–100.
6. Bano-Rodrigo A, Salcedo-Posadas A, Villa-Asensi JR, Tamariz-Martel A, Lopez-Neyra A,
Blanco-Iglesias E. Right ventricular dysfunction in adolescents with mild cystic fibrosis. J Cyst
Fibros. 2012;11(4):274–80.
7. Floccari F, Granata A, Rivera R, Marrocco F, Santoboni A, Malaguti M, et al. Echocardiography
and right ventricular function in NKF stage III cronic kidney disease: ultrasound nephrologists’
role. J Ultrasound. 2012;15(4):252–6.
8. Voelkel NF, Gomez Arroyo A, Drake J, Bigbee J, Kraskauskas D, Abbate A, et al. The impor-
tance of viewing the right ventricle and pulmonary circulation as an integrated functional unit.
Pulmonary Circulation. 2013;3(1):137–43.
Index
A chronic PH, 171

ACE inhibitors. See Angiotensin-converting chronic RV dysfunction, 173, 174
enzyme (ACE) inhibitors common, 169, 170
Acute decompensated right heart failure components, 169
(ADRFH), 439 decompensated LVF, 169
Acute respiratory distress syndrome intra-aortic balloon counterpulsation
(ARDS), 163, 164, 167, devices, 172
171–172, 183, 185, 190 intrinsic cardiac disease, 173
Acute right ventricular failure (RVF) LVAD recipients, 172
biochemical and molecular changes, mechanical ventilation, 172
166–169 obesity, 172–173
biomarkers, 162 PAH and CTEPH, 171
compensated and decompensated, 163 RV ischemia-reperfusion injury, 171
definitions, 162 sepsis, shock, hemorrhage/severe
diagnosis and risk stratification hypovolemia, 171
biomarkers, 175, 178 severe respiratory disease, 171–172
BNP and NT-proBNP, 175 management
cardiac troponins, 175, 178 diabolical effect, preload reduction, 184
echocardiography, 180–181 general measures, 182–184
electrocardiography, 178 inotropes and vasopressors (see
H-FABP, 178 Inotropes and vasopressor, RVF
history, patient factors and physical management)
examination, 173–175 principles, 182
invasive hemodynamic assessment, supraventricular arrhythmias, 184
181–182 therapies, 182, 185–186
noninvasive hemodynamic monitoring, treatment, 182, 183
182 ventilation and oxygenation strategies,
noninvasive methods, 178, 179 185
radiography, 179–180 volume, 184
signs and symptoms, 173 molecular mechanisms, 191
testing tools, 173, 176–177 pathophysiology, 163–167
dysfunction and failure, 163 physiology, 161
etiologies RV dysfunction, 162
ACS, 171 strategies, 190–191
acute PE and PH, 169, 171 ADRFH. See Acute decompensated right heart
BiVAD therapy, 172 failure (ADRFH)

Respiratory Medicine, DOI 10.1007/978-1-4939-1065-6
474 Index
Afterload non-genetic pathologies mimicking ARVC

anticoagulation, 404 myocarditis, 351
beat-to-beat adaptation, 20 RV dilation and dysfunction, 351
calcium channel blockers, 404 non-pharmacological treatment
diastolic function, 33 ICD therapy, 353
endothelin receptor blockers, 405 PVS, 353
homeometric adaptation, 20, 21, 27 RFA, 353
measurement of PVR, 25–26 sudden death, 352
oxygen, 403–404 VT and ICD shocks, 353–354
phosphodiesterase inhibitors, 405–406 pharmacological treatment, 354
prostacyclin analogues, 404–405 prevention
pulmonary hypertension, 33 family screening, 352
RV function, 402 physical activity, 352
systolic function measurements, 21, 23–24, pregnancy, 351–352
31–32 right bundle branch block (RBBB)
trial in PAH, 406–407 morphology, 340
AHF. See Anterior heart field (AHF) RV muscle diseases with genetic
Aldosterone, 127, 149, 309–310, 407 background
Alpha T-catenin (CTNNA3), 346 Brugada syndrome, 348
Angiography, 61–62, 81, 92, 169, 286 cardiac sarcoidosis, 349
Angiotensin-converting enzyme (ACE) dilated cardiomyopathy, 348–349
inhibitors, 15, 110, 297, idiopathic RVOT-VT, 348
349, 409 Uhl’s anomaly, 350–351
Anterior heart field (AHF) structural features and histopathology
cardiac development, 5, 6 clinical diagnosis, 342
myocardium to OFT, 5, 6 Epsilon wave, 341
proximal OFT (POT), 6 fibro-fatty infiltration, 340, 341
Anticoagulation, 180, 185, 404, 450 triangle of dysplasia, 340
APEO. See Arterial pro-epicardial organ symptoms, 339
(aPEO) types, 337–338
ARDS. See Acute respiratory distress Arterial coupling, RV
syndrome (ARDS) contractile reserve, 31–32
Arrhythmogenic right ventricular experimental pulmonary hypertension,
cardiomyopathy (ARVC) 24–25
candidate genes, 347 measurements of RV volumes, 33
cardiocutaneous disorders, 345, 346 pharmacology
clinical features and symptoms catecholamines, 25–26
biventricular arrhythmogenic epoprostenol or inhaled nitric oxide, 26
cardiomyopathy, 340 in experimental pulmonary
classic pattern, 339 hypertension, 25, 26
diagnosis, 339 inotropic drugs, 25
LDAC, 339–340 levosimendan, 26–27
symptoms and structural abnormalities, low-dose dobutamine, 26
339 milrinone, 27
definition and epidemiology, 338 pulmonary arterial hypertension, 26
desmosomal genes (see Desmosomes) sildenafil, 27
diagnosis vasodilators, 25
ECG changes in ARVC/D, 342 pressure measurements, 30
gold-standard diagnostic test, 342 pulmonary hypertension, 27–29
initial evaluation, 344 pump function graph, 30–31
Revised Task Force Criteria 2010, right heart catheterization, 32
342, 343 right ventricular contractility, 32
left bundle branch block (LBBB) systolic function, 32–33
morphology, 340 volume measurements, 29–30
Index 475
Arterial elastance, 22–24, 51 ventriculo-ventricular interaction, 110

Arterial pro-epicardial organ (aPEO), 6, 9 Atrioventricular canal (AVC), 6, 8
Athletic training, right heart Autophagy, 290–293, 295–296
CMR, 317 AVC. See Atrioventricular canal (AVC)
increased cardiac output during exercise,
315
PAP, 316–317 B
Pcwp and CO, 316 Balloon atrial septostomy (BAS)
Poiseuille’s law, 316 atrial septal defect, 420, 421
vasodilation, 315 Fick method, 421
AT1R antagonist, 409 right and left heart pressures, 420–421
Atrial septal defect (ASDs) Barker’s hypothesis, 45
atrial arrhythmias and left ventricular BAS. See Balloon atrial septostomy (BAS)
diastolic dysfunction, 87 Bernoulli equation, 59, 180, 226
communications, 84 Beta-adrenergic receptor (BAR) blockers,
description, 85 52, 295, 408–409
exercise intolerance, adolescent, 86–87 Biochemical and molecular changes, acute
LVEDP, 85–86 RVF
ostium secundum defect, 84 angiotensin II-and ET activation, 168
PAPVR outcomes, 87 calpain activation, 168
primum, 85 cardiomyocyte death, 166
right-to-left shunt, 86 fetal gene program, 168–169
symptoms, 86 inflammation, 166–167
Atrial septostomy (AS) macrophages, 166
acute physiologic effects, 431, 432 macroscopic and microscopic correlation,
BAS, 419–421 166–168
closure, 432–433 PE, 166
correlation, cardiac index, 427 pro-inflammatory biomarkers, 166
exercise endurance report, 429 reactive oxygen species (ROS), 167–168
experimental/computational models, Biomedical models, 63
430–431 Biventricular arrhythmogenic cardiomyopathy,
hemodynamic effects, 427, 428 340
long-term and short-term survival, 429 Biventricular circulation, systemic RV
PAH, 421–423 atrial switch operations (see Atrial switch,
Potts’ procedure, 433–434 biventricular circulation)
procedure-related mortality, 426 atrial-ventricular concordance, 103
right ventricular function, 429–430 ccTGA (see Congenital corrected
septostomy characteristics and outcome, transposition of the great arteries
421, 424–425 (ccTGA))
timing, 432 coronary blood flow, 104–105
Atrial switch, biventricular circulation DORV, 103
angiotensin-converting enzyme inhibition, end-diastolic volume, 103, 104
109–110 neonatal life, 104
detoxication, 110 ransposition abnormalities, CHD,
d-TGA, 108 103, 104
Fontan circulation, 109 stress flow dynamics, 105
long-term prognosis, 108 ventricle interactions, 104
Mustard procedure, 108–109 Blood flow velocity, 59
myocardial fibrosis, 110 Brugada syndrome, 348
pathophysiological differences, 109
reduction, LV hypertrophy, 110
RV ejection fraction, 108 C
Senning procedure, 108 Calcium channel blockers, 97, 164, 174, 404
subpulmonary left ventricle, 110 Canine model, 430
476 Index
Capillary rarefaction Cardiac output (CO)

endothelial cell damage, 293–294 athletic training, right heart, 315
RV ischemia and RV contractility, 294–295 fetal physiology, 48–49
VEGF gene expression, 294 Fontan circulation
Cardiac cycle, 21, 22, 25, 372 neo-portal system, 141–142
Cardiac development pulmonary bypassing, 143
anterior heart field (AHF), 5, 6 restrictions, 141, 143
early embryonic heart tube, 4 at rest, ventricular function and PVR,
FHF vs. SHF, 6–7 141, 142
LIM domain homeobox gene Isl1, 5 hemodynamic evaluation, 254, 255
looping and septation, 4, 5 RVF, 254, 255
outflow tract, 6 Cardiac Resynchronization-Heart Failure
posterior heart field, 6, 7 (CARE-HF) Trial, 362
primary heart tube, 4, 6 Cardiac ryanodine receptor (RYR2), 346
second heart field, 5, 6 Cardiac sarcoidosis, 349, 395
Cardiac epicardium (cEP), 9 Cardiac secretome, 310
Cardiac fibrosis Cardiopulmonary exercise test (CPET), 257
β2AR activation, 291 Cardiotonic therapy, 52
CTGF, 291 Carvajal syndrome, 345–346
fibrillar collagens type I and III, 290 Caveolin, 460, 462
TGF-β1 levels, 290–291 CEP. See Cardiac epicardium (cEP)
Cardiac hypertrophy CHD. See Congenital heart disease (CHD)
HDAC inhibitors, 289–290 CHF. See Congestive heart failure (CHF)
hypertrophic cardiomyopathy, 290 Children
mechanism of transition, 290 atrial switch operations, 108, 110, 111
positive and negative regulators, 290 ccTGA (see Congenital corrected
pressure–flow relationship, 288–289 transposition of the great arteries
right ventricular hypertrophy development, (ccTGA))
288 LV-DCM, 119
transcription factors, 290 LV failure (see Left ventricular heart
Cardiac magnetic resonance (CMR) imaging failure, children)
angiography, 61–62 CHRISTMAS trial, 295
diffusion-tensor imaging, 61–62 Chronic hypoxia exposure
3DWH, 61–62 adaptive RV hypertrophy, rats, 460
feature tracking, 61 carbon monoxide, 460, 461
image based modeling, 62–63 caveolin-1 KO, 460, 462
Lt-Gd-enhancement, 60 heme oxygenase-1 (HO-1) knockout, mice,
MR spectroscopy, 61 460, 461
phase contrast CMR, 58–59 monocrotaline-mediated lung injury,
pulmonary vascular function, 68–69 462–464
RV beyond pump function, 66–67 right ventricular pressure (RVSP)
RV diastolic function, 66 elevation, 460, 462
RV pump function and beyond, 57–58 Chronic lung diseases
RV systolic pump function, 64–65 COPD/emphysema, 391–394
RV tissue characterization and perfusion, 68 cystic fibrosis, 395–396
tagging for measuring tissue deformation, 61 pulmonary fibrosis, 394–395
tissue mapping, 61 treatment, 396
T1-mapping, 60 Chronic obstructive pulmonary disease
T1/T2 imaging, 60 (COPD)
Cardiac magnetic resonance imaging Burrows studies, 393
(CMR), 317 endothelium damage, 393, 394
Cardiac microcirculation, reprogramming, HFPEF, 394
304–305 intrathoracic pressures, 393
Index 477
microvascular endothelial cell dyskinesis, hypokinesis, 291–292

inflammation, 394 “Eisenmenger RV”, 286
myocardial microcirculation, 393, 394 endothelial–mesenchymal transition
pulmonary hypertension, 391 (EMT), 291
pulmonary vascular abnormalities, 391 hibernation, proteolysis, and autophagy,
RV wall thickness and RV basal strain, 392 292–293
University Hospital in Oslo, Norway, 392 intrinsic mechanisms and extrinsic
Chronic PAH, 308 influences, 284
Chronic right heart failure (RHF) metabolic remodeling, 295–297
acute ischemia/infarction, 209 postmortem coronary angiography, 286
dilated cardiomyopathy, 209, 210 pulmonary hypertension, 283–284
echocardiography right ventricle-free wall stress, 286–287
classic metrics, 210–211 RV free wall strain, 288
2D and 3D, 211 RVSP and mean right coronary artery
Doppler measurements, 211, 212 blood flow, 286–287
optimum stroke volume, 210, 211 Chronic right ventricular stress and failure
pressures overload, 209 animal models
pulmonary artery hypertension, 209, 210 monocrotaline (MCT) lung injury, 457
RV dysfunction, 209 PAB, 457–460
treatment rodent, 457
intrinsic right ventricular function, vascular remodeling, 457
407–411 hypoxia exposure (see Chronic hypoxia
palliative care, 411–412 exposure)
pharmacological treatment, 402 large animal models, 456–457
Preload, 403, 407 LV performance, mouse, 455
reducing afterload, 402–406 mechanisms, 455
ventricular interaction, 210 pulmonary hypertension
Chronic right ventricular failure (RVF) research, 455–456
exercise testing VEGF (see Vascular endothelial growth
CPET, 257 factor (VEGF))
iCPET, 257–259 RVH, 456
6MWT, 256–257 strain, 466
pathophysiology, 255–256 tools, 456
PH, 260 Circulite® Synergy® micropump, 446
hemodynamic evaluation Cleveland Clinic’s DexAide RVAD, 446
cardiac catheterization, research, Congenital corrected transposition of the great
249, 250 arteries (ccTGA)
cardiac index, 255 AV-block, 107
cardiac output, 254, 255 ccTGA morphology, 103, 104
catheterization technique, 249, 259 diagnosis, 105
diagnostic reference values, 254 Fontan circulation, 107
mean PAP, 250–251 hybrid surgical procedures, 106
PAWP, 253–254 intra-cardiac repair, 105
PH, 249, 254–255, 260 isolated, 105
PVR, 251–253 LVOTO, 107
RHC procedure, 249–250 Mustard/Senning operation, 107
thermodilution, 249 “natural and unnatural” history, 105
pathobiology obstructions, pulmonary outflow tract, 106
adrenergic receptor blockade, 295 pulmonary artery banding, 106
capillary rarefaction, 293–295 pulmonary hypertension, 107–108
cardiac fibrosis, 290–291 risk, infants, 106
cardiac hypertrophy, 288–290 stress, 107
cell congestive pathobiology, 292–293 tricuspid regurgitation (TR), 105
definition, 285 tricuspid valve abnormalities, 105
478 Index
Congenital heart disease (CHD) Desmosomes

biventricular and univentricular Fontan desmosomal genes
circulation, 80, 103 with autosomal dominant inheritance,
blood flow, 79 344, 345
features, 79 with autosomal recessive inheritance,
four-chamber MRI, restrictive 344–346
cardiomyopathy, 82–83 extra-desmosomal genes
four-chamber with tripartite RV, lamin A/C (LMNA) mutations, 347
79–80 ryanodine receptor 2, 346–347
hemodyanmic, percutatneous stent-value TGFB3 and TMEM43, 346
implantation, 82, 83 TTN gene mutations, 347
modification, 97 non-desmosomal genes, 338
neonatal myocardium and adult hear, Diastolic device, 127
differences, 82, 84 Diastolic dysfunction, LV, 373
overload Diastolic function, RV
pressure (see Pressure overloaded right acute or chronic hemodynamic load, 378
ventricle) nitroglycerin and nitropusside, effects, 378
volume (see Volume overloaded right right atrial pressure/PCWP ratio, 377–378
ventricle) sildenafil, 378
PH (see Pulmonary hypertension (PH)) Diastolic pressure gradient (DPG), 122, 254
pulmonary blood flow, 80 Diffusion-tensor imaging, 62, 63
right ventricular Digoxin, 408
angiography, 80, 83 Dilated cardiomyopathy (DCM), 209, 210,
stress factors, 84, 85 348–349. See also Left ventricle
tripartite morphology, PAT dilated cardiomyopathy (LV-DCM)
and intact ventricular septum, and RV
80–82 Diuretic therapy, 407
ventricular (dys-) function, 79 Doppler echocardiography
Congestive heart failure (CHF), 361 chronic right heart failure, 211, 212
Cor pulmonale, 391, 393, 396 hemodynamics, RV function
CPET. See Cardiopulmonary exercise test fractional shortening, outflow tract, 233
(CPET) myocardial strain, tissue, 234
Cystic fibrosis, 395–396 right atrial size and function, 233–234
RVOT, 232, 233
speckle tracking, 235
D tricuspid annular plane systolic
2D echocardiography, RV volume excursion, 232–233
determination, 216 pulmonary hypertension, 226
error, 215 Double outlet right ventricle (DORV), 103, 137
geometric reference model, 215 DPG. See Diastolic pressure gradient (DPG)
limitations, 215 3D Tagging techniques, 61
quantitation, 214 Ductus arteriosus (DA), 41–42
RV remodeling, 215–216 3D Whole heart (3DWH) imaging, 61–62
3D echocardiography, RV volume Dynamic hyperinflation, 391, 393
accurate analysis, 216
commercial products, 219–220
multiple 2D views, 219 E
volumetric, 216–219 Ebstein’s anomaly, 86, 88–90
Delayed gadolinium enhancement (DGE) Echocardiogram, 394–385
technique, 326 Echocardiography
Desmin (DES), 346, 457 chronic right heart failure
Desmocollin (DSC), 329, 344 classic metrics, 210–211
Desmoglein (DSG), 329, 344 2D and 3D, 211
Desmoplakin (DSP), Doppler measurements, 211, 212
329, 344, 345 right atrial pressure and RV dilatation, 457
Index 479
ECLS. See Extracorporeal life support (ECLS) RV structural changes

ECMO. See Extracorporeal cardiopulmonary animal experiments, 319
support (ECMO) cardiac remodeling, 318
“Eisenmenger RV”, 286 degrees of volume loading, 319
Emphysema. See Chronic obstructive endurance training on right heart, 318
pulmonary disease (COPD) training regimen, 327
End-diastolic volumes (EDVs), 21 uncertainty and future research, 329–330
Endothelial–mesenchymal transition (EMT), Exercise training, 318, 322, 325, 328, 410
9, 291 Extracorporeal cardiopulmonary support
Endothelin receptor blocker, 405 (ECMO), 450–451
End-systolic elastance (Ees), 21 Extracorporeal life support (ECLS)
End-systolic pressure (ESP), 21 ECMO, 450–451
End-systolic volume (ESV), 21 novalung, 449–450
EPDCs. See Epicardium derived cells traditional femoral vs. upper torso
(EPDCs) ambulatory, 449
Epicardium derived cells (EPDCs), 9, 11, 15 Extracorporeal pumps
Epicardium, role implanted extracorporeal devices, 444
cardiac epicardium, 9 surgically implanted extracorporeal
cardiac tube formation, 8–9 devices, 442–444
compact myocardial layer development, Extreme exercise
9–10 cardiac damage, 326
coronary vascularization, 9, 11 short-term injury and chronic remodeling,
EPDCs migration, 9, 11 331
primary heart tube, 8
RV and LV function, 9, 11
vPEO and aPEO, 9 F
Epidermal growth factor (EGF) receptor Failing right ventricle
blockers, 406–407 definition, 21
Exercise-induced right heart disease, athletes description, 265–266
“Achilles’ Heel”, 331 increased afterload, 34
athletic training, effects, 315–317 pathophysiology, 34, 35
cardiac structure and function phenotyping, improvement, 36
acute changes, 324 pressure–volume relationships, 35
arrhythmias, 324–325 pulmonary hypertension, 34
biomarkers in endurance exercise, sick lung circulation (see Sick lung
323–324 circulation and failing RV)
cardiac damage, 326 FAO. See Fatty acid oxidation (FAO)
chronic myocardial changes, 325–326 Fatty acid oxidation (FAO), 44, 295
exercise-induced cardiac remodeling, 330 Feature tracking, 61, 66
genetic predisposition, 329 Fenestration
healthy training vs. over-training, 327 construction, 141
hemodynamic stress, 327 treatment, 153–154
host and environmental factors, 330 Fetal gene program, 44–45, 168–169
myocardial ischemia, 328 Fetal physiology
RV and pulmonary vasculature metabolism, 44–45
PTAC, 321–322 oxygen tension, 44–45
pulmonary arterial hypertension, 321 RV function
VO2peak, 321–322 afterload, 47–48
RV functional changes contractility and cardiac output, 48–49
magnetic resonance imaging study, preload, 47
319–320 RV structure, 46–47
RV enlargement, 319 substrate utilization, 44
RV remodeling, 320 Fetal programming, 44–45, 53
480 Index
FHF. See First heart field (FHF) treatment

Fick method, 249, 257, 421 elevated systemic venous pressure, 151
First heart field (FHF), 5–7 fenestration, 153–154
Fontan circulation impedance and pulmonary vascular
advantages and disadvantages, 135 resistance, 151–152
cardiac output options, 155
neo-portal system, 141–142 strategy from birth, 138–139
pulmonary bypassing, 143 ventricular suction, 152–153
restrictions, 141, 143 valves, right atrium and pulmonary artery
at rest, ventricular function and PVR, connections, 139–140
141, 142 Four-dimensional flow applications (4D VEC
systemic ventricle functions, 141 CMRI), 59
construction Frank–Starling mechanism, 164, 268, 407
bidirectional Glenn shunt, 4-12 months,
140
fenestration, 141 H
neonatal period management, 140, 154 HDAC. See Histone deacetylase (HDAC)
pulmonary vascular resistance (PVR), inhibitors
140 Heart failure
1-5 years, 140–141 PAB, 381–382
extra cardiac conduit, 140 pressure–volume loops, 381, 382
functional impairment after operation pulmonary vascular afterload, therapy,
adolescents and adults, 144 379–381
cardiac output, rest and during exercise, pump mechanics, 375–377
144 RV anatomy and physiology
childhood, 144 cardiac cycle, 372
different loading conditions, single conus or outflow tract, 371
ventricle, 145–147 LV diastolic dysfunction, 373
pulmonary volume load, 146, 147 LV systolic function, 375
shunt procedure, 144 MESA study, 373
heart MVO2, 372
abnormal features, Fontan ventricle, occlusion, 371–372
149 sinus and conus, 371
chronic preload deprivation, 145 systolic coronary artery flow, 373
mechanical support, transplantation, TAPSE vs. PASP relationship, 373–375
154 RV diastolic function, 377–378
polymorphisms, 149 RV function, studies, 362–370
pressure-volume loops, ventricle, 145, RV systolic dysfunction, 362
148 HeartMate II®, 446
stressors, 145, 149 Heart transplantation, 154
ventricular end-diastolic pressure, 145, Heart-type fatty acid-binding protein
148–149 (H-FABP), 178
lateral tunnel, mid-1980s, 139–140 Heme oxygenase-1 (HO-1), 460, 461
modifications, 137, 138 Hemodynamics
vs. normal, rest and during exercise, 136, PH (see Pulmonary hypertension (PH))
137 primary right ventricular dysfunction, 232
PCPC, 139 RV failure, difficult conditions
pulmonary “A” tricuspid flow filling pattern, 235–236
and systemic circulation, 135, 136 cardiac tamponade, 238
vasculature, 149–150 constrictive pericarditis, 238
single ventricles function, 135, 137 diastolic function, 235
systemic venous return, 135, 136 E tricuspid flow filling pattern, 236
TCPC, 138 reference values, doppler echco, 236–237
Index 481
RV function, Doppler echocardiography oral vasodilators, 189–190

fractional shortening, outflow tract, 233 pulmonary vasodilators, 188
myocardial strain, tissue, 234 surgical and interventional strategies, 190
right atrial size and function, 233–234 Inotropic agents, 409–410
RVOT, 232, 233 Interstitial fibrosis, 126, 325, 396
speckle tracking, 235 Intrinsic right ventricular function
tricuspid annular plane systolic ACE inhibitors, 409
excursion, 232–233 AT1R antagonist, 409
RV’s sensitivity, 226 beta-blockers, 408–409
severity, tricuspid regurgitation, 238–240 chronic LHF, 407, 408
Hibernation, 292–293 digoxin, 408
Histone deacetylase (HDAC) inhibitors, exercise training, 410
289–290 inotropic agents, 409–410
HMG-CoA reductase inhibitors, 407 iron and anemia, 410
HVAD®, 446 possible therapies, 411
Hybrid approach RV failure, 407, 408
angiography, 125 Invasive cardio-pulmonary exercise test
borderline and hypoplastic structures, (iCPET)
123, 124 changes, PVR and PAWP, 259
Eisenmenger physiology, 125 elemination, PH, 257–258
Giessen, 111 left-sided diastolic dysfunction and PH,
infancy, 123 259
interatrial fenestration, 123–124 mPAP-CO relationship, 257
“out-of-proportion” pulmonary supine/upright cardiopulmonary,
hypertension, 123 257, 259
Potts-shunt, 123–125, 127 systolic pulmonary artery pressure,
valved Conduit, LPA and DAO, 125–126 258–259
Hypoxia inducible factor (HIF-1), 44, 294 Iron and anemia, 410
Hypoxic pulmonary vasoconstriction,
403–404
K
Kaplan–Meier plots, 362
I
ICPET. See Invasive cardio-pulmonary
exercise test (iCPET) L
Idiopathic pulmonary arterial hypertension Lamin A/C (LMNA), 346
(IPAH), children, 125 Late gadolinium enhancement (LGE)
Idiopathic RV outflow tract–ventricular approach, 59, 68
tachycardia (RVOT-VT), 348 Left-dominant arrhythmogenic
Image based modeling, 62–65 cardiomyopathy (LDAC), 339–340
Immune-modulating therapy, 411 Left heart ventricle. See Heart failure
Implantable cardioverter-defibrillator (ICD), Left ventricle dilated cardiomyopathy
351–354 (LV-DCM) and RV
Implantable devices, 446–447 children, 119
Inhaled nitric oxide (iNO) therapy, 53 diagnosis, 120
Inotropes and vasopressor, RVF management heart transplantation, 119–120
dobutamine, 186 idiopathic, 119
dopamine, 188 prognosis, 119
epoprostenol, 189 reversible pulmonary artery banding,
iNO stimuation, 188–189 120–122
levosimendan, 187–188 single RV, 120
milrinone, 187 systolic cardiac dysfunction, 119
norepinephrine, 188 therapeutics, 129
482 Index
Left ventricular assist device (LVAD) Magnetic resonance spectroscopy, 61

biventricular configuration, 451 Maximal elastance (Emax), 21–22
destination therapy, 440 Maximum pressure (Pmax) calculation, 22
fulminant myocarditis, 440 Mean pulmonary artery pressure (mPAP)
RV failure, 442 acetylcholine, 250, 251
thrombosis risk, 446 definition, 250
Left ventricular enddiastolic pressure left-sided heart failure, 250
(LVEDP), 85–86 physiological hemodynamic changes, 250
Left ventricular heart failure, children RHC technique, 250
biventricular disease, 117 Mean systemic filling pressure (Pms), 19–20
DCM (see Dilated cardiomyopathy Metabolic adaptation. See Fetal physiology
(DCM)) Metabolic remodeling
description, 118 cellular and molecular mechanisms, 296
Fontan circulation, 118 PAB-induced RV hypertrophy, 297
myocardial fibers, 117 reduced FAO, 295
practitioner summary, 128–129 VEGFB-dependent FA uptake, 296
RV MiR-150, 309
intrinsic mechanism, 118 MiR-424, 309
LAP, 118 MiR-503, 309
LV-DCM, 119–128 Mitochondrial DNA, 308
“out-of-proportion” hypertention, Molecular imaging, RV
117–119 angiogenesis, 273
TPG calculation, 119 apoptosis, 274
therapeutics, 129 hybrid PET-MRI, 275
TPG caluation, 117–118 MRS, 274
Left ventricular outflow tract obstruction neurohormonal system, 274
(LVOTO), 107 PET (see Positron emission tomography,
Lung-heart information transfer, 303 RVF)
LVAD. See Left ventricular assist device (LVAD) Monocrotaline-mediated lung injury
LV systolic dysfunction (LEPHT) trial, 380 adrenergic receptor blockade, 464
Crotalaria spectabilis, 462
lethal pulmonary hypertension and RVH,
M 462–463
Magnetic resonance angiography, 61–62 MCTP, 462
Magnetic resonance imaging (MRI), RV right ventricular function, 463
failure Multicenter Automatic Defibrillator
contractility, 269 Implantation Trial with Cardiac
diagnosis, PAH, 266 Resynchronization Therapy
high resolution imaging, 266 (MADIT-CRT) Trial, 362
remodeling and wall stress Multi-Ethnic Study of Atherosclerosis
assessment, mass, shape and volumes, (MESA) study, 373
268 Mustard procedure
CO, 267, 268 atrial switch
diagnosis, idiopathic PAH, 266–267 exercise and dobutamine stress, 108
dilatation, 268–269 pathophysiology, 109
eccentric remodeling pattern, 268 proceure, 108
oxygen delivery, 267 repair, d-TGA, 108
pressure overload, 268 ccTGA repair, 107
systolic RV function 6MWT. See Six minute walk test (6MWT)
description, 269 Myocardial infarction
ejection fraction, 269–270 inotropic impairment, 170
low stroke volume, 269 interrupt coronary blood flow, 163
regional ventricular wall deformation intrinsic cardiac disease, 173
and synchrony, 270–271 papillary muscle rupture, 166
Index 483
RV free wall hypokinesis, 180 dry cough, 412

treatment, RV failure, 183 dry mouth and thirst, 412
Myocardial metabolism, 44 dyspnea, 411
Myocardial oxygen consumption (MVO2), 372 fatigue, 412
Myocardial perfusion reserve (MPR), 68 malnutrition, 412
Myocarditis, 351, 440 pain, 412
Myocyte adhesion, 344 preload, 411
RVF, 411
PAP. See Pulmonary artery pressures (PAP)
N Paracorporeal support, 444–446
National Institutes of Health, 419 Partial cavo-pulmonary connection (PCPC),
Naxos disease, 337, 344–345 138–139
Neonatal transition, RV Patent foramen ovale (FO), 41–42
contractility and cardiac output, 51–52 Pathophysiology
fetal programming, 44 acute RVF
fetal RV function afterload sensitivity, 164–165
afterload, 47–48 contractility, 164
contractility and cardiac output, 48–49 mechanisms, 163, 164
preload, 47 perfusion, 165–166
fetal RV structure, 46–47 preload dependence, 163–164
function ventricular interdependence and
afterload, 51 dependence, 165
preload, 50–51 vicious cycle, 166, 167
functional and structural changes after chronic RVF, 255–256
birth, 41, 42 Mustard procedure, 109
metabolism, 52 RV failure, 34, 35
physiologic changes, 41, 42 PCPC. See Partial cavo-pulmonary connection
postnatal adaptation at birth, 49–50 (PCPC)
PPHN and failure of transition after birth, PDE5. See Phosphodiesterase 5 (PDE5)
52–53 Peak exercise oxygen consumption
prenatal echocardiogram, normal fetus, (VO2peak), 321–322
42, 43 PEP. See Pre-ejection period (PEP)
pulmonary vasodilation, 43 Persistent pulmonary hypertension of the
PVR, 41 newborn (PPHN)
RVH, 43 profound hypoxemia, 41
structure, 50 RV function and failure of transition after
“systemic ventricle” in utero, 42 birth, 52–53
Neurohormonal axis activation, 286 PGC-1 alpha, 294
Neutral endopeptidase (NEP) inhibitors, 411 Phase contrast CMR, 58–59
Novalung, 190, 449–451 PHF. See Posterior heart field (PHF)
Phosphodiesterase 5 (PDE5), 379
Phosphodiesterase inhibitor, 405–406
O Phospholamban (PLN), 346
OFT. See Outflow tract (OFT) PHT. See Primary heart tube (PHT)
Outflow tract (OFT) Physiology, right ventricle
anterior heartfield, myocardium, 5 “Anrep’s law of the heart”, 20
positioning: pulmonary push concept, 7, 8 arterial coupling (see Arterial coupling, RV)
beat-to-beat adaptation, preload or
afterload, 20–21
P diastolic function, 33
Palliative care EDVs, increased, 21
constipation, 411 Fontan circulation, 20
depressive symptoms, 412 homeometric adaptation, afterload, 21
digoxin and spironolactone, 412 LV contractility, increased, 20
484 Index
Physiology, right ventricle (cont.) associated heart/vessel malformations, 92–93

Pms, 19–20 contractile dysfunction, 91
Ppa-Q relationships, 20 Doppler, 92
PVR, increased, 19–20 massive pulmonary thrombo-and
RV failure, 21, 34–36 air-embolism, 91
SV, increased, 21 mild/moderate, 91
systolic function, 21–23 outcome after balloon valvuloplast, 92
ventricular hypertrophy, 21 pulmonary atresia and ventricular septal
ventricular interaction, 34 defect, 93
PITCH-HF (Phosphodiesterase Type 5 pulmonary valve stenosis, 91–92
Inhibition with Tadalafil Changes “repaired Tetralogy of Fallot”, corrective
Outcomes in Heart Failure), 380 surgery, 93–94
Plakoglobin (JUP), 329, 344–345 RV outflow tract obstruction and
Plakophilin (PKP), 329, 344–345 pulmonary hypertension, 91
Platelet activating factor (PAF), 306 sinus rhythm, 91
Platelet-derived growth factor (PDGF), 406 Pressure-Poisson equation, 59
Positron emission tomography (PET), RVF Pressure–volume relationships, 21, 22, 25, 35,
blood flow and oxygen balance 66–67, 375, 381, 382
11C-acetate tracers, 271, 272 Primary heart tube (PHT)
coronary and transmural, 273 cardiac development, 4, 6
impaired RV mechanical efficiency, cardiac valve formation and septation, 8
PAH, 271–273 Programmed ventricular stimulation (PVS),
myocardial oxygen consumption 353
(MVO2), 271, 273 Prostacyclin, 404–405
15O-labeled tracers, 271 Proteolysis, 292–293
metabolic remodeling, 271 Proteotoxicity, 292, 296
Posterior heart field (PHF), 6, 7 Pulmonary arterial banding (PAB)
Potts procedure acute effect, 121
anastomosis, 433–434 BLV/restrictive cardiomyopathy
shunt ccTGA, 120
intracardiac repair, 125 hypertrophy-fibrosis-angiogenesis
IPAH, children, 125 program, 122
pop-off valve function, 124 neonatal myocardium, 121
pulmonary to aortic communication, outcomes, 122
123, 125 outflow tract obstruction, 120
restrictive, 124 percutaneous de-banding, balloon dilation
valved Conduit, 126 procedure, 122
PPHN. See Persistent pulmonary hypertension rats and mouse model
of the newborn (PPHN) changes, RV myocardium, 459
Pre-ejection period (PEP), 375 differences, RV and LV pressure
Preload overload, 460
beat-to-beat adaptation, 20 lumen reduction, 459
chronic right heart failure, 403, 407 mast cells, 458–459
optimization, 407 microarray-based gene expression
PRSW, 32 analysis, 459–460
pump function graph, 30–31 pressure overload, RV, 458
SV/EDV, 29 strength and weaknesses, 457–458
Preload recruitable SW (PRSW), 32 surgical procedure, 458
Pressure–flow relationship, 288–289 reduction, end-diastolic volume, 121
Pressure overloaded right ventricle RV pressure overload, 381–382
adapted RV, 91 sub-aortic right ventricle,
afterload heart transplantation, 90–91 neonates, 120
angiography, 91, 92 surgical technique, 120
Index 485
Pulmonary arterial hypertension (PAH) myocardial performance index, 229

clinical/demographic/functional PAcT, 227, 229
characteristics, 421–423 PH assessment, 226, 228
future therapies, 406–407 pre-and post-capillary, 230–232
survival, 419 pressures, 226
targeting drugs, 419 PVR, 227
Pulmonary artery pressures (PAP), 28, 34, RAP estimation, 226–227
268, 317 tricuspid regurgitation velocity, 226, 227
Pulmonary banding increased afterload on RV function, 361
adjustable, 110 low flow RVAD, 447–449
surgical bilateral, 111 lung hyperinflation, 391
Pulmonary capillary wedge pressure (PCWP) LV diastolic dysfunction, 373
DPG, 254 “out-of-proportion”, 117, 123
left heart disease, 253 RHC, 259–260
mPAP, 253 RV-arterial coupling
PA pressure, 230 afterload, 29
pre-and postcapillary PH, 253 arterial uncoupling, 27
RV ejection fraction, 364 heterometric adaptation, 28
TPG, 253 homeometric adaptation, 28
WHO group 2 patients, 253 with idiopathic PAH, 27, 28
Pulmonary embolism RV failure, 29
acute, 170 with SSc-associated PAH, 27, 28
fibrinolysis, 187 RV failure, 34
long-term consequence, acute RV failure, 168 systolic function, 23
massive and submassive, 162, 175, 179, 185 Pulmonary vascular afterload, therapy
severity index, 175 α-1 adrenergic receptors, 381
thrombolytic therapy, 183 β-adrenergic blockade, 380–381
Pulmonary fibrosis, 394–395 CHAMPION study, 379
Pulmonary hypertension (PH) epoprostenol and endothelin receptor
acute or chronic hemodynamic load, 378 antagonists, 379
assessment of RV systolic function, 373 Kaplan–Meier survival curves, 379
CHD LEPHT trial, 380
genes encoding, 94 PDE5 inhibition, 379, 380
intrinsic mechanism, 94 PITCH-HF, 380
iPAH, 94, 95 RVEF, 379
morbidity and mortality, 94 sildenafil, 379–380
pharmacotherapy, 94, 96 VMAC trial, 379
preclinical stage, 94 Pulmonary vascular function, 68–69
prevalence, 94–95 Pulmonary vascular resistance (PVR)
shunt-dependent PAH and hypoxic vasoconstriction, 251
Eisenmenger’s syndrome, 96 outflow load, 251
therapies, 96 PH group, 251–252
treatment, acute right heart (RV) power generation, 252–253
failure, 94–96 PPHN, 41
uncorrected cardiac defects, 95 pulsatile flow, 252
vascular remodeling, 96 rarefaction, 251
CHF, 361–362 RV adaptation and remodeling, 19, 20
COPD/emphysema, 391, 392 steady state and resistance flow, 251
cor pulmonale, 396 Pulmonary vasculature
hemodynamics complications after Fontan repair, 150
Doppler technique, 226 evoluation, 150
early and late diastolic pressure, 226, 228 Fontan circulation, 149–150
IVRT, 227–229 palliation, 149
measurements, 231 shunting procedure, 149
mechanisms, 229 single ventricle congenital heart disease, 149
486 Index
Pulmonary vasodilators Revised Task Force Criteria 2010, 342, 343

acute RVF, 188 Right heart catheterization, 392, 395
epoprostenol, 189 Right heart failure
iNO, 188–189 AS (see Atrial septostomy (AS))
oral, 189–190 BAS, 420
surgical and interventional strategies, 190 Right ventricle (RV)
Pulsatile and continuous flow devices, cardiac development, 4–7
441–442 cell-or drug-based therapy, 4
Pulsatile Thoratec IVADT, 446, 447 characteristics, 3
Pump function clinical considerations, 14–15
cine CMR, 57–58 epicardium, role, 8–11
kinetic energy, 67 function (see RV function)
pressure–volume relations, 66–67 in left heart failure (see Heart failure)
RV systolic function, 64–65 morphology right vs. left ventricle, 11–12
tissue deformation, 66 myocardial architecture, 13
Pump mechanics, RV OFT positioning: pulmonary push concept, 7
acute pressure loading, phenylephrine, physiology (see Physiology, right
375, 376 ventricle)
converting-enzyme inhibition, 376 tricuspid orifice formation, 8
electrocardiogram tracings, 375–376 ventricular septation, 13–14
PEP and RVET, 375 Right ventricular assist device (RVAD)
pressure–volume relationships, 375 blood compatibility, 441–442
pulmonary impedance, 375, 377 cardiogenic shock, 451, 452
PVR. See Pulmonary vascular resistance design innovations focus, 441–442
(PVR) destination therapy, 440
echocardiographic manifestations, 440
ECLS, 449–451
R extracorporeal support, 442–444
RAAS. See Renin-angiotensin-aldosterone- hepatic congestion, 441
system (RAAS) hypervolemia and hypovolemia, 440
Radiofrequency ablation (RFA), 353 implantable devices, 446–447
“Randle Cycle”, 44 intravenous prostacyclins, 440
Renin-angiotensin-aldosterone-system paracorporeal support, 444–446
(RAAS), 274, 409 PH disease models, 447–449
Restrictive cardiomyopathy post-cardiac surgery RV failure, 440
asymptomatic child, 128 vasopressors, 440
BLV, 123–125 Right ventricular dysfunction, 325, 327–329
diastolic dysfunctional circulation, Right ventricular function, 429–430
122–123 RV ejection fraction (RVEF), 379
ECMO, 128 RV ejection time (RVET), 375
etiology, 126 RVF. See Acute right ventricular failure
heart transplantation, 126–127 (RVF); Chronic right ventricular
invasive hemodynamic assessment, 127 failure (RVF)
left-sided, 127 RV failure gene expression program, 292
left ventricular ejection fraction, 123 RV function
medical treatment, 127 before and after cardiac surgery, 240–241
PFO and Potts-shunt, 127 assessment, prognostic value
pre-transplant pulmonary hypertension, 128 cardiac conditions, 239
pulmonary hypertension, 127 cardiac resynchronization therapy, 239
Restrictive cardiomyopathy gradient. See ejection fraction, 239
Restrictive cardiomyopathy hepatic vein systolic flow reversal,
REsyncronization re-VErses Remodeling in 239, 240
Systolic left vEntricular dysfunction RV dysfunction, 239
(REVERSE) Trial, 362 tricuspid regurgitation, 239
Index 487
global, 220–222 pulmonary hypertension, pathogenesis,

left heart failure 306, 307
captopril and isosorbide dinitrate, pulmonary venous and arterial remodeling,
effects, 366 303–304
CHF, 361 synopsis, 309–310
converting-enzyme inhibition, 366–367 systems approach, 309–310
end-diastolic and end-systolic images, Single beat method, 22–23
367–369 Single ventricle
exercise capacity, 364, 366 different loading conditions, 145, 146
four chamber apical echocardiography, functions, 135, 137
362 mechanical support, heart transplantation, 154
gated equilibrium and first pass oxygen saturation, 135
techniques, 368–370 physiology, 147, 152
ischemic and nonischemic pressure-volume loops, palliation, 145, 148
cardiomyopathies, 361, 368, 370 pulmonary vasculature, 149
Kaplan–Meier plots, 362 stressors, 149
physiologic effects, 363–364 systemic and the pulmonary circulations, 135
pulmonary vascular impedance, 366 systolic dysfunction, 145
right vs. left-sided afterload reduction, Six minute walk test (6MWT), 256–257
366 Stroke volume (SV), 21
RV and LV ejection fraction, 364–366, SU5416, 464–465
368–369 Sudden cardiac death, 353
RV chamber, sources, 367 Syndrome of combined upper lobe
systolic or diastolic function, overload, emphysema, 395
362–363 Systemic right ventricle
regional biventricular circulation (see Biventricular
2D analysis, 222–223 circulation, systemic RV)
3D analysis, 223–226 univentricular circulation, 111–112
RV hypertrophy (RVH), 43 Systemic sclerosis (SSc)-associated PAH,
27, 28
Systolic dysfunction, 362
S Systolic function
Second heart field (SHF) cardiac cycle (pressure–volume loop),
cardiac development, 5–7 21, 22
FHF vs., 6 conductance catheter technology, 23
OFT malformations, 14 end-systolic elastance (Ees), 21
Senning procedure, 106–108 ESP and ESV, 21
Sepsis, acute RVF, 162–167, 169–171, 174, LV, 375
183, 185 maximal elastance (Emax), 21–22
SHF. See Second heart field (SHF) maximum pressure (Pmax) calculation, 22
Sick lung circulation and failing RV measurements of afterload, 23–24
cardiac microcirculation, reprogramming, pulmonary arterial hypertension (PAH), 23
304–305 pulmonary hypertension, 23
circulating cells, 305–306 single beat method, 22–23
circulating cellular microparticles, 306–308 Systolic pump function, 64–65
connecting miRNA and disease, 308–309
endothelial cell function, 303
endothelial cell microparticles, 306, 307 T
inflammation and cell death, circulating TandemHeartTM, 444
mediators, 308 Tei index, 33
“information transfer”, concept, 303 Tetralogy of Fallot, 64
lung endothelial dysfunction, 305 Therapy of right heart failure, 94–96
prostacyclin gene and protein expression, Tissue characterization and perfusion, 68
305 Tissue Doppler echocardiography, 61, 66
488 Index
Titin (TTN), 338 Vasodilation in the Management of Acute

T1-mapping techniques, 60 Congestive Heart Failure (VMAC)
T1 or T2 weighted images, 60 trial, 379
Total cavo-pulmonary connection (TCPC), 138 VCACs. See Ventriculo-coronary-arterial
Transforming growth factor beta-3 communications (VCACs)
(TGFB3), 346 “Velocity encoding” techniques (VEC CMR),
Transmembrane protein 43 (TMEM43), 346 58
Transpulmonary gradient Venous pro-epicardial organ (vPEO), 6, 9
Fontan surgery, 154 Ventricular septal defect (VSD), 11
PAWP, 253–254 Ventricular septation, 4, 5, 13–14
Transpulmonary passage of agitated contrast Ventricular suction
(PTAC), 321–322 hemodynamic effect, Fontan portal system,
Tricuspid regurgitation (TR) 152
ccTGA, 105 pulmonary venous atrial pressure
volume overloaded right ventricle after load, 153
dilated RV, diastole and systole, 90 contractility, 152–153
Ebstein’s anomaly and respiratory heart rate, 153
failure, 88–89 Ventricular tachycardia (VT), 353–354
lymphatic flow, 89 Ventriculo-coronary-arterial communications
PAT, 89 (VCACs), 11
pre-and postnatal parallel cirulation, 89 Visualization, RV volume
pulmonary valve, 89 assessment, 214
valve replacement, 90 bulging at base and apex, 212, 213
Tumor protein p63 (TP63), 346 dilatation, 214, 216
Type II programmed cell death, 292–293 ellipsoid geometry, volume and pressure
overload, 211, 212
evaluation, 211
U four-chamber apical bulging, 214, 215
Uhl’s anomaly, 350–351 idiopathic dilated cardiomyopathy,
Univentricular circulation, systemic RV, 212, 213
111–112 reconstruction, left and right ventricles,
212, 213
repaired tetralogy, 212, 213
V truncation and crescent shape, 213–214
Vascular endothelial growth factor (VEGF) Volume overloaded right ventricle
receptor blockade ASDs (see Atrial septal defect (ASDs))
hemodynamic measurement, 464, 465 dilatation, heart chamber, 98
microarray-based gene expression pulmonary valve regurgitation, 87–88
analysis, 464 tricuspid regurgitation, 88–90
molecular mechanisms, 466 VPEO. See Venous pro-epicardial organ
SU5416/hypoxia rats, 464–465 (vPEO)
signaling, 293, 294 VSD. See Ventricular septal defect (VSD)

The Right Ventrice in Health and Disease

Uploaded by

Document Information

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

The Right Ventrice in Health and Disease

Uploaded by

Copyright:

Available Formats

Respiratory Medicine

Series Editor: Sharon I.S. Rounds

More information about this series at http://www.springer.com/series/7665

The Right Ventricle

Videos to this book can be accessed at http://www.springerimages.com/videos/978-1-4939-1064-9

ISSN 2197-7372 ISSN 2197-7380 (electronic)

Library of Congress Control Number: 2014950066

© Springer Science+Business Media New York 2015

Printed on acid-free paper

Humana Press is a brand of Springer

Richmond, VA, USA Norbert F. Voelkel

Part I The Normal Right Ventricle

1 Normal Development and Morphology

Part II Congenital Abnormalities

5 Subpulmonary Right Ventricle in Congenital Heart Disease ............. 79

Part III Acute Right Heart Failure

9 Acute Right Ventricular Failure ............................................................ 161

Part IV Chronic Right Ventricular Failure

10 Echocardiography of Chronic Right Heart Failure ............................. 209

22 Animal Models of Chronic Right Ventricular

Epilogue ........................................................................................................... 471

Index ................................................................................................................. 473

Marc Gewillig, M.D., Ph.D. Department of Pediatric Cardiology, University

David L. Prior, M.B.B.S., Ph.D., F.R.A.C.P., D.D.U., F.C.S.A.N.Z. Department

Adriana L. Gittenberger-de Groot, Robert E. Poelmann,

In recent years, the relevance of knowledge on right ventricular (RV) characteristics

A.L.G.-d. Groot, Ph.D. (*) • M.R.M. Jongbloed, M.D., Ph.D.

© Springer Science+Business Media New York 2015 3

interesting that there is a difference in expression in cytochrome genes, necessary

Cardiac Development and Impact on the RV

Positioning of the OFT: The Pulmonary Push Concept

Tricuspid Orifice Formation

Role of the Epicardium in Development of the Compact

to relate it to non-compaction cardiomyopathies and the difference between RV and

Morphology Right Versus Left Ventricle (Fig. 1.5)

The RV morphology is clearly different from the LV based on a number of structural

30. Sedmera D, Pexieder T, Rychterova V, Hu N, Clark EB. Remodeling of chick embryonic

Robert Naeije, Ryan J. Tedford, and François Haddad

One must inquire how increasing pulmonary vascular

Introduction with Evolutionary and Historical Perspectives

The right ventricle (RV) is functionally coupled to the pulmonary circulation.

R. Naeije, M.D., Ph.D. (*)

© Springer Science+Business Media New York 2015 19

to 15–20 mmHg by an increase in effective blood volume and systemic nervous

Do the Laws of the Heart Apply to the RV?

The gold standard measurement of contractility in vivo is the maximal elastance

With increasing impedance in pulmonary hypertension, the shape of the RV

recently, a limited number of Emax determinations have been reported in patients

Coupling of Systolic Function to Afterload

Measurements of systolic function are ideally load-independent, which means con-

RV-Arterial Coupling in Experimental Pulmonary Hypertension

Table 2.1 RV-arterial coupling in experimental models of pulmonary hypertension

in pacing-induced heart failure was associated with RV-uncoupling due to the

Pharmacology of RV-Arterial Coupling

In patients with severe pulmonary hypertension right ventricular function is a major

Table 2.2 Effects of pharmacological intervention in experimental pulmonary hypertension

Table 2.3 RV-arterial coupling in patients with pulmonary arterial hypertension

Catecholamines may cause pulmonary vasoconstriction and tachycardia [47].

RV-Arterial Coupling Measurements in Patients

patients with SSc but without pulmonary hypertension maintained preserved

Simplified Methods for the Measurement

A ratio of elastances can be simplified to a ratio of volumes, provided ESV is mea-

Another simplified approach for the measurement of RV-arterial coupling intro-

Alternative Methods to Evaluate RV-Arterial Coupling