Essentials of Postgraduate Cardiology 2018 PDF

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ESSENTIALS OF
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Prelims_Kewal C Goswami (40 pgs).indd 1 05-11-2018 18:04:48

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Cardiological Society of India
ESSENTIALS OF
POSTGRADUATE
CARDIOLOGY
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Editor-in-Chief
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Kewal C Goswami MD DM
Professor
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Department of Cardiology
All India Institute of Medical Sciences
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New Delhi, India

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Co-Editors
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Rakesh Yadav MD DM Nitish Naik MD DM S Ramakrishnan MD DM

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Professor Professor Professor

Department of Cardiology Department of Cardiology Department of Cardiology
All India Institute of Medical Sciences All India Institute of Medical Sciences All India Institute of Medical Sciences
New Delhi, India New Delhi, India New Delhi, India
New Delhi, India

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Essentials of Postgraduate Cardiology / Kewal C Goswami
ISBN: 978-81-936703-4-7
Printed in India
Published and exclusively distributed by EVANGEL PUBLISHING

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CONTRIBUTORS
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EDITOR-IN-CHIEF
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Kewal C Goswami MD DM
Professor
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All India Institute Of Medical Sciences
New Delhi, India
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CO-EDITORS
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Rakesh Yadav MD DM Nitish Naik MD DM S Ramakrishnan MD DM
Professor
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Professor
Professor
New Delhi, India New Delhi, India New Delhi, India
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CONTRIBUTING AUTHORS
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Aayush Goyal Ajay Bahl Anandaraja Subramanian

Senior Consultant
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Department of Cardiovascular and Postgraduate Institute of Medical

Thoracic Surgery Education and Research Department of Cardiology
Indira Gandhi Government General
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All India Institute of Medical Sciences Chandigarh, India

New Delhi, India Hospital and Postgraduate Institute
Ajith Ananthakrishna Pillai Puducherry, India
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Abhinav Singhal Department of Cardiology

Jawaharlal Institute of Postgraduate Anil Bharani
Senior Resident
Former Professor and Head
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Department of Nuclear Medicine Medical Education and Research

Department of Medicine and
All India Institute of Medical Sciences Puducherry, India
Division of Cardiology
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New Delhi, India MGM Medical College and MY Hospital

Ajit Thachil
Principal Investigator
Consultant Cardiac Electrophysiologist
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Abhishek Goyal ICMR RF/RHD Registry

Lisie Hospital Indore, Madhya Pradesh, India
Assistant Professor
Kochi, Kerala, India
Hero DMC Heart Institute Anita Saxena
Akshyaya Pradhan
Dayanand Medical College and Professor
Assistant Professor All India Institute of Medical Sciences
Hospital Department of Cardiology New Delhi, India
Ludhiana, Punjab, India KG’s Medical University
Lucknow, Uttar Pradesh, India Anjali Bharani
Ahmed Y Salama Assistant Professor
Research Fellow, Echocardiography Amit Vora Department of Pediatrics
Laboratory, Cardiology Division Glenmark Cardiac Centre MGM Medical College, MY Hospital
University of Alabama at Birmingham Swami Krupa CHS and Chacha Nehru Bal Chikitsalaya
Birmingham, Alabama, USA Mumbai, Maharashtra, India Indore, Madhya Pradesh, India

Ankit Bansal Balachander Jayaraman BRJ Kannan
Associate Professor Department of Cardiology Senior Interventional and
Essentials of Postgraduate Cardiology
Department of Cardiology Jawaharlal Institute of Postgraduate Pediatric Cardiologist

GB Pant Institute of Postgraduate Medical Education and Research Vadamalayan Hospitals
Medical Education and Research Puducherry, India Madurai, Tamil Nadu, India
Maulana Azad Medical College
New Delhi, India Balu Vaidyanathan B Vinodkumar
Clinical Professor Physician
Head Fetal Caardiology Division Billroth Hospital
Annu Jose Amrita Institute of Medical Sciences Chennai, Tamil Nadu, India
Junior Consultant Amrita School of Medicine
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Pediatric Cardiology Kochi, Kerala, India
Calambur Narasimhan
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Lisie Hospital
Director
BC Srinivas Department of Cardiac
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Professor Electrophysiology
Arima Nigam Sri Jayadeva Institute of Department of Cardiology
Associate Professor Cardiovascular Sciences CARE Hospital
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Academic Block Bengaluru, Karnataka, India Hyderabad, Telangana, India
GB Pant Institute of Postgraduate
Chandramukhi Sunehra
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Medical Education and Research Bhanu Duggal
New Delhi, India Professor and Head Department of Cardiac Imaging
Arindam Pande
18 cie Department of Cardiology
All India Institutes of Medical Sciences
Rishikesh, Uttarakhand, India
Care Hospital
Hyderabad, Telangana, India
Consultant Interventional Cardiologist

Chetan D Patel
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Medica Superspecialty Hospital
Professor
Bharat Dalvi
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Kolkata, West Bengal, India

Department of Nuclear Medicine
Glenmark Cardiac Centre
Mumbai, Mahrashtra, India
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Arun K Chopra New Delhi, India

Director
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Fortis Escorts Hospital Bijesh Viswambaran CM Nagesh

Amritsar, Punjab, India Junior Consultant Associate Professor
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Pediatric Cardiology Department of Cardiology

Lisie Hospital Sri Jayadeva Institute of
Arun Sharma Kochi, Kerala, India Cardiovascular Sciences and Research
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Department of Cardiovascular Bengaluru, Karnataka, India

Radiology and Endovascular
Binay Kumar
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Interventions CN Manjunath
EP Fellow
All India Institute of Medical Sciences Professor and Director
Holy Family Hospital
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New Delhi, India Sri Jayadeva Institute of

Mumbai, Maharashtra, India Cardiovascular Sciences
Bengaluru, Karnataka, India
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Arvind Balaji Bishav Mohan

Senior Resident Professor Deepa S Kumar
All India Institute of Medical Sciences Dayanand Medical College and Assistant Professor
New Delhi, India Hospital Department of Pediatric cardiology
Unit Hero DMC Heart Institute SCTIMST
Thiruvananthapuram, Kerala, India
Ludhiana, Punjab, India
Avinash Anantharaj
Junior Consultant Devendra Kanshilal Sharma
Department of Cardiology BKS Sastry Department of Cardiology
Indira Gandhi Government General Senior Consultant Cardiologist Jawaharlal Institute of Postgraduate
Hospital and Postgraduate Institute CARE Hospitals Medical Education and Research
Puducherry, India Hyderabad, Telangana, India Puducherry, India
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Edwin Francis Gurpreet S Wander John Gorcsan III
Pediatric Cardiology Professor and Head Division of Cardiology
Contributors
Lisie Heart Institute, Lisie Hospital Department of Cardiology Washington University in St. Louis
Kochi, Kerala, India Hero DMC Heart Institute 660 S. Euclid Ave. Campus Box 8086
Dayanand Medical College and St. Louis, MO 63110, USA
Ganesan Karthikeyan Hospital
Professor Ludhiana, Punjab, India Justin Paul G
All India Institute of Medical Sciences Professor
New Delhi, India Institute of Cardiology
Hanan Fadala
Madras Medical College
Research Fellow, Echocardiography
Ganesh Kumar Kasinadhuni Chennai, Tamil Nadu, India
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Laboratory, Cardiology Division
Senior Resident
University of Alabama at Birmingham
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Cardiology Kailash Chandra
Birmingham, Alabama, USA
Postgraduate Institute of Medical Senior Resident
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Education and Research Post Graduate Department of
Chandigarh, India Harkrishnan S Cardiology
Sree Chitra Tirunal Institute for Jawahar Lal Nehru Medical College
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Gaurav Choudhary Medical Sciences and Technology Ajmer, Rajasthan, India
Assistant Professor Thiruvananthapuram, Kerala, India
Department of Cardiology Kanabar Kewal
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King George’s Medical University Senior Resident
Lucknow, Uttar Pradesh, India IB Vijayalakshmi
Professor Department of Cardiology
Gautam Singal
Senior Consultant
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Super Specialty Hospital
Postgraduate Institute of Medical
Education and Research
Bengaluru Medical College and Chandigarh, India
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Holy Family Hospital Research Institute
Kartikeya Bhargava
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New Delhi, India Bengaluru, Karnataka, India

Associate Director
Medanta Heart Institute
GC Khilnani
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Jaganmohan A Tharakan Medanta-The Medicity

Professor and Head Former Professor and Head Gurugram, Haryana, India
Department of Pulmonary Medicine
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and Sleep Disorders SCTIMST Kewal C Goswami
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All India Institutes of Medical Sciences Trivandrum, Kerala, India

New Delhi, India Professor
Jagdish C Mohan All India Institute of Medical Sciences
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Girish Kumar Parida

Senior Resident Chairman New Delhi, India
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Department of Nuclear Medicine

All India Institute of Medical Sciences Institute of Heart and Vascular Diseases KH Srinivasa
Jaipur Golden Hospital Professor
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New Delhi, India

New Delhi, India Sri Jayadeva Institute of
Girish MP Cardiovascular Sciences and Research
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Professor Bengaluru, Karnataka, India

Jayaranganath M
Professor and Head
GB Pant Institute of Post Graduate KK Talwar
Department of Pediatric Cardiology
Medical Education and Research Chairman
Sri Jayadeva Institute of
New Delhi, India Department of Cardiology
Cardiovascular Sciences and Research
Max Healthcare Institute Ltd
Bengaluru, Karnataka, India
Gurpreet S Gulati
Department of Cardiovascular KM Krishnamoorthy
Radiology and Endovascular Jay Relan Professor
Interventions Senior Resident Pediatric Cardiology
All India Institute of Medical Sciences All India Institute of Medical Sciences SCTIMST
New Delhi, India New Delhi, India Thiruvananthapuram, Kerala, India
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Krishnakumar S Madhu Shukla Monotosh Panja
Sree Chitra Tirunal Institute for Senior Clinical Associate Senior Consultant Interventional
Medical Sciences and Technology Department of Cardiology Cardiologist

Thiruvananthapuram, Kerala, India Institute of Heart and Vascular BM Birla Heart Institute
Diseases Kolkata, West Bengal, India
Krishnam Raju P Jaipur Golden Hospital
Cardiologist New Delhi, India Mumun Sinha
CARE Outpatient Centre DM Fellow
Hyderabad, Telangana, India Mahesh Kappanayil Department of Cardiovascular
Clinical Professor Radiology and Endovascular
Kshitij Sheth Department of Pediatric Cardiology Interventions
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Sir HN Reliance Foundation Hospital Amrita Institute of Medical Sciences All India Institutes of Medical Sciences
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Mumbai, Maharashtra, India and Research Centre New Delhi, India
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K Sivakumar M Zulfikar Ahamed
Head Mahim Saran Professor
Department of Pediatric Cardiology Senior Resident Senior Consultant
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Madras Medical Mission Department of Cardiology Pediatric Cardiology
Chennai, Tamil Nadu, India King George’s Medical University KIMS Hospital
Lucknow, Uttar Pradesh, India Thiruvananthapuram, Kerala, India
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Kumaran S
Assistant Professor Manoj Kumar Rohit
Institute of Cardoology
Madras Medical College
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Nageswara Rao Koneti
Chief Pediatric Cardiologist
CARE Hospital
Chennai, Tamil Nadu, India Postgraduate Institute of Medical Hyderabad, Telangana, India
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Education and Research
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Lakshmi Gopalakrishnan Chandigarh, India

Narendra Bagri
Senior Cardiologist
Department of Pediatrics
Southern Railway Headquarters Martin S Maron
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Hospital Director
New Delhi, India
Chennai, Tamil Nadu, India Hypertrophic Cardiomyopathy Center
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Division of Cardiology
Naveen Kumar
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Lakshmi Kumari Sankhyan Tufts Medical Center

800 Washington Street, Boston Department of Pediatric Cardiology
Department of Cardiothoracic Surgery
Massachusetts 02111 Max Hospital
New Delhi, India
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New Delhi, India

Mohan Nair
Navin C Nanda
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Lalit Kumar Coordinator and Head

Department of Medical Oncology Department of Cardiology Research Fellows, Echocardiography
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All India Institute of Medical Sciences Holy Family Hospital Laboratory, Cardiology Division
New Delhi, India New Delhi, India University of Alabama at Birmingham
Birmingham, Alabama, USA
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Laxmi H Shetty Mohit Bhutani

Assistant Professor Senior Resident Neeraj Awasthy
Department of Cardiology Department of Cardiology Department of Pediatric Cardiology
Sri Jayadeva Institute of Dr RML Hospital and Congenital Heart Diseases
Cardiovascular Sciences and Research New Delhi, India Max Hospital
Bengaluru, Karnataka, India New Delhi, India
Mohit D Gupta
Madhumanti Panja Professor Neeraj Pandit
Cardiology Trainee Department of Cardiology Professor and Head
RN Tagore International Institute of GB Pant Institute of Post Graduate Department of Cardiology
Cardiac Science Medical Education and Research Dr RML Hospital
Kolkata, West Bengal, India New Delhi, India New Delhi, India
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Nishanth KR Raghavan Subramanyan Raziye E Akdogan
Assistant Professor Head Research Fellow, Echocardiography
Contributors
Sri Jayadeva Institute of Department of Pediatric Cardiology Laboratory, Cardiology Division
Cardiovascular Sciences and Research Frontier Lifeline Hospital University of Alabama at Birmingham
Bengaluru, Karnataka, India Chennai, Tamil Nadu, India Birmingham, Alabama, USA
Nobuyuki Kagiyama Raghav Bansal Rishi Sethi

Postdoctoral Researcher Associate Consultant Professor
Division of Cardiology Max Super Speciality Hospital Department of Cardiology
Washington University New Delhi, India KG’s Medical University
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St. Louis, Missouri, USA Lucknow, Uttar Pradesh, India
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Rajesh Kalyankar
Parag Barwad DNB Cardiology RK Gokhroo
Associate Professor
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CARE Hospitals Principal and Controller
Cardiology Jawahar Lal Nehru Medical College
Hyderabad, Telangana, India
Postgraduate Institute of Medical and Associated Group of Hospitals
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Education and Research Ajmer, Rajasthan, India
Chandigarh, India Rajesh Kannan
Department of Radiology
R Krishna Kumar
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Amrita Institute of Medical Sciences
Pintu Sharma Clinical Professor and Head
and Research Centre
Department of Pediatric Cardiology
Rishikesh, Uttarakhand, India

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Amrita Institute of Medical Sciences
Rajesh Vijayvergiya
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Prakash C Negi Professor
Department of Cardiology R Saileela
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Professor and Head Cardiology

Advanced Cardiac Centre Consultant Pediatric Cardiologist
Indira Gandhi Medical College
Post Graduate Institute of Medical MIOT Centre for Children’s Cardiac Care
Shimla, Himachal Pradesh, India
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Education and Research Chennai, Tamil Nadu, India

Chandigarh, India
Pramod Sagar BK
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Senior Resident
Sachin Sondhi
Senior Resident Cardiology
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Department of Cardiology Rajiv Ananthakrishna

Sanjay Gandhi PGIMS Cardiology
Associate Professor
Lucknow, Uttar Pradesh, India Department of Cardiology Indira Gandhi Medical College
Shimla, Himachal Pradesh, India
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Sri Jayadeva Institute of

Cardiovascular Sciences and Research
Prashant Bhopate
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Consultant Pediatric Cardiologist

Begaluru, Karnataka, India Safal Singh
Children’s Heart Center Assistant Professor
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Kokilaben Dhirubai Ambani Hospital Department of Cardiology

Ramalingam Vadivelu
Mumbai, Maharashtra, India GB Pant Hospital
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New Delhi, India

Advanced Cardiac Centre
Preetam Krishnamurthy Post Graduate Institute of Medical
Senior Resident Education and Research Sakshi Sachdeva
Department of Cardiology Chandigarh, India Senior Resident
All India Institute of Medical Sciences Pediatric Cardiology
New Delhi, India All India Institutes of Medical Sciences
Ranjit Kumar Nath
New Delhi, India
Professor
PV Suresh Department of Cardiology
Senior Consultant Dr Ram Manohar Lohia Hospital and Samhita Kulkarni
Pediatric Cardiology Postgraduate Institute of Medical Registrar
Narayana Institute of Cardiac Sciences Education and Research SR Mehta Cardiac Insititute and
Bengaluru, Karnataka, India New Delhi, India Sir KP Trust Hospital
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Sandeep S Saurabh Kumar Gupta Siddharthan Deepti
Senior Resident Associate Professor Assistant Professor
Institute of Cardiology Department of Cardiology All India Institute of Medical Sciences

Madras Medical College All India Institute of Medical Sciences New Delhi, India
Chennai, Tamil Nadu, India New Delhi, India
Sivasubramanian Ramakrishnan
Professor
Sanjay G Saurabh Mittal All India Institute of Medical Sciences
Additional Professor of Cardiology Assistant Professor New Delhi, India
SCTIMST Department of Pulmonary Medicine
Thiruvananthapuram, Kerala, India and Sleep Disorders SK Dwivedi
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All India Institutes of Medical Sciences Professor
Sanjay Tyagi New Delhi, India
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Director Professor and Head King George’s Medical University
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Department of Cardiology Lucknow, Uttar Pradesh, India
SB Gupta
GB Pant Institute of Postgraduate
Consultant Physician
Medical Education and Research Snehal Kulkarni
Asian Heart Institute and Research
of
Maulana Azad Medical College Senior Consultant
Centre
New Delhi, India Pediatric Cardiology
Mumbai, Maharashtra, India
Division of Pediatric Cardiology
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Kokilaben Ambani Hospital
Sanjeev Asotra
Shibba Takkar Chhabra Mumbai, Maharashtra, India
Associate Professor
Cardiology
Indira Gandhi Medical College
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Dayanand Medical College and Snigdha Boddu
Senior Resident
Shimla, Himachal, Pradesh, India Hospital Unit Hero DMC Heart
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Institute
KG’s Medical University
Ludhiana, Punjab, India
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Sanjiv Sharma Lucknow, Uttar Pradesh, India

Professor and Head
Srinivas B Chikkaswamy
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Department of Cardiovascular Shiv Kumar Choudhary

Radiology and Endovascular Professor and Head Professor
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Interventions Department of Cardiovascular and

All India Institutes of Medical Sciences Thoracic Surgery Sri Jayadeva Institute of
og
New Delhi, India All India Institute of Medical Sciences Cardiovascular Sciences and Research
New Delhi, India Bengaluru, Karnataka, India
Santosh Kumar Chellapuram
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Sriram Rajagopal
Department of Medical Oncology
Shomu Bohora Chief Cardiologist
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Associate Professor of Cardiology Southern Railway Headquarters Hospital

New Delhi, India
UN Mehta Institute of Cardiology and Chennai, Tamil Nadu, India
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Research Center
Santosh Satheesh Ahmedabad, Gujarat, India S Shanmugasundaram
Additional Professor Professor
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Department of Cardiology Department of Cardiology

Jawaharlal Institute of Postgraduate Shyam S Kothari Emeritus Professor of Cardiology
Medical Education and Research Professor Dr MGR Medical University and
Department of Cardiology Cardiologist, Billroth Hospital
Puducherry, India
All India Institute of Medical Sciences Chennai, Tamil Nadu, India
New Delhi, India
Sasinthar Rangasamy Sudeep Kumar
Senior Resident Professor
Department of Cardiology Siddhant Trehan Department of Cardiology
JIPMER Artemis Hospital Sanjay Gandhi PGIMS
Puducherry, India Gurugram, Haryana, India Lucknow, Uttar Pradesh, India
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Sudhir S Shetkar Usha MK Vishal Batra
Consultant Associate Professor Assistant Professor
Contributors
Department of Cardiac Sciences Department of Pediatric Cardiology Department of Cardiology
Apollo Hospital Sri Jayadeva Institute of GB Pant Institute of Post Graduate
Nashik, Mahrashtra, India Cardiovascular Sciences and Research Medical Education and Research
Bengalurur, Karnataka, India New Delhi, India
Suresh Kumar
Varun S Narain
Senior Consultant and Head Vishwas Mohan
Professor and Head
Believers International Heart Centre Attending Cardiologist
Thiruvalla, Kerala, India Max Hospital
King George’s Medical University
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Lucknow, Uttar Pradesh, India New Delhi, India
Suruchi Hasija
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Associate Professor Vijaykumar JR Vivek Chaturvedi
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Department of Cardiac Anesthesia Senior Resident Senior Consultant Cardiology
All India Institutes of Medical Sciences Department of Cardiology Director, Cardiac Electrophysiology
New Delhi, India Sanjay Gandhi PGIMS Narayana Super Specialty Hospital
of
Lucknow, Uttar Pradesh, India Gurugram, Haryana, India
Sylvia Colaco
Fellow, Children’s Heart Center Vijay Kumar Trehan V Jacob Jose
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Kokilaben Dhirubai Ambani Hospital Director Professor Consultant
Mumbai, Maharashtra, India Ministry of Health
Tamiruddin A Danwade
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Medical Education and Research
Maulana Azad Medical College
Brunei
Department of Cardiology New Delhi, India Yash Lokhandwala

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CARE Hospital Arrhythmia Associates
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Hyderabad, Telangana, India Vikas Kataria Mumbai, Maharashtra, India

Senior Consultant
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U Ilayaraja Department of Cardiology Yash Shrivastava

Holy Family Hospital
Cardiologist Assistant Professor
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New Delhi, India

Billroth Hospital Department of Cardiology
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Vineeta Ojha Rishikesh, Uttarakhand, India

Ujjwal Kumar Chowdhury Department of Cardiovascular
Professor Radiology and Endovascular
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Cardiothoracic Sciences Centre Interventions Yuko Soyama

All India Institute of Medical Sciences All India Institute of Medical Sciences Washington University
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New Delhi, India New Delhi, India Saint Louis

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Uma Kumar Vinoth Doraiswamy Z Sajan Ahmad

Professor and Head Associate Consultant Pediatric Assistant Professor
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Department of Rheumatology Cardiologist Department of Cardiology

All India Institute of Medical Sciences CARE Hospital Pushpagiri Medical College
New Delhi, India Hyderabad, Telanagana, India Thiruvalla, Kerala, India
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PREFACE
It gives me immense pleasure and satisfaction in presenting the book titled Essentials of
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Postgraduate Cardiology to be released during the 70th annual conference of CSI 2018. The book
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covers a wide range of clinical and practical exam-oriented topics covering all essential aspects of
cardiology. We tried our best to keep the all the topics practical, up to date, relevant and interesting.
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I sincerely hope that this update will serve as a ready reckoner for postgraduate students and even the
practising cardiologist.
Modern-day cardiology is a beast that is difficult to tame—current-day treatment protocols are
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based on outcomes of large randomized controlled trials that draw strength from complex statistical
models (of which, I fear, most cardiologists know very little about). Interventional cardiology has continued its inexorable
progress, conquering frontiers that would have been felt impossible to conquer only a decade ago. Cardiac imaging has
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made even more remarkable progress with 3D imaging, intravascular probes, ultrafast CTs, plaque imaging and what not.
Electrophysiology has not been far behind either with newer computer-based technologies seeking to solve questions that
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would be difficult for physicians to interpret with their minds. My only concern is that the budding cardiologist has, and
again I cannot blame him for that, inadvertently chosen to sacrifice clinical and examination skills at the altar of modern
medicine. It is certainly more macho to diagnose severe mitral regurgitation by looking at PISA and EROA than to locate
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the hyperdynamic apex shifted into the axilla or assess the split of S2. The palpable P2 in the second intercostal space or
dilated pulmonary artery on the chest X-ray will draw only cursory, fleeting glance; greater time and skill would be spent
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on memorizing echo parameters of PAH. This tectonic shift in our perception of relevant clinical skills is there for all of us to
see—clinical cardiology seems to be on a deathbed. I was dismayed to read articles writing obituary for the stethoscope,
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the only instrument cardiologists wielded with considerable pride only two decades ago. It is for this very reason that I draw
immense pride and satisfaction to see this book delve largely on matters of clinical cardiology.
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Galaxy of national and international experts have penned down their thoughts, observations and clinical experience,
and I feel this book would stand the test of time. I am really thankful from the bottom of my heart and really appreciate their
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enthusiasm for this endeavor.

In the present scenario, a lot of literature is available in the field of cardiology. The problems we encounter in India are at
times unique and offer specific challenges. We realize the lack of consolidated literature focusing on ‘Indian’ and developing
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world problems like rheumatic heart disease, unoperated adults with congenital heart disease, pericardial diseases, EMF,
etc, which must be known to each and every fellow training in cardiology in India. Therefore, our goal was to create an
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academic resource to address the needs of a fellow preparing for the examinations. I am sure students taking up either DM/
DNB in cardiology will find it useful.
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An undertaking of this magnitude requires a team approach with immense dedication and coordination among all
the team members. The editorial team played a pivotal role in the planning, executing and editing the book. I would like
to place on record my sincere appreciation to my publishers, Evangel Publishing, for putting in their heart in making this
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book possible.
I would be failing in my duty if I do not acknowledge my family including my wife and mother for putting up with my
prolonged absences from home.
Kewal C Goswami

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CONTENTS
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Section 1 CLINICAL CARDIOLOGY
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Chapter 1. Jugular Venous Pulse: Elusive but Adorable...............................................3
Varun S Narain, Gaurav Choudhary
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Examination of the Jugular Venous Pulse 3
Interpretation of the Jugular Venous Pulse 4
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Identification of Waves 6
Abnormal Contours: What They Say 7
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Chapter 2. How to Measure Blood Pressure in

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Children and Adults? A Guide ...................................................................... 11
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Justin Paul G, Sandeep S, Kumaran S

History of Blood Pressure Measurement 11
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Noninvasive Techniques 11
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Present-day Methods 12
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Practical Points in Blood Pressure Measurement 13

Procedure of Measuring Blood Pressure 13
Ambulatory Blood Pressure Monitoring 14
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Blood Pressure Measurement in Special Populations 14

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Chapter 3. Peripheral Signs of Aortic Regurgitation: Revisited .............................. 17

S Shanmugasundaram, B Vinodkumar, U Ilayaraja
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Typical Arterial Pulse of Significant Aortic Regurgitation 17

Peripheral Signs of Aortic Runoff 18
Investigations 20
Chapter 4. Clinical Examination in Atrial Fibrillation.................................................. 21

Ganesh Kumar Kasinadhuni, Parag Barwad
Physical Examination 21
Systemic Examination 22

Chapter 5. Continuous Murmur ........................................................................................ 25
Ranjit Kumar Nath
Physiologic Classification 25
Differential Diagnosis 26
Chapter 6. Dynamic Auscultation ..................................................................................... 32

Rishi Sethi, Akshyaya Pradhan, Snigdha Boddu
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Physiological Maneuvers 32
Pharmacological Maneuvers 36
di

In
Section 2 VALVULAR HEART DISEASE—RHEUMATIC HEART DISEASE
of
Chapter 7. Challenges in the Diagnosis and
Management of Acute Rheumatic Fever .................................................. 39
ty
Anita Saxena
18 cie
Diagnosis of Rheumatic Fever 39
Major Criteria 40
20 o
Minor Manifestations 41
S
Management 42
al
Chapter 8. Pathogenesis of Rheumatic Fever and

ic
Rheumatic Heart Disease: What have we Learned?.............................. 46

Santhosh Satheesh, Sasinthar Rangasamy
og
Three Components of Rheumatic Fever Pathogenesis 46

Immunological Mechanisms in Acute Rheumatic Fever
ol

and Rheumatic Heart Disease 47

di
Controversies in Pathogenesis of Acute Rheumatic Fever/

Rheumatic Heart Disease 49
ar
Evolution into Chronic Rheumatic Heart Disease 50

Recent Conflicting Evidences in Rheumatic Heart Disease
C

Pathogenesis 50
Knowing the Pathogenesis of RHD:
How Does it Help in Tackling the Disease? 50
Chapter 9. Decline of Rheumatic Heart Disease: Is it Real? ..................................... 53

Prakash C Negi, Sanjeev Asotra, Sachin Sondhi
Methods of Detection 53
Data Sources for Estimation of Burden of RF/RHD 53
xviii

Epidemiological Trends of Burden of RHD in India 54
Decline of Rheumatic Heart Disease: Is it Real? 56
Contents

Estimated Burden of Disease 57

Challenges and Opportunities for Prevention
and Control of Rheumatic Fever/Rheumatic Heart Disease 57
Chapter 10. Clinical Assessment of Severity

of Valvular Heart Disease ................................................................................ 60
a
Ajith Ananthakrishna Pillai, Devendra Kanshilal Sharma,
di
Balachander Jayaraman
Mitral Stenosis 60
In

Mitral Regurgitation 64
Aortic Regurgitation 66
of

Acute Aortic Regurgitation 69

Aortic Stenosis 69
ty

Tricuspid Stenosis 71
18 cie

Tricuspid Regurgitation
Pulmonary Stenosis 72
71
20 o
Pulmonary Regurgitation 72
Multivalvular Lesions
S
72
al
Chapter 11. Subclinical Rheumatic Heart Disease ........................................................ 74

RK Gokhroo, Kailash Chandra
ic
Prevalence of Clinical and Subclinical RHD 74

og

Is Early Recognition Beneficial? 74

Diagnostic Criteria for Latent RHD 75
ol

Definite RHD 75
di
Borderline RHD 76
Limitations for WHF Criteria 76
ar

Targets for Screening 77

C
The Natural History of Subclinical RHD 77

Management of Definite RHD 77
Management of Borderline RHD 77
Chapter 12. Natural History of Mitral and Aortic Valve Regurgitation ................... 79
Sudhir S Shetkar, Sivasubramanian Ramakrishnan, Kewal C Goswami
Natural History of Mitral Regurgitation 79
Natural History of Aortic Regurgitation 81
xix

Chapter 13. Natural History of Rheumatic Mitral Stenosis ......................................... 87
Vivek Chaturvedi
Natural History of Mitral Stenosis in the

Era Prior to Definitive Therapy 87
Chapter 14. Percutaneous Transvenous Mitral

Commissurotomy: Tips and Tricks............................................................... 92
CN Manjunath, Vijaykumar JR, BC Srinivas
a
Anatomy and Pathophysiology 92
di

Indications for BMV 92
In
Contraindications 92
Technique 92
of
BMV Technique 93
Percutaneous Transvenous Mitral
Commissurotomy (PTMC) in Left Atrium Clot 96
ty
Manjunath’s Classification of LA Clot 98
18 cie
Lutembacher’s—ASD/RHD Severe MS
with Severe Submitral Disease 99
20 o
Chapter 15. Clinical Diagnosis of Tricuspid Valve Disease ........................................106
S
Sudeep Kumar, Pramod Sagar BK

al
Clinical Anatomy of Tricuspid Valve 106

Physiology 106
ic

Etiology of Tricuspid Valve Abnormalities 107

og
Tricuspid Stenosis 107

Tricuspid Regurgitation 107
ol
Symptoms of Tricuspid Valve Disease 110

Physical Signs 110
di

Effect of Various Maneuvers 112

ar
Electrocardiogram 113
Chest X-ray 113
C

Chapter 16. Atrial Fibrillation in Rheumatic Heart Disease ......................................115

Krishnakumar S, Harkrishnan S
Pathophysiology 115
Inflammation and Structural Remodeling 115
Pulmonary Veins, Electrical Remodeling and Stretch 115
Thromboembolism and Anticoagulation 116
Management 116
xx

Correction of Underlying Disorder 116
Control of Ventricular Rate 116
Contents
Rhythm Control 117
Chapter 17. Prevention of Rheumatic Fever/

Rheumatic Heart Disease .............................................................................119
Anil Bharani, Anjali Bharani
Epidemiology 119
a
Diagnosis of Rheumatic Fever 119
di
Prevention of Rheumatic Fever/Rheumatic Heart Disease 119
In
Section 3 VALVULAR HEART DISEASE—OTHERS
of
Chapter 18. Newer Valve Guidelines: What Suits
ty
Indians and What does not? ........................................................................127
18 cie
Rajiv Ananthakrishna, Srinivas B Chikkaswamy
Valvular Heart Disease: The Indian Perspective 127
20 o
General Considerations in Evaluating Valvular Heart Disease 127
Specific Valvular Lesions
S
128
Other Considerations 131
al
Common Case Scenarios in Routine Clinical Practice 131

The Future 132
ic
og
Chapter 19. Role of Two- and Three-dimensional

Echocardiography in Valvular Lesions .....................................................133
ol
Raziye E Akdogan, Ahmed Y Salama, Hanan Fadala, Navin C Nanda

di
Mitral Stenosis and Regurgitation 133

Aortic Stenosis and Regurgitation 138
ar
Tricuspid Stenosis and Regurgitation 141

Pulmonary Stenosis and Regurgitation 145
C

Chapter 20. Pitfalls in Assessment of Valvular Heart Disease ..................................148

Jagdish C Mohan, Vishwas Mohan, Madhu Shukla
Assessment of Mitral Regurgitation 148
Methods to Assess Severity of Rheumatic Mitral Regurgitation 150
Assessment of Mitral Stenosis 156
Assessment of Aortic Valve 165
Assessment of Aortic Regurgitation 172
xxi

Chapter 21. Nonrheumatic Mitral Regurgitation .........................................................180
CM Nagesh, Laxmi H Shetty
Mitral Valve Anatomy 180

Etiology 180
Pathophysiology 181
Clinical Features 182
Diagnosis 183
Quantitation of Primary and Ischemic Mitral Regurgitation 183
a
Treatment 185
di
Treatment in Primary Mitral Regurgitation 186
In
Treatment in Secondary Mitral Regurgitation 186
Percutaneous Techniques 186
of
Chapter 22. Bicuspid Aortic Valve in 2018: What we Must Know?.........................190
ty
KM Krishnamoorthy, Deepa S Kumar
Embryology 190
18 cie

Anatomy 190
Dysfunction of BAV 192
20 o
Anomalies of Aorta 192
S
Pathophysiology of Aortopathy 192

Genetics 192
al
Natural History 192

ic
Diagnosis 193
Intervention 194
og

Balloon Valvuloplasty 194

Surgical Aortic Valvuloplasty 196
ol
Indications of Surgery for Aortopathy 196

di
Pregnancy and BAV 196

Exercise and BAV 197
ar

C
Chapter 23. Low-gradient Aortic Stenosis .....................................................................199

Vishal Batra, Mohit D Gupta, Girish MP
Technical Pitfalls and Measurement Errors 199
Classical (Reduced Left Ventricular Ejection Fraction)
Low-flow, Low-gradient Aortic Stenosis 200
Paradoxical (Preserved Left Ventricular Ejection Fraction)
Low-flow, Low-gradient Aortic Stenosis 202
Normal-flow, Low-gradient Aortic Stenosis 202
xxii

Chapter 24. Infective Endocarditis: What is New? .......................................................204
SK Dwivedi, Mahim Saran
Contents
Prevention 204
Impact of Guideline Change 204
Prevention of Health Care-associated IE 205
Diagnosis 205
Imaging 205
a
Microbiology 206
di
Prognostic Assessment 206
Management 207
In

Antimicrobial Therapy 207

Surgical Indications 208
of

IE in Special Subgroups 208
ty
Chapter 25. Prophylaxis for Infective Endocarditis in India .....................................212
18 cie
KH Srinivasa, Nishanth KR
Rationale for Prophylaxis Against IE 212
20 o

Cardiac Conditions at Risk for IE 212

S

al
Chapter 26. Mechanical Prosthetic Valve Thrombosis ...............................................216

ic
Ganesan Karthikeyan
og
Incidence of Left-sided PVT 216

Clinical Presentation and Diagnosis of Left-sided PVT 216
ol
Management of Left-sided PVT 217

Recommendations for Management 217
di

ar
Chapter 27. Percutaneous Valve Interventions beyond

C
Transcatheter Aortic Valve Implantation ................................................219

Vijay Kumar Trehan, Safal Singh, Siddhant Trehan
Mitral Valve Repair 220
Mitral Valve Replacement 225
Percutaneous Therapies for Tricuspid Valve 229
Transcatheter Pulmonary Valve Implantation 231
xxiii

Section 4 CONGENITAL HEART DISEASE—KEY ISSUES
Chapter 28. Epidemiology of Congenital Heart Disease in India...........................235

Anita Saxena
Risk Factors 235
Incidence and Prevalence 235
Prevention 237
a
Current Status of CHD Care in India 239
di
In
Chapter 29. Assessment of Congenital Heart Defects
with Left-to-Right Shunts and Pulmonary
of
Hypertension for Operability ......................................................................243
R Krishna Kumar
ty
Objectives of the Review 244
18 cie
Correlating Preoperative Hemodynamics with
Lung Biopsy Findings and Clinical Outcomes 244
Clinical and Noninvasive Correlates of Hemodynamic
20 o
Changes in Left-to-Right Shunts 245
S
Accurate Hemodynamic Assessment in Shunt Lesions:

Who Needs it Most? 245
al
Role of Clinical Examination, ECG, Chest X-ray,

Echocardiography and Arterial Blood Gas 246
ic
Hemodynamic Assessment in the Catheterization Laboratory 247

og
Chapter 30. Pregnancy and Congenital Heart Disease..............................................252

ol
Arima Nigam
di
Physiological Changes During Pregnancy 252

ar
Maternal and Fetal Risk 253

High-risk Pathophysiologic States 254
C
High-risk Anatomic Lesions 255

Cardiovascular Drugs in Pregnancy 255
Recommendations Regarding Anticoagulation Management 255
Thrombolytic Therapy in Pregnancy 256
Percutaneous Intervention/Surgery During Pregnancy 257
Genetic Counseling 257
Mode of Delivery 257
Care in Puerperium 257
xxiv

Chapter 31. A Simplified Approach to the Management of
Congenitally Corrected Transposition of Great Arteries ...................259
Contents
R Suresh Kumar, R Saileela
Clinical Presentation and Natural History 259
Management 259
Heart Block in CCTGA 263
Pregnancy in CCTGA 263
a
Section 5 CONGENITAL HEART DISEASE—EVALUATION OF CHD
di
In
Chapter 32. ECG in Pediatric Cardiology .........................................................................267
BRJ Kannan
of
Basics of Recording and Interpretation 267
Normal Variations and Related Abnormalities 267
ty
Analysis of P Wave 271
Analysis of PR Segment 271
18 cie

Analysis of QRS Complex 273
Cardiac Position-related QRS Changes 274
Analysis of ST Segment 274
20 o

Analysis of T Wave 274

S

Some Disease-specific ECG Changes 275

al
Chapter 33. Chest X-ray in Congenital Heart Disease ................................................281

ic
Arun Sharma, Vineeta Ojha, Sanjiv Sharma

Technical Consideration 281
og

Sequential Approach for Interpretation 281

Chest X-ray and CHD Classification: Simplified Approach 284
ol
Chapter 34. Traps and Pitfalls in Echocardiographic Diagnosis .............................289

di
of Congenital Heart Disease

ar
K Sivakumar
Anatomical Errors 289
C

Functional Errors 294
Chapter 35. Fetal Echocardiography: Current Status and

Role in Management of Congenital Heart Defects .............................296
Balu Vaidyanathan
Concept of Universal Screening of Fetal Heart 296
3D/4D Stic Fetal Echocardiography 296
Impact of Fetal Echocardiography and Prenatal Diagnosis of CHD 297
xxv

Chapter 36. Advances in CT Angiography
for Congenital Heart Disease ......................................................................302
Arun Sharma, Gurpreet S Gulati

Challenges to Cardiac Imaging 302
Technical Improvements in Cardiac CT 302
Choosing the Optimal Imaging Modality in CHD 302
Clinical Applications of CT in CHD 303
Limitations 306
a

di
Chapter 37. Best Use of Cardiac MRI in Congenital Heart Disease ........................309
In
Mahesh Kappanayil, Rajesh Kannan
Cardiac MRI 309
of
Section 6 ACYANOTIC CONGENITAL HEART DISEASE
ty
18 cie
Chapter 38. Natural History of Ventricular Septal Defect .........................................319
Sakshi Sachdeva, Shyam S Kothari
20 o
Natural History of Ventricular Septal Defect 319
S

Chapter 39. Ventricular Septal Defect with Aortic Regurgitation..........................326

al
Manoj Kumar Rohit, Kanabar Kewal

ic
History 326
og
Epidemiology 326
Pathogenesis 326
ol
Morphology 327
di
Physiological Effects 327

Natural History 327
ar
Clinical Presentation 327

C
Treatment 328
Chapter 40. Imaging of Atrial Septal Defect ..................................................................332

Kshitij Sheth, Bharat Dalvi
Embryology of Interatrial Septum 332
Anatomy of Ostium Secundum Atrial Septal Defect 332
Types of Atrial Septal Defect 332
Echocardiographic Imaging of the Atrial Septal Defect 333
Three-dimensional Transesophageal 336
xxvi

Chapter 41. Lutembacher’s Syndrome ............................................................................340
Bhanu Duggal, Yash Shrivastava, Pintu Sharma
Contents
Epidemiology 340
Investigations 341
Chapter 42. Which Device for which Patent Ductus Arteriosus? ...........................344
IB Vijayalakshmi
a
Selection of Various Devices 344
di

Morphologic Classification of PDA 344
In
When is Each Device Used? 344
Amplatzer Vascular Plugs 347
of
Which Device in PDA With PAH? 347
Feasibility Test for Device Closure 348
ty
Chapter 43. Aneurysms of the Sinuses of Valsalva ......................................................351
18 cie
Kewal C Goswami, Sivasubramanian Ramakrishnan,
Siddharthan Deepti
20 o
Epidemiology 351
S
Pathological Anatomy and Etiology 351

al

Diagnosis 352
ic
Management 357
og
Chapter 44. Coarctation of Aorta in Adults: Diagnosis ............................................. 360

and Current Management Strategies
ol
PV Suresh
di
Classification 360
ar

Diagnostic Evaluation 361
C
Indications of Intervention 362
Section 7 CYANOTIC CONGENITAL HEART DISEASE
Chapter 45. Approach to Cyanosis in Newborn ...........................................................371

Anita Saxena
Normal Cardiopulmonary Adaptation at Birth 371
Causes of Central Cyanosis in the Newborn 372
xxvii

Initial Evaluation of the Newborn with Cyanosis 372
Hyperoxia Test 373
Approach to a Newborn with Cyanotic Congenital Heart Disease 373

Role of Pulse Oximetry 374
Chest Radiograph 374
Electrocardiography 374
Echocardiography 374
Initial Management 375
a
di
Chapter 46. Cyanosis in Adults ...........................................................................................378
Raghavan Subramanyan, R Saileela
In
Pathophysiology 378
Methemoglobinemia 379
of

Differential Diagnosis of Cyanosis 379

Hemoglobin Work-up in a Cyanotic Patient 381
ty

Treatment Strategy 382

18 cie
Chapter 47. Eisenmenger Syndrome: An Update........................................................384
Sylvia Colaco, Prashant Bobhate
20 o
Definition and Classification 384
S

Epidemiology 384
al
Classification 384
Pathophysiology 385
ic
Natural History 387

og

Cerebrovascular Events 389
ol
Pulmonary Dysfunction 389

Renal Function and Uric Acid Clearance 389
di

Other Miscellaneous Organ Involvement 389

ar
Investigations 389
Management Strategy 390
C
Other Conventional Therapies 391

Targeted Therapy 391
Surgical Management 393
Future Trends 393
Chapter 48. Adults with Repaired Tetralogy of Fallot .................................................397

Snehal Kulkarni
Surgical Repair of Unoperated TOF in Adults 397
Subsets Who Do Better On Long-term Follow-up 397
xxviii

Issues on Long-term Follow-up in Adults 398
Periodic Holter Monitoring 399
Contents
Computed Tomography 399
Magnetic Resonance Imaging 400
Nuclear Scintigraphy 400
Cardiac Catheterization and Angiography 401
Serial Estimation of Brain Natriuretic Peptide 401
Electrophysiology Study for Risk Stratification 401
a
Standardized Clinical Assessment and Management Plans 401
di
Pregnancy in Patients with TOF 401
Predictors of Complications on Follow-up 401
In

Reoperations in Adults with Repaired TOF 401

Percutaneous Pulmonary Valve Replacement/Implantation 401
of

Chapter 49. Single Ventricle Pathway: Simplified ........................................................403
ty
Nageswara Rao Koneti, Vinoth Doraiswamy
18 cie

Morphology 403
Hemodynamics 404
20 o
S
Investigations 404
Management 405
al
Long-term Follow-up of Fontan 408

ic
Chapter 50. Fontan Circulation: Simplified ....................................................................410

og
Jay Relan, Saurabh Kumar Gupta

Fontan Physiology 410
ol

Indications for Fontan Operation 410

di
Selecting a Patient for Fontan Operation 411

Preparing for Fontan Operation 411
ar

To Stage or Not to Stage Cavopulmonary Connection 412

C
Different Types of Fontan Circulation 414

Clinical Effects of Fontan Circulation 415
Long-term Effects and Complications 415
Outcome 417
Chapter 51. Ebstein’s Anomaly: What’s New?................................................................419

Jayaranganath M, Usha MK
Anatomy 419
Embryology 419
xxix

Arrhythmias 420
Etiology and Genetic Factors 421

Pathophysiology 421
Natural History 421
Examination 422
Treatment 424
a
Chapter 52. Total Anomalous Pulmonary
di
Venous Connection: An Overview ............................................................428
In
Sivasubramanian Ramakrishnan, Arvind Balaji, Kewal C Goswami
History 428
of
Prevalence and Etiology 428
Embryology 428
Morphology 428
ty

Associated Lesions 429

18 cie

Pathophysiology 429
Natural History 430
20 o
S
Other Imaging 433

Management 433
al
Chapter 53. Pulmonary Arteriovenous Malformations .............................................435

ic
Edwin Francis, Annu Jose, Bijesh Viswambaran

og
History 435
Etiology 435
ol


di
Investigations 436
Management 436
ar

C
Chapter 54. Systemic Effects of Cyanosis .......................................................................439

Neeraj Awasthy, Naveen Kumar
Systemic Problems with Cyanosis 439
Failure to Thrive 439
Cyanotic Spell 440
Brain Abscess 440
Hematological Complications 441
Vascular Complications 441
Renal Problems 442
xxx

Rheumatological Complications 442
Bacterial Endocarditis 443
Contents
Pulmonary Complications 443
Gallbladder stones 443
Ventricular Dysfunction 444
Dental abnormalities 444
Section 8 CARDIOMYOPATHY
a
di
Chapter 55. Outcomes of Dilated Cardiomyopathy in 2018....................................449
In
KK Talwar, Raghav Bansal
Epidemiology and Natural History 449
of

Etiological Classification of DCM 450

Evaluation of DCM 451
ty

Management of DCM 452

18 cie
Specific Considerations for Common Secondary Etiologies 454
Chapter 56. Genetics of Cardiomyopathies: An Overview .......................................460

20 o S
Ajay Bahl
General Principles 460
al
Dilated Cardiomyopathy 461

ic
Hypertrophic Cardiomyopathy 462

Idiopathic Restrictive Cardiomyopathy 462
og
Arrhythmogenic Right Ventricular Cardiomyopathy 462

Indian Context 462
ol
di
Chapter 57. Noninvasive Evaluation of

Suspected Heart Muscle Disease ..............................................................464
ar
Krishnam Raju P, Chandramukhi Sunehra

C
Cardiac Magnetic Resonance Imaging 466
Nuclear Cardiac Imaging 467
Cardiac Computed Tomography 467
Dilated Cardiomyopathy 467
Hypertrophic Cardiomyopathy 468
Noncompaction Cardiomyopathy 470
Restrictive Cardiomyopathy 471
Idiopathic Restrictive Cardiomyopathy 472
xxxi

Cardiac Amyloidosis 472
Nuclear Imaging in Cardiac Amyloidosis 474

Cardiac Sarcoidosis 474
Electrocardiogram 475
Cardiac Magnetic Resonance 475
Positron Emission Tomography (PET) 475
a
Anderson-Fabry Disease 476
di
Echocardiographic Features 476
In
Nuclear Imaging in Fabry Disease 476
Endomyocardial Fibrosis and Löffler’s Endocarditis 477
of

ty

Arrhythmogenic Right Ventricular Dysplasia 477

18 cie

Reversible Cardiomyopathies 478
Chemotherapy and Radiation-induced Cardiomyopathy 478
20 o
Chapter 58. Curable Forms of Ventricular Dysfunction .............................................481
S
Tamiruddin A Danwade, Calambur Narasimhan

al
Ischemic Cardiomyopathy (Coronary Artery Disease) 481

ic
Hypertensive Heart Disease 482

Diabetes Mellitus 483
og

Valvular Heart Disease 483

Alcoholic Cardiomyopathy 483
ol

Cocaine 484
di
Medications 484
Infectious Cardiomyopathy 484
ar

C
Chapter 59. Myocarditis: An Update ................................................................................492

Neeraj Pandit, Mohit Bhutani
Etiopathogenesis 492
Classification of Myocarditis 492
Investigations 493
Natural Course of Disease 494
Management 495
Future Directions 497
xxxii

Chapter 60. Tachycardiomyopathy ...................................................................................500
Vikas Kataria, Gautam Singal, Mohan Nair
Contents
Introduction 500
Definition 501
Epidemiology 503
Pathophysiology 503
a
Chapter 61. The Role of Cardiovascular Magnetic Resonance
di
in Risk Stratification of Hypertrophic Cardiomyopathy ....................506
In
Martin S Maron
Introduction 506
of
Cardiovascular Magnetic Resonance Characterization of
Left Ventricular Hypertrophy and Impact on Risk Assessment 506
Left Ventricular Apical Aneurysm: High-risk Subgroup 506
ty

CMR Tissue Characterization in HCM 507

18 cie

Late Gadolinium Enhancement and Sudden Death Risk
Pattern of Late Gadolinium Enhancement 510
508
Additional CMR Methods of Tissue Characterization 511

20 o

Quantification of Late Gadolinium Enhancement 512

S

Late Gadolinium Enhancement and Systolic Dysfunction 512

al
Chapter 62. Constrictive Pericarditis and Restrictive

ic
Cardiomyopathy: How to Differentiate? .................................................514

og
V Jacob Jose
Pathophysiology of Constriction 514
ol
Echo Doppler Signs 515

Cardiac Computed Tomography 517
di
Cardiac Magnetic Resonance (CMR) 517

ar
Multimodality Imaging 517

Invasive Hemodynamics (Cardiac Catheterization) 520
C
Chapter 63. Tubercular Pericarditis ...................................................................................523

GC Khilnani, Saurabh Mittal
Epidemiology 523
Pathogenesis 523
Clinical features 523
Diagnosis 524
Treatment 525
xxxiii

Chapter 64. Surgery for Chronic Constrictive Pericarditis, Tuberculous
Pericarditis and Effusive-Constrictive Pericarditis ...............................526
Ujjwal Kumar Chowdhury, Lakshmi Kumari Sankhyan, Suruchi Hasija

Etiological Search 526
Clinical Challenge and Diagnostic Dilemma of CCP 526
Surgical Techniques and Results 530
Post-pericardiectomy Low Cardiac Output Syndrome 530
Specific Disease Entities 531
a
Management 532
di
Tuberculous Pericarditis 532
In
Tuberculous Pericardial Effusion 532
Treatment 533
of
Chapter 65. An Update on Restrictive Cardiomyopathy ...........................................536
ty
Ramalingam Vadivelu, Rajesh Vijayvergiya
Etiology 536
18 cie


Diagnosis 536
20 o
Echocardiographic Findings in RCM 536
S
Hemodynamic in RCM 539

Common Causes of RCM 540
al
ic
Chapter 66. Tropical Endomyocardial Fibrosis?............................................................546

A Vanishing Curious Disease
og
Jaganmohan A Tharakan, Shomu Bohora, Sanjay G

Epidemiology 546
ol

Endomyocardial Fibrosis in India 547

di
Etiology of Endomyocardial Fibrosis 548

ar

Laboratory Investigations 548
C
Natural History and Management 549

Is the Incidence and Prevalence of EMF on the Decline—
A Vanishing and Curious Disease? 550
Chapter 67. Cardiac Amyloidosis: Diagnosis and Management ............................552

Santosh Kumar Chellapuram, Lalit Kumar
Pathophysiology 552
Clinical features 552
xxxiv

AL Amyloidosis 553
Cardiac Magnetic Resonance and Radionuclear Testing 553
Contents
Cardiac Biomarkers 554
Management of Cardiac Failure 555
Transthyretin-related Amyloidosis 557
Novel Strategies 557
Cardiac Transplantation 557
a
Chapter 68. Cardiac Sarcoidosis .........................................................................................559
di
Ajit Thachil
In
Incidence and Prevalence 559
Presentations 559
of
Prognosis 560
Diagnosis 561
ty
Imaging in Cardiac Sarcoidosis 563
18 cie
Treatment 566
20 o
Section 9 VASCULAR SYSTEM
S
al
Chapter 69. Imaging and Classification of Takayasu’s Arteritis ...............................575

Monotosh Panja, Arindam Pande, Madhumanti Panja
ic
Imaging in Takayasu’s Arteritis 575

og
Chest Radiographic Features 575

Ultrasonography 575
ol
di
Chapter 70. Immunotherapy for Nonspecific Aortoarteritis ...................................581

Narendra Bagri, Uma Kumar
ar
Disease Activity and Severity 581

C
Immunotherapy 582
Corticosteroids 582
Nonbiological Disease Modifying Antirheumatic Drugs 582
Other DMARDs 583
Biologic Disease Modifying Anti-rheumatic Drugs 584
Other Biological agents 584
Immunotherapy During Surgery and Perioperative Period 584
Follow-up 584
xxxv

Chapter 71. Interventions in Takayasu Arteritis (Nonspecific Aortoarteritis) ....586
Sanjay Tyagi, Ankit Bansal
Pathophysiology 586
Imaging for Interventions in Takayasu Arteritis 586
Interventions in Takayasu Arteritis 587
ARCH Artery Interventions 589
Recent Advances 593
a
di
Chapter 72. Aortic Diseases: When to Proceed with Surgery? ................................598
Shiv Kumar Choudhary, Aayush Goyal
In
Aortic Aneurysms 599
Acute Aortic Syndromes 601
of

Traumatic Aortic Injury 604

Arteritis 604
ty

18 cie
Chapter 73. Aortic Diseases: When and How to
Proceed for Interventional Management? .............................................607
20 o
Mumun Sinha, Sanjiv Sharma
S
Imaging of Aortic Diseases 607

Steno-occlusive Lesions of Aorta 608
al

Dilatative or Aneurysmal Lesions 609

ic
Aortitis 609
og
Aortic Dissection 610

Diseases Specific to Aortic Root and Ascending Aorta 611
ol
di
Chapter 74. Pulmonary Embolism: When to do What? .............................................615

Bishav Mohan, Shibba Takkar Chhabra
ar
Anticoagulation 615
C
Systemic Thrombolytic Therapy 616

Catheter-based Therapy 616
Chapter 75. Evaluation of Pulmonary Hypertension:

A Simplified Algorithm..................................................................................624
Abhishek Goyal, Gurpreet S Wander
Definition and Classification 624
Algorithmic Approach to Pulmonary Hypertension 624
xxxvi

Chapter 76. Recent Advances in the Management of
Idiopathic Pulmonary Artery Hypertension ..........................................630
Contents
Rajesh Kalyankar, BKS Sastry
Pharmacotherapy 630
Combination Therapy 630
Oral Anticoagulants 630
Stem Cell Therapy 632
Pulmonary Artery Denervation 632
a
Potts Shunt 632
di
Experimental Therapies 632
In
Chapter 77. Kawasaki Disease: What We Should Know? ...........................................635
of
M Zulfikar Ahamed, Z Sajan Ahmad
Historical Perspective 635
ty
Epidemiological Perspective 635
Pathology 636
18 cie

Clinical Diagnosis 636

Laboratory Evaluation 637
20 o
Cardiovascular Manifestations in KD 638
S
Other Abnormalities 640

Other Investigations 640
al
Natural History 640

ic
Special Concerns in KD 640

Treatment of KD 641
og

Standard Protocol Followed in Our Institution 642

Long-term Management 643
ol
Protocol for Management 644

di
Interventions in KD 644
Natural History 645
ar

Long-term Cardiac Damage 645

C
Indications for Coronary Angiography 645
Section 10 ELECTROCARDIOLOGY
Chapter 78. Common Pitfalls and Artifacts in ECG Interpretation ........................651

SB Gupta
Limitations 651
Normal ECG in Pathological Conditions 651
xxxvii

Common Pitfalls in Diagnosis of Coronary
Artery Disease on ECG 652
Abnormal ECG with Normal Hearts 654

Common Artifacts in ECG Interpretation 654
Lead Misplacements 656
Chapter 79. Computerized ECGs: Strengths and Limitations..................................663

Kartikeya Bhargava
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Computerized ECG: Methodology and Technical Aspects 663
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Accuracy of Computer-Interpreted Electrocardiograms 664
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Utility of Computer-Interpreted ECG in Specific Diagnosis 664
Computerized ECGs: Strengths and Limitations—
General Comments and Concluding Remarks 667
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Chapter 80. ECG Assessment of Supraventricular Tachycardia...............................675
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Amit Vora, Samhita Kulkarni
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Steps in the ECG Analysis of SVTs 675
ECG Analysis of Different SVTs 675
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Chapter 81. ECG Assessment of Wide QRS Tachycardia ............................................684

Binay Kumar, Yash Lokhandwala
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Types of Wide QRS Tachycardia 684

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Steps for Ventricular Tachycardia Discrimination 684

Assessment of QRS Regularity 685
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Identification of P Wave 687

Relationship between P and QRS 687
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Morphologic Analysis of the Wide QRS Complex:

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Comparison with Sinus Rhythm 688

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Chapter 82. Atrioventricular Block: Diagnosing the Level of Block.......................692

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Avinash Anantharaj, Anandaraja Subramanian

Localization of the Site of Block 693
Chapter 83. STEMI Equivalents ...........................................................................................699

Arun K Chopra
Isolated True Posterior Myocardial Infarction 699
Hyperacute T Waves 699
De Winter Sign 700
Isolated ST Depression in AVL 700
xxxviii

Wellens’ Syndrome 700
Isolated ST Elevation in AVR 700
Contents
New or Presumed New Left Bundle Branch Block 701
Stemi Equivalents in Paced Patients 703
Section 11 LET’S FACE THE VIVA
Chapter 84. Recent Advances in Echocardiographic Strain Imaging ...................709
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Nobuyuki Kagiyama, Yuko Soyama, John Gorcsan III
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Fundamentals of Strain Imaging 709
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Global Longitudinal Strain 709
Normal Longitudinal Strain Values 709
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Relationship of GLS to Ejection Fraction 710
GLS in Heart Failure with Reduced Ejection Fraction 710
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GLS in Heart Failure with Preserved Ejection Fraction 712
GLS in Acute Heart Failure 712
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Longitudinal Strain in Cardiac Amyloidosis 712
GLS in Monitoring Cardiotoxicity for Chemotherapy 713
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GLS in Valvular Heart Disease 713
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Chapter 85. Hemodynamic Assessment in the

Cardiac Catheterization Laboratory .........................................................716
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Jaganmohan A Tharakan, Sanjay G

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How to Perform an Invasive Hemodynamic Study? 716

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General Cues Obtained During any Hemodynamic Study 716

Provocative Maneuvers in Cardiac Catheterization Laboratory 717
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Evaluation of Patients with Congenital Heart Diseases 719

Evaluation of a Patient with Pulmonary Hypertension 721
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Transpulmonary Gradient, Diastolic Pulmonary Gradient 721

Heart Failure and Transplantation 721
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Pericardial Diseases 722

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Evaluation of Obstructive Lesions 722

Evaluation of Patients with Ischemic Heart Disease 725
Postmyocardial Infarction 728
Chapter 86. Interpretation of Catheterization Traces .................................................729

Sriram Rajagopal, Lakshmi Gopalakrishnan
Steps in the Process of Interpretation 729
Normal Physiology 729
Technical Aspects 730
Correlation of Pressure Traces with Electrocardiographic Events 731
xxxix

Chapter 87. Interpreting a Nuclear Stress Test..............................................................736
Girish Kumar Parida, Abhinav Singhal, Chetan D Patel
Patient Preparation 736

Stress Protocols 736
Radiotracers and Image Acquisition Protocol 737
Image Display 737
Interpretation 737
Gated SPECT Parameters 741
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Final Reporting of MPS 743
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Chapter 88. Cardiac Tumors: Practical Approach and Management ....................746
Kewal C Goswami, Preetam Krishnamurthy
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Epidemiology 746
Classification 746
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Histopathology 747
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Examination 749
Clinical Diagnosis 749
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Diagnostic Evaluation 751
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Management 753
Benign Cardiac Tumors 753
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Malignant Cardiac Tumors 755

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Index .................................................................................................................................................... 761

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Clinical Cardiology
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Jugular Venous Pulse: Elusive but Adorable

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How to Measure Blood Pressure in Children and Adults? A Guide
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Peripheral Signs of Aortic Regurgitation: Revisited

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Clinical Examination in Atrial Fibrillation

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Continuous Murmur
Ranjit Kumar Nath
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Dynamic Auscultation
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KG-1 (Sec-1).indd 1 02-11-2018 13:44:57
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KG-1 (Sec-1).indd 2 02-11-2018 13:44:57

Jugular Venous Pulse:
CHAPTER 1 Elusive but Adorable
a
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INTRODUCTION and could be used as a guide to intensify diuretic use. This
Examination of the jugular venous pulse (JVP) is is not true in case of raised JVP in RV infarction, where
In
an important initial step in the examination of the diuretic use may cause hypotension.
cardiovascular system. It is a treasure-chest of diagnostic
Jugular Venous Waveforms
of
possibilities. It is also the trickiest part of the examination,
often misinterpreted, underused, and even ignored. One It was Potain who first described the jugular venous
must learn to use JVP, not only for its merit of giving clues waveform; however, James Mckenzie named the JVP
ty
to the diagnosis, but also to understand the underlying waves and established it as an important part of the
hemodynamics of the condition, which would ultimately clinical examination.
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help in guiding management of the case in question.
This review will look at the anatomical, physiological,
technical, and applied aspects of the JVP.
External and Internal Jugular Veins
Before we begin the examination and interpretation of the
The systemic veins are thin walled mildly distensible JVP, it is important to identify the external and internal
20 o
reservoirs analogous to a partially filled surgical glove, jugular veins correctly. The external jugular vein (EJV)
S
filled in the upright position and collapsed above the level. runs from lateral to medial side of the neck across the
Tge blood flows up to. Blood flows in from the venous sternocleidomastoid muscle and can be made prominent
return (VR) and flows out by the pumping action of the
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by putting a forefinger just above the clavicle and pressing

right ventricle (RV), wherein the pressure is maintained by gently. Pressing at the angle of the jaw prevents filling from
variation in the RV contractility as dictated by the Frank–
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above and the height of the column of blood left in the

Starling law. Failure of this hemostatic mechanism leads to vein reflects the RA pressures. The internal jugular vein
excess volume and pressure and a rise in the JVP.1
og
(IJV) starts at the base of the neck and runs between the
two heads of the sternocleidomastoid to reach the angle of
EXAMINATION OF THE JUGULAR the jaw (Figure 1). The IJV may not be seen until there is
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VENOUS PULSE significant tricuspid regurgitation (TR). However, we look

at its conducted pulsations on the skin.
There are two parts to the examination of the JVP:
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Jugular Venous Pressure

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Vertical height of oscillating column of blood in the right

internal jugular vein (IJV) reflects the pressure changes
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in the right atrium during the cardiac cycle. The IJVs

being continuous with the superior vena cava (SVC)
act as ‘pulsating manometers’ for right-sided pressure.2
During the ventricular systole, it provides information
on right atrial (RA) pressure; while during the diastolic
phase, when the tricuspid valve (TV) is open, it reflects
the right ventricular (RV) diastolic pressure. The JVP may
underestimate RA pressures especially when the venous
pressures are high. This may be due to the valve near
the termination of the internal jugular vein. All in all, in
congestive heart failure, if the JVP is raised, RA pressure is Figure 1: Landmarks for identification of the external and
at least as high as or higher than the height of the column internal jugular veins
KG-1 (Sec-1).indd 3 02-11-2018 13:45:01

SECTION Three other questions need an answer: 4. In case of persistent left SVC, the pressure in the left IJV
Is this pulsation due to the internal jugular or the carotid? would be higher than the right due to greater emptying
1 In comparison to the carotid pulsation, jugular venous
pulsations are more laterally located, soft, diffuse,
resistance while draining into the coronary sinus. This
may be the case especially in atrial septal defect (ASD).
Clinical Cardiology
undulant, and hardly palpable with two crests and

two troughs (carotids have a single motion). Unlike INTERPRETATION OF THE JUGULAR
the carotids, jugular venous pulsations are obliterated
VENOUS PULSE
by slight pressure at the base of the neck. The height
of JVP varies with change in position, increases on Interpretation of the JVP is done under the following heads:
abdominal compression and falls during inspiration 1. Jugular venous pressure
(except in Kussmaul’s physiology). While the carotids 2. Respiratory variation
a
have a prominent positive pulsation, the movement of 3. Hepatojugular reflux/abdominal compression test
the jugular venous pulse is predominantly a descent.1 In 4. Waveforms.
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normal subjects, the descent of the carotids is rapid while Close adherence to details of methodology are essential
that of the jugulars, slow. for reliability and reproducibility in measuring the jugular
In
venous pressure and assessing waveforms.
Why choose the internal jugular vein (IJV) over external
jugular (EJV) vein?
Jugular Venous Pressure
of
1. The IJV is in direct line with the superior vena cava
(SVC) and thus courses directly into right atrium, while Positioning the Patient (Figure 2)
the EJV does not directly drain into the SVC taking two
The patient should be lying comfortably in a semi-
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almost 90 degrees bends before joining it.
reclining position with 45° angle between the trunk and
2. The course of EJV to the SVC passes through several
the bed with the head slightly turned towards the left
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facial planes and is prone to obstruction.
3. Thrombus formation in the bulb of the EJV can cause
partial obstruction and rise in pressure.
shoulder, so that the neck muscles are relaxed. It is helpful
to place a folded pillow behind the patients head, keeping
the shoulders on the mattress. Standing to the right, with
4. On lateral movement of the head, the contraction of
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a gentle pressure with the palm on the forehead turning
the platysma muscles can cause partial obstruction of
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the head away to the left, slightly raising the jaw, brings
the EJV and raise the pressure.
5. Because of the presence of valves in EJV pulsations the venous meniscus into the window of visibility. Natural
light is desirable for inspection; but, at times, the use of a
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may not be seen.

6. During conditions such as cardiogenic shock and even tangential beam of light at the skin with a torch from the
in congestive heart failure, because of vasoconstriction front or behind to casts shadows improves visibility of
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EJV may be small and barely visible. motion. One must keep the hand holding the torch steady
by keeping it on the chest or a pillow to prevent artefacts
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EJVs are still useful: Despite their limitations, the EJVs

are paradoxically better visualized and engorged when interfering with interpretation of the JVP.
pressure is raised versus the IJVs whose pulsations may 45 degrees inclination: Why?
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not be easy to see on the skin except when associated In a healthy person, the visible jugulars are fully collapsed
with a significant TR. At such times, the EJVs may be in the sitting posture and distended to a variable degree
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used for assessment of RA pressure. In fact, they may when supine. Selecting an appropriate intermediate
even be preferred due to their better visibility.3 Also, in position permits one to see the top of the pulsating
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case of severe TR when IJV pulsations cannot be relied column between the clavicle and the mandible. This
upon to assess RA pressure, the EJVs may be of sole help. angle is generally between 30 and 60 degrees. A standard
Checking the EJV also helps in quickly establishing the JVP of 45 degrees is chosen. Sitting up may be required if the
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as normal/raised. After light pressure has distended the upper level goes up to the jaw. Earlobe pulsations may be
initially collapsed vein, release should rapidly clear it if looked for. While no standard exists for the height of the
the pressure is normal. If the rise persists or the decline is vertical column in the sitting posture in normal pressures,
slow, the pressure is assumed to be raised.2 pulsations going up to the jaw at 90 degrees generally
Why the right IJV? means a pressure of 25 mm Hg or more.
1. The right IJV is in an almost straight line with the SVC Further, at 45 degrees inclination and a normal
and RA and thus better reflects the hemodynamic pressure of 8 mm blood column/water and assuming the
changes from the RA. mid-RA to be 5 cm from sternal angle and the vertical
2. There is greater filling of the right innominate vein distance from here to the clavicle being 3 cm any visibility
from the right side of the head. of the JVP above the clavicle at this inclination is a
3. The left innominate vein is prone to kinking or qualitative indication of it being raised (Figure 2). At 45
compression between the aortic arch and sternum, by degrees inclination, the upper limit of normal is 4.5 cm of
4 a dilated aorta, or by an aneurysm. blood column: easy to remember.
KG-1 (Sec-1).indd 4 02-11-2018 13:45:01

CHAPTER

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Figure 2: Positioning and method of measuring the jugular venous pulse
There is some concern that the RA pressure is Some suggest use of a tongue depressor with measure
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underestimated by adding 5 cm to the height of the JVP. markings in cm as the vertical tool and the carpenter’s
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A CT study has shown that the center of the RA was spirit level as the horizontal tool for comfort and accuracy,
5.4 cm from the sternal angle in the supine posture, and respectively; but this is rather cumbersome.
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increased to 8, 9.7 and 9.8 cm on torso rotation to 30, 45

and 60 degrees, respectively. There is also a wide range Calculation of Right Atrial Pressure
of variation from 5 to 30 cm at 30 degrees inclination. It
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Normally, the center of RA is 5 cm below the sternal angle.

is suggested to add 10 cm instead of 5 cm at elevations
Hence, 5 cm is added to the above measurement to obtain
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more than 45 degrees.4,5 The phlebostatic axis of Burch

the right atrial pressure. To convert cm of H2O to mm Hg, a
is a line representing the intersection of the mid-axillary
conversion factor as 1.36 cm of H2O or blood = 1 mm Hg is
line and the fourth intercostal space. It passes through
applied; another conversion is to multiply the height of the
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the posterior RA and has been suggested by some as

blood/water column by 0.74.6
a reference point for the RA, but it is useful only in the
Causes of raised central and RA pressures are
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supine posture and may not be relevant in the obese or

obstruction at the tricuspid valve, RV systolic and/or
those with barrel-shaped chests due to lung disease.1
diastolic failure such as in RV infarct, pulmonary
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hypertension, primary or secondary to left ventricular

Locating the Sternal Angle (Angle of failure, pulmonic stenosis, Bernheim effect, pericardial
Louis/Lewis/Ludwig)
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disease, primary tricuspid valve incompetence, generalized

It is the palpable transverse prominence at the junction of volume overload either iatrogenic or due to anemia, renal
the manubrium to the body of the sternum at the level of disease, large atrioventricular communications and
2nd costal cartilage and is taken as the reference zero point ASD.6,7
for measuring pressures.
Respiratory Variation
Measurement During inspiration, there is increase in visibility of JVP,
Two rulers are required, one placed horizontal to the especially the “a” wave (the ‘x’ and the ‘y’ descents may
upper level of pulsation and another taking the vertical also become prominent), while the mean jugular venous
distance of that ruler from the sternal angle. Measure the pressure falls. However, when there is inspiratory rise or
vertical distance (in cm) between the horizontal lines no fall in venous pressure when the heart is unable to
drawn from the upper level of venous pulsation and the accommodate increased volume, it is called Kussmaul’s
sternal angle as shown in Figure 2. sign. It is typically seen in constrictive pericarditis. 5
KG-1 (Sec-1).indd 5 02-11-2018 13:45:02

SECTION Other causes of a positive Kussmaul’s sign are: right
ventricular myocardial infarction (RVMI), restrictive
1 cardiomyopathy, massive pulmonary embolism, tricuspid
stenosis, right-sided tumors, and SVC obstruction. In the
Clinical Cardiology
SVC obstruction, the elevated JVP is nonpulsatile and

without any respiratory variation.
Hepatojugular Reflux
Hepatojugular reflux (HJR) is also known as Pasteur-
Rondot maneuver. Jugular venous pressure is raised in
a
congestive cardiac failure (CCF) with low output because
of both increase in volume and venous tone. While this
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tone volume increase persists, the JVP may be high but still
within the upper limits of normal and not visible. This may
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also occur with the use of diuretics. The use of abdominal
compression will uncover this situation by causing and Figure 3: Normal jugular pulse waveforms in relation to the
cardiac cycle and heart sounds
maintaining a rise in the upper level of venous pulsations
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in those with high venous, even high right atrial and right
ventricular tone. 8 The greater the rise, the greater the an upper limit of compliance; (ii) Displacement of blood
venous pressure. from the visceral vessels to larger vessels viz. SVC with
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This was originally called the hepatojugular reflux increased tone; (iii) The raised diaphragm decreases
(not reflex: there are no neurons involved here!) being the intrathoracic and mediastinal volumes available
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described by Pasteur in 1885 as a diagnostic test for
tricuspid regurgitation; 9 and, later by Rondot in 1898
for cardiac expansion, and (iv) Compression per se can
increase the venous tone.10
A positive test in those without isolated heart failure
in CCF. Hence, the name. It was later realized that
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decompressing the congested liver was not essential to means a capillary wedge pressure of 15 mm Hg or higher.
this sign and that it could be elicited even in those with no A false-positive test can occur in those with chronic
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hepatomegaly. We now know that the increase in the JVP obstructive lung disease, other lung conditions with loss of
can occur with compression anywhere over the abdomen, vital capacity, increased blood volume, and with increased
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though the best results come from pressing over the sympathetic stimulation such as nervousness, pain, acute
right upper quadrant.8 This should be avoided in case of infarct, or catecholamine infusions.10
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tender hepatomegaly. Hence, the better term would be

abdominal compression test. Waveforms
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There are two positive waves and two descents or troughs

Method seen in a normal JVP. Figure 3 illustrates the normal
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The palm of the right hand is placed either in the center jugular venous waves and their relation to the cardiac
of the abdomen or in the right upper quadrant of the cycle as well as heart sounds. Table 1 describes each wave
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abdomen. Let it be warm (a garment/sheet between the and the physiological basis for each waveform. Jugular
patient and the palm may be a good idea if it is cold). venous pulsations closely reflect transmitted changes
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Spreading the fingers prevents local pressure and pain. in RA pressures with a pulsation delay of approximately
Also, explaining the procedure to the patient and asking 60–110 msec.6
him/her not to hold the breath (lest one lands up with a
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Valsalva maneuver) helps. It is preferable to start with a IDENTIFICATION OF WAVES

gentle pressure building it up gradually to approximately
Identification of waves is easier described than is practical,
20–35 mm Hg pressure of 15 seconds duration. Normally
but with repeated practice, the skill is bound to improve
the pressure rises, but the rise is less than 3 mm Hg and
with time and experience.
this rise returns to normal within 10 seconds/a few beats. A
rise of at least 3 cm for the entire duration of compression
or may be even after release (more than 15 seconds) the Tips for the Board Examination
test is considered positive.8,10,11 Look more for the descents. Inward collapsing movements
Mechanism of rise of venous pressure on abdominal are easier to see.
compression are not clear but could include: (i) Increase Time with radial pulse and heart sounds: If the
in venous return cannot be accommodated by the already negative wave comes with the radial pulse, it is ‘x’. If the
volume loaded right heart with increased tone and on nadir coincides with S2, it is again ‘x’.
6
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CHAPTER
Table 1: Normal JVP waveforms and the genesis of production
‘a’ wave Occurs during atrial systole and is due to increased pressure because of atrial contraction. It is the dominant wave
occurring before carotid pulsation and S1 1

‘x’ descent Primarily due to atrial relaxation but the part of ‘x’ descent after the ‘c’ wave (‘x’) is contributed by the descent of the
tricuspid ring caudally during ventricular contraction
‘c’ wave Is seen on the ‘x’ descent and it is due to carotid artefact and in the recordings during cardiac catheterization is due
to the upward bulging motion of the closed tricuspid valve during isovolumetric ventricular contraction
‘v’ wave Seen due to rise in the right atrial pressure due to passive filling from the systemic veins and the tricuspid valve
closed during ventricular systole. ‘v’ peaks just after the S2 and can be timed with the downslope of the carotid pulse
a
‘y’ wave It is a negative deflection with fall in right atrial pressure due to opening of the tricuspid valve and continues during
the rapid filling phase of the right ventricle
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‘H’ wave Seen usually during slow rate. Occurs due to passive right heart filling during the diastole (Diastasis). It occurs just
prior to the ‘a’ wave. Pre-atrial systolic squeeze from the pulmonary veins has also been quoted as a cause
In
If you are looking at the positive waves, then that which ABNORMAL CONTOURS: WHAT THEY SAY
of
comes with S1 is ‘a’ and that with S2 is ‘v’.
‘a’ Waves
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Still not Sure: Correlate with Clinical Findings Tall ‘a’ Waves
Single wave: Atrial fibrillation: Say that the wave seen is ‘v’. It is seen when the RA contract against an appreciable
18 cie
Single wave: Sinus rhythm: Tricuspid regurgitation (TR):
‘v’ again.
resistance either at the tricuspid valve level (atresia,
s t e n o s i s, m y x o m a t h ro m b u s, c a rc i n o i d , l u p u s
endocarditis), intraventricular level (RV hypertrophy,
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Two waves: Rheumatic heart disease, heart failure, no TR: subvalve stenosis) or beyond (pulmonary stenosis or
Say both present; ‘a’ prominent. pulmonary regurgitation). Prominent ‘a’ wave of tricuspid
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Two waves: Congenital heart disease [pulmonary stenosis stenosis is shown in Figures 4A and B.
(PS), pulmonary arterial hypertension (PAH)] intact A Berheim phenomenon due to left ventricular
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septum, no TR: Say both present; ‘a’ prominent. hypertrophy has also been described as a cause of a tall ‘a’.
In the setting of congenital heart disease, large ‘a’
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Two waves: Cannot decide: Say both ‘a’ and ‘v’ prominent.
waves speak of intact interventricular and interatrial septa.
Constrictive pericarditis/restrictive cardiomyopathy When the ‘a’ waves are considerably large-more than
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(RCM) : Say both ‘x’ and ‘y’descents prominent. 4.5 cm at 45 degrees inclination-they may be called giant
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A B
Figures 4A and B: Jugular venous pulse in (A) Tricuspid stenosis: Tall ‘a’ with slow ‘y’ descent; (B) Tricuspid regurgitation: Loss of ‘x’ and
prominent ‘cv’ wave
KG-1 (Sec-1).indd 7 02-11-2018 13:45:03

SECTION
1
Clinical Cardiology
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A B
In
Figures 5A and B: Cannon waves in complete heart block. (A) Differentiation between a tall ‘a’ wave (presystolic); and (B) A cannon ‘a’ wave (systolic)
of
‘a’ waves. Seen better on tracings, they produce a flicker
in the right supraclavicular area. Giant ‘a’ wave may also
produce a knocking sound in the neck during inspiration.8
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Giant ‘a’ waves are presystolic, abrupt with collapsing
quality, and often palpable. They measure 6–15 cm
18 cie
higher than the ‘v’ waves and are referred to as jugular
Corrigans .11
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Cannon Waves
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They are extreme forms of tall ‘a’ waves seen when the RA
contracts against a closed tricuspid valve.
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Cannon waves offer diagnostic help in arrhythmias:

Irregular cannon waves are seen commonly with
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ectopic beats, and in complete heart block (rate slow)

(Figures 5A and B) and in ventricular tachycardia (fast Figure 6: Jugular venous pulse in atrial fibrillation: Absent ‘a’ waves,
og
rate). attenuated ‘x’ descent

Regular cannon waves can occur in atrioventricular
(AV) nodal and AV re-entrant tachycardias, slow
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Flutter waves are occasionally visualized. A giant silent

ventricular tachycardias, 2:1 AV blocks and first-degree
atrium as in Ebstein’s anomaly does not possess effective
AV blocks with such prolonged PR that the atrial systole
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mechanical systole and ‘a’ waves may be absent.

occurs during the preceding ventricular systole. Cannon
waves with auscultation of S1 can help in the differential
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diagnosis of wide QRS tachycardias. The absence of ‘x’ Descent

cannon ‘a’ waves and constant intensity of S1 suggests a
Attenuated/Absent ‘x’
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supraventricular rhythm with aberrancy.10

Cannon waves are more easily recorded (hence given When it is encroached upon by increasing degrees of TR
this name from appearance) than seen.11 (Figure 4B) or when there is absence/reduction of the
Pronounced efflux of blood during simultaneous descent of the base due to poor contractility of the right
contraction of the atria and ventricles during junctional ventricle as in RV infarct or because of atrial fibrillation/
tachycardia gives a feeling of neck pulsations as in a frog. flutter, the Frank–Starling effect is weakened, the descent
Hence, called frog positive by Brugada.12 of base is absent.
Absent ‘a’ Wave Increased Depth of the ‘x’ Descent

Most common with atrial fibrillation (Figure 6) where an Increased volume in the RV as in atrial septal defect, total
absent ‘a’ wave is accompanied by an attenuated ‘x’ and a anomalous pulmonary venous connection, pulmonary
dominant ‘y’ descent. regurgitation increases right ventricular contractility
8
KG-1 (Sec-1).indd 8 02-11-2018 13:45:04

exaggerating the descent of base, and hence the ‘x’ CHAPTER
descent.
In cardiac tamponade, RA filling is uni-modal occurring
only in systole. Hence, a prominent ‘x’ descent. The
1

absence or limitation of RA filling during diastole flattens
or eliminates the ‘y’ wave. The ‘x’ descent is prominent
along with a steep ‘y’ in constrictive pericarditis and
restrictive cardiomyopathy.
‘v’ Waves
a
Large ‘v’ Waves
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They are usually recognized by their association with
deeper ‘y’ descents. They are produced because of greater
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RA filling as in tricuspid regurgitation (TR) (Lancisi sign).
A large ‘v’ wave fused with the ‘c’ wave is seen in severe TR
and the descent is replaced by the ‘cv’ wave that is followed
of
by a steep ‘y’ descent due to increased flow and gradient
across the tricuspid valve in early diastole (Figure 4B).
Due to increased influx of blood into the right IJV which
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in straight line with the RA through the SVC, a right to left
Figure 7: Jugular venous pulse in atrial septal defect: Prominent ‘a’,
‘head bob’ may be seen on frontal examination.8 ‘v’, ‘x’, and ‘y’
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A large ‘v’ wave due to increased right atrial filling is
also seen in ASD (which also has a deeper ‘x’ descent)
(Figure 7), total anomalous pulmonary venous drainage,
Deep ‘y’ (rapid emptying of a large amount of blood
from RA
absent pericardium, and hyperdynamic circulatory states.
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Reduced or loss of compliance of the RA as in constrictive
Pericardial Disease
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pericarditis or after surgery also gives large ‘v’ waves. In right

ventricular hypertrophy of pulmonary outflow obstruction In cardiac tamponade, ‘x’ is prominent and the ‘y’ is
almost absent (atrial filling is unimodal: occurs only
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or heart failure where the end-diastolic pressure is raised,

the RA pressure is already high (AV valve is open), when its in systole).
filling starts, giving a more prominent ‘v’ wave.8,11 In constrictive pericarditis, both ‘x’ and ‘y’ are present
ic

with a dominant ‘y’ (atrial filling is bimodal but most

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‘y’ Descent right ventricular filling occurs in early diastole).

A dominant ‘x’ with a fair almost equal ‘y’: Effusive
Slow Descent constrictive pericarditis or milder form of constriction.
ol
Seen typically in tricuspid stenosis due to atrial outflow

obstruction (Figure 4A) and in RV hypertrophy due to Pulmonary Artery Hypertension11
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outflow resistance—a steep descent rules out a significant x > y: Right ventricle is compensated
tricuspid valve obstruction. x = y: Beginning of right ventricular decompensation
ar
x < y: Right ventricle is decompensated.

Rapid or Sharp Descent
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Prominent sharp descents occur in conditions of increased Congenital Heart Disease

‘v’ wave. In constrictive pericarditis, we have a very rapid
Tetralogy of Fallot (TOF): Usually normal unless in
sharp ‘y’ without ‘v’ prominence (Friedrich’s sign). Similar
failure as in adult TOF or associated comorbidities.
findings are found in restrictive cardiomyopathy.
Pulmonic stenosis with intact interventricular septum:
Specifics Right-to-left shunting at atrial level; raised JVP; ‘a’
prominent; tricuspid leak; prominent ‘v’ and ‘y’ waves.
Atrial Septal Defect (Figure 7) Tricuspid atresia : Raised JVP ; restrictive ASD;
Prominent and widened ‘a’ (>0.18 sec)(stronger atrial prominent ‘a’ wave.
contraction: Frank–Starling law) Transposition of great vessels with increased pulmonary
Deep ‘x’ (Stronger RV contraction with increased blood flow; raised JVP; ‘a’ wave may be prominent.
descent of base) Eisenmenger syndrome: Small dominant ‘a’ in one-
Large steep ‘v’ (increased filling of RA) fourth of all cases.
9
KG-1 (Sec-1).indd 9 02-11-2018 13:45:04

SECTION A giant (6 cm or more) ‘a’ wave is seen in a small 3. Vinayak AG, Levitt J, Gehlbach B, et al. Usefulness of the
percentage of Eisenmenger ASD, rarely to never in those external jugular vein examination in detecting abnormal
1 with ventricular septal defects or patent ductus arteriosus.
If there is accompanying tricuspid leak, ‘v’ waves can
central venous pressure in critically ill patients. Arch Intern
Med. 2006;166(19):2132-7.
Clinical Cardiology
become prominent.11 4. Devine PJ, Sullenberger LE, Bellin DA, et al. Jugular
venous pulse: window into the right heart. South Med J.
CONCLUSION 2007;100(10):1022-7.
5. Seth R, Magner P, Matzinger F, et al. How far is the sternal
In an age of advances in technology, neglect of physical
angle from the mid-right atrium. J Gen Intern Med.
signs referred to as hyposkillia13 is a malady plaguing the
2002;17(11):852-6.
cardiologists at many levels of seniority and experience. As
6. Kanu Chatterjee. Physical exam. In: Manual of Cardiac
a
persons involved in dealing with a large number of patients
Diagnosis. Kanu Chatterjee, Mark Anderson, Donald H
where and to whom technology is not immediately
di
Eistad, Richard E Kerber (eds). New Delhi:Jaypee Brothers
available and as teachers who have the responsibility of
Medical Publishers, 2014.
taking clinical skills forward from our generation to the
In
7. Willems J, Roelandt J, Kesteloot H. The jugular venous
next, honing and stressing upon their improvement is
pulse tracing. Proc Vth European Cong Cardiol, 1968. pp. 433.
important. The JVP assessment is not easy but continuing
8. Constant J. Jugular pressure and pulsations. Essentials of
to focus and sharing ones findings with peers and senior
of
Bedside Cardiology. Humana Press, 2003. pp. 63-88.
colleagues who have had more experience will certainly
9. Pasteur W. Note on a new physical sign of tricuspid
lead to improvement in the diagnostic acumen. After all,
regurgitation. Lancet. 1885;2:524-5.
Wenckebach first diagnosed the phenomenon, named
ty
10. Theo E Meyer, Mark H Drazner, Susan B Yeon. Examination
after him, not by the ECG but by looking at the jugular
of the jugular venous pulse, 2018.
venous pulsation.
REFERENCES
18 cie 11. Oomen K George, Bobby John. Jugular venous pulse. In:
Cardiology Clinical Methods. V JacobJose, S Ramakrishnan
(eds). New Delhi:Jaypee Brothers Medical Publishers, 2017.
1. Chua Chiaco JM, Parikh NI, Fergusson DJ. The
20 o
pp. 23-40.
jugular venous pressure revisited. Cleve Clin J Med. 12. V Jacob Jose, S Ramakrishnan. History taking. Cardiology
S
2013;80(10):638-44. Clinical Methods. New Delhi:Jaypee Brothers Medical

2. Constant J. Using internal jugular pulsations as a Publishers, 2017. pp. 11.
al
manometer for right atrial pressure measurements. 13. Herbert L Fred. Hyposkillia: Deficiency of clinical skills. Tex
Cardiology. 2000;93(1-2):26-30. Heart Inst J. 2005;32(3):255–7.
ic
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How to Measure Blood Pressure
CHAPTER 2 in Children and Adults? A Guide
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INTRODUCTION
Hypertension is a cause of significant morbidity and
In
mortality in the population. The patients have to bear costs
for their treatment and the pill burden adds on to their
of
difficulty. The overall crude prevalence of hypertension
in India was 25.3% with significant differences noted
between rural and urban parts. Globally, however, the
ty
overall prevalence of hypertension in adults aged 25 and
more was 40% in 2008.
18 cie
The concept of hypertension has undergone several
changes over the years. Revolutionary changes with
respect to our understanding of the pathophysiology,
diagnosis and therapeutics have taken place relatively
20 o
recently over the past hundred years. The discovery of
S
thiazide diuretics in the late 1950s made some progress Figure 1: An artist’s impression of Hales’ experiments to determine
towards management of hypertension. The Veterans blood pressure of a horse
Affairs Cooperative trial started in 1964 demonstrated
al
that treatment of diastolic blood pressure (BP) to less if mercury is used for measuring BP, the height of the
than 90 mm Hg reduced cardiovascular (CV) events column required will be 13.6 times less and measurement
ic
significantly. Numerous trials on hypertension after that can be done with greater ease. Further, the silvery
have consistently demonstrated the benefit of lowering appearance of mercury imparts greater visibility. The
og
BP. The diagnosis of hypertension relies heavily on height, to which the mercury column rises, is reported as
accurate measurement. This article gives an outline on unit of pressure in mm of Hg. It was Poiseuille who first
innovated the use of mercury for measuring arterial BP.
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measurement of BP in adults and children and highlights

the associated practical challenges. This earned him a gold medal at the Royal Academy of
Medicine.
di
HISTORY OF BLOOD PRESSURE Later, Ludwig, in 1847, developed the kymograph which
MEASUREMENT gave a primitive graphical representation of the arterial
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The path-breaking concept of pressure within the pulse. Initial equipment used in measuring BP although
conceptually great was invasive and cumbersome for
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cardiovascular system (CVS) was demonstrated by the

pioneering work of Stephen Hales. He tied a mare down clinical use. This provoked a search for development of
alive and after opening its left crural artery, inserted a noninvasive techniques of BP measurement. Simultaneous
brass pipe whose bore was one-sixth an inch of a diameter developments in physics, science and technology have led
(Figure 1). He fixed a glass pipe of the same diameter to further innovations and we now have the measuring
nearly nine meters in length. He noticed that after untying devices which are non-invasive and comfortable for use.
the ligature, the blood column rose to 8 feet and 3 inches
and at its maximum height would rise and fall after each NONINVASIVE TECHNIQUES
pulse 2 to ever 4 inches. Thus, it was in 1733 that the first
measurement of BP was made. The First Sphygmomanometer
In 1855, Lord Vierordt postulated that BP can be estimated
Use of Mercury in Measuring Blood Pressure by applying counter-pressure causing the pulsation in
Mercury is a stable fluid at room temperature, with a an artery to cease. He developed a device which could
specific gravity of 13.6. This means that compared to water estimate the BP using this principle (Figure 2).
KG-2.indd 11 02-11-2018 13:44:46

SECTION
1
Clinical Cardiology
Figure 2: Vierordt’s sphygmograph. Figure 3: Marey’s modification.

A direct sphygmograph attributed to Marey, was
a
The pad is applied over the radial artery. Weights are placed in the
large cup until a pulse wave is traced out, then weights are placed a modification of Vierordt’s syphgmograph
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in the smaller cup which acts as a fine adjuster
In
However, this device was cumbersome and the process
was tedious and difficult. This device was subsequently
modified by Marey in 1860 (Figure 3). Potain added to the
of
design. Thus, there was a gradual improvement in the style
of measuring BP with new methods slowly being accepted
(Figure 3).
ty
Riva Rocci Cuff: It was in 1896, that Riva Rocci reported a
18 cie
method which involved compression of the arm around
its whole circumference by a rubber bag (tube of a bicycle
wheel) which was surrounded by some inexpansible
20 o
material. The pressure in the cuff was measured using a
mercury manometer, and was steadily increased until the
S
radial pulse could no longer be palpated. Subsequently,

the pressure was slowly released watching the mercury
Figure 4: Riva Rocci’s demonstration of measurement of
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level in the manometer fall. The reading at which pulse blood pressure.
reappeared was taken as the systolic BP. The present-day Riva Rocci used a narrow cuff which rendered readings inaccurate.
ic
technique uses this same principle (Figure 4). It was later modified by Von Recklinghausen who used a wider cuff
to obtain accurate readings
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PRESENT-DAY METHODS
makes them less dependable. The pressure is registered by
The currently used sphygmomanometers are in fact a
a system of metal bellows that expands as the cuff pressure
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progressive modification of previous primitive models.

increases and a series of levers that register pressure on a
There are three main methods of BP measurements
circular scale. They can lose their stability over time.
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in adults which are widely practiced in clinical use.

These include mercury sphygmomanometer, aneroid
Oscillometric Methods
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manometer, and oscillometric manometers. These

methods have their own advantages and disadvantages. This is currently the recommended method for BP
measurement. The oscillometric devices work on the
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Mercury Sphygmomanometer principle that blood flowing through an artery causes

vibrations in the arterial wall which can be detected and
This is the most widely used method in most developing
transduced to electric signals that can be presented as a
countries. However, it is losing its charm due to rising
digital readout.
environmental concerns. The appropriate use of mercury
The cuff in oscillometric method is placed on the
sphygmomanometer and its practical challenges are
arm. It uses fuzzy logic to decide how much cuff should
discussed later in this chapter.
be inflated to reach a pressure almost 20 mm Hg over the
systolic BP for any individual. When the cuff is inflated
Aneroid Manometers to reach this pressure, no blood flow occurs through the
These have the advantage of being portable but have the artery. As the cuff is deflated below the systolic BP, blood
disadvantage of losing its calibration over time which flow is re-established and sets up a detectable vibration
12
KG-2.indd 12 02-11-2018 13:44:47

in the arterial wall, which is sensed by the transducer and Apparatus Factors CHAPTER
this marks the systolic BP. When the cuff pressure falls
2
An ideal BP apparatus should be easy to carry, free from
below the patients’ diastolic pressure, blood flow becomes repeated calibration and should reproduce the same
smooth through the artery, and the vibrations cease,
results when repeatedly tested. Before checking the BP of

which marks the diastolic BP. These digital devices deflate
a patient it should be ensured that the rubber tubing, cuff,
at about 4 mm Hg per second making them sometimes
and connections are all intact. It should be ensured that
seem slower to use than the auscultatory aneroid devices,
the initial displayed reading starts at zero.
but they are more accurate.
The size of the cuff is different for adults and children.
Ideally, the cuff bladder should encircle at least 80% of the
Digital Sphygmomanometer patient’s arm circumference and the ideal width is at least
a
This is a hybrid device using features of both electronic and 40% of the patient’s arm circumference. The cuff size in
auscultatory method. The mercury column is replaced by children depends upon the age group.
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an electronic pressure gauge as is used in oscillometric The cuff should be wrapped around the bare arm
devices. BP is measured using the standard auscultatory snugly; approximately two finger breadth above the
In
technique. The cuff pressure is usually displayed as a cubital fossa with the center of the cuff placed over the
simulated mercury column, as a digital readout or as a brachial artery.
simulated aneroid display.
of
The other newer techniques of measurement includes PROCEDURE OF MEASURING BLOOD
finger cuff method of Penaz, ultrasound techniques and
PRESSURE
ty
tonometry, which are not in wide clinical use.
Both palpatory and auscultatory methods are used for
measuring the BP. First, the approximate systolic BP
PRACTICAL POINTS IN BLOOD PRESSURE
MEASUREMENT
18 cie should be identified using palpatory method. The cuff
is initially inflated up to a point when the radial pulse
disappears. It is then slowly deflated until radial pulse
Patient Factors
20 o
reappears. This point is taken as approximate systolic BP.
Site of Measurement
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Subsequently, the auscultatory method is used to

accurately measure the systolic and diastolic BPs. The cuff
The standard location for BP measurement is the upper
is inflated to about 30 mm Hg above the estimated systolic
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arm although measurements at the wrist, finger, thigh

and leg are possible. However, it is important to know BP and then deflated at the rate of 2 mm Hg per second.
The diaphragm of the stethoscope is placed over the
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that systolic and diastolic BPs vary according to the site

of the arterial tree but variations in mean arterial BP are brachial artery just under the lower margin of the cuff to
auscultate for Korotkoff sounds.
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generally minimal.
The Korotkoff sounds originate from a combination of
turbulent blood flow and oscillations set up in the arterial
Effects of Body Posture wall. These sounds have been classified into five phases:
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There is no consensus as to whether measurement has Phase 1: Appearance of clear tapping sounds which
to be made in supine or seated position, although most

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corresponds to the appearance of a palpable pulse

guidelines recommend sitting. Phase 2: Sounds become softer and longer
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Phase 3: Sounds become crisper and louder
Phase 4: Sounds become softer and muffled

Effects of Arm Position
Phase 5: Disappearance of sounds.
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There is progressive increase in the pressure of about 5-6 Systolic BP corresponds to appearance of the first
mm Hg as the arm is moved from horizontal to vertical
Korotkoff sound. This is slightly lower than the direct
position (due to increase in hydrostatic pressure).
intra-arterial BP. Phase 5 is taken as the diastolic BP.
This is slightly higher than the direct intra-arterial BP
Other Factors value. Phase 4 of Korotkoff, which marks the onset
The patient must be seated comfortably with the back and of muffling of sounds, is taken as the diastolic BP in
arm supported. The patient should refrain from talking pregnant women, in patients with arteriovenous fistulas,
or doing any physical activity. Fist should be open and and in aortic regurgitation as the Korotkoff sounds are
not clenched. Caffeine, nicotine, and exercise should be audible even after complete deflation of the cuff. The
avoided 30 minutes before BP measurement. Ideally, BP above-said conditions are characterized by widened pulse
is measured after short period of rest of about 5 minutes. pressure.
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KG-2.indd 13 02-11-2018 13:44:47

SECTION Auscultatory Gap Conditions where BP measurement could be difficult:
Atrial fibrillation
1
During the measurement of BP, the Korotkoff sounds
Cardiogenic shock
may become inaudible between systolic and diastolic
Burns
BPs and then reappear as cuff deflation continues. This
Clinical Cardiology
Absent limbs
phenomenon is known as auscultatory gap (gap in
Heart failure
auscultation of Korotkoff sounds). This can lead to false
Skin diseases
overestimation of the diastolic BP. If only auscultatory
Aortoarteritis
method is used, without using the palpatory method,
Embolism to peripheral vessels.
auscultatory gap can lead to underestimation of systolic
pressure also. This is often observed in older patients
Self-Blood Pressure Monitoring
a
who have a wide pulse pressure due to the stiffening of
arterioles. Auscultatory gap can be prevented by raising Home-based monitoring of BP has been practiced for
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the arm overhead for about 30 seconds before checking several years. Initially, aneroid sphygmomanometers
the BP in the usual position. This maneuver decreases were used which is now replaced by devices which use
In
the vascular volume in the limb and increases inflow oscillometric technique. Home-based BP measurement
enhancing the Korotkoff sounds. has advantages in that it is relatively cheap and provides
an opportunity to monitor BP over prolonged periods. It is
of
Sources of Error in Measurement noted that home-based measurements are usually lower
of Blood Pressure than clinic measurements and when accurately measured
can improve both therapeutic compliance and BP control.
ty
Inadequate cuff size: It is the most common cause of
error in BP measurement.
AMBULATORY BLOOD PRESSURE

18 cie
White coat effect: In some patients, the BP is found to
be elevated only in the presence of a physician. When
measured in other places including at work or at home,
MONITORING
It is a noninvasive, fully automated technique in which
the BP is found to be lower.
20 o
BP is recorded over an extended period of time typically
Recent ingestion of pressor substances can increase BP. over 24 hours. Typically, ambulatory blood pressure (ABP)
S
Terminal digit preference: This is due to a difference devices use oscillometric method for determination of BP.
in the actual BP value measured by the clinician and The standard equipment includes a cuff which is usually
al
the reported value, related to subconscious preference tied to the nondominant upper arm, a small monitor
to include certain terminal digits in the value. Zero is attached to a belt and a tube connecting the monitor to the
ic
often the preferred terminal digit (measured value may cuff. A typical session involves recording BP once every
be 142 or 138, but the clinician may report a value of 15 to 30 minutes (which is programmable) over 24 hours
og
140). preferably on a workday.

Smoking: It can lead to transient increase in systolic BP. The data are stored in the monitor and then transferred
Cuff inflation hypertension: In occasional patients, to system. The software analyzes the data and gives the
ol
there may be a transient but substantial increase report by an hour and period—daytime, night time, and
of up to 40 mm Hg coinciding with cuff inflation. 24-hour BP. The systolic and diastolic BPs are recorded.
di
Therefore, it is required that cuff be inflated gradually The ABP monitoring has the following advantages.
and deflated gradually at 2 mm Hg/sec. Lower rates First, it helps to identify the usual level of BP outside the
ar
diminishes Korotkoff sounds, resulting in slightly clinic setting and, therefore, helps to specifically identify
higher diastolic BPs. people with white coat hypertension. Second, it helps
to identify the individual’s BP variations (spontaneous
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Masked hypertension: This is characterized by lower

BP readings in the office and higher readings when BP variations, dippers and nondippers, etc.) which help
measures elsewhere like at work or at home and this in risk stratification. Lastly, it helps to identify patients
is usually lifestyle that can be attributed to it such as with gross discrepancy between home- and clinic-based
alcohol consumption , smoking, physical activity away measurements.
from clinic, etc.
Pseudohypertension: This entity seen is seen when BLOOD PRESSURE MEASUREMENT IN
peripheral vessels become rigid as a result of advanced SPECIAL POPULATIONS
arteriosclerosis. The cuff has to be inflated at higher
pressures to compress them resulting in overtly high Children
BP measurements. The distal radial pulse may be The BP in children is measured using the standard
palpable even after the cuff is fully inflated. auscultatory method. Oscillometric method is generally
14
KG-2.indd 14 02-11-2018 13:44:47

used in newborn and young infants as well as in the ABP measurements in adults will help elucidate symptoms CHAPTER
intensive care setting. The right arm is generally preferred such as episodic faintness and nocturnal dyspnea.
as it can be used to compare with reference tables. Correct
sized cuff should be used in children. Using regular cuffs in Obese
2

children can lead to underestimation of BP. Measurement of BP in obese individuals has greater
The prerequisites for measuring BP in children are practical challenges. The cuff size should be of adequate
similar to that for adults. Children preferably can have the size to give an accurate estimate. However, it is often
BP measurements taken when supine; however, the feet difficult to get the appropriate cuffs for these persons. This
of the child be on the floor rather than dangling from the can lead to overestimation of BP in these individuals.
bedside. Repeated measurements are necessary before
terming a child as a hypertensive. Infants should have the Arrhythmias
a
measurements taken when supine. It is recommended
Arrhythmias set up vibrations in vessel wall which
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that an average of multiple BP measurements be taken for
interfere with BP measurement. The variability in cardiac
weeks or months. Role of ambulatory and home-based BP
output induced by arrhythmia can lead to beat-to-beat
In
monitoring is not clear in children.
The BP in children is measured using the standard and temporal variations in the BP.
auscultatory method. Oscillometric method is generally
Pregnancy
of
used in newborn and young infants as well as in the
intensive care setting. The right arm is generally preferred In pregnancy, the presence of hyperdynamic circulation
as it can be used to compare with reference tables. Correct necessitates that the fourth stage of Korotkoff sounds
ty
sized cuff should be used in children. Using regular cuffs in be used as cutoff for determining diastolic BP. The BP
children can lead to underestimation of BP. measured does not vary much between sitting and left
18 cie
The prerequisites for measuring BP in children are
similar to that for adults. Children preferably can have the
lateral positions.
BP measurements taken when supine; however, the feet Chronic Kidney Disease
20 o
of the child be on the floor rather than dangling from the
In patients with chronic kidney disease (CKD), there is
bedside. Repeated measurements are necessary before
S
calcification of vessel wall which can affect BP measure-

terming a child as a hypertensive. Infants should have the
ment.
measurements taken when supine. It is recommended
al
that an average of multiple BP measurements be taken for

weeks or months. Role of ambulatory and home-based BP
Diabetes Mellitus
The presence of autonomic dysfunction and the co-
ic
monitoring is not clear in children.

“Flush technique of measurement of blood pressure existence of other comorbid illnesses in diabetic patients
og
can be used in infants. The sphygmomanometer cuff is can influence BP measurement.

applied to the wrist or ankle. An elastic bandage is wrapped
around the wrist [or ankle] beginning from the digits up to CONCLUSION
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the proximal edge of the cuff. The sphygmomanometer is The BP is a ver y impor tant deter minant of the
then inflated rapidly to about 300 mm Hg and the elastic cardiovascular risk of a patient. It is very important to
di
wrapping is removed. The manometer pressure is then know not only the techniques of its measurement but also
gradually released at the rate of 5 mm Hg. With gradual to know the methodology underlying these techniques
ar
release there is a distinct blush of the blanched portion of and the difficulties and errors that could arise. Accurate
the extremity. The reading at this point approximates mean measurement of the technique is important to risk
blood pressure. This method is considered to be a reliable
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stratify, prognosticate, and advise appropriate steps in

method for blood pressure measurement in infants”.
management.
Elderly
SUGGESTED READING
Elderly often have isolated systolic hypertension due
1. Arthur J Moss, Wilbert Leibling, Wallace O Austin, Forrest
to hardening of blood vessels, due to arteriosclerosis. H Adams. Determination of blood pressure in infants – use
The other factors, such as BP variability, presence of of the flush technique. Los Angeles – California Medicine.
comorbidities, intercurrent illness, polypharmacy, and 1957;87(3):166-7.
defective autoregulation, complicate BP measurement 2. Bilo G, Sala O, Perego C, et al. Impact of cuff positioning
in the elderly. In elderly, the BP should be measured in on blood pressure measurement accuracy: may a specially
both sitting and standing positions to look for orthostatic designed cuff make a difference? Hypertension Res.
hypotension which is common in these individuals. The 2017;40:573-80.
15
KG-2.indd 15 02-11-2018 13:44:47

SECTION 3. Booth J. A short history of blood pressure measurement. 6. Pickering TG, Hall JE, Appel LJ, et al. Recommendations for
Proc R Soc Med. 1977;70(11):793-9. blood pressure measurement in humans and experimental
1 4. Geldsetzer P, Manne-Goehler J, Theilmann M, et al.

Diabetes and hypertension in India: A nationally repre-
animals: Part 1: blood pressure measurement in humans:
a statement for professionals from the Subcommittee of
sentative study of 1.3 million adults. JAMA Intern Med. Professional and Public Education of the American Heart
Clinical Cardiology
2018;178(3):363 -72. Association Council on High Blood Pressure Research.

5. Kotchen TA . Histor ical trends and milestones in Hypertension. 2005;45(1):142-61.
hypertension research: a model of the process of trans- 7. Saklayen MG, Deshpande NV. Timeline of history of
lational research. 2011;58(4):522-38. hypertension treatment. Front Cardiovasc Med. 2016;3:3.
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of
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Peripheral Signs of Aortic
CHAPTER 3 Regurgitation: Revisited
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INTRODUCTION and chronic in duration with preserved left ventricular
Clinical examination of the heart is a rewarding exercise, function. In chronic AR with significant LV dysfunction,
In
capable of offering a gratifying experience. Most of the the peripheral signs may not manifest well because the
structural cardiac diseases can be diagnosed at the stroke volume is less and the LV ejection is less forceful.
bedside and the diagnostic tools, however sophisticated In acute AR, the peripheral signs are again absent despite
of
they are, offer a marginal incremental benefit. Laboratory the regurgitation being severe. It is because the LV is
techniques are, however, required to precisely quantify the unprepared to meet the additional load of regurgitation,
LVEDP rapidly increases to very high levels and mitral
ty
disease, identify associated lesions that are clinically silent
and to establish the etiopathology. It is appropriate here to valve closes prematurely thereby resulting in reduction
of stroke volume and cardiac output with compensatory
18 cie
recall one of our mentors who used to tell us that: “Properly
elicited history establishes the hemodynamic situation,
inspection and palpation at the bedside would evince the
increase in heart rate and peripheral arterial resistance.
With diminished stroke volume and ejectile force of LV
exact lesion(s) and the severity and auscultation merely and increased peripheral arterial resistance, the pulse
20 o
helps the clinician to confirm the diagnosis made already, will be of smaller volume with narrow pulse pressure; and
S
and to identify associated lesions”. Look, feel and listen are hence, the peripheral signs are conspicuous by their
the three cardinal aspects of a comprehensive physical absence. Coexisting stenotic lesions, such as mitral
examination and application of this principle forms the stenosis and aortic stenosis, may also mask the peripheral
al
basis of diagnosis of aortic run-off situations causing the signs.

typical peripheral signs in the arterial tree.
ic
Though aortic regurgitation (AR) can be diagnosed TYPICAL ARTERIAL PULSE OF SIGNIFICANT
with confidence, when a typical early diastolic murmur is
og
AORTIC REGURGITATION
present along the left sternal edge, simple observation of
the behavior of the arterial pulse might offer an easy way The pulse volume is larger because of wide pulse pressure,
of identifying AR and the other ‘aortic runoff’ situations. the upstroke is steep due to rapid ejection, the peak is ill-
ol
Aortic regurgitation and certain other diseases, such sustained and the downstroke is steep due to peripheral
as large patent ductus arteriosus (PDA), and ruptured run-off. This results in the characteristic ‘Waterhammer’
di
aneurysm of sinus of Valsalva (RSOV), have the common quality (an abrupt thud imparted to the palpating finger
hemodynamic hallmarks of larger stroke volume of due to rapid upstroke) and the collapsing nature (a feeling
ar
left ventricle (LV) causing an increase in systolic blood of pulse quickly fading away from the palpating finger, due
pressure (BP) and lowered peripheral arterial resistance to rapid downstroke which in turn is caused by runoff into
C
causing a decrease in diastolic pressure. The net result the periphery). The collapsing nature of the pulse is mainly
is wide pulse pressure, which may produce an array of due to the rapid downstroke in midlate systole, rather than
interesting clinical findings, generally grouped together as that happens in diastole. One may recall that the dicrotic
peripheral signs. More than the wider pulse pressure, it is notch in AR occurs lower down in the descending limb
the rapid ejection of blood into a dilated more compliant and thus the collapsing quality is mainly felt in systole
arterial system with subsequent rapid emptying into rather than in diastole. Waterhammer refers to the toy of
the dilated distal arterial bed that is responsible for the Victorian era in which a glass tube with vacuum is filled
behavior of the arterial pulse. One should remember that with water or mercury partially. The vacuum causes the
the run-off into the periphery occurs both during systole liquid in the tube to abruptly shift to the other end when the
and diastole. Reflected waves from the distal bed are often glass tube is inverted giving rise to the abrupt thud to the
unimpressive in AR, because of highly compliant arterial holding hand. Similar feeling is imparted to the palpating
system. Obviously, such peripheral signs of AR manifest finger in AR, because of rapid ejection of larger volume of
when the regurgitation is moderate to severe in nature blood into the arterial system with an ill-sustained (sharp)
KG-3.indd 17 02-11-2018 13:44:37

SECTION peak. Both the waterhammer quality (rapid upstroke) and Corrigan sign is dancing of carotids caused by abrupt
the collapsing quality (rapid downstroke) are better felt distension and rapid collapse. Corrigan pulse refers
1 when the examiner encircles the patient’s wrist with his
hand in such a way that the distal palm (the most sensitive
to the tactile qualities of the pulse of aortic runoff. Sir
Dominic Corrigan wrote a seminal paper on AR in
Clinical Cardiology
part of the palm) is on the radial pulse and the arm of 1832, when he was at Jervis Street Hospital, Dublin,
the patient is quickly raised above the head. In the past, Ireland.
it was commonly taught that the typical features of the Locomotor brachii is rhythmical pulsation of a
pulse are better felt by this maneuver because the arteries serpentine brachial artery. This sign may at times
in the upper limb are brought in vertical line to the aorta be present in thin built elderly individuals, due to
that allows greater degree of regurgitation into LV. In true atherosclerotic changes causing tortuosity and wide
sense, the phenomenon is likely to be due to reduction of pulse pressure due to increased stiffness of arteries.
a
volume of blood which results in increase in compliance Duroziez sign refers to the double intermittent
di
of the distal arteries when the upper limb is elevated. The murmur heard over femoral arteries. Paul Duroziez,
increase in compliance is responsible for the exaggeration a French physician, described this in 1861. Proximal
In
of rapid upstroke and rapid downstroke.1 compression either by a finger or by tilting the edge
of the diaphragm upwards causes a systolic bruit;
and, distal compression by a finger or by caudal
Wide Pulse Pressure
of
tilting of the edge of stethoscope diaphragm causes a
Pulse pressure, the difference between systolic blood diastolic bruit. This was originally attributed to systolic
pressure (SBP) and diastolic blood pressure (DBP), is turbulence created by partial proximal pressure of
considered to be wide if it is >50 mm Hg or when the ratio
ty
femoral artery and retrograde flow towards aorta with
of pulse pressure/systolic BP is > 0.5. Wide pulse pressure distal compression. But the diastolic component is
is a characteristic finding in aortic run-off situations and
18 cie
is the hemodynamic abnormality that is responsible for
most of the peripheral signs. However, age-related loss of
probably a local phenomenon of accentuating the
brief reversal of flow as observed by Doppler study
and electromagnetic flow recordings.2 It was shown by
elasticity of large conduit vessels may also result in wide Luisada that the optimal compressive force would be
20 o
pulse pressure. required to evoke this sign—about three quarters of
S
the pulse pressure above the diastolic pressure.3

Bisferiens Pulse Pistol shot sound is a sharp sound heard over the
femoral artery during rapid ejection of large volume
al
It is a form of twice beating pulse, characterized by a

large volume pulse with two peaks, both being present of blood into the arterial tree. Sometimes, two sounds
will be heard with each heart beat—Traube’s double
ic
in systole. In Latin, ‘bis’ means twice and ‘ferire’ means

beat. The bisferiens character is better felt in carotids tone.
og
and when marked aortic run-off occurs, distal pulses Quincke’s pulse is the capillary pulsation (normally
such as brachial may also exhibit this feature. Apart from capillary flow is nonpulsatile) detected at the nail bed as
manually feeling the two peaks, one would also be able intermittent blanching of skin when illuminated from
ol
to hear double Korotkow sounds with each pulse during the palmar aspect of finger with gentle compression
BP recording. The mechanism of bisferiens pulse is of nail. If a glass slide is kept over the lips, alternate
di
attributed to the Venturi forces that are created at the root blanching and filling can be identified. By hooking
of aorta, when a large volume of blood is ejected rapidly. the patient’s fingertips, the examiner can identify the
ar
The suction that is induced by the Venturi forces causes accentuated pulsation of digital arteries.
Hill’s sign: In 1909, Hill described disproportionate
a dip in forward flow into the arterial tree. The two peaks
elevation of lower limb blood pressures when
C
of bisferiens pulse should not be called as percussion and

compared to upper limb blood pressure, in patients
tidal waves, as the reflection of incident wave does not
with AR.4 This sign is also known as popliteal–brachial
occur in conditions such as AR, in which condition the
gradient. When popliteal BP is recorded by cuff
systemic arterial resistance is low.
method, the systolic pressure is 0–20 mm Hg higher
than the brachial systolic pressure in normals. In those
PERIPHERAL SIGNS OF AORTIC RUNOFF with AR, this discrepancy is exaggerated and Hill’s
Wide pulse pressure, rapid upstroke and downstroke sign is considered to be present when the difference
of the pulse seen in aortic run-off conditions may be exceeds 20 mm Hg. Arbitrarily, the severity of AR
accompanied by many signs known by eponyms, called was determined by clinicians at the bedside based
peripheral signs of aortic runoff. Most of them are now on the magnitude of difference—20–40 mm Hg in
antiques of clinical medicine because of no added value moderate AR, 40–60 mm Hg in moderately severe AR
in diagnosis. and >60 mm Hg in severe AR. Frank et al. did find a
18
KG-3.indd 18 02-11-2018 13:44:37

similar rough correlation between the severity of AR in pulsations tend to become obvious. In normals, only CHAPTER
angiography and the magnitude of BP difference.5 the retinal veins pulsate and the retinal arteries do not.
However, studies done later have confirmed that
the intra-arterial pressures recorded directly by
It was initially believed that the transmitted pressure
from the arteries to the veins across the vitreous is
3
Peripheral Signs of Aortic Regurgitation: Revisited

catheterization, did not differ between upper and responsible for venous pulsations—decrease in size
lower limb arteries, with both systolic and diastolic in systole and increase in size in diastole by passive
pressures being identical. 6 Hence, this sign is now compression. But the important determinant of venous
considered to be an artifact possibly caused by the pulsation is now believed to be the gradient of pressure
BP recording technique. It is well understood that across the venous wall inside the globe and outside it.
when arm BP cuff is used on the thigh, it will obviously Intraocular pressure increases by 1.5 mm Hg in systole
show higher readings, as the smaller cuff used on and the retinal venous pressure also increases by the
a
larger sized limb is expected to give higher readings. same magnitude because of the transmitted pressure
di
But the exaggerated difference between lower limb to the thin-walled veins across the intraocular fluid.
BP and upper limb BP is noticeable even when the Outside the eyeball, it travels in the subarachnoid
In
appropriately sized thigh cuff is used. It is then possibly space and the cerebrospinal fluid (CSF) pressure
due to the fact that higher than the usual cuff pressures increases only by 0.5 mm Hg in systole and falls by 0.5
are needed to obliterate popliteal pulse, because the mm Hg in diastole. This creates a gradient of 1 mm
of
thigh is conical, it is more muscular than the arm and Hg between the intraocular veins and the extraocular
the femoral artery cannot be compressed effectively vein in systole, which results in emptying (collapse)
against the bone because of anatomical relationships. of retinal veins in systole and filling (expansion) in
ty
Because of similar anatomical reasons, the lower limb
diastole. Retinal vein pulsation is present in nearly
pressures are found to be higher than the upper limb
90% of normals, better seen in the vessels close to the
18 cie
pressures, even when the ankle pressures are recorded.
Leg muscle bulk is only slightly more than that of
arm, but the conical shape and inability to effectively
disc and better elicited by gentle pressure on eyeball
through the eyelids. If CSF pressure increases, retinal
vein pulsation may cease to occur; and, in glaucoma
compress the tibial arteries against the bone would be
20 o
too, the venous pulsations may disappear.8
the reasons for a higher reading obtained at ankle.
Landolfi sign is pulsatile iris causing rhythmical
S

In a study done on 83 patients with significant AR,
alteration of pupil size.
cardio ankle vascular index (CAVI) was measured using
Ashrafian sign: It denotes pulsatile pseudoproptosis, a
parameters such as pulse wave velocity, pulse pressure
al
rhythmical anterior propulsion of both eyes in systole.

in the brachial and ankle arterial pressure readings,
Bozzolo sign is pulsatile nasal mucosa.
ankle brachial blood pressure difference (ABD), ankle
ic
Dennison sign (Shelly sign) is pulsatile cervix.

brachial index (ABI), ejection time, and upstroke time.
Drummond sign is pulsatile systolic expulsion of air
og
Ankle brachial blood pressure difference was 38.0 ±

16.4 mm Hg in patients with AR, while it was 18.9 ± 13.2 from nostrils when mouth is closed.
mm Hg in normal controls. ABI was 1.30 ± 0.14 in AR
Lincoln sign refers to the rhythmic movement of leg
crossed over the other. This was diagnosed in hindsight
ol
and 1.12 ± 0.09 in normals. Ejection time was longer

and upstroke time was shorter in AR.7 on Abraham Lincoln, the 16th US President, who had
Marfan’s syndrome with AR. A blurred photograph was
di
Alfred de Musset sign is anteroposterior bobbing of

the head. Bobbing of the head may be present in severe believed to be caused by the leg movement because of
bounding pulse.
ar
tricuspid regurgitation (TR) also. But in TR, the head

bobbing is sideways. Palmar click refers to the pulsating palms—palpable
Mayne sign refers to >15 mm Hg diastolic pressure systolic flushing of palms.
C

reduction with arm elevation. Morton and Mahon sign refers to facial flushing and
Rosenbach sign is the systolic pulsation of enlarged blanching.
liver. Lighthouse sign refers to blanching and flushing of
Gerhardt sign (Sailer’s sign) is systolic pulsation of forehead.
enlarged spleen Muller sign is pulsating uvula.
Becker sign: It refers to the presence of retinal arterial Minervini’s sign refers to pulsation of tongue.
pulsations. Normally, the retinal arteries do not pulsate Penny sign is pulsation seen on an urticarial rash.
because they are small end arteries and their pulsations Sherman sign is a prominent and easily palpable
are dampened when the central retinal artery passes dorsalis pedis in elderly, in whom the dorsalis pedis
through the tight compartment of optic nerve sheath. is often unimpressive due to commonly occurring
When there is wide pulse pressure with increased peripheral arterial disease.
systolic and decreased diastolic pressure, the arterial Watson pulse refers to the waterhammer pulse.
19
KG-3.indd 19 02-11-2018 13:44:37

SECTION Nwosu, from Nigeria, has added a few more aortic runoff situation but also indicate that the lesion is of
signs detectable at bedside in patients with aortic hemodynamic significance. Such bedside signs come to
1 regurgitation: (a) Pistolshot sounds over carotids; (b)
Pulsation of eyelids due to pulsatile zygomaticofacial
help when the investigation findings provide overlapping
values.
Clinical Cardiology
artery; (c) Visible pulsation (bobbing) of abdomen

and legs; (d) Visible pulsation of superficial temporal REFERENCES
arteries; (e) Visible and palpable pulsation of digital
1. Warnes CA, Harris PC, Fritts HW. Effect of elevating the
and metacarpal arteries, and (f ) Bobbing of hands
wrist on the radial pulse in aortic regurgitation: Corrigan
synchronous with the bobbing of head.9 revisited. Am J Cardiol. 1983;51(9):1551-3.
Our teachers have noticed another sign encountered
2. Folts JD, Young WP, Rowe GG. A study of Duroziez’s murmur
in severe aortic regurgitation—pulsation of the entire of aortic insufficiency in man utilizing an electromagnetic
a
bed/cot synchronous with hyperkinetic arterial pulse. flowmeter. Circulation. 1968;38(2):426-31.
di
The eponyms de Musset sign and Lincoln sign were 3. Luisada AA. On the pathogenesis of the signs of Traube and
named after patients in whom the sign was detected. Alfred Duroziez in aortic insufficiency. A graphic study. Am Heart
In
de Musset was a French poet who suffered from syphilitic J. 1943;26:721-36.
AR and the bobbing head was noted and described by his 4. Hill I, Flack M, Holtzmann W. The measurement of systolic
brother. The other eponyms refer to the physicians who pressure in man. Heart. 1909;1:73-82.
5. Frank MJ, Casanegra P, Migliori AJ, Levinson GE. The
of
have described the finding.
clinical evaluationof aortic regurgitation. Arch Intern Med.
1965;116:357-65.
INVESTIGATIONS
6. Kutryk M, Fitchett D. Hill’s sign in aortic regurgitation:
ty
Investigations have yielded widely varying sensitivity and enhanced pressure wave transmission or artefact? Can J
specificity of some of these peripheral signs. Sensitivity Cardiol. 1997;13(3):237-40.
18 cie
and specificity of Corrigan sign ranged from 38–95% and
16%, respectively; Duroziez sign 33–81% and 35–100%, and
Hill sign 0–100% and 71–100%. Obviously, the sensitivity
7. Shiraishi H, Shirayama T, Maruyama N, et al. Usefulness
of peripheral arterial signs in the evaluation of aortic
regurgitation. J Cardiol. 2017;69(5):769-73.
20 o
was close to 100%, whenever the aortic regurgitation was 8. Jacks A S, Miller N R. Spontaneous retinal venous pulsation:
severe.10 aetiology and significance. J Neurol Neurosurg Psychiatry.
S
2003;74(1):7-9.
9. Nwosu PU. New peripheral signs of chronic aortic
CONCLUSION
regurgitation seen in five patients in the north of Nigeria
al
While most of the peripheral signs are of historic and literature review. Intl J Multidisc Curr Res. 2017;5:865-
importance, the presence of wide pulse pressure with 72.
ic
rapid upstroke, ill-sustained peak and collapsing quality 10. Babu AN, Kymes SM, Carpenter Fryer SM. Eponyms
with or without bisferiens quality should be recognized and the diagnosis of aortic regurgitation: What says the
og
by the examining physician. Such findings not only imply evidence? Ann Intern Med. 2003;138(9):736-42.
ol
di
ar
C
20
KG-3.indd 20 02-11-2018 13:44:37

Clinical Examination in
CHAPTER 4 Atrial Fibrillation
a
di
INTRODUCTION entry circuits may prevent its recurrence.7 Familial history
Atrial fibrillation (AF) is the most common cardiac should also be considered. History of precipitating factors,
In
arrhythmia encountered in clinical practice. 1 It is such as alcohol and caffeine, and substance abuse, such
responsible for approximately one-third of hospital as cocaine, should be sought. History of dermatological
disorders, such as psoriasis, and history of snoring and
of
admissions. It is associated with increased risk of stroke
and all-cause mortality.2 One-fourth of the patients may excessive daytime somnolence, heat intolerance, alopecia,
be asymptomatic, especially elderly. In recent years, there and tremors should be noted.
ty
was increase in burden of AF, incidence, prevalence, and
mortality associated with AF.3 So, a thorough knowledge PHYSICAL EXAMINATION
18 cie
about this arrhythmia is necessary to increase its detection
and correct the reversible causes, to avoid complications
of treatment and to reduce morbidity and mortality
Physical examination always begins with circulation,
airway, breathing, and vital signs which help in deciding
the urgency with which treatment or intervention should
associated with it.
20 o
be given. In a patient, who is hemodynamically unstable,
Clinical presentation may be due to arrhythmia itself intervention precedes everything. Hemodynamic
S
or as a part of another disease leading to AF. Dyspnea, instability attributed to arrhythmia can occur at very
effort intolerance, angina, palpitations, and presyncope/ rapid ventricular rates, aortic stenosis, hypertrophic and
syncope are common presenting symptoms.4 Almost one-
al
restrictive cardiomyopathy, and in patients with diastolic

fourth of the patients may be asymptomatic in-spite of dysfunction. Treatment includes DC cardioversion
arrhythmia being detected on electrocardiogram during
ic
if the onset of AF is less than 48 hours. Otherwise,

routine hospital visits.5 Patients may also present with transesophageal echocardiography (TEE) to look for left
thromboembolic phenomena or signs and symptoms of
og
atrial (LA)/left atrial appendage (LAA) clot and proceed

heart failure due to tachycardia-induced cardiomyopathy.6 with cardioversion if it is not showing any clot. In case of
Initial evaluation of patients who present with AF nonavailability of TEE, intravenous (IV) heparinization
ol
should include assessment of hemodynamic stability followed by DC cardioversion can be done. 8 Physical
for further management. Assessment of patients who examination also helps in revealing the underlying causes
di
are hemodynamically stable begins with history taking and squeal of AF.
to characterize the type and duration of arrhythmia,
ar
precipitating factors, history of any pharmacological or

previous direct current (DC) cardioversion or ablation Pulse
done to terminate the arrhythmia. History of any structural Assessing heart rate gives a clue about hemodynamic
C
heart disease or systemic disease responsible of the status and adequacy of rate control. Irregularly irregular
arrhythmia should be sought. As already mentioned, its pulse (chaotic) is characteristic. It describes unpredictable
incidence increases with age, but AF can also present in irregular radial or ventricular beats. The volume of pulse is
young population with predisposing conditions. In elderly, variable. Observation of irregular pulse for just 20 seconds,
it may be related to age-related changes in the atria or due remarkably increases the probability of detecting AF [late
to associated diseases. In young, it may be associated with recurrence (LR = 24.1)].9 Chaotic pulse can also be found
rheumatic heart disease, cardiomyopathies, structural in cases with multiple multifocal premature complexes
heart disease, pericardial disease, and other causes which can be differentiated at bedside from AF by
of multivalvular heart disease. Isolated AF in young examining jugular venous pulse and rhythm of ventricular
individuals suggest supraventricular tachycardia (SVT), pulse. The difference between apical/ventricular pulse
like atrioventricular node re-entrant tachycardia (AVNRT) and radial pulse is called pulse deficit. Traditionally, it has
or atrioventricular re-entry tachycardia (AVRT), with been associated with AF, but it can also occur in patients
accessory pathways are responsible, and ablation of re- with premature complexes and rapid heart rates. Pulse
KG-4.indd 21 02-11-2018 13:44:25

SECTION deficit >10/min suggestive of AF, whereas <10/min can rate should be less than the heart rate as too rapid deflation
occur in multiple premature complexes and multifocal may underestimate systolic BP and overestimate diastolic
1 atrial tachycardia. Examination of JVP with both X and Y
descents gives clue to diagnosis. Also, in multiple VPCs,
BP.13 Automated oscillometry may be inaccurate in AF14
and not recommended. Beat-to-beat variations in mean
Clinical Cardiology
pause followed by another beat; whereas in AF, pause can and pulse pressure may distort relationship between cuff
be followed by even longer pause as the interval between pressure and oscillometric wave amplitude in AF affecting
ventricular beats is random. Pulse rate can be regular at its accuracy. Automated techniques may be reasonably
extremely rapid ventricular rates, accelerated junctional accurate for systolic BP but overestimates diastolic BP.
rhythm, and high degree atrioventricular (AV) block Recently, automated BP monitors are used to detect AF in
with escape rhythm or paced rhythm. Irregularly regular asymptomatic elderly hypertensive patients. Sensitivity for
pulse occurs in Wenkebach type exit block. Patients can detecting AF was 100% and specificity was 94% for Omron
a
have well-controlled heart rates in the range of 60–90/ M6 device compared with 92% and 97% respectively, for
di
min or rate < 60/min (AF with slow ventricular rate) or Microlife BPA 200 plus device.15
rate >110/min (AF with fast ventricular rate). Bradycardia
In
may indicate drug toxicity or electrolyte abnormalities, Jugular Venous Pulse
and sick sinus syndrome and tachycardia may indicate
Examination of jugular venous pulse (JVP) is invaluable
poor drug compliance or any other precipitating events.
to diagnosis along with irregular pulse in AF. Normal
of
High-volume pulse may give clue to the presence of aortic
JVP has two peaks A and V waves (C wave cannot be
valvular disease (may be a part of rheumatic and other
recognized on clinical examination) along with two
multivalvular diseases or isolated to aortic valve), and
troughs X and Y descents. In AF, there is loss of A wave
ty
other hyperdynamic states such as hyperthyroidism, etc.
(no atrial contraction) and X descent.16 Only V and Y
All peripheral pulses to be palpated which may indicate
waves are prominent (single crest and trough). Onset
18 cie
peripheral vascular disease increasing the likelihood of
coronary artery disease or an embolic phenomenon in
patients with acute presentation.
of AF alters JVP in some clinical conditions, such as
constrictive pericarditis and restrictive cardiomyopathy,
which otherwise is a clue to diagnosis at bedside. Also,
20 o
examination of JVP gives a clue to differentiate AF from
Blood Pressure multiple premature complexes, both of which can
S
Hypertension is an important risk factor for AF and both have pulse deficit on clinical examination (two troughs
diseases are associated with increasing age. Hypertension present). Elevation of JVP suggests a primary cardiac
al
with left ventricular hypertrophy (LVH) causing diastolic pathology that may be the cause of atrial fibrillation.
dysfunction with raised filling pressures, increases
ic
incidence of AF [similar to aortic stenosis (AS) with LVH Neck Examination

and diastolic dysfunction]. Hypertension in AF also
og
Neck examination may also show pretracheal swelling,

increases the risk for stroke and contributes to increased
exophthalmos, heat intolerance, and alopecia along with
mortality and morbidity. Hypertension is associated with
other symptoms gives a clue to hyperthyroidism. Carotid
left atrial stasis, thrombi10 and aortic atherosclerosis which
ol
bruits may suggest PAD, and may be associated with CAD.

increases risk for thromboembolism. Blood pressure
The presence of ecchymosis and racoon eyes may
(BP) should be taken in both the upper and lower limbs
di
suggest amyloidosis as the etiology. Marfanoid habitus

along with ankle brachial index giving a clue to peripheral
may give clue to valvular etiology for the arrhythmia. Skin
arterial disease (PAD) which may be associated with
ar
examination may show plaque sign of psoriasis which is

coronary artery disease (CAD). Wide pulse pressure
an established risk factor for AF. Morbid obesity along with
may again give clues to aortic valvular disease or other
history of snoring and daytime somnolence gives clue to
C
hyperdynamic states, decreased vessel wall compliance,

obstructive sleep apnea. Cachexia and signs of peripheral
and narrow pulse pressure, may give clue to left ventricular
congestion may suggest congestive cardiac failure (CCF)
dysfunction.
or liver disease or renal disease. The presence of recent
In AF variations, filling times, stroke volumes, and
surgical scars may suggest postoperative arrhythmia.
contractility lead to increased beat-to-beat BP variability
Family history along with lentigines may suggest
which affects both auscultatory and oscillometric
association between cardiac tumor and arrhythmia.
methods.11 Pulse palpation while measuring BP during
auscultatory method is recommended for diagnosis of
AF in patients with age 65 years and above. 12 Current SYSTEMIC EXAMINATION
guidelines recommend repeated BP measurements with In patients with rheumatic heart disease, AF is more
auscultatory method in AF. Using this method, there may common with mitral valve disease. In mitral stenosis
be difficulty in interpretation of muffled sounds leading (MS), the onset of AF depends both on severity and age
to intra- and interobserver variability of BP. The deflation of the patient, consistent with the natural history of AF
22
KG-4.indd 22 02-11-2018 13:44:26

in general population. 17 In mitral regurgitation (MR), and systemic hypertension. The S4 is absent with the onset CHAPTER
its incidence depends on the age of the patient and left of AF in these conditions. THe AF can occur in one-third of
atrium (LA) dimension. In a set of patients with MR, left
atrial compliance is high and enlarged LA predisposes to
patients of constrictive pericarditis. Raised JVP with rapid
X and Y descents,22 pericardial knock, and ascites precox
4
Clinical Examination in Atrial Fibrillation

AF. The AF incidence further increases with combined MS suggests constrictive pericarditis. But with the onset of
with MR due to massively enlarged LA. The onset of AF AF, JVP has single Y descent. The presence tumor plop
marks progression of the disease in both the conditions. suggests atrial myxoma.
Tapping apex without any shift, loud S1, opening snap Loud P2 component of the second heart sound with
(OS) followed by mid-diastolic murmur with presystolic signs of peripheral congestion suggests pulmonary
accentuation suggests MS. In AF, S1 becomes variable hypertension and right heart failure. Large pretricuspid
in intensity (although loud) and there is no presystolic shunts can have right atrium (RA) enlargement and
a
accentuation of diastolic murmur. However, sometimes, predisposition for AF. Wide fixed split is suggestive of atrial
di
presystolic component can be heard during short R-R septal defect (ASD). Post-tricuspid shunts can have AF
intervals. A holo-diastolic murmur following OS in AF with CCF or after Eisenmenger disease. Cyanotic heart
In
is consistent with significant MS. Soft S1, displaced ill- disease with multiple arrhythmic episodes on history
sustained apex with pansystolic murmur radiating to and multiple clicks on examination gives clue to Ebstein’s
axilla or base is suggestive of MR. Rheumatic heart disease anomaly.
of
(RHD) patients with chronic MR have compliant enlarged The presence of fine crepitation on lung auscultation
LA predisposing to AF. The AF in patients with chronic MR may suggest congestive failure. Wheeze and ronchi may
is clue to its severity. Pansystolic murmur of MR does not suggest lung disease in appropriate clinical scenario.
ty
vary in intensity with cycle lengths in AF.18 Absent breath sounds can occur in pleural effusions which
The AS is suggested by pulsus parvus tardus, heaving may be due to failure or due to primary lung disease.
18 cie
and sustained apex, ejection systolic murmur radiating
to carotids, and presence of S4. The AF occurs late in the
course of aortic valve disease. Increased left ventricular
Ascites, jaundice, gynecomastia, spider nevi, and
palmer erythema may suggest alcoholic liver disease and
cardiomyopathy. Ascites precox (early onset of ascites)
20 o
end-diastolic pressure (LVEDP) secondary to severe AS
along with elevated JVP and other symptoms of right heart
and LV dysfunction in aortic regurgitation (AR) causes left
S
failure gives clue to constrictive pericarditis rather than

atrial enlargement and AF. The onset of AF suggests poor
liver disease. Pain in the left hypochondrium may suggest
prognosis in conditions with raised LVEDP and diastolic
splenic infarct due to systemic embolization and pain
al
dysfunction such as the AS, HCM, RCM, and diastolic heart

in the right hypochondrium may be due to congestive
failure. All these have to depend on atrial booster pump
hepatopathy.
ic
action which is lost in AF. With AF, S4 is absent. In patients

Unilateral weakness or sensory loss, aphasia, history
with calcified valves, selective transmission of high-
of dizziness, and swaying, all may suggest embolic
og
frequency sounds to apex (Gallavardin phenomenon), can

phenomena due to arrhythmia. Examination findings
confuse with MR. In patients of AS with AF, beat-to-beat
of exaggerated reflexes may suggest old cerebrovascular
variation in the ejection systolic murmur (ESM)19 intensity
ol
events, or may be due to hyperthyroidism.

differentiates it from pansystolic murmur (PSM) of MR
which remains constant. The AF generally occurs with LV
di
dysfunction in AR which leads to systolic decapitation of REFERENCES

BP and attenuation of peripheral signs. 1. Chugh SS, Blackshear JL, Shen WK, et al. Epidemiology and
ar
The CCF can cause AF by increasing LA size and filling natural history of atrial fibrillation: clinical implications. J
pressures. The AF can cause CCF due to tachycardia- Am Coll Cardiol. 2001;37(2):371-8.
C
related cardiomyopathy. Coexistence of AF and CCF 2. Roger VL, Go AS, Lloyd-Jones DM, et al. Heart disease and
occurs in approximately 40% of patients.20 On clinical stroke statistics–2012 update: a report from the American
examination, the presence of displaced, sustained apex Heart Association. Circulation. 2012;125(1):e2-220.
3. Chugh SS, Havmoeller R, Narayanan K, et al. Worldwide
with apical systolic murmur and S3 can give clue to left
epidemiology of atrial fibrillation: a Global Burden of
ventricular dysfunction.
Disease 2010 Study. Circulation. 2014;129(8):837-47.
Double apical impulse (spike and dome) with S4
4. Lip GY, Beevers DG. ABC of atrial fibrillation. History,
and apical systolic murmur is suggestive of hypertrophic epidemiology, and importance of atrial fibrillation. BMJ.
cardiomyopathy. The systolic murmur of hypertrophic 1995;311(7016):1361-3.
cardiomyopathy (HCM) responds unpredictably to 5. Furberg CD, Psaty BM, Manolio TA, et al. Prevalence of
changing cycle lengths in AF. Long pause may make the atrial fibrillation in elderly subjects (the Cardiovascular
murmur louder or softer or may not change it.21 The S4 can Health Study). Am J Cardiol. 1994;74(3):236-41.
also be seen in other conditions with diastolic dysfunction 6. Gopinathannair R, Etheridge SP, Marchlinski FE, et al.
such as restrictive cardiomyopathy, diastolic heart failure, Arrhythmia-induced cardiomyopathies: mechanisms,
23
KG-4.indd 23 02-11-2018 13:44:26

SECTION recognition, and management. J Am Coll Cardiol. 14. Mancia G, Fagard R, Narkiewicz K, et al. 2013 ESH/
2015;66(15):1714-28. ESC Practice Guidelines for the management of arterial
1 7. Wutzler A, von Ulmenstein S, Attanasio P, et al. Where

there’s smoke, there’s fire? Significance of atrial fibrillation
hypertension. Blood Press. 2014;23(1):3-16.
15. Marazzi G, Iellamo F, Volterrani M, et al. Comparison of
in young patients. Clin Cardiol. 2016;39(4):229-33.
Clinical Cardiology
Microlife BP A200 Plus and Omron M6 blood pressure

8. King DE, Dickerson LM, Sack JL. Acute management of monitors to detect atrial fibrillation in hypertensive
atrial fibrillation: Part II. Prevention of thromboembolic patients. Adv Ther. 2012;29(1):64-70.
complications. Am Fam Physician. 2002;66(2):261-4. 16. Hartman H. The jugular venous tracing. Am Heart J.
9. Morgan S, Mant D. Randomised trial of two approaches to 1960;59:698-717.
screening for atrial fibrillation in UK general practice. Br J 17. Acar J, Michel PL, Cormier B, et al. Features of patients with
Gen Pract. 2002;52(478):373-80. severe mitral stenosis with respect to atrial rhythm. Atrial
10. Zabalgoitia M, Halperin JL , Pearce L A , et al.
a
fibrillation in predominant and tight mitral stenosis. Acta
Transesophageal echocardiographic correlates of clinical
Cardiol. 1992;47(2):115-24.
di
risk of thromboembolism in nonvalvular atrial fibrillation.
18. Karliner JS, O’Rourke RA, Kearney DJ, et al. Haemodynamic
Stroke Prevention in Atrial Fibrillation III Investigators. J
explanation of why the murmur of mitral regurgitation in
Am Coll Cardiol. 1998;31(7):1622-6.
In
independent of cycle length. Br Heart J. 1973;35(4):397-401.
11. Kollias A, Stergiou GS. Automated measurement of office,
19. Henke RP, March HW, Hultgren HN. An aid to identification
home and ambulatory blood pressure in atrial fibrillation.
of the murmur of aortic stenosis with atypical localization.
Clin Exp Pharmacol Physiol. 2014;41(1):9-15.
of
12. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/ Am Heart J. 1960;60:354-63.
HRS guideline for the management of patients with atrial 20. Wang TJ, Larson MG, Levy D, et al. Temporal relations of
fibrillation: executive summary: a report of the American atrial fibrillation and congestive heart failure and their
ty
College of Cardiology/American Heart Association Task joint influence on mortality: the Framingham Heart Study.
Force on practice guidelines and the Heart Rhythm Society. Circulation. 2003;107(23):2920-5.
13.
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Circulation. 2014;130(23):2071-104.
Manolis AJ, Rosei EA, Coca A, et al. Hypertension and atrial
fibrillation: diagnostic approach, prevention and treatment.
21. Kramer DS, French WJ, Criley JM. The postextrasystolic
murmur respons e to gradient in hyper tro phic
cardiomyopathy. Ann Intern Med. 1986;104(6):772-6.
Position paper of the Working Group ‘Hypertension 22. el-Sherif A, el-Said G. Jugular, hepatic, and precordial
20 o
Arrhythmias and Thrombosis’ of the European Society of pulsations in constrictive pericarditis. Br Heart J.
S
Hypertension. J Hypertens. 2012;30(2):239-52. 1971;33(2):305-12.

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KG-4.indd 24 02-11-2018 13:44:26

CHAPTER 5 Continuous Murmur
Ranjit Kumar Nath
a
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INTRODUCTION Abnormal communications between systemic and
Continuous murmur is defined as a murmur that begins pulmonary arteries:
In
— Patent ductus arteriosus (PDA)
in systole and continues uninterrupted through the
— Aortopulmonary window (AP window)
second heart sound into all or part of diastole.1 It has
— Truncus arteriosus with pulmonary stenosis
of
to be remembered that when the murmur crosses over
— Anomalous origin of left coronary artery from
from systole to diastole, the following criteria have to be
pulmonary artery (ALCAPA)
fulfilled:
ty
— Bronchial collaterals in pulmonary atresia or
There is no change in the character of the murmur
tetralogy of Fallot (TOF) physiology
from systole to diastole.
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The second heart sound (S ) or its components are
2
enveloped or masked by the murmur.
Murmurs do not follow the boundary of the systole
— Different surgical shunt created as palliation in
TOF physiology such as Blalock-Taussig shunt (BT

shunt), Waterston-Cooley shunt, and Pott’s shunt.
Abnormal communications between systemic arteries
20 o

and diastole of the cardiac cycle, hence no break in
to right heart:
between the systolic and diastolic components.
S
— Ruptured sinus of Valsalva aneurysm (RSOV)

Murmurs may not occupy the whole length of systole
— Coronary cameral fistula.
(holosystolic) or diastole (holodiastolic); rather, they
al
Critical narrowing of an artery leading to turbulent

start in systole and continue to occupy part or whole
flow:
of diastole.
ic
— Proximal coronary stenosis

The basic mechanism of the murmur is the presence
— Coarctation of aorta (CoA)
of a continuous significant pressure gradient producing
og
— Peripheral pulmonary stenosis.

turbulent flow between two vessels or chambers during
Change or increase in venous flow leading to
both systole and diastole. Intracardiac murmurs can
turbulence:
ol
seldom be true continuous murmurs as there is hardly a

— Venous hum
continuous pressure gradient. Pathological continuous
— Anomalous pulmonary venous connection
di
murmurs are mostly produced due to a communication

— Portosystemic shunts.
between high pressure arterial vascular beds to low
Arteriovenous fistulas:
ar
pressure structures, either to venous system or right-sided

— Systemic: Congenital, hemodialysis, post-
cardiac chambers, including pulmonary circulation.
traumatic, femoral artery puncture site
C
A continuous murmur is often helpful in diagnosing a

— Pulmonary: Diffuse small, localized large (solitary
disease or abnormality comprehensively if we meticulously
or multiple).
listen to the murmur in relation to its site, pattern,
Excessive flow through an area or organ due to
associated clinical signs, along with a meticulous history.
physiological or pathological changes:
— Mammary soufflé
PHYSIOLOGIC CLASSIFICATION — Mitral stenosis or atresia with a restrictive atrial
Continuous murmurs can be grouped based on the type septal defect (ASD)
of communication that is causing the turbulent flow — Hemangioma
producing the murmur. The following are the different — Hyperthyroidism
conditions that can produce a continuous murmur — Hyperemia of neoplasm: Hepatoma, Paget’s
according to different physiological mechanisms:2 disease, renal cell carcinoma.
KG-5.indd 25 02-11-2018 16:49:43

SECTION DIFFERENTIAL DIAGNOSIS murmur. Table 1 shows different characteristic points in
differentiating them.
1
Long cardiac murmurs may sometimes mimic continuous
murmurs and they need to be looked carefully to
Patent Ductus Arteriosus
differentiate from true continuous murmurs. Two such
Clinical Cardiology
conditions are to-and-fro murmurs and combined systolic Patent ductus arteriosus (PDA) produces the classical
and diastolic murmurs. To-and-fro murmurs are due to continuous murmur due to the persistent flow from aorta
flow in one direction during systole and flow in the reverse to pulmonary artery through the patent duct during both
direction during diastole through the same orifice or systole and diastole. The murmur is of mixed frequency
valve.3 Typical examples are murmurs of aortic stenosis and harsh, crescendo during systole, peaks just before
(AS) and aortic regurgitation (AR) or pulmonary stenosis or after the S2, and tapers off during late diastole, when
the murmur is decrescendo and smooth. The murmur
(PS) and pulmonary regurgitation (PR). But they are not
a
is commonly associated with a thrill and best heard in
true continuous murmurs as the murmurs of stenosis
di
the left second intercostal space or just below the left
are rough, medium pitched, diamond shaped, and gets
clavicle. The typical murmur is also called the machinery
tapered towards the end of the systole, ending in or before
In
murmur because of its rough, crescendo-decrescendo
the aortic component of the second heart sound (A 2) or
nature or Gibson’s murmur after the classical description
the pulmonary component of the second heart sound (P2).
by George Alexander Gibson in the year 1900. Multiple
The diastolic murmur is high pitched, blowing character
of
clicks are heard at the peak of the murmur, called Eddy
starting after the A2 or P2. So, there is change in character
of murmur at the boundary of systole and diastole of the
cardiac cycle and has a gap at this point with two different
ty
picking of the murmurs during systole and diastole.
Moreover, the second heart sound is well audible in these
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conditions unless the valves are grossly deformed or
damaged. The combined systolic and diastolic murmurs
A
are not due to flow through the same orifice or valve,

20 o
rather they are combinations of systolic murmur of one
pathology and diastolic murmur of another. Typical
S
example is the presence of a ventricular septal defect B

(VSD) with AR, or combined mitral regurgitation (MR)
al
with AR. They occupy varying lengths of systole or diastole

and different character of murmurs in systole and diastole.
ic
For example, the VSD murmur is high pitch pansystolic

at left sternal border and the AR murmur is early diastolic C
og
at left second or third parasternal area, but when the

murmurs are traced to the infraclavicular area, there is Figures 1A to C: Different types of murmurs. (A) Continuous
a gap heard in between the two murmurs loosing the murmur that peaks near S2 with A2 and P2 enveloped by the murmur;
ol
continuity. Also, the S2 and its components are well heard (B) To-and-fro murmur that indicates combination of two murmurs;
(C) Combined systolic and diastolic murmur
and the peaking of the murmurs are different and do not
di
Abbreviations: S1: first heart sound, A2: aortic component of second

peak around S2. Figures 1A to C depicts different types heart sound, P2: pulmonary component of second heart sound, ec:
of murmurs that need differentiation from a continuous ejection click
ar
Table 1: Clinical characteristics to differentiate between a continuous murmur, to-and-fro murmur, and combined
C
systemic and diastolic murmur

Characteristics Continuous murmur To-and-fro murmur Combined systolic and diastolic murmur
Direction of flow Unidirectional, single murmur Systolic in one direction and Not through same orifice or valve.
diastolic in reverse direction. Two Combination of different orifices or valves
separate murmurs from same valve producing two murmurs
Classic example PDA AS + AR VSD + AR
S2 Masked in the murmur Separate Separate
Peaking of murmur One peak, either systolic or Separate peak in systole and Separate peak in systole and diastole
diastolic or at S2 diastole
Source of murmur Extracardiac or extracardiac to Intracardiac Intracardiac
cardiac shunt mostly
Gap at S2 Absent Present Present
Abbreviations: PDA: patent ductus arteriosus; AS: aortic stenosis; AR: aortic regurgitation; VSD: ventricular septal defect; S2: second heart sound
26
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CHAPTER
Continuous Murmur
a
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A B
In
Figures 2A and B: (A) PDA in the short axis view with color Doppler imaging; (B) Continuous-wave Doppler interrogation showing a
persistent gradient during systole and diastole that peaks around S2
of
sounds, signifying stretching of a large ductus with high reported to be from the right coronary sinus (76.9%)
flow and increased pulmonary artery (PA) pressure, which followed by non-coronary sinus (18.3%) and common
originate both in the pulmonary artery and the aorta. The cardiac chamber of rupture is right ventricle (58.65%)
ty
pulmonary ejection clicks originate in maximally dilated followed by right atrium (24%) producing a continuous
pulmonary arteries and at the peak of systolic stretching, murmur.7 When ruptures to right atrium (RA), it produces
18 cie
which become more intense and occur later with
expiration. Additional sounds in midsystole correspond to
a true continuous murmur with louder systolic component
as the gradient during systole is very high. The jet of blood
the reaching of the aortic pressure peak at the ductus.4 The coming from posterior located aorta to anterior RA
20 o
murmur intensity and duration increases with isometric produces a thrill that feels very superficial and classical
hand grip, sometimes bringing out the silent diastolic feeling of ‘purring of a cat’. The murmur is best heard
S
component and disappear or decrease in intensity and in the lower left and right sternal border and over the
duration with Valsalva maneuver. With increasing grades xiphoid process. When ruptures to right ventricle (RV), the
al
of pulmonary artery hypertension (PAH), the murmur diastolic component of the murmur is more pronounced
shortens, first to disappear is the diastolic component as the intensity of the systolic component can be reduced
ic
and with severe PAH, the PDA may be silent. The S2 is due to: (1) elevated RV systolic pressure due to PAH, (2)
normally split with a small shunt and normal pulmonary narrowing of the tract due to contraction of the ventricle
og
artery pressure. Large shunt flowing across the PDA (Qp/ during systole, or (3) Venturi effect of the LV to aortic
Qs >2) can be associated with left ventricular (LV) type forward flow beyond the origin of the fistula. The murmur
of apex, LV third heart sound (S3), mid-diastolic murmur is best heard in the mid-to-lower left parasternal area.
ol
(MDM) across the mitral valve, single or paradoxically RSOV may be associated with a VSD in 44% of cases and
split S2, and a high volume pulse with wide pulse pressure AR in 43.3%,7 which is difficult to hear separately and the
di
producing a collapsing pulse. 5 S 2 is mostly masked in presence of a VSD murmur will make systolic component
the murmur but the P2 gets loud due to PAH, which can of the RSOV murmur more intense and the presence
ar
be well heard as described by Gibson in his description of AR will make diastolic component of the continuous
of both the cases.6 With the development of severe PAH murmur more prominent. Large RSOV is associated
C
and reversal of the shunt (Eisenmenger physiology), the with a dynamic precordium and congestive heart failure.
murmur disappears and differential cyanosis appears in Associated clinical findings may help in determining the
which desaturated pulmonary artery blood crossing the site of rupture of an aneurysm and they are summarized
PDA to the lower extremities, producing cyanosis and in Table 2.
clubbing of the toes. Figures 2A and B show 2D and color
Doppler echocardiography of a PDA with continuous- Coronary Cameral Fistula
wave Doppler showing persistent gradient from aorta to
Coronary cameral fistulas represent a communication
PA which produces a continuous murmur.
between coronary artery and any chamber of the heart,
coronary sinus (CS), vena cava, or PA. Most commonly
Ruptured Sinus of Valsalva Aneurysm they involve the left coronary artery and drain into
The sinus of Valsalva aneurysm may be congenital or the right-sided cardiac chambers, CS or PA producing
acquired due to trauma or post-endocarditis and can continuous murmurs. They may also originate from two
rupture to any cardiac chamber. Major site of origin is coronary arteries and can have multiple drainage sites.8
27
KG-5.indd 27 02-11-2018 16:49:48

SECTION Table 2: Clinical signs that may help in differentiating the site of rupture of a sinus of Valsalva aneurysm into RA or RV
1
Clinical findings RSOV to RA RSOV to RV
Site of murmur Left and right lower sterna border and over Mid-to-lower left sterna border
xiphoid
Clinical Cardiology
Intensity of the continuous murmur More in systole More in diastole

Thrill Very superficial, typical ‘purring of cat’ Diffuse
JVP Prominent a wave Prominent v/cv wave depending upon the
severity of TR
S3 Both RV and LV Mostly LV
MDM Both in tricuspid and mitral area In mitral area
a
Hepatic pulsation Diastolic Systolic
Abbreviations: RSOV: ruptured sinus of Valsalva; RA: right atrium; RV: right ventricle; JVP: jugular venous pressure; TR: tricuspid regurgitation;
di
S3: third heart sound; LV: left ventricle; MDM: mid-diastolic murmur
In
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ty
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20 o S
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ic
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Figure 3: Best audible sites of murmurs of coronary cameral fistulas A. RCA to RA; B. RCA to CS; C. RCA to RV;
ol
D. LCA to PA; E. LCA to CS or RCA to PA, or LCX to CS; F. LCA to PA or apex of RV, or LCX to CS; G. LCA to RV
Abbreviations: RCA: right coronary artery; RV: right ventricle; RA: right atrium; CS: coronary sinus;
di
LCA: left coronary artery; LCX: left circumflex artery; PA: pulmonary artery.
ar
The site of best audibility of the murmur is different mostly have identical aortic and pulmonary artery
and depends upon the origin of the fistula and the site pressure. In isolated patients with small AP window, there
C
of draining that is depicted in Figure 3.3 These fistulas can be a loud continuous murmur that peaks in systole
produce a continuous murmur with increased intensity and has louder systolic component. They are best heard in
during systole with a systolic peak and both the systolic the left third intercostal space and are not associated with
and diastolic components of the murmur are smooth. multiple clicks or Eddy sounds of PDA. Associated features
Since the coronary cameral fistulas are not associated with of PAH are mostly present in majority of patients with AP
a large left-to-right shunt, there is hardly any sign of aortic window.
runoff like wide pulse pressure or very low diastolic blood
pressure. Coarctation of Aorta
A continuous murmur can be heard in very tight coarctation
Aortopulmonary Window of aorta (CoA), due to a continuous gradient across the
A continuous murmur is most unlikely in patients with coarctation, and the murmur is best heard over the back
aortopulmonary (AP) window since they are large and in the interscapular region or over the vertebrae. But the
28
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CHAPTER
Continuous Murmur
a
di
In
A B
of
Figures 4A and B: (A) Mild coarctation producing only systolic gradient; (B) Very tight coarctation gives continuous high gradient,
producing a continuous murmur
ty
common source of a continuous murmur in coarctation Mammary Soufflé
is the collateral vessels including intercostal collaterals
18 cie
and the murmur is diffuse over the precordium and the
back. Figures 4A and B show continuous-wave Doppler
Continuous murmur can be heard in 10 to 15% of women
in late pregnancy and early postpartum period. The
murmur is audible over the precordium in second to
echocardiography of two different patients with CoA, one
fourth intercostal space, over the breast, having maximum
20 o
with mild CoA with only systolic gradient but the other
intensity during systole. The murmur starts after the origin
is with tight CoA giving continuous systolic and diastolic
S
of the systole with a delay because of the time required for

gradient which can produce a continuous murmur.
the blood to reach the mammary artery, which is thought
to be the origin of the murmur. Light pressure with the
al
Venous Hum diaphragm of the stethoscope increases the intensity

The venous hum was first described by Pontain in 1867, and
ic
of the murmur and firm pressure causes reduction or

is the most common physiological continuous murmur. It disappearance of the murmur.
og
is commonly found in young children and adolescents,

best heard in the supraclavicular region either medial Pulmonary Arteriovenous Fistula
to or in-between the two heads of sternocleidomastoid
Diffuse, small, capillary level pulmonary arteriovenous
ol
muscle. It is more commonly heard in the right side and

becomes prominent with head rotated to the opposite side fistulas (AVF) cause central cyanosis, clubbing with
normal electrocardiogram, normal chest X-ray, normal
di
and chin lifted up in sitting position. Murmur disappears

with manual compression over the neck above the site cardiac examination, and structurally normal heart in 2D
echocardiography. They can hardly produce any murmur.
ar
of murmur, when head is rotated toward the same side,

and changing posture from sitting to supine position. The Large AVF, which can be solitary or multiple, can produce
murmur is often harsh and when heard below the clavicle, continuous murmur over localized part of chest wall
C
it causes confusion with a PDA murmur. The murmur overlying the fistula. They can be diagnosed by performing
is louder during diastolic phase and during inspiration. contrast echocardiography with agitated saline during
The theory behind the origin of the murmur is not clear. echocardiographic examination. The small bubbles of the
It may be because of: (1) the convergence of the venous agitated saline after reaching the right cardiac chambers
flow from left, right, and the internal jugular vein (IJV) at from brachial vein should disappear in the pulmonary
this point producing the turbulence, (2) rapid descent of circulation; but if they reappear in the left chambers after
the jugular blood column to the superior vena cava, (3) a gap of 5 to 7 cardiac cycles, the diagnosis of pulmonary
relatively small thoracic inlet in children up to age six or AVM is confirmed. The bubbles cross from the pulmonary
seven years producing turbulent flow in jugular veins,5 or artery, through the fistula, to the pulmonary venous side
(4) the angulation of the IJV by the transverse process of and travel to the left atrium. Figure 5 is an angiographic
the atlas while sitting and rotating the head, disturbing the picture of a localized pulmonary AVF in the lower lobe of
laminar venous flow. left lung.
29
KG-5.indd 29 02-11-2018 16:49:51

SECTION
1
Clinical Cardiology
a
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In
of
ty
Figure 5: Selective pulmonary angiography showing a large pulmonary arteriovenous fistula producing a localized continuous murmur
18 cie
Extracardiac Arteriovenous Fistula
They can be congenital, spontaneous, or acquired
common source of pulmonary blood flow in pulmonary
atresia or TOF physiology, especially in the adult TOF.
Some of them may be very large, causing increased
secondary to trauma, iatrogenic after catheterization,
20 o
surgically created for hemodialysis. They produce a pulmonary blood flow and no murmur. But normally they
develop stenosis at their origin and cause continuous flow
S
continuous murmur localized to the area over the fistula

and the systolic component of the murmur having from the arterial bed to the pulmonary bed producing a
increased intensity. These murmurs disappear with the continuous murmur. The source of continuous murmurs
al
compression of the fistula. Compression of the artery in CCHD can be:11

Patent ductus arteriosus (PDA)
proximal to the fistula produces bradycardia by stimulation
ic
Aortopulmonary collaterals (bronchial collaterals,

of baroreceptors, named Nicoladoni-Branham sign, and
origin of left or right pulmonary artery from aorta with
sudden release of the pressure leads to reflex tachycardia.
og
stenosis, coronary to pulmonary artery fistula)

Total anomalous pulmonary venous connection
Continuous Murmurs in Cyanotic Congenital (TAPVC)
ol
Heart Disease Pulmonary arteriovenous fistula
Continuous murmur is a very common clinical finding Stenosis of pulmonary artery (right, left, or both
di
in patients with continuous murmurs in cyanotic pulmonary artery)

congenital heart disease (CCHD). Though the PDA can Persistent truncus arteriosus
ar
be the source of such murmur, there are other causes of Surgically created shunts.
continuous murmurs in this group of patients. Campbell

Surgically Created Shunts
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and Deuchar9 reported their incidence of 91% in a series

and the murmurs were loud, heard best on the right side They are the communications surgically created between
in nearly one-third, on the left side in half, and equally arterial bed (aorta or its branches) and the pulmonary
heard in both sides in the remaining. The murmurs were artery branches for maintaining pulmonary circulation
also heard in the back. In another series of patients with when there is significant reduction in pulmonary blood
large VSD and pulmonary atresia, Zutter and Somerville10 flow due to severe PS or pulmonary atresia. Continuous
reported that the presence of a continuous murmur gradient across the shunt produces a continuous murmur
below the left clavicle is always associated with a PDA; localized to the chest wall overlying the shunt. The
and, if the murmur is heard in another site along with murmur is helpful in clinically following-up a child as
left infraclavicular area, large aortopulmonary collateral absence of a murmur with worsening cyanosis indicates
arteries were the cause of the murmur. Hypertrophied acute thrombotic occlusion of a shunt. History of a surgery
bronchial arteries or branches of thoracic aorta or its in the past and its location in the chest wall gives the clue
branches to the pulmonary artery branches are the of presence of a shunt. Color Doppler echocardiography
30
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CHAPTER
Continuous Murmur
a
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In
A B
Figures 6A and B: (A) Color Doppler image of a modified Blalock-Taussig shunt (BT shunt) in a patient of tetralogy of Fallot; (B) The continuous-
of
wave Doppler interrogation showing a continuous gradient during both systole and diastole being the source of a continuous murmur
ty
of a modified Blalock-Taussig shunt (BT shunt) with 5. Tandon R. Bedside Approach in the Diagnosis of Congenital
continuous-wave Doppler showing persistent gradient Heart Diseases.2nd edn. New Delhi: Sitaram Bhartia
in Figures 6A and B.
18 cie
across the shunt produces a continuous murmur is given Institute of Science & Research, 2011.
6. George Alexander Gibson. Diseases of the Heart and Aorta.
Young J Pentland, New York: The Macmillan Company.
1898, pp. 310-2.
20 o
REFERENCES 7. Choudhary SK, Bhan A, Sharma R, et al. Sinus of valsalva
aneurysms: 20 years’ experience. J Card Surg. 1997;12(5):
S
1. Perloff JK, Braunwald E. Physical examination of the heart

300-8.
and circulation. In: Braunwald’s Heart Disease: A Textbook 8. Armsby LR, Keane JF, Sherwood MC, et al. Management
of Cardiovascular Medicine.5th ed. Philadelphia: WB
al
of coronary artery fistulae. J Am Coll Cardiol. 2002;39(6):

Saunders Company;1997. pp. 43-5. 1026-32.
2. Ginghina C, Nastase OA, Ghiorghiu I, et al. Continuous 9. Campbell M, Deuchar DC. Continuous murmur in cyanotic
ic
murmur – the auscultatory expression of a variety of congenital heart disease. Br Heart J. 1961;23(2):173-93.
pathological conditions. J Med Life. 2012;5(1):39-46. 10. Zutter W, Somerville J. Continuous murmur in pulmonary
og
3. Jules Constant. Essentials of Bedside Cardiology. New atresia with reference to aortography. Br Heart J. 1971;
Jersey: Humana Press Inc. Totowa, First Indian reprint 33(6):905-9.
2003:234-41. 11. Ongley PA, Rahimtoola SH, Kincaid OW, et al. Continuous
ol
4. Hubbard TF, Neis DD. The sounds at the base of the heart in murmurs in tetralogy of Fallot and pulmonary atresia with
cases of patent ductus arteriosus. Am Heart J. 1960;59:807-15. ventricular septal defect. Am J Cardiol. 1966;18(6):821-6.
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CHAPTER 6 Dynamic Auscultation
a
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INTRODUCTION Table 1: Classification techniques of dynamic auscultation
Dynamic auscultation is the technique of altering
In
Physiological Pharmacological Simple postural
circulatory dynamics by physiological and pharma maneuvers maneuvers changes
cological maneuvers and observing the effects of these
Valsalva maneuver Amyl nitrite inhalation Left lateral-MS
of
maneuvers on heart sounds/murmurs.
With the advent of echocardiography and other widely Sudden standing Methoxamine/ Sitting up and
available modes of noninvasive diagnosis, the fine art of from squatting or phenylephrine leaning forward
lying down
ty
clinical examination is losing its importance. However,
despite all the new age tools, the technique of performing Muller maneuver Stretching of neck
18 cie
methodical clinical examination is the fundamental
backbone of any training in cardiology and forms the basis
of all further diagnostic tests.
Passive leg elevation
Sudden squatting
Before performing and speaking about it in clinical
20 o
Isometric exercise
examination, the following fundamental philosophical
Abbreviations: MS, mitral stenosis; AR, aortic regurgitation.
S
points of dynamic auscultation should be kept in mind:13

Dynamic auscultation should only be performed when
we have faintly heard heart sounds or murmurs that Practically, this can be done by asking the patient to
al
we want to accentuate by performing some special take a deep inspiration, followed by forced expiration
augmentation tests. Or, we have confusion in similar against a closed glottis for 20 seconds. (Examiner may
ic
sounding heart sounds or murmurs and we want place flat of hand on the abdomen to provide the patient
to differentiate between them. So, it is the really not the force, against which to strain).
og
judicious for us to perform or to speak about dynamic There are four stages of Valsalva maneuver (Table 2
auscultation when we have clearly heard and well and Figure 1).
defined murmurs/heart sounds.
ol
Dynamic auscultation should be taken as part of the

Clinical Implications
entire clinical picture and should not be taken as a
di
standalone gold standard tool for making a dogmatic Pressure and Heart Rate Response (Figure 1)
clinical diagnosis. Square-wave response: This is seen in conditions like
ar
The techniques of dynamic auscultation can be broadly left heart failure, mitral stenosis (MS), and atrial septal
classified into physiological maneuvers, pharmacological defect (ASD). During Valsalva maneuver, blood pressure
C
maneuvers, and maneuvers that relate to simple change in increases in stage I (normally), but remains elevated
posture of the body (Table 1). in all subsequent stages due to abolished stage II and
loss of overshoot in stage IV. This is seen when lungs are
PHYSIOLOGICAL MANEUVERS overloaded with fluid and this excessive volume continues
to empty in the LV even during straining. So, there is little
Valsalva Maneuver4 effect of fall in systemic vascular return on LV volume and
Method hence, blood pressure (Figures 2A to C).
The maneuver is performed by asking patient to exhale
forcefully into mercury manometer to generate and Physiological Changes
maintain a pressure of 40 mm Hg for 20 seconds. Stage II (Figure 3).
KG-6.indd 32 02-11-2018 13:44:10

Table 2: Stages of Valsalva maneuver CHAPTER
6
Stages Blood pressure Heart rate
1. Onset of straining (1st 10 sec) ↑ ↓
Aortic compression due to raised intrathoracic pressure
2. Continued expiration (10–20 sec) ↓ ↑
Due to venous compression and decreased venous return
3. End of expiration ↓↓ ↑↑
Due to increased capacitance of pulmonary bed
4. Recovery 5–10 sec after stopping expiration ↑ ↓
Overshoot due to sympathetic activation
Note: Normally changes in intensity of murmur are only recorded in stage 2.
a
Caution: Valsalva maneuver should not be performed in ischemic heart disease patients and patients of severe left ventricular (LV) outflow
obstruction.
di
the mitral valve to prolapse early in the systole. This makes
In
the click move closer to S1 and the murmur to become
longer.
of
Rapid Standing from Squatting or Lying
Posture
ty
Method
18 cie Physiologically, effects of rapid standing from squatting
or lying down posture are similar to Valsalva stage II.
The patient must be in squatting position for at least
20 o
30 seconds. The patient is asked to stand rapidly from
squatting position and changes in heart sound and
S
Figure 1: Pressure and heart rate response during normal and murmur are seen at 15–20 seconds.
Valsalva maneuver
al
Response in Specific Diseases Clinical Implications

Similar to stage II Valsalva, this maneuver leads to
ic
Hypertrophic obstructive cardiomyopathy: Murmur of

hypertrophic obstructive cardiomyopathy (HOCM) starts decreased venous return, decreased LVEDV, and
og
well after S1 and it has a crescendodecrescendo pattern. decreased stroke volume. These physiological changes
Basic pathology is the dynamic obstruction of LVOT by result in narrow splitting of A2P2, soft S3, S4, softer
combined effect of systolic increase in thickness bulge in murmur of pulmonary stenosis (PS), aortic stenosis (AS),
ol
LV cavity of already hypertrophied septum and systolic tricuspid regurgitation (TR), mitral regurgitation (MR),
anterior motion (SAM) of anterior mitral leaflet (AML). tricuspid stenosis (TS), mitral stenosis (MS), louder
di
Any factor which decreases LV size [left ventricle end HOCM murmur, click of MVP moves closer to S1 and the
diastolic volume (LVEDV)], such as decreased preload, murmur becomes longer.
ar
decreased afterload, and increased contractility, will

increase murmur of HOCM (Figure 3).
Müller Maneuver
C
Mitral valve prolapse: Basic pathology in mitral valve This maneuver is commonly known as opposite of
prolapse (MVP) is the prolapse of mitral leaflet above Valsalva maneuver.
annulus during ventricular systole. It is said that mitral
valve leaflet and chordae are too big for left ventricle;
so, they prolapse into left atrium during ventricular Method
systole when a critical LV volume is reached (midtolate It is done as the patient’s nares are held closed and then
systole). Click in MVP occurs in midlate systole because patient has to suck forcibly into a manometer to generate
of billowing of mitral valve (MV) leaflets and tensing of a negative pressure of 40–50 mm Hg for 10 seconds and
chordae and is synchronous with maximum prolapse of changes are seen in the intensity of murmur at the end of
involved leaflet. Murmur usually begins with the click and 10 seconds.
then fans out up to A2. Practically, this is done by asking the patient to inspire
Any maneuver which decreases LV size (LVEDP) leads forcefully for 10 seconds while the patient’s nares are
to early attainment of critical volume of LV which causes pinched and mouth firmly sealed.
33
KG-6.indd 33 02-11-2018 13:44:11

SECTION
1
Clinical Cardiology
a
di
In
B
of
ty
C
18 cie
Figures 2A to C: (A) Normal: sinusoidal response with sounds intermittent during strain and release; (B) Briefly audible sounds during initial
20 o
strain phase and absence overshoot suggests only impaired systolic function in the absence of fluid overload; (C) Persistence of Korotkoff
sounds throughout strain phase suggests elevated left ventricular filling pressures known as square root pattern
S
al
ic
og
ol
di
Figure 3: Physiological changes during stage II Valsalva maneuver and its effect on heart sounds and murmurs
ar
Abbreviations: LVEDV, left ventricle end-diastolic volume; AS, aortic stenosis; PS, pulmonary stenosis; AR, aortic regurgitation; PR, pulmonary
regurgitation; MR, mitral regurgitation; TR, tricuspid regurgitation; MS, mitral stenosis; TS, tricuspid stenosis; HOCM, hypertrophic obstructive
cardiomyopathy; MVP, mitral valve prolapse
C
Clinical Implications lie down from the standing posture. The changes in
This maneuver leads to increased venous return which murmur or heart sound are noticed after 15–20 seconds.
leads to increase in rightsided murmurs, increase in A2 Physiology and effects are almost similar to Muller’s
P2 gap, and increase in right ventricle (RV) S3 and S4. maneuver, but are more pronounced (Figure 4).
Passive Leg Elevation or Sudden Lying Down Clinical Implications

Method Physiologically, this maneuver leads to increased venous
In this maneuver, the patient is asked to lie in supine return, which leads to increased RV stroke volume; and
position and passive elevation of both the legs is done after a few beats, this leads to increased LVEDV and
straightly for 15–20 seconds or the patient is asked to increased LV stroke volume. The increased RV stroke
34
KG-6.indd 34 02-11-2018 13:44:12

CHAPTER
Figure 4: Physiological changes during passive leg elevation or sudden standing
Abbreviations: RV, right ventricle; LV, left ventricle; SV, stoke volume; PS, pulmonary stenosis; TS, tricuspid stenosis; TR, tricuspid regurgitation;
AS, aortic stenosis; MS, mitral stenosis; MR, mitral regurgitation; MVP, mitral valve prolapse; HOCM, hypertrophic obstructive cardiomyopathy
a
di
In
of
ty
18 cie
20 o S
Figure 5: Physiological effects of sudden squatting and effects on heart sounds and murmurs
Abbreviations: BP, blood pressure; LV, left ventricle; LVEDP, left ventricle end-diastolic pressure; SV, stoke volume; PS, pulmonary stenosis; AS,
aortic stenosis; TS, tricuspid stenosis; MS, mitral stenosis; AR, aortic regurgitation; MR, mitral regurgitation; VSD, ventricular septal defect; TOF,
al
tetralogy of Fallot; PDA, patent ductus arteriosus; HOCM, hypertrophic obstructive cardiomyopathy; MVP, mitral valve prolapse
ic
volume leads to widely split A2P2, louder RV S3, S4, tetralogy of Fallot (TOF), ventral septal defect (VSD),
louder rightsided murmurs like PS, TS, and TR. The and patent ductus arteriosus (PDA). Due to combination
og
increase in LVEDV leads to softer HOCM murmur and the of increased preload and afterload, there is increase in
click of MVP moves later in systole with a shorter murmur. murmur intensity of HOCM, click of MVP is delayed, and
The increase in stroke volume leads to louder LV S3, S4 the murmur of MVP shortens.
ol
and louder leftsided murmurs such as MS, MR, and AS.

Isometric Exercise
di
Method
Sudden Squatting
To perform this maneuver, the patient is asked to tightly
ar
Method grip a calibrated hand grip device or handball with both

The patient is asked to squat suddenly from standing the hands simultaneously and sustain it for at least 20–30
C
seconds (care should be taken not to perform Valsalva

position (Valsalva maneuver to be avoided) and changes
maneuver). This maneuver is most useful for leftsided
in murmur or heart sounds are heard just after squatting
lesions and it should not be done in patients with coronary
(Figure 5).
artery disease (CAD) and ventricular arrhythmia.
Clinical Implications Clinical Implications

Physiological effect of this maneuver is simultaneous Physiologically, there is transient but significant increase
increase in venous return and systemic vascular resistance. in systemic vascular resistance, increase in heart rate,
This leads to increased stroke volume, increased blood increase in stroke volume, increase in cardiac size, and
pressure, and increased LV size (LVEDV). Increased stroke increase in LV filing pressures. Clinical effects on heart
volume leads to increased S3, S4 sounds, louder murmurs sounds and murmurs are as follows:
of PS, AS, TS, and MS. Increased systemic vascular Murmur of AS is diminished due to reduction of
resistance leads to increased louder murmurs of AR, MR, pressure gradient across aortic valve
35
KG-6.indd 35 02-11-2018 13:44:13

SECTION Murmur of AR, rheumatic MR and VSD increases due contractility and thus decreased cardiac output. They
to increase in SVR are contraindicated in chronic heart failure (CHF) and
1 LVS3 and LVS4 accentuated due to increase in LV filling
pressures
hypertension (HTN).
The effects of methoxamine and phenylephrine on
Clinical Cardiology
Murmur of MS becomes louder due to increase in flow heart sounds are reduced S1, louder A2, prolonged A2OS
across valve interval and variable response of S3 and S4.
Murmur of HOCM decreases due to increase in LV Methoxamine and phenylephrine accentuate the
volume electrolytedriven mobilization (EDM) (EDM) of AR,
Click and murmur of MVP delayed due to increase in paradoxical septal motion (PSM) of MR, murmur of VSD,
LV volume, but the murmur of MVP becomes louder. TOF, and continuous murmurs of PDA and arteriovenous
fistula (AVF). Also, the systolic murmur of HOCM softens
a
(increased LV size), click and murmur of MVP delayed
PHARMACOLOGICAL MANEUVERS
di
(increased LV size). Due to decrease in cardiac output,
Amyl Nitrite ejection systolic murmur (ESM) of AS, functional systolic
In
murmurs, and MDM of MS are diminished.
Method
An ampoule of amyl nitrite (0.3 mL) is crushed into a gauze Clinically Dynamic Auscultation Helps to
Differentiate
of
piece and the patient is asked to take 3–4 deep breaths
with the gauze piece near the patient’s nostril. Changes in AS and HOCM
the murmur are noticed in the first 15–30 seconds. Squatting (AS murmur increases, HOCM murmur
ty
Physiologically, in the first 30 seconds, there is intense diminishes)
vasodilation leading to decreased arterial pressure. In Valsalva/standing (AS murmur diminishes, HOCM
18 cie
the next 30–60 seconds, there is reflex tachycardia and,
therefore, increased cardiac output.
murmur accentuates).
AS and MR
Handgrip (AS murmur diminishes, MR murmur
20 o
Clinical Implications accentuates)
S
Due to decreased aortic pressure, amyl nitrite accentuates Phenylephrine (AS murmur diminishes, MR murmur
the murmurs of AS (increased gradient across aortic valve), accentuates)

HOCM (decreased afterload), MS (reflex tachycardia) and Postventricular premature contractions (VPC) (AS
al
diminishes the murmurs of AR, MR, VSD, PDA, and TOF. murmur accentuates and MR murmur diminishes)
Amyl nitrate (AS murmur accentuates and MR murmur
Amyl nitrite is very useful in differentiating:
ic
diminishes).
Middiastolic murmur (MDM) of MS vs. Austin flint
og
murmur of AR (MS murmur is accentuated and Austin MS and Austin flint

flint is diminished) Amyl nitrite (MS murmur accentuates and Austin flint
TOF vs. isolated PS (TOF murmur is diminished and PS murmur diminishes).
ol
murmur is accentuated)
PS and small VSD
MR vs. TR (MR murmur is diminished and TR murmur
Amyl nitrite (PS murmur accentuates and VSD murmur
di
is accentuated)
diminishes)
AR vs. PR (AR murmur diminishes and there is no
Phenylephrine (PS murmur diminishes and VSD
ar
change in PR murmur).
murmur accentuates).
Methoxamine and Phenylephrine

C
REFERENCES
Method 1. Lembo NJ, Dell’ Italia LJ, Crawford MH, O’Rourke RA.
Methoxamine is administered at 3–5 mg IV (intravenous) Bedside diagnosis of systolic murmur. N Engl J Med.
to increase arterial pressure by 20–40 mm Hg for 1988;318:15728.
10– 20 min. Phenylephrine is administered at 0.5 mg IV 2. Grewe K, Crawford MH, O’Rourke RA. Differentiation of
to elevate systolic pressure around 30 mm Hg for 3–5 min. cardiac murmurs by dynamic auscultation. Curr Probl
Phenylephrine is preferred due to shorter duration action. Cardiol. 1988;13:669721.
3. Braunwald E, Perloff JK. Physical examination of the heart
and circulation. In: Braunwald E, Zips DP. Libby P (Eds):
Clinical Implications Heart disease, 6th edn Philadelphia,WB Saunders; 2001.
Physiologically, there is increased systemic arterial 4. Nishamura RA, Tajik AJ. The valsalvsa maneuver and
pressure that causes reflex bradycardia and decreased response revisited. Mayo Clin Proc. 1986;61(3):2117.
36
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S
Valvular Heart E
a
Disease—Rheumatic
di
C
In
Heart Disease
of
T
ty
Challenges in the Diagnosis and Management of Acute Rheumatic Fever
Anita Saxena
18 cie
Pathogenesis of Rheumatic Fever and Rheumatic Heart Disease:
What have we Learned?
I
20 o
Decline of Rheumatic Heart Disease: Is it Real?
S

Clinical Assessment of Severity of Valvular Heart Disease
al
Ajith Ananthakrishna Pillai, Devendra Kanshilal Sharma, Balachander Jayaraman
O
Subclinical Rheumatic Heart Disease
ic

og
Natural History of Mitral and Aortic Valve Regurgitation

N
Natural History of Rheumatic Mitral Stenosis
ol
Vivek Chaturvedi
di
Percutaneous Transvenous Mitral Commissurotomy: Tips and Tricks

ar
Clinical Diagnosis of Tricuspid Valve Disease

C
Atrial Fibrillation in Rheumatic Heart Disease
2
Prevention of Rheumatic Fever/Rheumatic Heart Disease
KG-7 (Sec-2).indd 37 02-11-2018 13:48:40

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20 o S
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KG-7 (Sec-2).indd 38 02-11-2018 13:48:40

Challenges in the Diagnosis
CHAPTER 7
and Management of Acute
Rheumatic Fever
Anita Saxena
a
di
INTRODUCTION cases detected by echocardiography being asymptomatic
Rheumatic fever is an acute, diffuse, and nonsuppurative and subclinical.6-8
In
inflammatory disease that occurs as a delayed complication
after an untreated or partially treated pharyngotonsillitis, DIAGNOSIS OF RHEUMATIC FEVER
of
the infection itself sometimes being asymptomatic. It is There is no single confirmatory clinical sign or laboratory
caused by group A β-hemolytic Streptococcus, specifically, test. Diagnosis is based on the Jones criteria, which have
Streptococcus pyogenes. The process is triggered by an recently been updated for the first time since 1992. A
ty
inappropriate immunological response, both humoral single set of diagnostic criteria has become insufficient
and cellular, and results from a complex interaction to encompass the variability in the clinical profile of
18 cie
among individual susceptibility, environment and the
bacteria. The exact nature of this response is incompletely
understood. The disease is characterized by four distinct
acute episodes related to different populations in diverse
geographic settings. Additionally, the concept of cardiac
involvement in the absence of auscultatory findings,
phases. The initial streptococcal pharyngotonsillitis is
20 o
the so-called subclinical carditis, has emerged from the
followed by a latent period and then by the acute and
widespread use of Doppler echocardiography. Taking into
S
chronic phases. The chronic phase is also known as

account the technological advances and new evidence
rheumatic heart disease (RHD), when the cardiac lesions
from epidemiological data, the Jones criteria were
remain as sequela of the acute phase. Rheumatic fever
al
last reviewed and updated9 in the year 2015 (Table 1).

(RF) has the potential to involve multiple organs systems
Firstly, subclinical carditis was incorporated as a major
including the heart, joints, brain, and subcutaneous and
ic
manifestation for all patient populations. Secondly, with

cutaneous tissues. Cardiac injury is the most important
the introduction of two different sets of diagnostic criteria
manifestation, and it is the damage to the heart that
og
based on population risk, monoarthritis, or polyarthralgia

produces its clinical, social, and economic impact.
were considered a major criterion for arthritis, and low-
Although RF has declined in Europe and North
grade fever was included as a minor manifestation, both
ol
America over the past 4 to 6 decades, this preventable

conditions applied only for moderate- and high- risk
disease continues to be both socially and clinically
devastating in low- and middle-income countries, with populations. Moderate–high risk is defined as coming
di
significant rates of morbidity and mortality. 1, 2 Acute from a population with an RF incidence of ≥2 per 100,000
episodes of RF are still a cause of death in childhood and school-aged children (usually 5–14 years old) per year or
ar
its sequela are the major causes of cardiovascular death in an all age RHD prevalence of >1 per 1,000 people per year.
children and young adults. The five most characteristic clinical features
C
The RF is more frequent among children and constitute the major manifestations, namely carditis,
adolescents between the ages 5 and 15, and has a peak arthritis, chorea, subcutaneous nodules, and erythema
of incidence around the ages of 8 to 9 years. These ages marginatum, independent of their severity. Classically,
coincide with the peak of streptococcal pharyngotonsillitis arthritis and carditis, isolated or combined are seen most
in school-aged children, this infection being less frequently. Chorea is less common, and the other major
common in late adolescence and in adults. Likewise, manifestations are rare. The minor manifestations are
RF is uncommon in children under 4 years of age, and frequent and mostly related to the underlying systemic
exceedingly rare under the age of 2.3-5 inflammation. These clinical and laboratorial findings
In recent years, epidemiological studies, including are nonspecific but supportive of the diagnosis when
surveys using portable echocardiographic screening, have accompanying a major manifestation. In addition to the
described RHD burden in Africa, Asia, and Oceania, with Jones criteria, other non-specific clinical findings may also
prevalence varying between 2% and 6% and around 90% of be present during the course of the acute episodes.
KG-7 (Sec-2).indd 39 02-11-2018 13:48:43

SECTION Table 1: Revised Jones criteria 2015 update with indolent carditis. This subacute condition is more
frequently seen in young children and shows insidious
2
For all patient populations with evidence of preceding GAS
infection onset and slow progression over several weeks or months.
By the time of evaluation, the acute phase reactants and
Diagnosis: Initial acute
Valvular Heart Disease—Rheumatic Heart Disease
rheumatic fever: 2 major manifestations levels of antistreptococcal antibodies may be normal. 9

or 1 major plus 2 minor For the diagnosis of a recurrent attack, the complete set
manifestations of Jones criteria is not needed when faced with a reliable
Diagnosis: Recurrent acute history of a previous episode of RF, or an established
rheumatic fever: 2 major or one major plus 2 chronic RHD. The diagnostic requirements are two
minor or 3 minor
major or one major and two minor or at least three minor
Low-risk populations* manifestations, along with supporting evidence of a
a
Major manifestations Minor manifestations recent streptococcal infection. Diagnostic categories
di
Carditis Fever (>38.5º) described as ‘possible’ and ‘probable’ RF have been used
zClinical or subclinical to include patients, who did not meet the Jones criteria for
In
Arthritis Polyarthralgia a definitive diagnosis of an acute episode although RF is
z Polyarthritis only
the most likely diagnosis.10-12
Chorea Prolonged PR
of
Subcutaneous nodules ESR ≥ 60 mm in the first hour MAJOR CRITERIA
Erythema marginatum and/or CPR ≥ 3.0 mg/dL
Moderate- and high-risk populations*
Carditis
ty
Carditis
The cardiac involvement is variable ranging from
z Clinical or subclinical Fever (>38º) subclinical to severe presentation with heart failure and
Arthritis
z Monoarthritis or polyarthritis
z Polyarthralgia
18 cie
Monoarthralgia
fulminating evolution. The severity of carditis is the
most important prognostic factor. Rheumatic carditis
is characterized by pancarditis. The determinants of
20 o
Chorea Prolonged PR morbidity and mortality, nonetheless, are the degree and
Subcutaneous nodules ESR ≥ 30 mm in the first hour extent of endocarditis, represented by the damage in the
S
cardiac valves. The cardiac involvement tends to appear

Erythema marginatum and/or CPR ≥ 3.0 mg/dL
early, and is usually diagnosed within the first 3 weeks of
Abbreviations: CRP, C-reactive protein; ESR, erythrocyte sedimentation
al
rate the acute episode. Carditis is reported to be seen in up to

* See text for complementary information. three-fifths of first attacks although more recent series of
ic
Source: Gewitz MH, Baltimore RS, Tani, Sable CA, Shulman ST, patients have shown higher rates when echocardiography
Carapetis J, et al. On behalf of the American Heart Association is included in the evaluation.13, 14
Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease
og
of the Council on Cardiovascular Disease in the Young. Revision of the Pericarditis may rarely occur as a part of pancarditis.
Jones criteria for the diagnosis of acute rheumatic fever in the era of It produces pericardial effusion, mostly mild, and
Doppler echocardiography: a scientific statement from the American does not cause constriction. Similarly, myocarditis is
ol
Heart Association. Circulation. 2015;131(20):1806-18.

rare. Congestive heart failure (CHF) in RF is not due to
primary myocarditis but results from significant valvular
The diagnosis of a first episode of RF includes the
di
dysfunction secondary to valvulitis.

combination of two major, or one major and two minor Endocarditis is the diagnostic hallmark of rheumatic
manifestations, supported by evidence of a preceding
ar
carditis, being expressed by valvitis. The inflammatory

infection with the group A Streptococcus. When clinical or process affects the mitral and aortic valves. Mitral
subclinical carditis is considered as a major manifestation,
C
regurgitation is the dominant valvar lesion in over 90% of

a prolonged P-R interval cannot be included as minor patients; it may be associated aortic regurgitation. Isolated
manifestation in the same patient. Similarly, in the aortic regurgitation is seen in less than 5% of cases.
presence of arthritis, mono- or polyarthralgia cannot Subclinical carditis: Silent carditis, diagnosed by
be considered as a minor manifestation. Once other Doppler echocardiography has been accepted as part
diagnoses are excluded, Sydenham’s chorea and indolent of the spectrum of rheumatic carditis. It is found in
carditis are exceptions to the strict adherence to the patients with isolated arthritis and/or pure chorea,
Jones criteria. Since Sydenham’s chorea usually occurs without auscultatory findings of valvar dysfunction,
as a late manifestation of the disease, evidences of the but with a pathological pattern of valvar regurgitation
inflammatory process and of the preceding streptococcal revealed by Doppler echocardiographic interrogation. As
infection could have already subsided when the major trivial valvar leaks are commonly identified by Doppler
manifestation becomes evident. Similarly, the evidence echocardiographic investigation in normal subjects at all
of a streptococcal infection is not required for patients ages, it is essential to use strict criterions to differentiate
40
KG-7 (Sec-2).indd 40 02-11-2018 13:48:43

pathological from physiological regurgitation. The finding MINOR MANIFESTATIONS CHAPTER
of a subclinical carditis has been included in the most
7
The minor manifestations are nonspecific, providing
recent revision of Jones criteria for diagnosis of RF. support for diagnosis when associated with a major
manifestation. Arthralgia is the most common minor

Polyarthritis criteria; joint pain shows the characteristics of polyarthritis
Polyarthritis is the most frequent major manifestation without features of inflammation. Fever is usually present
seen in older children, adolescents and adults, but is in the early stage of the disease, commonly of low-grade,
the least specific clinical finding of RF. Polyarthritis is and can persist for 2 to 3 weeks.9 There is no characteristic
nonsuppurative, asymmetric, migratory, and self-limited. pattern, and it is rare for the temperature to rise higher
There is a marked preference to involve the peripheral than 39°C. The laboratory data included among the minor
manifestations, as with the clinical findings, are also
a
large joints, particularly of the legs. The small joints of the
hands and feet, the shoulders and hips are less commonly nonspecific. A prolonged P-R interval can be found in
di
affected. The spine is rarely involved. Tenderness and healthy people. Regarding the patterns of the acute phase
severe pain, out of proportion to the findings of the reactants, both the rise and fall of the serum concentration
In
physical examination, are the most prominent features. of C-reactive protein occurs earlier than the erythrocyte
Redness, swelling, and heat are usually less marked. sedimentation rate, which may remain elevated for 3-6
Salicylates and nonsteroidal anti-inflammatory agents months, more frequently for more than 4 weeks.
of
produce a marked and prompt relief of the symptoms
and signs. Usually, the arthritis heals without anatomical Clinical Features not included
deformities or functional abnormalities. Monoarthritis is in Jones Criteria
ty
less common, but has been included as a major criterion Epistaxis is an uncommon presentation, and abdominal
in recent revision for moderate- and high-risk populations.
Sydenham’s Chorea
18 cie pain, mainly around the navel, may precede the major
manifestations. Rheumatic pneumonia is rarely seen.
Manifestations, such as anorexia, listlessness, fatigue,
anemia, weight loss, and pallor, are described, but are
20 o
Sydenham’s chorea, chorea minor, or St. Vitus’ dance,
affects children and adolescents, more commonly related to systemic inflammation and to the severity of the
S
in prepubertal females. The latent period, after the clinical presentations, mainly carditis.
streptococcal infection, is longer than for arthritis and
Challenges in Diagnosis of Rheumatic Fever
al
carditis, varying from 1 to 7 months. Chorea may occur as

an isolated manifestation, the so-called pure chorea, or An early diagnosis is important as it may prevent
ic
less frequently in association with carditis or arthritis.15 progression of damage to the cardiac valves. As no
It is usually a self-limited disorder, characterized by laboratory finding is specific, the history and physical
og
muscular weakness, hypotonia, and emotional instability, examination remain the basis for the diagnosis. The
besides involuntary and purposeless but conscious established guidelines, although very useful, cannot
movements of the skeletal muscles. One-fifth of patients substitute the physician’s experience and common
ol
have hemichorea, with the manifestations limited to one sense. As a systemic disease, with a wide spectrum of
side of the body. manifestations and multiple associations, diagnostic
di
problems can be present, since several other conditions

Subcutaneous Nodules and Erythema can fulfill the Jones criteria. On the other hand, not all
ar
Marginatum patients with an acute episode meet these diagnostic

Subcutaneous nodules are one of the most characteristic requirements. Even in areas where RF is still prevalent, its
C
major criteria, but are rarely seen. They have a diagnostic frequency and severity have decreased, resulting in less
characteristic presentations.
value as are invariably associated with severe carditis. The
nodules are seen over the extensor surface of joints and Carditis: Significant cardiac involvement is easy to
bony prominences, are small, firm, painless, and freely diagnose but clinical characterization of mild, subclinical,
movable under the skin. or smoldering cardiac involvement is difficult. These
Er y t h e ma ma rg i nat u m i s a v e r y u n c o m m o n circumstances have potential implications in prognosis,
manifestation; it is seen as a macular rash over trunk; when the risks of recurrences and worsening of the valvar
blanches on pressure, has a serpiginous or circular form, lesions are taken into account. Considering that almost
is painless and nonpruritic. The rash is characteristically 50% of adults presenting with an established rheumatic
evanescent or transient, may last minutes, more usually valvar disease do not give any preceding history of RF,
days. The lesions are more easily seen in fair-skinned underdiagnosis is very common. Similarly, children with
patients, and may become more apparent with the innocent murmurs or murmurs caused by congenital
application of heat. cardiac defects may be wrongly diagnosed as having RF.
41
KG-7 (Sec-2).indd 41 02-11-2018 13:48:43

SECTION Polyarthritis/polyarthralgia: A number of illnesses MANAGEMENT
in children can give rise to symptom of polyarthritis,
2
Apart from mild cases, most individuals with suspected
particularly when the articular involvement is the sole RF are hospitalized for diagnostic work-up and to
manifestation of the acute phase. The difficulties increase initiate treatment. Management of the acute episode
with the presence of atypical presentations of arthritis. includes eradication of tonsillar and pharyngeal group
Also, premature use of aspirin or other anti-inflammatory A Streptococcus, treatment of the acute inflammatory
agents may mask the diagnosis. Usually, the joint phase, which is supportive and focuses on providing
involvement is an early and self-limited manifestation. symptomatic relief of arthritis, supportive care for carditis,
Milder forms of arthritis/arthralgia may contribute to and education for the patient and family, especially for
misdiagnosis, mainly when the symptoms and signs have emphasizing the importance of secondary prophylaxis.
already subsided at the clinical examination. Furthermore,
a
After obtaining a throat swab, penicillin is commenced
the differential diagnosis between polyarthritis and to eradicate group A Streptococcus from the pharynx.
di
polyarthralgia is difficult, if based exclusively on clinical Either oral phenoxymethylpenicillin (penicillin V), 250 mg
history. There are many diseases that may currently fulfill twice daily in children or 500 mg twice daily in adolescents
In
the Jones criteria in their early stage, or mimic the acute for 10 days, or a single dose of intramuscular benzathine
rheumatic process very closely. The differential diagnosis penicillin (benzathine benzylpenicillin) can be given
includes rheumatoid arthritis, serum sickness, other until the patient is established on long-term secondary
of
arthropathies, infective endocarditis, Henoch–Schönlein antibiotic prophylaxis. For patients with penicillin allergy,
purpura, acute leukemia, poliomyelitis, and acute erythromycin is the recommended alternative antibiotic.
appendicitis. Viral myocarditis, viral pericarditis, systemic
ty
lupus erythematosus, and other collagen disorders may Management of Clinical Manifestations
affect both the joints and the heart.
18 cie
Recurrence of rheumatic fever: The diagnosis of recurrences
can also be challenging. In patients with cardiac murmurs
Bedrest: The recommended duration and strictness of
bedrest is variable depending on the manifestations and
severity of the clinical presentation. The recommendation
20 o
from a previous attack, a more precise diagnosis of of prolonged bedrest is based primarily on reducing
recurrence can only be established if pericarditis is found, cardiac work in those with carditis, and avoiding as
S
or if a different valve is damaged producing new murmur. much as possible the use of the involved joints in those
Recent worsening of cardiac status could also represent a with arthritis. Strict bedrest is no longer recommended
al
recurrence, although it can also result from the evolution for most patients with rheumatic carditis, it should be
of severe RHD. limited to patients with a more significant involvement of
ic
In many instances, a given presentation may not the heart with CHF, and to those with arthritis of the legs.
fulfill the updated Jones criteria, but the clinician with The rest need not be strict, and it should be followed by
og
a vast experience of dealing with cases with RF may still supervised activities for the following weeks. Patients with
suspect that RF is the diagnosis. This is more likely to cardiomegaly, and congestive failure, should be made to
happen in high prevalence settings. In such situations, rest over the first 3–4 weeks, and then gradually allowed
ol
clinicians should use their discretion and clinical acumen activities.

to make the diagnosis and manage patients accordingly. Carditis: Anti-inflammatory drugs have been extensively
di
In genuinely uncertain cases, it is reasonable to consider employed in the treatment of carditis, showing a prompt
the diagnosis of RF and offer secondary prophylaxis effect in terms of cardiac symptoms. Salicylates are used
ar
for 12 months followed by re-evaluation to include for those with no or mild forms of carditis, corticosteroids
a careful history, physical examination and a repeat are used for patients with moderate or severe carditis,
C
echocardiogram.9 especially for those with CHF. Prednisone is usually

The supporting evidence of recent streptococcal preferred, initial dose of 1–2 mg/kg, given for 2–3 weeks
infection and rise in acute phase reactants are not followed by a gradual tapering, total duration of the
specific for the disease, but are useful to characterize the treatment should be 8–12 weeks. Some authors have
presence of the inflammatory process. Besides the minor recommended an overlapping therapy with the aim to
manifestations, other clinical features, such as fatigue and prevent rebounds, with the introduction of salicylates
anorexia, contribute to the diagnostic approach when they as the dose of corticosteroids is reduced. In addition,
are not part of the cardiac failure. As the clinical features supportive measures include the treatment of CHF and
are crucial for a better understanding of the course of arrhythmias. Diuretics, angiotensin-converting enzyme
the disease, a period of closer observation sometimes is (ACE) inhibitors should be used in patients with significant
needed to clarify the diagnosis. valvular regurgitation and/or left ventricular dysfunction.
42
KG-7 (Sec-2).indd 42 02-11-2018 13:48:43

CHAPTER
Table 2: Treatment of major manifestations of carditis
Clinical manifestation
Severe carditis
Treatment schedule
Prednisone 2 mg/kg/day once daily
7

Moderate carditis Prednisone 1–2 mg/kg/day once daily
or
Aspirin 75–100 mg/day divided into 4 doses
Mild carditis Aspirin 75–100 mg/day divided into 4 doses
Polyarthritis Aspirin 75–100 mg/day divided into 4 doses
or
Naproxen 10–20 mg/kg/day
a
Chorea Carbamazepine 4–10 mg/kg/day
or
di
Valproic acid 20–30 mg/kg/day
or
In
Haloperidol 2–6 mg/day
of
Cardiac surgery is best deferred in the acute stage as the Challenges in Management
valve repair is difficult and less durable. However, urgent of Rheumatic Fever
surgery may be required due to very severe mitral and/
For many people with mild-to-moderate carditis, the
ty
or aortic regurgitation with heart failure or in those with a
degree of valvular regurgitation stabilizes or improves
flail leaflet due to chordae tendinae rupture. Repair of the
within 12 months after diagnosis. Individuals who
patients.16
18 cie
valve is to be preferred over valve replacement in young
experience severe carditis during the initial episode, or
recurrences of RF, are at greatest risk of severe chronic
Arthritis: Salicylates are the first-line treatment; these RHD,4 which is associated with an increased risk of heart
20 o
agents usually have a dramatic effect on the inflammatory failure, infective endocarditis, pregnancy complications,
stroke, arrhythmias, and premature death. As mentioned
S
process, with prompt improvement. However, paracetamol

should be used till confirmation of diagnosis. The full earlier, the treatment of RF is largely supportive and does
dose is given for the first 2 weeks and subsequently is not alter the natural history of the disease in most cases.
al
gradually reduced to up to 60 mg/kg over the next 2–3 However, these medicines including drugs for control of
weeks (Table 2). A smaller or a larger dose can be used, heart failure, arrhythmias need to be taken regularly in
ic
depending on the clinical response to treatment, and advanced level of rheumatic carditis.
may be maximized for those failing to respond to lower The most important aspect of treatment is preventing
og
doses. A higher dose, such as 100 mg/kg, is required by few the recurrence of RF, as each recurrence tends to worsen the
patients. Naproxen is an alternative therapy for patients damage to valves increasing its severity. The recurrences
who are allergic to or intolerant of aspirin. It has similar are prevented by means of continuous use of antibiotics,
ol
analgesic potency as salicylate but does not have the risk independently from the type of clinical manifestation
of Reye’s syndrome, a rare complication of salicylate. in the acute phase or the presence of sequela. This
di
is called secondary prevention. Effective secondary

Sy d e n h a m’s c h o re a : Is o l at e d c h o re a i s t re at e d prevention results in reduction in hospitalization,
ar
symptomatically. The patients should be kept in a quiet disability, intervention, and mortality rates. Therefore,
environment to protect them from external stimulation careful attention to ensure good adherence to secondary
C
and stress. As most drugs used for chorea are not without prophylaxis (mostly by benzathine penicillin) is required.
side effects, treatment should be considered, if symptoms The regimes for secondary prevention are shown in
affect the normal activities significantly or patient has risk Table 3.17,18 Benzathine penicillin remains the drug of
of injury. Valproic acid and carbamazepine are preferred choice and the most effective to prevent recurrences.
over haloperidol as haloperidol has significant side effects. The use of four-weekly benzathine penicillin has been
Carbamazepine should be used initially and valproic acid considered the standard regimen; however, in populations
given for refractory cases (Table 2). with a high prevalence of RF, shorter intervals have been
Anti-inflammatory agents are usually not indicated, recommended. This measure is supported by observations
because chorea often occurs after the resolution of of higher rates of recurrent episodes related to monthly
the systemic inflammatory process. A short course of prophylactic regimens when compared to three-weekly
corticosteroids may be considered for severe refractory intervals. The use of the long-acting intramuscular
cases. penicillin is more effective than oral penicillin. Adequate
43
KG-7 (Sec-2).indd 43 02-11-2018 13:48:43

SECTION Table 3: Drugs and regimes for secondary prophylaxis
2
Drug Dose Interval of doses
Benzathine Penicillin G (deep IM injection) If body weight > 27 kg: 12 lakh unit Every 21 days’
To be given after sensitivity test. Contraindicated if Penicillin allergy present If body weight ≤ 27 Kg: 6 lakh unit Every 14 days’
Penicillin V (oral) 250 mg Two times a day

To be given one hour before or two hours after meals. Contraindicated if
Penicillin allergy present
Erythromycin ethyl succinate (oral) 250 mg Two times a day
Contraindicated in liver disease
a
levels are less predictable with the use of oral medication, Identifying local health facility for each patient.
contributing to higher risks of recurrences. Education of affected patients and their families about
di

importance of regular prophylaxis.

Challenges to Secondary Prophylaxis Reliable supply of safe, good quality penicillin.
In

Training of manpower for safe penicillin injection.

Patient-related challenges: These include low levels of
Encouraging staff to use pain-reducing mechanisms.
education of patients and families and poor level of
of
understanding of the disease and importance of secondary
prophylaxis. Since RF primarily affects poor patients, CONCLUSION
the inability to afford the medicine and cost of travel to a The RF continues in developing countries including
ty
health facility for injection is also responsible for lack of India. The recent updated Jones criteria for moderate-
compliance. Some communities tend to have distrust with and high-risk population assist in diagnosis of RF, but
18 cie
health services and would rather go for alternate therapy
and indigenous medicines for their symptoms.
clinicians should use their clinical acumen in cases where
these criteria are not fully satisfied so as not to miss cases
Health system-related challenges: Limited knowledge with RF. The management of acute episode is largely
20 o
amongst physicians practicing in metro cities, where symptomatic. The main thrust should be on prevention
of recurrences by instituting secondary prophylaxis.
S
poor patients are unable to access health care, has given

an impression that RF is declining. A number of private Adherence with prophylaxis can be improved by various
health facilities refuse to administer penicillin injections means; perhaps, the most important is educating the
al
for fear of allergic reaction, which is very rare in children. patients and their families.
Since there is no national policy for prevention and control
ic
of RF and RHD, the health systems do not maintain any REFERENCES

register nor do they track patients with RF.
og
1. Carapetis JR, Steer AC, Mulholland EK, et al. The global

Penicillin-related challenges: Penicillin is the cornerstone burden of group A streptococcal diseases. Lancet Infect Dis.
of any prevention program for RF, it is required for 2005;5(11):685–94.
ol
treatment of bacterial sore throat as well as for long-term 2. Seckeler MD, Hoke TR. The worldwide epidemiology of
acute rheumatic fever and rheumatic heart disease. Clin
secondary prophylaxis. Unfortunately, neither long-acting
Epidemiol. 2011;3:67–84.
di
benzathine penicillin nor oral penicillin is available on

3. Tani LY, Veasy LG, Minich LLA, et al. Rheumatic fever in
a regular basis. In fact, some of the states in India have
children younger than 5 years: Is the presentation different?
ar
banned the use of penicillin in private hospitals. The Pediatrics.20 07;112(5):1065-8.

quality of some of the available brands is also suspected. As 4. Canter B, Olguntürk R, Tunaoglu FS. Rheumatic fever in
the margin of cost benefit is very low, most pharmaceutical
C
children under 5 years old. Pediatrics. 2007;114(1):329-30.

companies are not interested in producing this drug. Pain 5. Chockalingam A, Gnanavelu G, Elangovan S, et al. Clinical
during injection of long-acting penicillin further deters spectrum of chronic rheumatic heart disease in India. J
patients from taking it on a regular basis. Heart Valve Dis. 2003;12(5):577-81.
6. Beaton A, Okello E, Lwabi P, et al. Echocardiography
Measures to Improve Secondary Prophylaxis Rates screening for rheumatic heart disease in Ugandan
schoolchildren. Circulation. 2012;125(25):3127-32.
These include: 7. Roberts K, Maguire G, Brown A, Atkinson D, Reményi
Dedicated staff to supervise secondary prophylaxis B, Wheaton G, et al. Echocardiographic screening for
coordination. rheumatic heart disease in high and low risk Australian
Development of registries at hospital/state/national
children. Circulation. 2014;129(19):1953-61.
levels to track patients. 8. Saxena A, Desai A, Narvencar K, et al. Echocardiographic
Strong staff-patient relationship, community-based prevalence of rheumatic heart disease in Indian school
service delivery. children using World Heart Federation criteria - A multi
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site extension of RHEUMATIC study (the e-RHEUMATIC and Secondary Prevention of Acute Rheumatic Fever and CHAPTER
study). Int J Cardiol. 2017;249:438-42. Rheumatic Heart Disease: 2014 Update.
9. Gewitz MH, Baltimore RS, Tani LY, et al. On behalf of the
American Heart Association Committee (on Rheumatic
13. Juneja R, Tandon R. Rheumatic carditis: a reappraisal.
Indian Heart J. 2004;56(3):252-5.
7
Fever, Endocarditis, and Kawasaki Disease of the Council

14. Kassem AS, el-Walili TM, Zaher SR, et al. Reversibility of
on Cardiovascular Disease in the Young): Revision of the mitral regurgitation following rheumatic fever: clinical
Jones criteria for the diagnosis of acute rheumatic fever in profile and echocardiographic evaluation. Indian J Pediatr.
the era of Doppler echocardiography: a scientific statement 1995;62(6):717-23.
from the American Heart Association. Circulation. 15. Mota CC, Meira ZM. Rheumatic fever. Cardiol Young.
2015;131(20):1806-18. 1999;9(3):239-48.
10. Ralph A, Jacups S, Kay McGough K, et al. The challenge 16. Finucane K, Wilson N. Priorities in cardiac surgery for
of acute rheumatic fever diagnosis in a high-incidence rheumatic heart disease. Glob Heart. 2013;8(3):213-20.
a
population: a prospective study and proposed guidelines 17. World Health Organization. Rheumatic fever and
di
for diagnosis in Australia’s Northern Territory. Heart Lung rheumatic heart disease. World Health Organ Tech Rep Ser.
Circ. 2006;15(2):113-8. 2004;923:1-122.
11. RHD Australia (ARF/RHD writing group), National Heart
In
18. Dajani A, Taubert K, Ferrieri P, Peter G, Shulman S. Treatment
Foundation of Australia and the Cardiac Society of Australia of acute streptococcal pharyngitis and prevention of
and New Zealand. Australian guidelines for prevention, rheumatic fever: a statement for health professionals.
diagnosis and management of acute rheumatic fever and Committee on Rheumatic Fever, Endocarditis, and
of
rheumatic heart disease (2nd edition). 2012. Kawasaki Disease of the Council on Cardiovascular Disease
12. Heart Foundation of New Zealand. New Zealand in the Young, the American Heart Association. Pediatrics
Guidelines for Rheumatic Fever. Diagnosis, Management 1995;96:758-64.
ty
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Pathogenesis of Rheumatic
CHAPTER 8
Fever and Rheumatic Heart
Disease: What have we Learned?
a
di
INTRODUCTION understood. The pharyngeal lymphoid tissue is considered
Acute rheumatic fever (ARF) is a nonsuppurative important in the initiation of abnormal immune response.
In
inflammatory sequelae of group A Streptococcus (GAS) GAS can be broadly divided into two classes based upon
pharyngitis occurring after a 2 to 3-week latent period in the C repeat regions of the M protein. One is associated
with pharyngitis and the other, impetigo.9 The presence
of
children aged 5–15 years presenting as fever, polyarthritis,
pancarditis, chorea, and skin manifestations. Rheumatic of impetigo is associated with acute glomerulonephritis
heart disease (RHD) is a delayed sequelae of initial or (AGN) but not with ARF. The M types 1, 5, 6, 14, 18, and 24
are considered to be ‘rheumatogenic’.10 So, the particular
ty
recurrent ARF characterized by chronic progressive
valvopathy which occurs in 60% of patients with ARF.1 strain of GAS may be crucial in determining disease
process. In addition, bacterial genetic patterns determine
18 cie
The exact pathogenesis leading to the occurrence of
ARF remains elusive and is continually evolving. It seems
clear that pharyngeal infection by GAS is essential although
the site of infection. The strains with patterns A, B and C of
emm genes which code for M protein are associated with
the cause is multifactorial.2 Genetic susceptibility and pharyngitis, whereas strains with D and E patterns are
20 o
environmental issues play an important role. Autoimmune associated with impetigo.11
S
response called ‘molecular mimicry’ is considered to exert

a pivotal role in the commencement of the disease. Host Susceptibility
al
There is equal incidence of ARF in males and females, but

THREE COMPONENTS OF RHEUMATIC FEVER RHD is more common among females. This paradox could
PATHOGENESIS
ic
be explained by:
Increased susceptibility to develop autoimmune
Pathogen
og
diseases in females.
The link between GAS and autoimmunity has evolved Social factors, such as involvement in child-raising,
since the early reports of ARF and RHD.3-5 ARF is the increase the likelihood of streptococcal infection.
ol
result of autoimmune response to pharyngitis caused by Decreased access to medical care due to sociocultural
Streptococcus pyogenes, the sole member of GAS. There is issues.

di
a strong epidemiological association between GAS throat The genetic component for determining susceptibility
infection and ARF suggesting ‘causation’ as evidenced by is supported by the following:
ar
the following: Only 0.3–3% of people with GAS pharyngitis develops
ARF outbreaks closely follow epidemics of strepto-

ARF.12
coccal pharyngitis or scarlet fever.6 High concordance among twins (risk 44% in
C
Optimal antibiotic treatment of a documented

monozygotic and 12% in dizygotic twins).13
streptococcal sore throat significantly decreases ARF It is likely that the susceptibility to RHD is polygenic
incidence.2 following a nonmendelian pattern of inheritance with
Appropriate antibiotic prophylaxis prevents ARF
variable and incomplete penetrance. 14 Several major
recurrence.7 histocompatibility complex (MHC)-related, and non-
Antistreptococcal antibodies, such as antistreptolysin
MHC-related candidate genes and loci are identified to
O (ASO), hyaluronidase, and streptokinase, are seen in be associated with RHD, the most consistent of which is
most patients with ARF irrespective of preceding sore the MHC class II allele, human leukocyte antigen (HLA)
throat.8 DR-7. Other MHC class II alleles, such as HLA DR-2, DR-4,
DR-1, DRw6, and DRw53 were shown to be associated with
Link between the Pharynx and the Heart ARF in people from different countries.15 The presence of
Why ARF is associated with only pharyngitis and not a non-MHC-related marker in B cell known as ‘D8/17+’
with any other disease caused by GAS, remains poorly might identify a population at risk of ARF.16 Polymorphisms
KG-8.indd 46 02-11-2018 13:48:29

involving several genes that code for proteins involved antigen: N-acetyl-β-d-glucosamine (NABG) were shown CHAPTER
both in the innate and adaptive immune pathways confer to exhibit cross reactivity to antigenic epitopes in the host
susceptibility to ARF/RHD. Several proteins, such as
toll-like receptor 2, ficolin 2, mannose-binding lectin 2,
tissues, such as cardiac myosin, producing tissue injury in
ARF.25 Particularly, M protein shares structural homology
8
Pathogenesis of Rheumatic Fever and Rheumatic Heart Disease: What have we Learned?
HLA class II alleles, interleukin-1 receptor antagonist, with cardiac myosin, tropomyosin, actin, keratin, laminin,
tumor necrosis factor α, and transforming growth factor and vimentin.26 Both humoral and cell-mediated cross-
β-1, were identified to determine susceptibility in recent reactive immune responses play contributory role in
genome-wide association studies.17,18 pathogenesis.
The strongest evidence for the role of molecular
Environmental and Social Factors mimicry comes from ‘Lewis rat model’ where passive
transfer of GAS-specific T cell lines to naïve rats resulted in
a
Environmental risk factors, such as household crowding
valvulitis.27 Immunization with GAS antigens in Lewis rat
and poor living conditions, can facilitate spread of GAS and
di
models led to formation of autoantibodies and valvulitis28
increase the risk of ARF. In fact, one of the most important
or behavior similar to those in Sydenham’s chorea.29
factors contributing to the decline of ARF incidence in
In
Also, cross-reactive antibodies, which could recognize
developed countries is reduced overcrowding.19 ARF and
several types of epitopes, were defined in human studies
RHD relate to poverty and are described as classic diseases
of molecular mimicry between the Streptococcus and
of ‘social injustice’.20 ARF and RHD became rare in wealthy
of
heart.25,30-32
nations. At present, these are common in low- and middle-
income nations and in some indigenous populations in
Humoral Immune Response and Endothelial
wealthy nations where GAS may not be treated. Whenever
ty
there is social disruption and war, resurgence of RHD
Injury: Primary Event in Rheumatic Heart
occurs through displacement, overcrowding and poor Disease
18 cie
living conditions.21 Low socioeconomic status and limited
access to health care lead to increased incidences of
Antibody-mediated response initiates rheumatic carditis
followed by cellular infiltration resulting in further
ARF and RHD in rural areas and urban slums. There is damage. Antistreptococcal antibodies were shown to be
20 o
insufficient evidence whether malnutrition is directly cytotoxic to human valvular endothelium and basement
membrane. 25 Direct anti-endothelial antibodies were
S
associated with ARF and RHD.

demonstrated in 40% of RHD patients. 33 Activation of
IMMUNOLOGICAL MECHANISMS IN ACUTE endothelium occurs by autoantibodies which target
al
‘laminin’ and other glycosylated proteins on the surface

RHEUMATIC FEVER AND RHEUMATIC HEART
valvular endothelium that cross-react with group A
DISEASE
ic
carbohydrate.25 Endothelial overexpression of vascular

RHD is considered as an autoimmune disease with a cell adhesion molecule-1 (VCAM-1) occurs which
og
component of active inflammation both acutely and facilitates infiltration of CD4+ and CD8+ lymphocytes into
chronically. Inflammatory markers, such as C-reactive the subendothelium.34 Once endothelium is damaged,
protein (CRP), fibrinogen, interleukin 6 (IL-6), IL-8, and Type IV collagen is exposed, and continuous damage
ol
tumor necrosis factor alpha (TNF-α), are found to be of the valve occurs by non-cross-reactive anti-collagen
expressed.22 High levels of high sensitivity-CRP (hs-CRP) antibodies (Figure 1).35
di
levels are shown to correlate with more rapid progression Cross-reactive autoantibodies target intracellular
of mitral stenosis.23 antigens but for disease pathogenesis, the antibodies must
ar
Pharyngeal infection with GAS leads to activation of target the endothelial surface.
innate immune system leading to antigen presentation to
C
B and T cells (Figure 1). CD4+ T cells are activated, and B Cellular Immune Response in Rheumatic
cells produce specific immunoglobulin G (IgG) and IgM Heart Disease
antibodies.24
The characteristic histological finding in myocardium and
endocardium of a rheumatic heart is the granulomatous
Molecular Mimicry ‘Aschoff body’ made up of T-cells, B-cells, macrophages,
‘Molecular mimicry’ is a process by which immune large mononuclear cells and neutrophils (Figure 1).
tolerance is breached through immune stimulation by Rheumatic mitral valve predominantly contains CD4+
foreign antigens, which then results in immune activity T-cells, macrophages, and IL-17 and IL-23 producing
against structurally similar self-antigens. In fact, ARF/ cells. 36 Further, the presence of cross-reactive and
RHD is regarded as the best example of molecular mimicry autoreactive T-cells against GAS M-protein and cardiac
in human pathological autoimmunity. Antibodies to proteins such as myosin, human light meromyosin,
the GAS antigens, alpha helical coiled coil structures tropomyosin, and the valvular protein laminin strongly
in streptococcal ‘M protein’ and group A carbohydrate support cellular pathogenicity in ongoing RHD.
47
KG-8.indd 47 02-11-2018 13:48:30

SECTION
2
a
di
In
of
ty
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20 o S
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Figure 1: Pathogenesis of rheumatic fever. 1. GAS pharyngitis leads to antigenic presentation of pathogenic peptides to T-cells. 2. In
immunologically susceptible individuals, the innate and adaptive (both humoral and cellular) immune responses gets activated leading to
the development of cross-reactive antibodies and cross-reactive T-cells which incites immune response in the joints, heart, skin, and brain
leading to different manifestations of ARF. 3. In the heart, valve damage is initiated by ‘endothelial activation’ by cross-reactive antibodies
which trigger increased expression of vascular cell adhesion molecule-1 (VCAM-1). This facilitates T-cell infiltration leading to cytokine-
mediated immune damage. Exposure of Type-IV collagen can lead to production of collagen-specific antibodies which can cause further
damage. 4. In the brain, autoantibodies can target dopamine receptors and lysoganglioside leading to increased release of dopamine by the
neurons thereby causing rheumatic chorea
Abbreviations: ARF, acute rheumatic fever; GAS, group A Streptococcus; IL, interleukin; IFN, interferon; NABG, N-acetyl-β-d-glucosamine; PARF,
peptide associated with rheumatic fever; TNF, tumor necrosis factor; VCAM-1, vascular cell adhesion molecule-1
Many researchers have suggested a ‘two-hit hypothesis’ antibody allowing M protein-specific T cells to enter the
operating in the damage to the valve. 34,37,38 The valve valve and produce disease. Valve inflammation leads
48 endothelium becomes activated by group A carbohydrate to edema, cellular infiltration, neovascularization of
KG-8.indd 48 02-11-2018 13:48:31

the previously avascular valve, fibrinous vegetations through an octapeptide motif in M protein called ‘PARF CHAPTER
especially in the rough zone of anterior mitral leaflet, and (peptide associated with rheumatic fever)’ inciting an
chordal elongation eventually leading to scarring of valves
with repeated attacks of ARF.
anticollagen antibody response (Figure 1).
There are multiple evidences supporting the collagen
8
autoimmunity hypothesis. Several surface components
Epitope Spreading of GAS strains, such as M type 3 and 18, were suggested
to form a complex with human collagen type IV in
An ‘epitope’ is the part of an antigen molecule to which an
subendothelial basement membranes through PARF
antibody attaches itself. Reactivity is induced to epitopes
which binds to CB3 region of type IV collagen with high
that are distinct from the original disease-inducing
affinity.45 Mice immunized with M proteins containing
epitope, with the result that these epitopes now become
PARF develop non-cross-reactive anticollagen antibodies.
a
the target of the immune response leading to recognition
Sera from Indian patients with ARF have elevated
of several self-antigens after the initial response.
di
anticollagen antibodies.46 Previous description of collagen
In RHD, repeated GAS pharyngitis due to rheu-
autoimmune diseases, such as Goodpasture syndrome
matogenic strains containing cardiac myosin-like
In
and Alport syndrome, exists which acts through similar
sequences in the M protein may be crucial in mimicry and
mechanisms. Antibodies against collagen, however, do not
breaching immunological tolerance, inducing epitope
induce valvulitis in animal models. Therefore, molecular
spreading and initiating disease in susceptible patients.39
of
mimicry is still regarded as the probable mechanism
leading to induction of autoimmunity and initiation of
Pathogenesis of Noncardiac Manifestations in valve damage.
Acute Rheumatic Fever
ty
Disease pathogenesis in Sydenham’s chorea is antibody CONTROVERSIES IN PATHOGENESIS OF
18 cie
mediated and molecular mimicry has been demonstrated
between group A carbohydrate epitope, NABG and
several antigens found in basal ganglia of the brain such
ACUTE RHEUMATIC FEVER/RHEUMATIC
HEART DISEASE
as Dopamine receptors D1 and D2, 40 lysoganglioside,32 In spite of multiple available evidences, several questions
20 o
and tubulin. 41 Binding of cross-reactive antibodies to remain unanswered with regard to the pathogenesis of
S
these receptors lead to activation of calcium/calmodulin- ARF/RHD.

dependent protein kinase II (CAMK2) which in turn
Why Only the Valves Get Scarred?
al
increases tyrosine hydroxylase and release of excess

dopamine resulting in chorea and neuropsychiatric One of the unsolved mysteries of ARF/RHD is why the
symptoms of ARF (Figure 1).40,42
ic
disease has a propensity to scar only the cardiac valves

Arthritis in ARF may be due to the deposition of with all other involved tissues healing without residual
og
immune complexes in synovium and collagen in joints damage. The possible explanations are:
leading to inflammatory cell recruitment. Erythema Endothelial heterogeneity: The endothelium lining the
marginatum may be due to antibodies against group cardiac valves differs considerably in their behavior
ol
A carbohydrate which cross-react with ‘keratin’ and compared to endothelium in other parts of the
subcutaneous nodules may be a delayed hypersensitivity circulatory system. In fact, even within a valve, cells at
di
against GAS antigens (Figure 1).43 different parts show heterogeneity.47

Healing ability: The endothelium in other affected areas
Collagen Autoimmunity Hypothesis:

ar
(joints, basal ganglia and skin) exhibits an immense

Emerging Concept capacity to heal quickly. But ‘the unique anatomy’ of
C
The molecular mimicry hypothesis fails to deliver a single the valve—an avascular structure with a small core
common mechanism explaining the multisystem nature of of connective tissue covered by endothelium on both
ARF. Also, how specific damage to cardiac valvular tissue sides without any muscle tissue—explains the residual
occurs and why myocardium is spared is unexplained damage which occurs selectively in a rheumatic valve.
by this theory. Further, involvement of several cross- ‘A vicious inflammatory cycle’ ensues due to the
reactive antibodies and multiple streptococcal antigens abundant expression of adhesion molecules, such as
in the pathogenesis indicates a gross failure of a highly VCAM-1 and P-selectin, on the surface of a rheumatic
evolved human immune system which is unlikely. So, valve and involvement of connective tissue leading
an alternative hypothesis44 without molecular mimicry to neovascularization and healing with progressive
has been proposed which gives some insights to some scarring.48
unanswered questions. It involves direct interaction Inflammation in multiple systems, such as joints, skin,
of streptococcal M protein with CB3 region of type IV and brain including the valves, eventually heals completely
collagen in the subendothelial extracellular matrix (ECM) in ARF, but the valves become permanently dysfunctional
49
KG-8.indd 49 02-11-2018 13:48:31

SECTION due to scarring. Even though ARF is characterized by mitral regurgitation (MR) or mixed mitral valve disease,
involvement of all three layers of the heart, valvular lesions is not understood clearly. It is proposed that all patients
2 most likely lead to chronic disease and heart failure. start with MR of variable severity depending upon the
severity of carditis. Those with severe MR most likely
Why Left-sided Heart Valves are more remain with this lesion or may develop associated MS due
to commissural fusion, leaflet thickening, and subvalvular
Commonly involved in Rheumatic Heart
disease. Whereas development of pure MS may be due
Disease?
to recurrent carditis of milder degree, a slower evolution
Histopathology of heart valves in patients dying of ARF of the disease or greater predisposition for commissural
indicates that microscopic involvement of tricuspid and fusion.53
pulmonary valves occurs in 100% cases.49 But, clinically
a
mitral valve involvement is the most common followed by
RECENT CONFLICTING EVIDENCES IN
aortic valve. Tricuspid valve involvement is less frequent
di
and pulmonary valve involvement is rare. The probable
RHEUMATIC HEART DISEASE PATHOGENESIS
explanation to this is that equivalent damage occurs in New genetic and epidemiological data support skin
In
all the valves with improved healing in the lower pressure infection as the trigger for ARF. 54,55 In Australian
system of the right compared with the left. aboriginal communities, where incidences of ARF
and RHD are amongst the highest in the world,
of
GAS throat colonization and symptomatic GAS
Does Myocardial Damage Occur in Acute
pharyngitis are rare.56 Instead, pyoderma is the most
Rheumatic Fever? common manifestation of GAS. Further, group C and
ty
Multiple clinical, echocardiographic and pathological G streptococci were more commonly isolated from
studies have found that myocardial damage does not the pharynx and they seem to exchange key virulence
occur in ARF. 18 cie
Endomyocardial biopsy in ARF hardly shows any
determinants with GAS. These evidences suggest that
GAS pyoderma or non-GAS infections may be involved
myocardial necrosis thereby not satisfying the ‘Dallas in the pathogenesis of ARF and the epidemiology of
20 o
criteria’ for the definition of myocarditis. Instead, ARF appears to vary from region to region.57
Aschoff nodules were found in up to 40% of cases.50
S
Though there is enough evidence that demonstrate

Even in patients with cardiac failure, myocardial cross-reactive antibodies and T cells involved in
damage does not occur. Instead, the pathology suggests pathogenesis, it does not confirm that ‘molecular
al
an ‘interstitial carditis’ picture.51 mimicry’ is the ‘triggering event’ in RHD. Humoral

Markers of myocardial damage, such as creatinine
and cellular autoreactivity in RHD could just be an
ic
kinase and troponins, does not seem to elevate ‘epiphenomenon’.57

significantly in cases of ARF even in patients with Evidence of active viral coinfections, such as coxsackie
og
dilated heart or cardiac failure.46 B, was found in ARF and has been suggested as an
Cardiac failure resolves completely after surgical mitral immunological trigger for RHD.
valve replacement suggesting that it was due to acute
ol
volume overload secondary to MR and not due to KNOWING THE PATHOGENESIS OF RHD: HOW
myocarditis.52
DOES IT HELP IN TACKLING THE DISEASE?
di
Even though rheumatic carditis was classically

described as ‘pancarditis’ involving all three layers of
The World Heart Federation (WHF) aims to decrease
ar
the heart—the endocardium, the myocardium and the RHD deaths in patients below 25 years by 25% by 2025.
pericardium, the term ‘myocarditis’ does not appear to be An improved understanding of the disease might help
C
an apt description. in directing the resources effectively.

Effective methods for primary prevention or specific
medical therapy can be made available.
EVOLUTION INTO CHRONIC RHEUMATIC Identifying various characteristics of ‘rheumatogenic’
HEART DISEASE versus ‘nonrheumatogenic’ GAS strains by bacterial
Most of the valvular lesions reduce in severity as the acute genome-wide association studies facilitates the
illness resolves, but it can be perpetuated by repeated production of an effective vaccine to induce a protective
attacks of ARF and by hemodynamic factors leading to mucosal or systemic immune response.
chronic RHD. In addition to this, the magnitude of host Knowledge about molecular pathogenesis opens
immune response and the severity of the first episode new possibilities for immunotherapy such as T-cell
of carditis also determine whether the valve remains vaccination.
permanently damaged. Why some patients develop Identification of predisposing or protective genetic
predominant mitral stenosis (MS) and some develop pure variations for RHD by large genome-wide human
50
KG-8.indd 50 02-11-2018 13:48:31

studies will help in guiding prospective pathogenesis 14. Bryant PA, Robins-Browne R, Carapetis JR, et al . Some CHAPTER
studies. of the people, some of the time: susceptibility to acute
Treatment can be targeted to prevent a coinfection. rheumatic fever. Circulation. 2009;119(5):742−53.
15. Ayoub EM, Barrett DJ, Maclaren NK, et a l. Association of
8
class II human histocompatibility leukocyte antigens with
CONCLUSION rheumatic fever. J Clin Invest. 1986;77(6):2019–26.
The ARF and RHD are established as a disease of ‘microbial- 16. Khanna AK, Buskirk DR, Williams RC, et al. Presence of a
induced autoimmunity’. Though the existing hypothesis of non-HLA B cell antigen in rheumatic fever patients and
‘molecular mimicry’ is established to play the key role in their families as defined by a monoclonal antibody. J Clin
pathogenesis, the exact trigger for the disease is unknown Invest. 1989;83(5):1710–6.
17. Gray LA, D’Antoine HA, Tong SYC, et al. Genome-wide
and needs to be clarified by additional research. Large
analysis of genetic risk factors for rheumatic heart disease
a
genome-wide association studies, prospective studies of
in Aboriginal Australians provides support for pathogenic
bacteriological surveillance in high-risk group, and studies
di
molecular mimicry. J Infect Dis. 2017;216(11):1460–70.
involving molecular typing methods and DNA microarray 18. Parks T, Mirabel MM, Kado J, et al. Association between
are needed to unravel the immunopathogenesis of RHD. a common immunoglobulin heavy chain allele and
In
rheumatic heart disease risk in Oceania. Nat Commun.
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9. Bessen D, Jones KF, Fischetti VA. Evidence for two distinct lesions of rheumatic heart disease patients. Int Immunol.
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Protein: Structure, function and immunology. In: Narula J, experimental autoimmune valvulitis. J Cardiovasc Transl
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autoantibody-mediated neuronal cell signaling in
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Sydenham chorea. Nat Med. 2003;9(7):914-20. the CB3-region of collagen IV in PARF-induced acute
33. Scalzi V, Hadi HA, Alessandri C, et al. Antiendothelial cell rheumatic fever. PLoS One. 2009;4(3):e4666.
antibodies in rheumatic heart disease. Clin Exp Immunol. 46. Gupta M, Lent RW, Kaplan EL, et al. Serum cardiac troponinI
2010;161(3):570–5. in acute rheumatic fever. Am J Cardiol. 2002;89(6):779–82.
34. Roberts S, Kosanke S, Terrence Dunn S, et al. Pathogenic 47. Butcher JT, Simmons CA, Warnock JN. Mechanobiology of
mechanisms in rheumatic carditis: focus on valevnudloatrh the aortic heart valve. J Heart Valve Dis. 2008;17(1):62–73.
elium. J Infect Dis. 2001;183:507–11. 48. Gulizia JM, McManus BM. Immunopathologic studies of
35. Martins TB, Hoffman JL, Augustine NH, et al. Comprehensive rheumatic fever. In: Narula J, Virmani R, Reddy KS, Tandon
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analysis of antibody responses to streptococcal and R, (ed). Rheumatic fever. Washington DC: Amer Reg Path
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tissue antigens in patients with acute rheumatic fever. Int AFIP. 1999. pp. 235–44.
Immunol. 2008;20(3):445–52. 49. Gross L, Friedberg CK. Lesions of the cardiac valves in
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of mononuclear cells and T cell subsets in rheumatic 50. Narula J, Chopra P, Talwar KK, et al. Does endomyocardial
valvulitis. Clin Immunol Immunopathol. 1989;52(2):225– biopsy aid in the diagnosis of active rheumatic carditis?
37. Circulation. 1993;88(5 Pt 1):2198-205.
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37. Ellis NMJ, Li Y, Hildebrand W, et al. T cell mimicry and 51. Narula J, Narula N, Southern JF, et al. Endomyocardial
epitope specificity of cross-reactive T cell clones from biopsy in rheumatic carditis. In: Narula J, Virmani R, Reddy
rheumatic heart disease. J Immunol. 2005;175(8):5448–56. KS, Tandon R, ed. Rheumatic fever. Washington DC: Amer
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38. Faé KC, da Silva DD, Oshiro SE, et al. Mimicry in recognition Reg Path AFIP. 1999. pp. 319–28.
of cardiac myosin peptides by heartintralesional T 52. Kinsley RH, Girdwood RW, Milner S. Surgical treatment
2006;176(9):5662–70.
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cell clones from rheumatic heart disease. J Immunol.
39. Guilherme L, Faé K, Oshiro SE, et al. Molecular pathogenesis

during the acute phase of rheumatic carditis. In: Nyhus
LM, editor. Surgery Annual Vol 13. New York: Appleton-
Century-Crofts. 1981;13:299–323.
of rheumatic fever and rheumatic heart disease. Expert Rev 53. Essop MR, Peters F. Contemporary issues in rheumatic
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Mol Immunol. 2005;7(28):1–15. fever and chronic rheumatic heart disease. Circulation.
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40. Cox CJ, Sharma M, Leckman JF, et al. Brain human 2014;130(24):2181–8.
monoclonal autoantibody f rom Sydenham chorea targ 54. Williamson DA, Smeesters PR, Steer AC, et al. M-protein
ets dopaminergi c neurons in transgenic mice and signals analysis of Streptococcus pyogenes isolates associated with
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dopamine D2 receptor: implications in human disease. J acute rheumatic fever in New Zealand. J Clin Microbiol.
Immunol. 2013;191(11):5524–41. 2015;53(11):3618−20.
ic
41. Kirvan CA, Cox CJ, Swedo SE, et al. Tubulin is a neuronal 55. Parks T, Smeesters PR, Steer AC. Streptococcal skin
target of autoantibodies in Sydenham’s chorea. J Immunol. infection and rheumatic heart disease. Curr Opin Infect
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2007;178(11):7412–21. Dis. 2012;25(2):145−53.

42. Kirvan CA, Swedo SE, Kurahara D, et al. Streptococcal 56. McDonald MI, Towers RJ, Andrews RM,et al. Low rates of
mimicry and antibody-mediated cell signaling in the streptococcal pharyngitis and high rates of pyoderma in
ol
pathogenesis of Sydenham’s chorea. Autoimmunity. Australian aboriginal communities where acute rheumatic
2006;39(1):21–9. fever is hyperendemic. Clin Infect Dis. 2006;43(6):683–9.
di
43. Carapetis JR, Beaton A, Cunningham MW,et al. Acute 57. McDonald M, Currie BJ, Carapetis JR. Acute rheumatic
rheumatic fever and rheumatic heart disease. Nat Rev Dis fever: a chink in the chain that links the heart to the throat?
Primers. 2016;2:15084. Lancet Infect Dis. 2004;4(4):240–5.
ar
C
52
KG-8.indd 52 02-11-2018 13:48:31

CHAPTER 9
Decline of Rheumatic Heart
Disease: Is it Real?
a
di
INTRODUCTION METHODS OF DETECTION
Rheumatic fever (RF)/rheumatic heart disease (RHD) is The detection of RF/RHD in the population is challenging.
In
the result of autoimmune response triggered by group The RF/RHD are detected based on symptoms, audible
A beta-hemolytic streptococcal pharyngitis leading to murmurs, and echocardiography evidence of structural
of
immune-inflammatory injury to cardiac valves. The and functional abnormalities of the affected valves. The
inflammatory injury of pericardium and myocardium is ability to detect murmurs, differentiating functional
transient and self-limiting without leaving any squeal. from pathological murmurs depends upon clinical skills
ty
The valvular injury is the main cause of acute and long- of the physician, settings of auscultation, etc. Thus,
term morbidity and mortality in patients with acute RF auscultation-based methods of screening RF/RHD has its
18 cie
and RHD, respectively.1,2 The risk of RF/RHD is primarily
determined by the host, agent, and environmental factors.3
The RF/RHD is considered to be a physical manifestation
limited sensitivity and specificity. The morphological and
Doppler-based detection of RHD in echocardiography
study has high sensitivity and specificity in detection
of poverty. The distribution of the burden of RF/RHD being more objective and subject to validation. The
20 o
mirrors the distribution of human development index in echocardiography detects RHD in patients without being
S
given geographical region, state, nation, and globally. The clinically evident called subclinical RHD. The prevalence
socioeconomic state, access, and quality of healthcare of subclinical RHD is about 7 to 10 times higher than
services are important determinants of the burden of
al
clinically evident RHD. However, the clinical significance

RF/RHD. The incidence of RF/RHD has practically of subclinical RHD needs to be validated in future long-
disappeared in developing countries. 4 However, RF/
ic
term follow-up studies.

RHD continues to be a major cause of disease burden The severity and nature of valvular dysfunction in RHD
among children, adolescents, and young adults in low-
og
is variable from patient to patient. The hemodynamically

income countries and even in high-income countries with insignificant valvular dysfunctions may be asymptomatic,
socioeconomic inequalities. The burden of RF/RHD is may not be evident on clinical examination thus escapes
ol
likely to be variable between countries, within the country, detection. Thus, the variable prevalence of RHD reported
within states depending upon the socioeconomic status, may be partly related to differences in the methodology
and state of health systems.5-8 The major determinant of the
di
adopted for screening.

persistent burden of RF/RHD in developing countries are
ar
due to poor standards of living conditions, overcrowding,

DATA SOURCES FOR ESTIMATION
lack of strong population-based surveillance system for
pharyngitis, RF and RHD for effective implementation of OF BURDEN OF RF/RHD
C
primary and secondary preventive interventions. 9 The Hospital admission data, hospital- and population-based
Indian Council of Medical Research (ICMR) initiated registry data, and population-based active surveillance
community control and prevention of RF/RHD through studies are databases that could be used to estimate the
hospital-based passive surveillance and implementation burden and their trends in a population. The hospital
of secondary prophylaxis under Jai Vigyan mission admission and hospital-based registries data may provide
mode project from 2000 to 2010.10 There is no structured a rough estimation of the burden of clinically symptomatic
program at a national level for prevention and control patients from the population that is served by the hospital.
of RF/RHD. However, changing socioeconomic state, In hospital admission data, the relative proportion of RF/
improved living conditions, and improving connectivity RHD is subject to vary with changes in the incidence of
and access to health care centers after adopting a policy other diseases and admission policy followed by a given
of economic liberalization and globalization since 2000 is hospital, thus affecting the reliable estimate of the trends
expected to have translated into a decline in the burden of of the burden of RF/RHD. Population-based registry
RF/RHD in India. data provide more reliable estimates of burden and
KG-9.indd 53 02-11-2018 13:48:11

SECTION their trends of symptomatic patients. The prospective derived from hospital statistics if the data is derived from
active surveillance of the population is the only method the same hospital over a different time period. But data of
2 to determine the burden of any given disease and their
trends. In India, there are no hospital- and population-
this kind is scaring. A study from territory care center in
Odisha showed no change in admission rate over a decade
based registries or systematically done periodic active and still there was admission rate of 50% in 2013.19
surveillance studies on the country representative sample
to estimate the burden and trends of RF/RHD. The data Population-based Survey Studies
available are individual investigator-led survey studies
Data from population-based surveys (Table 2) are likely
done mostly in school children of urban and some rural
to give us reliable estimates of the prevalence of RF/RHD.
areas. The registry studies and population-based survey
There is no data available about the prevalence of RF/RHD
studies reveal the prevalence of RHD peaks around 30–40
a
based on active surveillance studies in a representative
years or so. Thus, the prevalence reported in school age
sample of the country or the state. The available data are
di
group may be an underestimation of disease burden.
based on estimation done in cities or rural areas of certain
regions of the states in different points of time using
In
EPIDEMIOLOGICAL TRENDS OF BURDEN either clinical screening method alone or confirmed by
OF RHD IN INDIA echocardiography. The prevalence of RF/RHD reported
The burden of RF/RHD has been estimated and from cities of Agra, Chandigarh and Delhi based on
of
reported since 1960s from hospital-based data (Table clinical examination alone in the late 1960s and the early
1), population-based [(Table 2) and school-based 1970s ranged from 1.8 /1000 to 4.58/1000.20-24
(Table 3) survey studies using different case definition,
ty
and screening methods. There are no survey studies School-based Surveys
estimating the burden of RF/RHD based on national and
18 cie
state representative samples using uniform screening
method at different timeline to evaluate the trends of the
Survey studies with clinical screening method (period 60s
to 90s ): The estimation of prevalence of RF/RHD among
burden of RF/RHD in India. school children done in the period from 70s till 90s was
20 o
based on clinical screening method alone (Table 3A).
Thus, reported figures of prevalence have the limitation
S
Hospital Admission Data

of sensitivity and specificity of the cases reported. The
Hospital admission data (Table 1) shows a decline in reported prevalence from different regions of the country
al
admission rates of RF/RHD overtime period. The RF/RHD in urban and rural school children varied from 1 to 11 per
accounted for 30–50% of total admissions till the early 80s 1000.25-32
and it declined to 5–26% in the late 1990s.11-19 Whether
ic
the declining trends in admission rate truly reflects the Survey studies with clinical screening confirmed by
e c h o c a rd i o g ra p h y ( p e r i o d 1 9 9 0 s t o 2 0 0 0 ) : T h e
og
decreasing incidence is much to be debated. Inadequacy

of hospital statistics, varied hospital admission policies, epidemiological studies with clinical screening followed
and a large number of corporate hospitals coming up by confirmation of suspected cases with echocardiography
ol
can cause significant bias in hospital-based data. The using Doppler-based WHO criteria in urban and rural
emergence of an epidemic of CAD and lack of interest school children in different regions of the country from
di
among cardiologists in RHD has further compounded the early 1990s to the early 2000s reported prevalence
the problem. The only useful forgone conclusion can be ranging from 1.3/1000 to 6.4/1000 (Table 3B). The
ar
reported variation in the prevalence of RF/RHD may be an

C
Table 1: Hospital-based RHD studies done in India

Author Study area Year Percentage
11
Kutumbiah Madras 1941 39.5%
Sanjeevi 12 Bombay 1946 46.8%
Vakil 13 Bombay 1954 24.7%
Padamavati14 Delhi 1958 39.1%
15
Devichand Shimla 1959 50.6%
16
Mathur Agra 1960 35.1%
Malhotra17 Punjab 1963 27.6%
18
Banerjea Calcutta 1965 44.6%
Routray19 Orissa 2003 45%
[Madras (Chennai); Bombay (Mumbai); Calcutta (Kolkata)]
54
KG-9.indd 54 02-11-2018 13:48:12

Table 2: Population-based RHD surveys in India (clinical screening) CHAPTER
9
Author Age group Number Study area Year of survey Prevalence per 1000
20
Roy 5–30 4847 Ballabhgarh 1969 2.2
Mathur21 5–30 7953 Agra 1971 1.8

22
Berry 5–30 19768 Chandigarh 1972 1.87
23
Grover et al. 5–15 31200 Rural area of Ambala, Haryana 1988–91 0.9
Lalchandani et al.24 7–15 3963 Rural area of Kanpur 2000 4.58
Table 3: School surveys on prevalence of rheumatic heart disease
a
Author Period Area Population Age group Prevalence
di
(A) Clinical screening only:
ICMR25 1972–75 Agra, Alleppy, Delhi, Hyderabad 133000 – 6–11
In
Koshi et al.26 1975–78 Vellore 3890 4–16 4.4
27
ICMR 1982–90 Delhi 13509 5–15 2.9
28
ICMR 1984–87 Delhi, Varanasi, Vellore 52793 – 1.0–5.7
of
Patel et al.29 1986 Anand 11346 8–18 2.03
30
Avasthi 1987 Ludhiana 6005 6–16 1.3
ty
Padamavati31 1984–94 Delhi 40000 5–10 3.9
32
Kumar et al. 1992 Churu 10168 5–15 3.34
Agarwal et al. 34
1988–9123
1991
18 cie
(B) Clinical screening followed by echocardiographic confirmation:
Grover et al.23 Ambala
Aligarh
31200
3760
5–15
5–15
2.1
6.4
20 o
Gupta et al.35 199235 Jammu 10263 6–16 1.3
36
Thakur et al. 1992–93 Shimla 10805 5–16 2.98
S
37
Vashistha et al. 1993 Agra 8449 5–15 1.42
Kaul et al.39 1999–2000 Srinagar 4125 5–15 5.09
al
38
Jose et al. 2001–02 Vellore 229829 6–18 0.68
ICMR10 2002–05 Kochi, Vellore, Chandigarh, Indore, Shimla, 100269 5–15 0.43–1.47
ic
Dibrugarh, Waynard, Jodhpur, Jammu, Mumbai

Misra et al.40 2003–06 Gorakhpur 118212 4–18 0.5
og
41
Periwal et al. 2006 Bikaner 3292 5–14 0.67
42
Negi et al. 2007–08 Shimla 15145 5–15 0.59
ol
Rama et al.33 2011 Prakasam AP 4213 5–16 0.7

(C) Echocardiographic screening:
di
Bhaya et al.43 2007–09 Bikaner 1059 6–15 51

44
Saxena et al. 2008–10 Ballabgarh 6270 5–15 20.4
ar
33
Rama et al. 2011 Prakasam AP 4213 5–16 7.6
Thangjam et al.45 2011–13 Manipur 3015 5–15 4
C
Ana Karina et 2011–13 Goa 2023 5–15 16

al.46
Nair et al.47 2013–14 Trivandrum 2006 5–15 5.83
indication of a varied burden of RF/RHD across different consistent decline in the burden to less than 1/1000 across
regions, urban and rural areas, and/or temporal trends the country compared to figures reported from survey
apart from methodological related factors.23,33-38 studies before 2000 (Figure 3). The survey study done by
Survey studies with clinical screening confirmed by our group in urban and rural school children of Shimla
echocardiography after 2000: The survey studies in school in the early 90s and mid-2000, using similar screening
children done after 200010,33,39-42 using similar screening methods in the same geographical region, demonstrated
methods that were followed in the 90s to 2000 revealed about a five-fold decline in the prevalence of RF/RHD.42
55
KG-9.indd 55 02-11-2018 13:48:12

SECTION This decline was associated with improvement in the
indicators of socioeconomic state and health care services.
2 Echo-based screening studies in school children after
2000: The auscultation-based screening method has low
sensitivity and specificity. The patients with RF/RHD with

the mild valvular damage that may be asymptomatic and
without an apparent murmur on auscultation thus could
be missed on clinical screening. The ability to detect subtle
signs of valvular dysfunction also would depend upon
clinical skills of the investigator. Thus, the auscultation-
a
based detection of RHD has limited sensitivity for
detection of children with minimal valvular dysfunction.
di
The echo-based survey studies 33,43-47 using evidence- Figure 1: Trends of change in GDP of India from financial year
based echocardiography criteria among school children 91 to 2015
In
in different parts of the country and other developing Abbreviation: GDP, gross domestic product
countries have reported the prevalence of subclinical RHD Source: Handbook of Statistics on the Indian Economy,
Reserve Bank of India
many folds higher than clinically evident RHD (Table 3C).
of
The clinical significance of subclinical RHD needs to be
established in appropriately designed large future studies
in terms of probability of their progression and the efficacy
ty
of secondary prophylaxis on the progression of valvular
dysfunction.
18 cie
DECLINE OF RHEUMATIC HEART DISEASE:
IS IT REAL?
20 o
Systematic review of available data on epidemiological
S
studies of RF/RHD conducted in different points of time

using clinical screening followed by echocardiography
al
confirmation as the methods of detection of RF/RHD,

across the country by individual authors and ICMR lead
Figure 2: Trends of changes in prevalence of RF/RHD from
ic
multicentric survey studies suggest declining trends

early 1990s to late 2000 using clinical screening confirmed with
especially after 2000 onwards (Figures 1 to 3). The two-
echocardiography
og
point survey study done over a gap of about 15 years

among school children of an urban and rural area of
Shimla by our group using similar screening methods also
ol
demonstrated five-fold decline in the prevalence of RF/

RHD.42 The reasons for the declining trends could be the
di
improvement in the socioeconomic state of our country

(Figure 1), access and affordability of healthcare services,
ar
and change in health-seeking behavior of the community

leading to timely treatment of acute pharyngitis could be
some of the important factors responsible for declining
C
incidence of RF/RHD.
It is important to recognize that India is witnessing
transitions in socioeconomic and health care sector and
also there is a rapid urbanization. However, there are wide
disparities in socioeconomic state and quality and access
to healthcare services across the states, within state and
urban and rural areas. Since RF/RHD is believed to be a
physical manifestation of poverty, the burden of RF/RHD
is likely to be variable across the state. Unfortunately, no
temporal data is available from states with poor health Figure 3: Trends of change in prevalence of RF/RHD in ICMR-led
indicators to get insights about the disease trends. multicentric survey studies across country over a period of 40 years
56
KG-9.indd 56 02-11-2018 13:48:13

ESTIMATED BURDEN OF DISEASE primary health care services for detection of children with CHAPTER
streptococcal pharyngitis, opportunistic screening for RF/
9
From available data from RHD studies, the estimated
average prevalence is 0.5/1000 children in the age group RHD, and implementing evidence-based primary and
of 5-15 years. There are expected to be more than 3.6 secondary preventive interventions. Establishing strong

million patients of RHD estimated from 2011 Census. 48 population-based registry centers for surveillance for
Almost 44,000 patients are added every year and expected monitoring trends, management practices, and outcomes
mortality of 1.5-3.3% per year. These figures still may be that are important to evaluate the impact of primary
the underestimation of disease as no data is available preventive intervention implemented at community
from large populous, underdeveloped states such as Bihar, and health system level are required. The community-
Jharkhand, etc. level interventions through existing community health
a
volunteers (ASHAs) would play an important role in
Limitations of all available data on trends of the burden
di
primordial and primary prevention through community
of RF/RHD in India: The prospective active surveillance
data of country and/or state representative sample is health literacy initiatives as shown by Cuban experience.50
In
lacking to evaluate the trends of prevalence and incidence There is a need for allocating more funds in the health
of RF/RHD in our country. There is lack of studies from sector in prevention and control programs rather than
most of the underdeveloped states of India, where the in curative healthcare services, if we aim to decrease
of
prevalence of the disease is likely to be high. The available the disease burden and promote public health in a cost-
reports on the prevalence of RF/RHD also are limited by effective manner in India.
methodological strength and statistical rigors, variable The RHD has been forgotten by Western developed
ty
methods of screening, nonuniform diagnostic criteria, countries and there is a clear-cut decline in new research
-the variable competence of survey teams to detect in the West. We need to invest in new research to fulfill
18 cie
cases, different referral criteria for echocardiographic
screening, and varied echocardiographic criteria used.
the gaps of understanding of the disease. Making RHD
a notifiable disease like in New Zealand, Australia, and
The participation rate of eligible population, urban-rural South Africa and starting a national program can fill the
20 o
population, etc. is not reported in a number of studies. gaps of implementation in care of RF/RHD.51 Availability
S
Thus, reported figures of a burden of RF/RHD trends need of penicillin is a burning issue in most of the states
to be viewed in this context. Though results of studies over in India. Healthcare personnel involved in providing
al
the time period are showing declining trends of RHD, they injections must be educated about skin testing, proper
cannot be extrapolated to the whole of the country. technique, and allergic reactions thus improving the
ic
secondary prophylaxis rates, which can lead to control of

CHALLENGES AND OPPORTUNITIES FOR RHD by preventing reoccurrences.52
og
PREVENTION AND CONTROL OF RHEUMATIC As we can nar row dow n and fill the gaps of
FEVER/RHEUMATIC HEART DISEASE understanding of disease with new research and carry
out better implementation in health care delivery, we are
ol
The RF/RHD continues to be an important cause of

heading in the right direction to control or even think of
disease burden in India affecting the population in their
di
eradicating the disease.

prime and productive phase of the life. India is a young
country having 65% of the population younger than 35
ar
years of age. Since RF/RHD affects predominately affects CONCLUSION

the younger population, their impact on productivity of The RF/RHD is the disease of poverty. India having
C
the country is pronounced. Thus, it is imperative that the more than 1.3 billion population with wide social and
country must invest in prevention and control of RF/RHD. economic disparities, RF/RHD will continue to be a major
The health professionals have an important advocacy public health problem. Although data on incidence and
role to play to influence policy makers for initiating policy prevalence on a nationally represented sample is lacking,
interventions for prevention and control of RF/RHD. The there is an indication of declining trends, especially after
RF/RHD is a preventable cause of disease burden. The 2000 mirroring with improving economic growth of the
most effective intervention for prevention of RF/RHD country. There is a need for establishing population-
could be to create enabling environment through policy based surveillance system in the country for monitoring
intervention to promote sanitation, hygiene, better living trends, management practices, and outcomes to formulate
conditions, nutrition, and access to affordable and quality informed guidelines for initiating contextual interventions
healthcare equitably49 and health system strengthening of for the prevention and control of RF/RHD.
57
KG-9.indd 57 02-11-2018 13:48:13

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2
1. Taranta A, Markowitz M. Rheumatic Fever. 2nd edn.
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9. Carapetis JR. Rheumatic heart disease in developing Assoc Physicians India. 1986;34(12):837-9.
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19. Mishra TK, Routray SN, Behera M, Pattnaik UK, Satpathy factors. J Epidemiol Community Health. 1996;50(1):62-7.
C. Has the prevalence of rheumatic fever/rheumatic heart 37. Vashistha VM, Kalra A, Kalra K, et al. Prevalence of
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39. Jose VJ, Gomathi M. Declining prevalence of rheumatic a North-Eastern Indian state (Abstract). Ann Pediatr CHAPTER
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Indian Heart J. 2003;55(2):158-60.
40. Misra M, Mittal M, Singh R, et al. Prevalence of rheumatic
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41. Periwal KL, Gupta BK, Panwar RB, et al. Prevalence 47. Nair B, Vishwanthan S, Koshy AG, et al. Rheumatic heart
of rheumatic heart disease in children of Bikaner: an disease in Kerala: A vanishing entity? An echo Doppler
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2006;54:279-82.
48. Saxena A. Epidemiology of rheumatic heart disease in India
42. Negi PC, Kanwar A, Chauhan R,et al. Epidemiological
and challenges to its prevention and control. J Preventive
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India. Indian J Med Res. 2013;137(6):1121-7.
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49. Niinan S, Edmond K, Krause, et al. The top end rheumatic
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50. Nordet P, Lopez R, Duenas A, et al. Prevention and control
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the RHEUMATIC (Rheumatic Heart Echo Utilisation and 2008;19(3):135-40.
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TH, et al. Prevalence of subclinical RHD detected by fever patients in long-term benzathaine penicillin G:
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echocardiography-Doppler study using WHF 2012 criteria
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20 o S
al
ic
og
ol
di
ar
C
59
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Clinical Assessment of Severity
CHAPTER 10 of Valvular Heart Disease
Ajith Ananthakrishna Pillai, Devendra Kanshilal Sharma,
Balachander Jayaraman
a
di
INTRODUCTION end of 10 years. Most if not all mitral stenosis cases have
C linical diagnosis of hear t dis eas e by physical significant MR (clinical or subclinical) to begin with and
In
over the years, the severity of MR comes down and they
examination and cardiac auscultation still enthrals an
develop progressive commissural fusion culminating in
astute clinical cardiologist despite the widespread usage
significant obstructive lesion. There is striking difference
of
of echocardiography. Physical examination still wields
in the natural history and rate of progression of MS in the
the charm in engaging the physician to diagnose and
tropical countries compared to the western world. In the
differentiate various forms of valve disease. Moreover,
developed countries, it takes more than 5 years for MS to
ty
cardiac auscultation in itself is so much exciting and
develop and it takes another 5 to 10 years to progress to a
thrilling in assessing the severity of individual lesions in
symptomatic status. In tropical countries, the entire latent
multivalve case scenarios.
18 cie
In this manuscript, we attempt to elucidate the clinical
assessment of valve disease. The write up has been made
period between acute rheumatic fever and severe MS can
be shorter than 5 years. Though less frequent in India
now, “Juvenile MS” is a major problem in many African
20 o
keeping in mind the learning objectives of medicine post-
countries.
graduates and cardiology trainees.
S
The pathological hallmark of rheumatic MS is

commissural fusion leading to narrowing of the orifice.
MITRAL STENOSIS Chordal and cuspal fusion can also contribute to the
al
Etiology of mitral stenosis (MS) is nearly always rheumatic. narrowing but seldom exist without commissural fusion.
Less frequent causes include congenital lesions, mitral Normal mitral valve area is 4 to 6 sq.cms in an adult.
ic
annular calcification, connective tissue disorders and Significant diastolic transmitral gradient and an audible
storage disorders. Mitral annular calcification, a disease of murmur develop when the orifice is reduced to less
og
the elderly usually leads to mitral regurgitation and often than 2.5 sq. cms. MV area less than 1 sq. cm per square
co-exists with calcific aortic valve disease and degenerative meter surface area is considered very severe MS and will
involvement of the conduction system. Congenital mitral ordinarily require intervention. MS leads to increase in LA
ol
stenosis and LV inflow obstruction—Parachute mitral pressure and pulmonary venous hypertension. Normal
valve, anomalous mitral arcade, supravalvular mitral ring LA pressure is 8 to 12 mm Hg. In severe cases of MS, LA
di
and cortriatriatum usually present in childhood. pressures will be more than 25 mm Hg. This leads to
Approximately 50% of patients with rheumatic MS passive pulmonary arterial hypertension (PAH).
ar
have a history of acute rheumatic fever in childhood. In PAH in MS is also contributed by reactive pulmonary
the remaining half, it is believed to be secondary to sub- hypertension (precapillary, ‘second stenosis’) and
C
clinical carditis. Carditis is very frequent when rheumatic obliterative PAH (in long standing cases).
fever occurs in children below the age of 5 years and is
unusual with first attack of rheumatic fever occurring later History
in adult life. It is interesting to note that though pancarditis Gradually progressive dyspnea on exertion is the most
is known to occur in acute rheumatic fever, clinically common symptom in MS. As the commissural fusion and
significant myocarditis is unusual. Endocarditis mainly narrowing of the MV orifice gradually develop over a span
manifests as MR in isolation or with AR. Isolated aortic of several years, the symptoms are also usually slowly
valve involvement without MR is uncommon and raises progressive. This reflects pulmonary venous hypertension
doubt about the etiology. MR is contributed by valvulitis, and the increased effort required for the inflation of
chorditis and annulitis. The natural history of MR is the alveoli due to capillary and venous engorgement.
variable. 70% of mild MR tend to disappear on follow up Exertion leads to enhanced venous return, increase in
whereas only around one third of severe MR who presented the cardiac output and reduction of the diastolic filling
with heart failure are likely to have a normal heart at the period. When pulmonary capillary pressure exceeds 25
KG-10.indd 60 02-11-2018 13:48:03

mm Hg, transudation of fluid occur into the interstitium Physical Findings and Assessment of CHAPTER
(interstitial pulmonary edema) and later into the alveoli Severity of MS
(alveolar pulmonary edema). Paroxysmal nocturnal
dyspnea (PND) is a very important symptom and usually General Appearance
10

is indicative of severe disease. Though not included in In cases of severe MS, especially with major PAH, “mitral
the NYHA classification, most of the patients with PND facies” may be observed, i.e. a patchy, pinkish purple
will have marked restriction of ordinary activity and appearance of the cheeks resulting from dilated venules.
come under NYHA class III. Orthopnea indicates severe Such subjects often manifest peripheral cyanosis as well.
and advanced disease. Hemoptysis in MS can be due to
multiple factors—rupture of bronchopulmonary veins Jugular Venous Pulse
due to pulmonary venous hypertension (pulmonary
a
JVP is normal in MS unless there is associated AF, PAH or
apoplexy), pulmonary edema (including the pink frothy
RV failure.
di
sputum classically described with PND), lower respiratory
tract infection and pulmonary infarction (in long-standing
Arterial Pulses
In
cases usually with AF).
Atrial fibrillation is a common arrhythmia in patients The arterial pulse in MS has a normal or decreased pulse
with severe MS. It is related not only to the severity of MS volume and a normal contour.
of
but also to the age of the individual and the initial age
of rheumatic fever and the number of recurrences and Cardiac Examination
the severity and extent of carditis during the previous
Precordium: Cardiomegaly is not a feature of isolated MS.
ty
episodes. AF is uncommon in juvenile MS even when it is
It can occur with pulmonary hypertension, RV systolic
severe but is common in elderly with milder degree of MS.
dysfunction and TR. The apex beat may be sometimes
18 cie
Majority of MS patients above the age of 50 years are in
AF (almost 80%) and this predisposes to thromboembolic
episodes. 80% of patients with MS who develop stroke are
displaced laterally in some post op cases (post-closed
mitral valvotomy with left anterolateral thoracotomy).
Palpable S1 is felt inside or at site of LV apex beat. An
in AF. Development of AF leads to significant deterioration
20 o
increased P2 and less commonly, a pulmonary artery lift
of the functional class in MS patients due to increase in
S
may be felt at the 2nd to 3rd left ICS. The opening snap
the LA pressure. This is primarily related to the reduction
(OS) often is palpable in the region between lower left
in the duration of the diastolic filling period due to the
sternal border and the cardiac apex. A diastolic thrill at the
increase in the heart rate and also due to the lack of
al
apex may occasionally be detected in the left decubitus

mechanical atrial contribution to left ventricular filling.
position.
An individual can become symptomatic for the first
ic
Apex impulse is best examined in left recumbent

time with the onset of AF. Acute pulmonary edema can
position. The apex impulse is normal or of decreased
og
occur in a comparatively mildly symptomatic person.

amplitude, non-sustained and never associated with a
Paroxysmal AF could be the reason for the variation in
palpable S4 or S3 unless an additional valve abnormality is
the symptomatic status in some individuals on different
present, such as MR or AS.
ol
occasions. Fast irregular palpitations if present certainly

suggest development of AF but may not be present in all Right ventricular impulse: It is detected as a gentle, low
di
patients. As the disease progresses, PAH tends to become amplitude RV lift at the 3rd to 5th left ICS adjacent to
progressively severe and patient tends to develop right sternum. To detect parasternal impulse firm pressure with
ar
ventricular failure and secondary tricuspid regurgitation. heel of the hand must be used. In individuals with severe
Fatigue becomes an important symptom and can be PAH, RV impulse can be very prominent, careful visual
more disabling than dyspnea on exertion. Pedal edema, inspection can detect lateral retraction of the chest wall
C
abdominal distension and other evidence of right heart between normal left and right ventricular areas. In severe
failure will become evident. degrees of RV enlargement, the apex beat may be formed
Pregnancy is poorly tolerated by patients with by the right ventricle. When PAH is severe right ventricular
significant MS. Increase in heart rate, blood volume S4 or even rarely RVS3 is may be palpable.
and cardiac output lead to increase in LA pressure and
pulmonary venous hypertension. Dyspnea and even acute Heart Sounds
pulmonary edema can occur for the first time during
A loud S1 and an opening snap are hallmark features of
pregnancy. Symptoms usually will be prominent by the mid
MS. An accentuated P2 suggests associated PAH.
second trimester, when the hemodynamic abnormalities
are pronounced. Severe MS is a contraindication for First Heart Sound: S1 is loud and snapping in MS. The
pregnancy and should be identified and corrected before increased S1 is audible throughout the precordium and is
becoming pregnant. heard maximally between lower sternal edge and the apex.
61
KG-10.indd 61 02-11-2018 13:48:03

SECTION Table 1: Factors affecting A2-OS interval in MS
2
Associated condition Effect on A2-OS interval
Systemic hypertension Increase
Mitral regurgitation Decrease
Aortic regurgitation Decrease or increase

Aortic stenosis Increase
Calcified mitral valve Increase
LV dysfunction Increase
Bradycardia Increase
Tachycardia Decrease
a
Old age Increase
di
In
Table 2: Differentiating features between A2-OS and A2-P2
Features A2-OS A2-P2
Best heard Between apex and left sternal border At pulmonary area
of
Interval 0.04–0.14 sec <0.03 sec
Postural variation Widens on standing Narrows on standing
ty
Respiratory variation Narrows during inspiration Widens during inspiration
18 cie
The loud S1 is often palpable. Loud S1 and loud OS can
occur only when the mitral leaflets have sufficient mobility
pressure, rate of decline of LV pressure during isovolumic
relaxation, associated aortic valve disease, decreased LV
and pliability to move rapidly into all open or closed compliance and MV calcification. Table 1 shows factors
20 o
position. When cardiac output is reduced as in CCF, severe affecting A2-OS interval in MS.
S
PAH, associated aortic valve disease or LV dysfunction, Opening snap should be differentiated from pulmonary
both S1 and OS will have decreased amplitude. In cases component of S2 as well as LVS3. The A2-OS interval does
with long PR interval, S1 may be softer than expected, and not vary appreciably with the phases of respiration. OS is
al
in AF S1 will be variable. a higher pitched sound and is better audible at the apex or
midway between apex and left sternal border. The split of
ic
Opening snap: It results from the maximal opening

the second heart sound is best appreciated over the upper
excursion of the mitral valve cusps into the LV cavity in
left sternal border. The split widens during inspiration and
og
early diastole after LV pressure falls below that in the

narrows or become single during expiration. The LVS3 is
LA. The OS does not represent the onset of mitral valve
a localized low pitched sound better appreciated over the
opening, but occurs 20–40 msec after LA-LV pressure
ol
apex in left lateral position and is often palpable. Table 2

crossover. The pliability of the valve is indicated by the
shows differentiating features between A2-OS and A2-P2,
loudness, pitch and “crispness”of the opening snap.
di
while Table 3 shows differences between A2-OS and

Widely audible high pitched crisp opening snap indicates
A2-S3.
pliable anterior mitral leaflet whereas localized soft dull
ar
opening snap suggest a nonpliable valve. The timing of Murmur:Typical murmur of MS is mid diastolic low
OS with respect to aortic component (A2) of S2 is useful pitched, rough, rumbling with presystolic accentuation,
C
in determining the severity of MS. A short A2-OS interval best heard over the apex, with the bell of the stethoscope in
suggests severe MS and long interval indicates mild MS. the left lateral position with breath held in expiration. The
The duration of A2-OS interval in MS ranges from 0.04 to murmur has two components: an early diastolic murmur
0.14 sec. In cases of severe MS, A2-OS interval is typically that begins with or just after the OS and corresponds to
less than 0.08 sec. A2-OS interval more than 0.10 sec. rapid filling phase of the diastole, and a late diastolic or
is considered long. The A2-OS interval and the Q-S1 presystolic murmur that follows the left atrial contraction
intervals are variable in AF. It is decided by the preceding and represents sudden increase in transmitral flow and
cycle length. If the preceding cycle length is short, LA velocity prior to the valve closure. If MS is mild or moderate
pressures will be high and hence the A2-OS interval will be there will not be adequate LA–LV gradient during late
short for the subsequent cycle. Q-S1 (Q-M1) minus A2-OS diastole and murmur will be only mid diastolic. In severe
interval is called Well’s index and is fairly constant for the MS and or at rapid heart rates there is continuous late
varying cycle lengths in AF. However, in addition to LA diastolic gradient and long diastolic murmur. In patients in
pressure, A2-OS relationship is affected by peak systolic AF, the presystolic component of the mid diastolic murmur
62
KG-10.indd 62 02-11-2018 13:48:03

Table 3: Differentiating features between A2-OS and A2-S3 CHAPTER
10
Features A2-OS A2-S3
Best heard At apex or midway between apex and left sternal border Apex
Interval 0.04–0.14 sec 0.10–0.20 sec

Pitch High Low
Postural variation Widens on standing No change
Table 4: Factors decreasing the intensity of diastolic

rumble of MS
a
Low flow states
Severe MS
di
zz
zz Severe PAH
zz CCF
In
zz AF with fast ventricular rate
Features of mitral valve

z Extensive calcification of mitral apparatus
of
zz Subvalvular chordal obliteration
zz Left atrial thrombus protruding into mitral orifice
zz Poster medial deviation of mitral orifice
ty
Associated lesions
zz Aortic stenosis
zz Aortic regurgitation
zz Atrial septal defect
zz PAH with marked RV dilation
Inability to localize cardiac apex

18 cie
Obesity
20 o
zz
zz COPD
S
is often absent. In patients with moderately severe MS who obstruction. A number of maneuvers will enhance the
al
are in AF a presystolic murmur or accentuation may be severity of MS murmur like, coughing, standing from
heard during short cycle lengths. Presence of presystolic squatting and sustained handgrip. Amylnitrate is useful
ic
accentuation for the mid diastolic murmur if present in differentiating MS murmur from Austin Flint murmur
suggests a pliable valve. The pre-isovolumic contraction of AR. In MS reflex tachycardia caused by inhalation of
og
period is prolonged in MS due to the high LA pressure and amylnitrate will accentuate the murmur while Austin
because the stiffness of the mitral valve has to be overcome. Flint murmur will attenuate due to decreased regurgitant
The LV has to build up a higher pressure to exceed the LA volume. The Valsalva maneuver may bring out the mid
ol
pressure and hence the cross over point is delayed. This is diastolic rumble. During strain phase of Valsalva the
reflected as a pronged Q-S1 interval. There is continuing
di
murmur dampens, but 6 to 8 beats after release the

flow from the LA to LV during this very early ventricular murmur intensity increases due to increased heart rate
systole— pre-isovolumic contraction phase. As the mitral
ar
and cardiac output. A number of factors may decrease the

valve orifice is being reduced by LV contraction, the intensity of MS murmur, they are enlisted in Table 4.
velocity of forward flow increases as long as the pressure is
Severe MS is suggested by (Box 1):
C
higher in the LA than in the LV. A calcified nonpliable valve

1. Presence of significant symptoms especially Class III
will not lead to an augmentation of the diastolic gradient
and above and or presence of PND. Orthopnea and
as it cannot freely float up during the pre-isovolumic
right heart symptoms indicate severe disease.
phase. The length of the murmur directly correlates
2. Presence of severe PAH is usually correlated
with severity of mitral obstruction. Tachycardia causes
mitral diastolic murmur to become more prominent. So with severe disease. Though passive pulmonary
the severity of obstruction is best gauged at slower heart hypertension is invariably present in all patients with
rates. The bell of the stethoscope should be used with MS, reactive and obliterative pulmonary hypertension
light pressure for detection of very faint murmur. The indicates severe disease (characterized by prominent
left recumbent is mandatory to enhance detection of low parasternal heave, easily palpable second heart sound,
frequency vibrations. The low intensity murmur of MS is palpable pulmonary artery pulsations, pulmonary
well localized and does not radiate much. The loudness ejection click, early diastolic murmur of pulmonary
of murmur does not correlate well with the severity of regurgitation (Graham Steel murmur) and secondary
63
KG-10.indd 63 02-11-2018 13:48:04

SECTION
Box 1: Features of severe MS
2 zz
zz
Symptoms: Class III/IV, PND, orthopnea and right heart failure
Evidence of severe PAH
zz Short A2–OS interval

zz Length of the mid-diastolic murmur
tricuspid regurgitation murmur. “a” wave in the JVP of these individuals reactive pulmonary hypertension
will be prominent and evidence of right heart failure set in early and can go into right heart failure. It is fairly
including elevated mean JVP, pedal edema and common to find chronic rheumatic heart disease patients
a
hepatomegaly may also be evident. Significant TR presenting with right heart failure but on evaluation are
di
leads to obliteration of the x descent, positive systolic found to have normal LV systolic function. Acute MR is a
wave (CV wave), tall V wave and prominent y descent. clinical syndrome where patients present with severe MR
In
In AF, “a” wave disappears. over a short span of time into LA which is not prepared
3. Short A2–OS interval. This interval represents the to accept the volume load. LV also does not have the
isovolumic relaxation period. A2–OS interval less than compensatory mechanisms activated to accommodate
of
70 msec suggests severe MS the volume overload. The LA pressure steeply increases
4. Length of the mid-diastolic murmur. This is especially and the patient can go into acute pulmonary edema.
reliable in the presence of AF than in sinus rhythm. Classical example will be chordal rupture leading to flail
ty
The cycle length is variable in AF. In a long cycle, if mitral leaflet and acute severe MR in the background of
the diastolic murmur is extending into most of the myxomatous degeneration of the MV. Chordal rupture can
18 cie
diastole, it is correlated with severe MS.
The presence of thrill usually indicates severe MS.
also occur in acute rheumatic fever, infective endocarditis,
acute myocardial infarction or following trauma.
Sudden onset of dyspnea in a patient with MR
20 o
may suggest chordal rupture, rheumatic reactivation,
MITRAL REGURGITATION infective endocarditis or development of atrial fibrillation.
S
The t w o common etiological factors for mitral Possibility of progression of coronary artery disease
regurgitation (MR) are chronic rheumatic heart disease should also be considered in those above the age of 40
al
and myxomatous degeneration of the mitral valve. Other years especially in the presence of atherosclerotic risk
etiologies include congenital, acute rheumatic fever, factors. Symptomatic deterioration with onset of AF is due
ic
ischemic (papillary muscle dysfunction), mitral annular to the increase in heart rate and more number of “v waves”
calcification, infective endocarditis and various connective in LA per minute, contributing to the increase in the mean
og
tissue disorders. Hypertrophic cardiomyopathy with LA pressure.

obstruction is associated with subaortic obstruction
and MR. Restrictive cardiomyopathy—left ventricular Clinical Assessment of Severity
ol
endomyocardial fibrosis is frequent in the state of Kerala. AF is a common arrhythmia in patients above the age of
The symptoms in chronic MR are decided by the 50 years. The pulse in chronic severe MR is described as
di
severity of the lesion, the rapidity with which it develops, pseudo-collapsing. The pulse volume is normal or low,
the compliance characteristics of the LA and the left as the effective forward stroke volume is reduced. Abrupt
ar
ventricular function. Chronic severe MR developing ejection into the low pressure LA is responsible for the
gradually over long span of time in the presence of a abnormal character of the pulse. The apex beat may be
C
compliant LA is well tolerated. The only two symptoms shifted down and out with a forceful or hyperdynamic
are palpitations due to volume overload of the LV and character indicative of LV volume overload situation. The
exertional fatigue due to reduced effective forward stroke palpating finger over the apex is elevated above the plane
volume. In such patients onset of dyspnea on exertion of the adjacent ribs but will be confined to not more than
indicates onset of left ventricular dysfunction. Unless initial half of systole. A systolic thrill may be palpable over
surgical correction is done without delay, the deterioration the apex. A third heart sound can also be palpable. The
may be fast and irreversible. But in those patients with less diastolic flow murmur of severe MR being medium pitched
compliant LA, especially if MR had occurred relatively can produce an apical thrill and occurs after the palpable
rapidly over a shorter span of time, the LA pressure tend third heart sound. A late parasternal lift is a feature of
to increase and they present with dyspnea on exertion. chronic severe MR. It is because of the forceful posteriorly
The symptoms may simulate predominant rheumatic directed jet into LA. This should be differentiated from left
mitral stenosis. In the third group of patients with non- parasternal heave of right ventricular hypertrophy. Left
compliant LA, the LA pressure tend to rise fast and in some parasternal heave is defined as the sustained lift of the
64
KG-10.indd 64 02-11-2018 13:48:04

lower left costochondral junctions, present throughout filling pressure leads to atrial dilatation and subsequent CHAPTER
systole. The pulmonary artery pulsations as well the forceful atrial contraction (Frank Starling mechanism).
pulmonary valve closure may be palpable with pulmonary
arterial hypertension.
Severe MR is suggested by (Box 2) cardiomegaly,
forceful apex beat, late parasternal lift, LVS3, widely split
10

Auscultation usually reveals reduced intensity of first S2, mitral mid diastolic flow murmur and evidence of
heart sound. First heart sound can be loud in combined pulmonary arterial hypertension. AF does not have a direct
lesions with both MR and MS. First heart sound can also be relation to severity but more often occur in those with
loud in mitral valve prolapse with redundant mitral leaflets severe MR. Similar to MS, the threshold for AF reduces
similar to loud aortic valve closure sound in a functionally with advancing age. With the onset of left ventricular
normal bicuspid aortic valve. Also, non-ejection click can dysfunction which delays A2, the previously widely split
fuse with the first heart sound if the prolapse occurs early second heart sound can become closer. Also, pulmonary
a
in systole. This will be more apparent in the standing arterial hypertension can reduce the pulmonary hang-out
di
posture, when S1 nonejection click interval tend to narrow time which can lead to narrowing of the split of the second
down. Left ventricular third heart sound is a low pitched heart sound.
In
sound better heard with the bell of the stethoscope, Cardiac enlargement out of proportion to clinically
lightly applied to the chest wall. The second heart sound assessed MR should suggest primary myocardial disease
is characteristically widely split in chronic severe MR, associated with LV dysfunction and functional MR due to
of
because of earlier aortic valve closure due to reduced left annular dilatation and non coaptation of the valve leaflets.
ventricular ejection time. Loud pulmonic valve closure This is often observed in dilated cardiomyopathy and
sound and pulmonary ejection click suggest pulmonary coronary artery disease. Loud and prominent murmurs
ty
arterial hypertension. are often absent in contrast to MR of rheumatic etiology or
The intensity of the pan systolic murmur over the mitral valve prolapse.
18 cie
apex may not have direct relation with the severity of
MR. The MR murmur of rheumatic etiology and mitral
valve prolapse tend to be loud whereas the murmur
Acute MR is a medical emergency usually presenting
as acute pulmonary edema. The LA pressure tracing will
demonstrate a very prominent v wave due to the direct
20 o
in myocardial disease like dilated cardiomyopathy or transmission of LV systolic pressures into LA. Evidence of
related to coronary artery disease tend to be less loud. The heart failure will be evident. The S1 tends to be soft and
S
murmur related to paravalvular leak of a mitral prosthetic S4 will be loud and often palpable. S3 is invariable and
valve may be so soft that it can be completely missed P2 will be loud. The MR murmur can have a late systolic
al
on clinical examination. Presence of left ventricular decrescendo character due to the reduced gradient at end
third heart sound and mitral mid diastolic flow murmur systole due to high LA pressures.
ic
indicates severe MR. This murmur is low pitched and

decrescendo and may be associated with a thrill.
Mitral Valve Prolapse
og
Fourth heart sound is an atrial sound recorded from

the ventricle. Left ventricular fourth heart sound is not This is the most common cause for MR in the western
a feature of chronic severe MR. It is especially absent world and the most common cardiac lesion predisposing
ol
in rheumatic MR due to two reasons—LV tend to be to infective endocarditis. The unique dynamic auscultatory
compliant and atrial contribution to ventricular filling findings help in differentiating mitral valve prolapse
di
may not be required. LA is often damaged due to previous (MVP)-MR from rheumatic etiology for MR. The patient
episodes of rheumatic carditis and long standing atrial should be examined in the supine, left lateral and standing
ar
distension related to chronic severe MR. These fibrotic positions. Examination during squatting, isometric
changes in the LA can prevent it from generating forceful handgrip and strain phase of Valsalva maneuver are
atrial contraction. Till the onset of systolic dysfunction, also helpful. The most important finding is the non-
C
LV filling pressures will be normal. Loud LV S4 can be ejection click and the late systolic murmur. Late systolic
audible in hypertrophic cardiomyopathy and in those with murmur is defined as one which starts after a gap from
underlying coronary artery disease. LV S4 is also a very the first heart sound and reaches up to the second heart
important finding in acute MR. Marked increase in the LV sound. Late systolic murmurs can be short or long. The
Box 2: Clinical features of severe MR

zz Cardiomegaly
zz LVS3
zz Widely split S2
zz Mitral mid diastolic flow murmur
zz Evidence of pulmonary arterial hypertension
65
KG-10.indd 65 02-11-2018 13:48:04

SECTION S1 nonejection click interval and the occurrence of the late in the natural history and often indicates the onset
late systolic murmur are dependent on the preload, of left ventricular dysfunction. If dyspnea occurs early in
2 afterload and contractility. Any maneuver that decreases
LV volume results in early occurrence of prolapse. This
the clinical course of AR, one must consider associated
mitral valve disease or acute AR. Associated coronary
includes reduction in venous return (preload), reduction artery disease should also be considered especially with
of impedance to LV emptying (afterload), tachycardia concomitant atherosclerotic risk factors.
and augmentation of LV contractility. Increase in venous Myocardial ischemia can occur in severe AR.
return, increase in impedance to LV emptying, reduction Myocardial oxygen requirement is increased by increased
of myocardial contractility and bradycardia tend to delay wall tension and LVH. Fall in diastolic blood pressure can
the onset of mitral valve prolapse. The S1 nonejection reduce the coronary perfusion especially in the presence
click interval will be delayed. LV size decreases with of slow heart rate. Nocturnal angina is known to occur
a
sudden standing and during the strain phase of Valsalva in patients with chronic severe AR. It can occur even in
di
maneuver. Both these lead to reduced S1 nonejection patients who may not have exertional angina.
click interval and longer MR murmur. Passive leg raising,
In
squatting and isometric hand grip delay the click and the Physical Examination and Assessment
onset of the murmur. of Severity
Blood pressure: With increasing amount of aortic reflux,
of
AORTIC REGURGITATION the systolic blood pressure increases and the diastolic
Aortic regurgitation (AR) occurs when the aortic blood pressure decreases. In hemodynamically significant
valve leaflets are not able to coapt and close the aortic
ty
AR, diastolic pressure typically falls below 70 mmHg
orifice completely during diastole. This can be due to and systolic pressure may rise to 140 to 150 mm Hg.
abnormalities of the valve leaflets, dilatation of the aortic
18 cie
root or a combination of both. In the adult, rheumatic
heart disease, infective endocarditis and annulo-aortic
Measurements of diastolic BP using cuff, in patients with
significant AR show readings down to 0 mm Hg. In such
patients, point of muffling of Korotokoff sound should
ectasia (aortic root dilatation) related to connective be taken as diastolic BP. In children and young adults,
20 o
tissue disorders are important causes for severe AR. Para- the systolic blood pressure is seldom very high since
S
prosthetic valve leaks are also emerging as an important the vasculature is highly compliant. The diastolic blood
etiological factor. VSD with aortic valve prolapse leading pressure tends to be low. But in the elderly, the increase in
to AR is probably the commonest cause in a child. stroke volume leads to significant increase in the systolic
al
Bicuspid aortic valve and systemic hypertension are blood pressure because of the less compliant remodelled
common causes for mild AR. Bicuspid aortic valve with vasculature. Tachycardia shortens the duration of diastolic
ic
aortic valve prolapse and aortic root dilatation due to reflux thus increasing diastolic BP. Bradycardia on other
the accompanying aortopathy can produce severe AR
og
hand, prolongs diastolic reflux accentuating fall in

and can sometimes present acutely. Marfan syndrome diastolic BP. A difference in systolic BP between the arms
is known to produce aortic root dilatation and AR. The and the legs of greater than 40 to 50 mm Hg is generally
ol
underlying pathology of cystic medial necrosis can lead to seen in patients with significant AR (Hill’s sign).
aortic dissection which itself can produce or worsen AR.
Arterial pulse: The arterial pulse in significant AR is high
di
Syphilis, ankylosing spondylitis and rheumatoid arthritis

amplitude. The pulse is collapsing in nature due to low
are encountered less frequently as an etiological factor.
systemic vascular resistance and early diastolic runoff
ar
Chronic severe AR leads to diastolic overload of the

of blood into the LV which results in rapid unloading of
LV, which undergoes dilatation and ejects more blood per
the aorta. Thus the classic carotid pulse of AR is having
beat. Increase in stroke volume leads to higher cardiac
C
increased force or amplitude of ejection followed by an

output, systolic hypertension and wide pulse pressure.
abrupt falling away or collapse. As the disease progresses
The hemodynamic abnormalities include increase in
arterial pulsations are easily seen in the sternal notch and
LV diastolic volume, increase in LVEDP, increase in LV
supraclavicular areas.
systolic pressure and eccentric LV hypertrophy. The intra-
myocardial wall stress in AR is increased to a much higher Bisferiens pulse: Bisferiens pulse is characteristic of AR. It
extent than chronic severe MR. The major hemodynamic has got two systolic peaks, and is best felt with light finger
abnormality in chronic severe MR is increase in preload pressure over the carotid arteries. The bisferiens pulse is
whereas in chronic severe AR, it is a combination of usually present in moderate to severe AR. It can also occur
increase in preload and afterload. in combination lesions in which AR is the more dominant
Chronic severe AR is generally well tolerated. The lesion than AS and also classically in hypertrophic
main symptom of the patient with chronic severe AR is cardiomyopathy with obstruction. The precise underlying
palpitations. Dyspnea on exertion usually occurs very mechanism is still not clear.
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KG-10.indd 66 02-11-2018 13:48:04

Table 5: Peripheral signs of AR CHAPTER
10
Corrigan sign Prominent carotid and supraclavicular pulsations
Alfred de Musset sign Head nodding with heart beat

Landolfi sign Change in pupil size with heart beat
Muller sign Uvula pulsation
Becker sign Retinal artery pulsations
Rosenbach sign Liver pulsations
Gerhardt sign Spleen pulsations
Quincke sign Digital capillary pulsations
a
Lighthouse sign Blanching and flushing of the forehead
di
Traube sign “Pistol shot”—systolic and diastolic booming sound over femoral artery
Duroziez sign Intermittent to and fro femoral artery systolic and diastolic murmur generated by light
In
compression with the bell of a stethoscope
Hill sign Lower limb systolic BP exceeding upper limb systolic BP by more than 20 mm Hg
Water-Hammer pulse High volume abruptly collapsing pulse
of
Mayne sign Diastolic BP drop of >15 mm Hg with arm raised
Lincoln sign Pulsatile popliteal
ty
Sherman sign Dorsalispedis pulse unexpectedly prominent in age >75 years
18 cie
Peripheral signs: The sudden rise and fall of arterial pulse
wave causes a distinctive pounding or collapsing quality of
Second heart sound: Longer LV ejection time delays the
aortic valve closure. Low systemic vascular resistance
that is accentuated in peripheral arteries. Marked systemic due to chronic severe AR can delay the aortic hangout
20 o
vasodilation may produce noncardiac phenomena such interval and can also rarely contribute to delayed aortic
S
as increased sweating, warm flushed skin and accentuated valve closure. Second heart sound is usually closely split.
retinal vein pulsations. These signs are not specific for AR Paradoxical splitting of S2 is uncommon unless there is
underlying LBBB. A2 is soft in valvular AR because of the
al
and can be seen in patients with a hyperkinetic circulation

and marked arterial vasodilation from other causes. damaged leaflets. But A2 can be normal or even loud in
annulo aortic ectasia where the leaflets are usually normal.
ic
Various eponymous peripheral signs of AR are listed in

Table 5. The classical example is the loud ringing second heart
sound (tambour sound) described in syphilitic AR.
og
Precordium: The apex impulse in mild to moderate

AR is normal in size but is often hyperdynamic. Thus Third heart sound: Unlike the situation in severe MR,
presence of left ventricular third heart sound indicates
the amplitude is increased but there is no leftward
ol
LV dysfunction. One has to be careful in attributing an

displacement of the impulse. With advancing disease, the
audible LVS3 in a child or youngadult to LV dysfunction
di
hyperkinetic impulse becomes more prominent and the

because of the likelihood of a physiological third heart
cardiac apex is displaced inferiorly and laterally. When
sound. But presence of an LV S3 in an older adult or elderly
ar
LV dilation or LV dysfunction sets in the apex impulse

nearly always indicates LV dysfunction.
becomes sustained. In severe AR, the apex impulse is
typically found in left anterior axillary line at the 5th or 6th Fourth heart sound: Audible S4 is found in moderate to
C
intercostal space, usually occupies at least two interspaces severe AR. Prolonged PR interval increases the audibility
and is sustained into late systole. The area medial to the LV of S4. Presence of S4 indicates an elevated LVEDP and
apex may demonstrate prominent retraction. A palpable decreased LV compliance.
S4 may be found in lateral decubitus position suggestive of Ejection sounds: Aortic ejection clicks can be audible with
an elevated LVEDP and decreased LV compliance. congenital bicuspid aortic valve and in the presence of
a dilated aortic root. In severe AR, the ejection click may
Heart Sounds merge with S1 and longer be audible as separate entity.
First heart sound: The first heart sound is usually normal
in mild to moderate AR. It can be soft with the onset of left Murmur
ventricular dysfunction and in the presence of a prolonged Three different murmurs may be found in patients with
PR interval. AR. (1) The classic decrescendo diastolic murmur from
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KG-10.indd 67 02-11-2018 13:48:04

SECTION reflux of blood into the LV. (2) An ejection systolic murmur Systolic murmur: A systolic ejection murmur is common
due to large stroke volume, increased rate of ejection and in moderate to severe AR. It results from an abnormally
2 abnormal valve morphology. (3) The Austin Flint murmur large stroke volume that is ejected with rapid force across
a deformed valve into an enlarged proximal aorta. This
heard as a low pitched diastolic murmur beginning in mid
diastole and found only in severe AR. murmur is short and peaks before second half of systole if
there is no aortic valve obstruction.
Diastolic murmur: The characteristic murmur of AR is a
high pitched, soft, blowing, decrescendo early diastolic Austin flint murmur: Austin Flint murmur is a low pitched,
apical diastolic rumble audible in severe AR. Its presence
murmur best heard along the left sternal border. The
indicates a large diastolic leak with a regurgitant fraction
maximal diastolic pressure difference between the aorta
of over 50%. It is due to the AR jet impinging on the septal
and LV occurs immediately after LV isovolumic relaxation
a
surface of the anterior mitral leaflet and pushing it up,
when LV diastolic pressure falls to its lowest in early
creating a relative mitral stenosis. It has a mid-diastolic
di
diastole. For this reason the murmur may have a brief and a presystolic component. Unlike the diastolic murmur
early crescendo contour which may produce a “gap” of organic MS, presystolic accentuation does not usually
In
between A2 and apparent onset of diastolic murmur. It is happen. LV dysfunction leads to premature closure of the
better heard with the patient sitting up, leaning forward mitral valve and the Austin Flint murmur gets truncated.
and breath held in expiration. It is better appreciated Elevation of the LV diastolic pressure by the regurgitant
of
with the diaphragm of the stethoscope. Faint early jet can exceed the LA pressure. This can produce diastolic
diastolic murmurs can be accentuated by increasing the MR in pre-systole. This also can possibly contribute to the
peripheral resistance—squatting, isometric hand grip and Austin Flint murmur. Onset of LV dysfunction should be
ty
administration of a vasopressor drug like phenylephrine. A clinically suspected in the presence of reduction in the
soft AR murmur can disappear during pregnancy because intensity of first heart sound, audible third heart sound
18 cie
of the fall in peripheral resistance. In the presence of
dilated aortic root and ascending aorta and when marked
and when the pre systolic component of the Austin Flint
murmur disappears. Because the Austin Flint murmur is
directly related to degree of AR manoeuvres that increase
atherosclerotic tortuosity pushes the ascending aorta
20 o
diastolic reflux will accentuate the murmur, and those that
anteriorly and to the right, the early diastolic murmur can
decrease the degree of AR will attenuate it. Thus handgrip,
S
be better audible along the right sternal border than the left
mild exercise, application of a bilateral blood pressure
sternal border. In older adults, especially those with COPD
cuff and squatting all intensify the Austin Flint murmur,
al
or CCF, the AR murmur may be maximal or may be heard while amyl nitrate diminishes the intensity. Various
only at the LV apex. In short patients, the AR murmur may differentiating features of Austin flint murmur of AR and
ic
be best heard in the axilla (Cole Cecil murmur). In AR due diastolic rumble of MS are enlisted in Table 6.
to perforation or rupture of an aortic cusp or retroversion Severe AR is suggested by (Box 3) high volume
og
of a leaflet, the murmur may be musical that may wax or collapsing pulse, cardiomegaly, forceful apex beat,
wane throughout the diastole, and is called “cooing dove” narrowly split second heart sound, long early diastolic
or “seagull” murmur. murmur and presence of Austin Flint murmur. Presence
ol
di
Table 6: Differentiating features between murmur in MS and Austin Flint murmur of AR

Austin Flint Mitral stenosis
ar
Left ventricular heave Common Absent

RV lift Absent Present
C
S1 Normal to decreased Loud

Opening snap Absent Present
S3 Present Absent
Amyl nitrate inhalation Murmur attenuates Murmur accentuates
Box 3: Clinical features of severe AR

zz High volume collapsing pulse
zz Cardiomegaly
zz Narrowly split second heart sound
zz Long early diastolic murmur
zz Austin Flint murmur
68
KG-10.indd 68 02-11-2018 13:48:04

of peripheral signs indicate significant “run-off ” and decade. Degenerative disease affecting a trileaflet aortic CHAPTER
wide pulse pressure suggesting severe AR. Significant valve is the commonest cause for AS in the elderly. This
symptoms, left ventricular dysfunction and pulmonary
hypertension are correlated with severe AR.
more often happens in individuals with some structural
abnormality of the valve like congenital cuspal inequality.
10

Aortic sclerosis slowly develops which in some individuals
ACUTE AORTIC REGURGITATION progresses to severe AS. Unlike rheumatic etiology,
commissural fusion is not a feature of bicuspid aortic valve
Acute or subacute bacterial endocarditis, aortic dissection,
and degenerative calcific AS. Mild-to-moderate AS is likely
aortic valve perforation or rupture secondary to trauma or
to progress over the years and such individuals require
myxomatous degeneration are the most common causes
regular follow up. This is in contrast to mild to moderate
for acute AR. It is a life-threatening condition due to sudden
pulmonic valve stenosis which remains stable and is
a
reflux of an excessive amount of blood into LV, which is
unlikely to progress over the years.
unable to accommodate the large regurgitant volume.
di
Almost half of patients with severe AS are asympto-
As management entails prompt surgical intervention
matic. Because many of these elderly individuals are
accurate diagnosis and differentiation from chronic AR
In
sedentary, functional assessment of the symptoms may
is mandatory. Table 7 shows differentiating features
be difficult. The three important symptoms of patients
between acute and chronic AR.
with severe AS are effort related greying of vision (near
of
syncope and syncope), effort angina and dyspnea on
AORTIC STENOSIS exertion. As many of the middle aged and elderly have
Valvular aortic stenosis (AS) has three major causes: multiple atherosclerotic risk factors, associated coronary
ty
rheumatic, congenital and degenerative. Rheumatic heart artery disease is common which may also contribute to
disease is an important cause for AS in the developing the symptoms. Natural history series have demonstrated
18 cie
countries. It usually co exists with significant mitral valve
disease and or AR. Isolated aortic stenosis is seldom due
to rheumatic etiology. Congenital bicuspid aortic valve
that the average survival after the onset of angina is 5 years
and that after syncope is 2 to 3 years. The survival is less
than 2 years after the onset of dyspnea due to LV systolic
is seldom stenotic at birth. In the common variety, the dysfunction. But it is important to remember that some
20 o
left and right coronary cusps are fused and lead to fish patients can have long standing mild dyspnea on exertion
S
mouth opening. Over the years, degenerative changes and due to LVH and diastolic dysfunction. But a distinct
calcification set in and is responsible for the reduction in deterioration in the symptomatic status is often correlated
al
the aortic valve area. Usually this happens beyond the third with the onset of LV systolic dysfunction.
ic
Table 7: Features of acute vs. chronic AR

Feature Chronic AR Acute AR
og
Presentation Often symptomatic Pulmonary edema, heart failure

Systolic blood pressure Increased Normal or slightly decreased
ol
Diastolic blood pressure Decreased Normal or slightly decreased

Pulse pressure Increased Normal or slightly increased
di
Heart rate Normal Sinus tachycardia common

Peripheral pulses Bisferiens and increased amplitude Unremarkable
ar
Peripheral signs Present Absent

Jugular venous pulse Normal Mean pressure may be elevated
C
Precordial motion LV impulse in 5/6th ICS, left anterior axillary line, Normal to slight LV enlargement. Bifid diastolic
hyperdynamic or heaving. Palpable S3 or S4 common impulse with palpable S3, sustained late diastolic
motion. RV impulse if severe PAH
S1 Normal to decreased Decreased to absent
S2 Often unremarkable Single, soft to absent A2, increased P2
S3 Very common Always present
Ejection click May be present Common
AR murmur Medium frequency, usually holdiastolic. May be short Medium frequency, often harsh, musical if
with rapid decrescendo, Intensity grade 3 unless CCF ruptured cusp, usually not holodiastolic may be
present very short, rapidly decrescendo, intensity may be
very soft
Austin Flint murmur Common Always present
Systolic murmur Flow murmur at aortic valve Mitral regurgitation murmur
69
KG-10.indd 69 02-11-2018 13:48:05

SECTION Normal aortic valve area is 3 to 4 square cm2. Reduction Presence of a thrill indicates that AS is present but does not
of valve area doesnot result in pressure drop across the necessarily indicate severe obstruction.
2 valve at rest until at least 60% of the valve area is narrowed
(AVA approximately 1 cm2). Symptoms start to appear Heart Sounds
when valve is reduced by 60–75% resulting in calculated

First heart sound: S1can be normal or may be reduced in
valve area of 0.7–0.8 cm2.
intensity but is never accentuated in isolated AS.
The major hemodynamic abnormalities in AS are
low stroke volume and elevated LV pressures. The LV Second heart sound: The amplitude of the aortic ejection
undergoes concentric hypertrophy to compensate for click and A2 are closely related. Both are prominent in a
increased resistance to outflow, this causes a very thick subject with pliable non-calcified bicuspid valve. Both
walled chamber with no dilatation of the LV cavity. The are decreased in intensity in the presence of calcium
a
diastolic pressures are elevated because of the concentric and significant valvular thickening. The characteristic
di
LVH and diastolic dysfunction leading to sympathetic alteration of S2 is an increase in the Q-A2 interval with A2
vasoconstriction. Later systolic dysfunction tends to moving into P2 and a tendency for S2 to become single.
In
develop because of excessive afterload, decreased LV The delay in A2 is due to: (1) an increased duration of LV
contractility, myocardial fibrosis and accompanying ejection and (2) the prolonged time for LV pressure to
ischemia. Even in cases without evident LV dysfunction, drop below aortic pressure at end systole due to a large LV-
of
LV will not be able to increase the cardiac output in aortic gradient. During paradoxical split, the split is wider
relation to exercise. Severe AS carries a significant risk of and better appreciated during expiration. The presence
arrhythmias and sudden cardiac death. Those with high of paradoxical splitting of S2 in a case of AS in absence of
ty
systolic gradients, marked LVH, myocardial fibrosis and bundle branch block is indicative of severe obstruction.
myocardial ischemia are at higher risk of sudden cardiac
Third heart sound: Presence of S3 in an adult patient of AS
totally asymptomatic.
18 cie
death (SCD). SCD is comparatively less in those who are
is suggestive of significant LV dysfunction or CCF.
Fourth heart sound: Audible left ventricular fourth heart
20 o
Physical Findings and Assessment of Severity sound in children or young adults with aortic stenosis
indicates severe obstruction. But an audible LVS4 does not
S
Arterial pulse: The pulse in severe AS is classically

have the same significance in elderly with aortic stenosis.
described as parvus (low volume) et tardus (slow rising).
Audible S4 is common in people above the age of 60 years,
This character abnormality is best appreciated over the
al
especially in the presence of systemic hypertension and

carotids. There is an associated systolic thrill or shudder
or coronary artery disease. But palpable S4 in any age is
on the upstroke of the pulse. The pulse pressure is narrow.
ic
considered abnormal. Presence of LVS4 in a person under

In children and young adults, the systolic blood pressure
the age of 40 years indicates a peak gradient of at least 50
tends to be low. But in elderly with severe calcific AS, it is
og
mm Hg.
not uncommon to have systolic blood pressure above 160
mm Hg. This is a reflection of the inelasticity of the aorta Aortic ejection click
An aortic ejection click which is constant (non phasic)
ol
and the non-compliant vasculature. The estimation of

severity of AS from carotid pulse analysis is unreliable. and heard over the base as well as sometimes over the
apex indicates non calcified valve and may be audible in
di
Precordium: The apex impulse is characteristically

congenital AS in children and young adults. As the valve
described as heaving—the palpating finger is elevated
leaflets get calcified, loud ejection clicks are unusual
ar
above the plane of the adjacent ribs and is sustained for

beyond the age of 40 years even with bicuspid aortic
more than half of systole. There is little or no leftward
valves. Aortic ejection clicks are usually absent in
C
displacement of apex impulse. The duration and force

rheumatic AS. Presence of ejection click does not correlate
of the LV impulse is increased due to increased LV
with severity of AS.
mass, high intraventricular pressure and obstruction to
ventricular outflow. Murmur
A presystolic distension of LV (equivalent of The turbulent flow across the stenotic aortic valve produces
palpable S4) may be felt over the apex in the left lateral a harsh crescendo decrescendo ejection systolic murmur
position. In absence of other cardiovascular conditions, that begins after S1 and ends before S2. The murmur of
a palpable S4 correlates with a LV—aortic gradient of severe AS is described as rasping, grunting or coarse and
greater than or equal to 70 mm Hg. A systolic thrill may maximal at the second right intercostal space. In some
be felt at the first or second right intercostal space, with patients the murmur may have maximum intensity in
radiation upward and rightward towards the neck and second or third left intercostal space (Erb’s area) and in
right shoulder. The thrill is better appreciated in expiration older patients with large chests or COPD, the murmur may
with the patient sitting up in the leaning forward position. be loudest at the apex. The murmur is characteristically
70
KG-10.indd 70 02-11-2018 13:48:05

Box 4: Clinical features of severe AS CHAPTER
10
zz Slow rising, low volume pulse, narrow pulse pressure
zz Heaving apex
zz Palpable thrill

zz Paradoxically split S2
zz LV S4
zz Long and late peaking ejection systolic murmur
zz Apico-carotid delay
conducted to both carotids. The length of the murmur is symptoms. AF is common. Physical examination will
a
proportional to the severity of valvular obstruction. The reveal low volume pulse. JVP will be elevated and “a” waves
di
later the peak of the crescendo and longer the duration will be prominent and the Y descent will be slow because
of the murmur, the more severe is the stenosis. A murmur of the slow emptying of blood from RA to RV. Auscultation
In
that peaks in second half of systole indicates severe over the lower left sternal border will reveal a mid-diastolic
stenosis. The high frequency components of the ejection murmur, characteristically increasing with inspiration
systolic murmur selectively tend to radiate to the apex and (Carvallo’s sign). Unlike MS, loud mid-diastolic murmurs
of
may sound musical or cooing simulating the murmur of are unusual. Most of the patients will be in AF and a faint
MR. This is called the Gallavardin phenomenon. This is mid diastolic murmur over the left sternal border can be
especially common in elderly patients with calcific aortic picked up during inspiration on careful auscultation. In
ty
stenosis. This is less frequent in rheumatic AS because patients in sinus rhythm, pre-systolic expansion of the
the commissural fusion may prevent the leaflets from liver may be possible. A high index of suspicion is required
18 cie
vibrating and producing pure frequencies. The presence
of coexistent AR will increase the stroke volume which in
to diagnose organic tricuspid valve disease.
turn will increase length and intensity of the AS murmur. TRICUSPID REGURGITATION
20 o
The murmur of severe AS can become short and soft
Primary organic disease of the tricuspid valve leading to
with the onset of LV dysfunction because of the marked
S
inadequate closure of the tricuspid orifice is rare. It can

reduction in stroke volume.
occur in rheumatic heart disease in association with mitral
Severe AS is indicated by (Box 4) slow rising, low
and often aortic valve disease. Ebstein anomaly, carcinoid
al
volume pulse, narrow pulse pressure, heaving apex with

heart disease and infective endocarditis are other causes.
palpable presystolic expansion over the apex, palpable
Right ventricular endomyocardial fibrosis, a form of
ic
thrill over upper right sternal and or left sternal border, soft
restrictive cardiomyopathy can also lead to low pressure
S1, Paradoxically split S2 with a muffled aortic component
og
tricuspid regurgitation (TR). Isolated TR encountered in

and an audible LVS4 over apex. The harsh ejection
clinical practice is almost always secondary to pulmonary
systolic murmur will be long and late peaking. Evidence of
arterial hypertension, annular dilatation and right
pulmonary hypertension and heart failure are indicators
ol
ventricular dysfunction. In hypertensive TR, the systolic

of severe lesion. But associated mitral valve disease should
pressure is reflected into the RA which is often markedly
be ruled out.
di
dilated. AF is a common arrhythmia. Pedal edema and

ascites are the usual symptoms. JVP shows obliterated x
TRICUSPID STENOSIS
ar
descent, prominent CV wave (systolic wave), tall V waves

Normal tricuspid orifice measures 5 to 7 square cm. TV area and prominent y descent. Findings of PAH will be evident.
C
less than 1 square cm indicates severe tricuspid stenosis Murmur due to secondary TR (high pressure TR) is a high
(TS). Rheumatic TS almost always occur with mitral valve pitched pansystolic murmur maximally audible over the
disease and associated aortic valve disease. Pathology lower left sternal border characteristically increasing
is similar to rheumatic MS—commissural fusion often with inspiration. It may be accompanied by RVS3 and a
associated with subvalvular pathology. Carcinoid disease mid-diastolic flow murmur. Sometimes in severe pure MS
and congenital causes including Ebstein malformation with severe PAH and right ventricular dysfunction, the TR
of the tricuspid valve are the other two etiological factors. murmur may be widely audible including the lower left
The left heart symptoms related to mitral valve disease sternal border and the apex which is formed by the RV.
(dyspnea on exertion, PND, hemoptysis, pulmonary Because the LV is displaced more posteriorly and because
edema) will be attenuated by the more proximal stenotic of the reduced forward flow across the mitral valve, the
lesion. The clinical picture will be dominated by low mitral mid-diastolic murmur may be totally inaudible
cardiac output and systemic venous congestion. Fatigue, (silent MS). The TR murmur may be mistaken for MR. The
pedal edema and abdominal distension are the usual inspiratory augmentation of the murmur and the other
71
KG-10.indd 71 02-11-2018 13:48:05

SECTION findings of severe PAH and TR helps in the differentiation. widely split with reduced intensity of P2. With severe PS,
The inspiratory augmentation will be reduced or lost the murmur tends to be longer, late peaking and extending
2 with the onset of significant right ventricular dysfunction.
Systolic hepatic pulsations are observed with severe TR.
beyond A2, which is often inaudible. The second sound
will be widely split with muffled P2. With very severe PS,
The murmur of primary TR (low pressure TR) tends to the murmur has an asymmetric kite-shape (late peaking)
be low to medium pitched. It is often soft and has a late reaching up to a delayed inaudible P2. A2 will also be
systolic decrescendo due to equalization of pressures inaudible as the loud murmur extends well beyond that.
between RV and RA. Inspiratory augmentation is usually Audible S4 is correlated with severe PS.
less striking. In conditions like RVEMF and RV infarction,
the murmur may be soft or inaudible. PULMONARY REGURGITATION
a
PR is usually secondary to pulmonary hypertension.
PULMONARY STENOSIS Congenital pulmonary valve regurgitation is uncommon
di
Right ventricular outflow tract obstruction can be valvular, leading to low pressure pulmonary regurgitation (PR).
supra valvular and subvalvular/infundibular. As an Postoperative tetralogy of Fallot with trans-annular
In
isolated anomaly, “mobile dome-shaped” pulmonary patch is a frequently encountered etiological factor.
valve stenosis is the most common type of right ventricular An impulse will be usually palpable in the second
outflow tract obstruction. Different types of physical and third left intercostal space close to the sternum.
of
appearances/facies are described in pulmonary stenosis Parasternal pulsations are usually seen but sustained left
(PS). Round bloated facies is known to occur in infants with parasternal heave is unusual. The diastolic murmur of
mobile dome shaped PS. Noonan syndrome, congenital low pressure PR is low to medium frequency, is crescendo
ty
rubella syndrome, William syndrome and Alagille decrescendo and starts slightly after the pulmonary valve
syndrome are well known to be associated with RVOT closure sound. It is usually short in duration because
18 cie
obstruction. The pulmonary valve in Noonan syndrome
is usually dysplastic—three thickened immobile cusps
of equalization of pressures in mid to late diastole. The
murmur is occasionally louder in inspiration and is often
without commissural fusion and a non-dilated pulmonary associated with a thrill. A pulmonary mid-systolic ejection
20 o
trunk. The predominant site of obstruction in the other murmur is usually present. The second heart sound is
S
three syndromes is usually in the pulmonary artery and normally split or shows wide variable split and P2 is soft
the branches (supravalvular or peripheral PS). or even inaudible. The murmur sounds very much like
The “a” wave in the JVP tends to be prominent in a mid-diastolic murmur. In contrast, the murmur of PR
al
significant PS. The height of “a” wave increases related to pulmonary hypertension tends to be higher
progressively as the stenosis increases. Moderate to severe pitched and starts immediately after the pulmonary valve
ic
PS with intact inter ventricular septum is associated closure sound. The P2 is loud and often palpable. Constant
with left parasternal heave. Systolic thrill is sometimes vascular pulmonary ejection click is almost invariable.
og
palpable in moderate to severe PS. It is maximal in the Left parasternal heave due to systolic overload of the
second left intercostal space with radiation upward and right ventricle is seen in those with intact inter ventricular
to the left because the intrapulmonary jet is directed septum. As the diastolic gradient between pulmonary
ol
upward and towards the left pulmonary artery. Pulmonary artery and right ventricle persists throughout diastole,
ejection click coincides with abrupt superior movement the murmur tends to be long and even pan diastolic. The
di
of the mobile dome shaped pulmonary valve. It is phasic murmur of hypertensive PR classically has a decrescendo
and better audible during expiration. Ejection sounds character and does not show respiratory variation.
ar
are absent with immobile dysplastic valves. The S1–EC

interval varies inversely with the degree of stenosis. It is
MULTIVALVULAR LESIONS
C
decided by the pressure difference between the right atrial

“a” wave and the pulmonary artery diastolic pressure. The commonest etiology with multi valvular lesions is
Pre-systolic opening of the pulmonary valve is possible rheumatic heart disease. The mitral valve is almost always
in very severe PS, when the right atrial “a” wave exceeds involved followed by aortic valve involvement. Clinically
the pulmonary artery diastolic pressure. The severity of significant tricuspid valve involvement is uncommon and
RVOT obstruction decides the duration of right ventricular pulmonary valve is usually not involved. Calcific aortic
ejection and the length of the ejection systolic murmur. valve disease can co-exist with mitral annular calcification
With mild PS, the systolic murmur tends to be symmetric and MR. Connective tissue diseases can produce AR
and ends before the aortic component of the second heart due to annuloaorticectasia and MR due to myxomatous
sound. The split of the second heart sound will be near degeneration of mitral leaflets and MR. Carcinoid heart
normal and the intensity of P2 will be preserved. With disease is known to produce right sided valve involvement.
moderate PS, the murmur ends at the aortic component Infective endocarditis can sometimes involve both mitral
of the second heart sound. The second sound tends to be and aortic valves because of the extension of the infective
72
KG-10.indd 72 02-11-2018 13:48:05

process. Rarely congenital LV outflow obstruction can co- MS and AS CHAPTER
exist with mitral inflow obstruction. The clinical findings
10
Patients will have low volume pulse. Sytolic blood pressure
of organic tricuspid valve involvement are usually subtle
will be normal or low. Presence of atrial fibrillation in
and can be easily missed unless very specifically looked
aortic stenosis will give a clue as to the presence of mitral

for. The faint systolic murmur of organic TR and the
valve disease. Severe aortic stenosis will soften S1. A2
short murmur of organic TS will be audible only on deep
intensity is also reduced. The elevated LV end diastolic
inspiration or passive leg raising. It will be difficult to pick
pressures in aortic stenosis will lessen theLV-LA gradient
up these murmurs when the loud left sided murmurs are
in late diastole thus shortening the length of mitral
easily audible over the precordium.
diastolic murmur. The diastolic murmur may all together
absent making it a silent MS. Presence of opening snap will
MS and MR
a
give us clue for presence of MS.
These two lesions frequently co-exist. The etiology is
di
almost always rheumatic heart disease. Mitral annular
AS and AR
calcification leads to predominantly MR but can also
In
produce some degree of stenosis. It usually occurs in The pulse volume will depend on the significance of AS,
elderly individuals. Congenital mitral valve disease is but generally high volume even with severe AS if AR is
infrequently encountered in children. Increase in the atleast moderate or severe. The systolic decapitation effect
of
mitral inflow in MR can exaggerate the clinical features of of AS will make the pulse pressure narrow. Cardiomegaly
associated MS. One should find out if the early diastolic indicates significant AR. The systolic murmur of organic AS
sound is an opening snap or an LVS3. Classically opening will be long and late peaking, as opposed to the functional
ty
snap is a loud high pitched widely audible crisp sound. flow murmur of AR which is early peaking. Prominent
Usually it is audible with maximum intensity midway conduction to carotids is another clue as the existence of
18 cie
between apex and left sternal border. LVS3 is a low pitched
sound best appreciated in the left lateral position with the
organic AS. The length and peaking of murmur thus gives
us a clue as to the presence of organic AS. The A2 will be
bell of the stethoscope. It is very often localized and may be further soft and delayed leading to paradoxical splitting in
20 o
palpable. Presence of a third heart sound practically rules severe AS.
out any significant MS. The mid-diastolic murmur heard
S
in chronic severe MR follows the LVS3 and is decrescendo

SUMMARY
and does not have a pre systolic component. First heart
al
sound tends to be loud in MS but is often soft in MR. S1 can We have made an attempt to elaborately discuss the
sometimes be loud in mitral valve prolapse because of the different clinical examination finding in valvular heart
ic
fusion of S1 with an early non-ejection click. Significant disease. However, we believe that the clinical findings
MR in the presence of MS is suggested by the presence of do vary from patient to patient depending on patient
og
LV type of forceful apex beat (shifted down and out) and physique, chest wall thickness, hemodynamic state
pan-systolic murmur over the apex. Widely split second like presence of heart failure, etc. The most challenging
heart sound may suggest significant MR. part would be the multivalve state were in identifying
ol
the severity of individual lesions will continue to be

MS and AR challenging at the same time exciting for an enthusiastic
di
clinical cardiologist.
MS being the proximal lesion can affect the assessment
ar
of AR. As a general statement, the severity of AR can be SUGGESTED READING

under estimated. Around one-third of patients with severe
1. Abrams J. Essentials of cardiac physical diagnosis.
MS and pulmonary arterial hypertension have reduced
C
Philadelphia: Lea & Febiger; 1987.

pre load to the LV and hence reduced cardiac output. In
2. Babu AN, Kymes SM, Carpenter Freyer SM. Eponyms
such patients the pulse pressure tends to be less wide and
and the diagnosis of aortic regurgitation: what says the
the peripheral signs of AR may be less than expected. In a evidence? Ann Intern Med. 2003;138(9):736-42.
patient with AR, associated MS is suggested by presence 3. Chandrasekhar Y, Westaby S, Narula J. Mitral stenosis.
of AF, loud S1, presence of opening snap, diastolic thrill Lancet. 2009;374(9697):1271-83.
over the apex, presence of pre-systolic accentuation for the 4. Constant J. Essentials of bedside cardiology. Totowa NJ:
mid diastolic murmur and evidence of pulmonary arterial Humana Press; 1992.
hypertension. Opening snap may be soft or even inaudible 5. Mackenzie J. The study of the pulse. Arterial, venous and
in MS patients who have associated significant AR. This hepatic and of the movements of the heart. Edinburgh:
is because of the AR jet impinging on the ventricular side Pentland; 1902.
of anterior mitral leaflet restricting the excursion and 6. Perloff JK. The physiologic mechanisms of cardiac and
opening. vascular physical signs. J Am Coll Cardiol. 1983;1:184-98.
73
KG-10.indd 73 02-11-2018 13:48:05

Subclinical Rheumatic
CHAPTER 11 Heart Disease
a
di
SUMMARY survival benefit. Ignorance of prophylaxis in early phase
Rheumatic heart disease (RHD) can be considered as a along with poor socioenvironmental conditions leads to
In
continuum of pathological process which progresses from repeated attacks of ARF and reduces the latent period of
a subclinical stage to overtly clinical established disease RHD. This explains the usually long latent period seen in
patients from developed countries, and an earlier onset of
of
entity and is a long-term sequelae of acute rheumatic
fever (ARF). In the last few decades, with the advent of clinical RHD in the poor countries like India. RHD, when
easily available echocardiograms and early secondary diagnosed in the latent phase, by means of screening
echocardiography, has been termed latent or subclinical
ty
prophylaxis even in the developing countries, a remarkable
decrement in the global burden of the RHD has been RHD, and further classified as borderline or definite.2
18 cie
noticed. Underdeveloped countries still remain a hub for
this disease. The rheumatic process if diagnosed before
clinical symptoms develop, i.e. in the early stage/latent
PREVALENCE OF CLINICAL AND
SUBCLINICAL RHD
period is referred as ‘subclinical RHD”. Criteria have been The prevalence of RHD, based on previous studies is varies
20 o
developed by World Heart Federation (WHF) to identify the among different parts of the world and ranges between 3.4
S
disease in its early phase and to differentiate it from normal to 444 cases per 1,00,000.3 Prevalence of clinical RHD in
physiological variants. Early institution of secondary India is 0.8/1000, based on a survey study among school
prophylaxis, in this cohort, will halt the disease process and children in northern India,whereas it is 20.4/1000 for
al
improve morbidity as well as mortality of RHD. subclinical RHD, which is significantly higher and assures
the role of screening echocardiography. 3 The burden
ic
INTRODUCTION of RHD worldwide ranges from 62 million to 78 million

people, resulting in 1.4 million deaths per year from RHD
og
Twenty first centur y, labeled as the era of non-

communicable diseases, is more so relevant for the and related complications.4
developed part of the world. But still the developing W i t h t h e a d v e n t o f n e w e c h o c a rd i o g r a p h i c
ol
countries, is struggling with infectious diseases. This also techniques, RHD process has been tried to be fully
holds true for rheumatic heart disease (RHD), which is addressed but variations in reporting still exist. In light
of these existing differences, World Heart Federation
di
a common cause of cardiovascular morbidity, especially

in children and young adults, only next to congenital (WHF) had developed standardized echocardiographic
criteria for RHD diagnosis. 5 WHF has classified the
ar
heart defects. RHD is a sequelae of acute rheumatic fever

(ARF), and attributed mostly to the lower socioeconomic echocardiographic findings as definite RHD, borderline
status with overcrowding and poor sanitation status. The RHD and normal. ‘Definite RHD’ and ‘borderline RHD are
C
improved socioeconomic status with revolutionary use further subcategorized on into four and three subgroups
of benzathine penicillin in early phases of the disease respectively. Criteria to differentiate pathological mitral
process or even after pharyngitis, almost eliminated regurgitation (MR) and aortic regurgitation (AR) from
advanced RHD from the developed countries. However, in functional variants have also been described, enabling
countries like India, though the prevalence has decreased, definite diagnosis of early subclinical RHD.
the burden of RHD is significant. These criteria enable early, rapid and consistent
According to a recent multinational registry (REMEDY) diagnosis of RHD in individuals where clear history of ARF
report, RHD is mostly diagnosed in advanced stages is lacking.
(63.9%) 1 , when valve replacement remains the only
management option left. RHD pathogenesis can be IS EARLY RECOGNITION BENEFICIAL?
considered as a long-term continuous process, where Recognition of rheumatic process in early phase with
interventions in the early phase have been shown to timely initiation of secondary prophylaxis is the main
minimize the structural damage of heart and offers concern as it has been shown to halt the progression of
KG-11.indd 74 02-11-2018 13:47:55

the disease process, leading to improved morbidity and Subcategory A—RHD of the Mitral Valve with CHAPTER
mortality in these patients. Regurgitation
The emphasis on mass screening of population
by echocardiography is to provide the actual data
Defined as pathological MR and at least two morpho- 11
logical features of RHD of the mitral valve. Grade B

regarding RHD burden in the community and for better
recommendation for this subcategory inclusion in
understanding of the pathophysiologic process of
‘definite RHD.’
rheumatism. This in turn may help in the planning and
implementation of various RHD control programs at
national or international levels. However, direct benefits of Subcategory B—RHD of the MV with Stenosis
screening echocardiogram for recognition of RHD burden, Defined as mitral stenosis (MS) with a mean gradient
and the influence it has on the natural course of disease, is ≥4 mm Hg and at least two morphological changes of RHD
a
yet to be established. of the MV. Grade B recommendation for this subcategory
di
inclusion in ‘definite RHD’.
DIAGNOSTIC CRITERIA FOR LATENT RHD
In
According to WHF guidelines, suspected RHD cases
Subcategory C—RHD of the Aortic Valve
should undergo echocardiography with the knowledge of
patient’s clinical profile and pretest probability of RHD. It Defined as pathological aortic valve (AV) and at least two
of
is important to exclude other possible causes of valvular morphological features of RHD of the AV.This subcategory
heart diseases (congenital/acquired/degenerative) before only applies to individuals aged <35 years. Grade B
stamping a rheumatic etiology. recommendation for this subcategory inclusion in
ty
Echocardiographic criteria for ‘definite RHD’ and ‘definite RHD’.
‘borderline RHD’ are depicted in Boxes 1 to 3.
DEFINITE RHD
18 cie Subcategory D—Multivalvular RHD
Subcategory D of ‘definite RHD’ is ‘borderline’ disease of
Before interpreting echocardiograms, the pretest both the AV and MV, as defined below. In individuals aged
20 o
probability of RHD in the individual must be assessed. The ≤20 years, this subcategory has a grade C recommendation
S
subcategories of ‘definite RHD’ are as follows: for its inclusion in the ‘definite RHD’ category.
al
Box 1: 2012 WHF criteria for echocardiographic diagnosis of RHD

Echocardiographic criteria for individuals aged ≤20 years
ic
Definite RHD (either A, B, C, or D):

(A) Pathological MR and at least two morphological features of RHD of the MV
og
(B) MS mean gradient ≥4 mm Hg*

(C) Pathological AR and at least two morphological features of RHD of the AV‡
(D) Borderline disease of both the AV and MV§
ol
Borderline RHD (either A, B, or C):

(A) At least two morphological features of RHD of the MV without pathological MR or MS
(B) Pathological MR
di
(C) Pathological AR
Normal echocardiographic findings (all of A, B, C, and D):
ar
(A) MR that does not meet all four Doppler echocardiographic criteria (physiological MR)
(B) AR that does not meet all four Doppler echocardiographic criteria (physiological AR)
(C) An isolated morphological feature of RHD of the MV (for example, valvular thickening) without any associated pathological stenosis or
C
regurgitation
(D) Morphological feature of RHD of the AV (for example, valvular thickening) without any associated pathological stenosis or regurgitation
Echocardiographic criteria for individuals aged >20 years
Definite RHD (either A, B, C, or D):
(A) Pathological MR and at least two morphological features of RHD of the MV
(B) MS mean gradient ≥4 mm Hg*
(C) Pathological AR and at least two morphological features of RHD of the AV, only in individuals aged <35 years‡
(D) Pathological AR and at least two morphological features of RHD of the MV
*Congenital MV anomalies must be excluded. Furthermore, inflow obstruction due to nonrheumatic mitral annular calcification must be
excluded in adults.
‡
Bicuspid AV, dilated aortic root, and hypertension must be excluded.
§
Combined AR and MR in high prevalence regions and in the absence of congenital heart disease is regarded as rheumatic.
Abbreviations: AR, aortic regurgitation; AV, aortic valve; MR, mitral regurgitation; MS, mitral stenosis; MV, mitral valve; RHD, rheumatic heart
disease; WHF, World Heart Federation.
75
KG-11.indd 75 02-11-2018 13:47:56

SECTION Box 2: Criteria for pathological regurgitation has been shown to improve the sensitivity of the criteria
(at the expense of specificity) in individuals aged ≤20
2
Pathological mitral regurgitation
(All four Doppler echocardiographic criteria must be met) years, as this age group benefits the most from early
zz Seen in two views detection and secondary prevention. Beyond 20 years of
zz In at least one view, jet length ≥2 cm*
age, mild valvular regurgitation is relatively common,7 and

zz Velocity ≥3 m/s for one complete envelope
zz Pansystolic jet in at least one envelope use of the term ‘borderline RHD’ category is not, therefore,
Pathological aortic regurgitation
entertained (level 2+ evidence). Echocardiographic
(All four Doppler echocardiographic criteria must be met) findings that fulfill criteria for ‘borderline RHD’ represent
zz Seen in two views early RHD in some individuals,6 but might even represent
zz In at least one view, jet length ≥1 cm*
normal findings in others.8 Thus, these echocardiographic
zz Velocity ≥3 m/s in early diastole
zz Pandiastolic jet in at least one envelope

findings should be interpreted in the light of individual’s
a
*A regurgitant jet length should be measured from the vena contracta
pretest probability of RHD. The subcategories of
di
to the last pixel of regurgitant color (blue or red). ‘borderline RHD’ (A–C) are listed below:
In
Subcategory A—Morphological Features of
Box 3: Morphological (Echocardiogram) features of RHD
the MV
Features in the MV
AMVL thickening* ≥3 mm (age-specific)‡ Characterized by at least two morphological features of
of
zz
zz Chordal thickening
§
RHD of the MV without pathological MR or MS. Grade
zz Restricted leaflet motion
zz Excessive leaflet tip motion during systole

|| C recommendation for this subcategory inclusion in
‘borderline RHD’.
ty
Features in the AV
zz Irregular or focal thickening¶
Subcategory B—MV Regurgitation
zz Coaptation defect
zz Restricted leaflet motion
zz Prolapse
18 cie Defined as pathological MR. Grade B recommendation for
this subcategory inclusion in ‘borderline RHD’.
Important considerations
20 o
*AMVL thickness should be measured in diastole at full excursion, at the
thickest portion of the leaflet. It is cimportant to include focal thickening, Subcategory C—AV Regurgitation
S
beading, and nodularity. The frame with maximal separation of chordae

from the leaflet tissue is to be carefully selected and it is important Defined as pathological AR. Grade B recommendation for
to ensure optimal gain settings without harmonics and a ultrasound this subcategory inclusion in ‘borderline RHD’.
al
frequency ≥2.0 MHz.

‡
Age-specific cutoffs for AMVL thickening include: ≥3 mm for individuals
LIMITATIONS FOR WHF CRITERIA
ic
aged ≤20 years; ≥4 mm for individuals aged 21–40 years; ≥5 mm for

individuals aged>40 years. Harmonic imaging tends to overestimate
The WHF criteria (2012) were introduced to pick-up
the measurements, and a thickness up to 4 mm should be considered
og
normal in those aged ≤20 years. the earliest RHD changes on valvular apparatus and to
§
Restricted leaflet motion of either the AMVL or the PMVL is usually differentiate the early rheumatic changes from normal
secondary to commissural fusion, chordal fusion or shortening or and other etiologies. Most important aspect of RHD
ol
leaflet thickening.
||
screening is to recognize the subtle structural changes
Excessive leaflet tip motion is the result of elongation of the primary
chordae, and is defined as displacement of the tip of an involved on the valve leaflets. The guidelines do not define the
di
leaflet towards the left atrium resulting in abnormal coaptation and standardized screening protocol to identify these minor
regurgitation. Excessive leaflet tip motion does not need to meet the and specific changes. These criteria are formulated
standard echocardiographic definition of MV prolapse disease, as it
ar
on basis of 2D, color-Doppler, and continuous-wave-

refers to a different disease process. This feature applies to only those
aged <35 years. In the presence of a flail MV leaflet in the young (≤20 Doppler echocardiography findings. All these modalities
years), this single morphological feature is itself sufficient to meet the may not be available in the portable echocardiography
C
morphological criteria for RHD (exception to the criteria “at least two machines those are used for screening in the developing
morphological features of RHD of the MV”).
¶ countries, especially at the community level, which may
In the parasternal short axis view, the right and noncoronary aortic cusp
closure line may appears echogenic, giving an appearance of thickened underestimate the disease burden. So, authorities argue
valve, in healthy individuals and this should be considered as normal. for the role of these portable machines in screening of
Abbreviations: AMVL, anterior mitral valve leaflet; PMVL, posterior latent RHD cases. Newer echocardiographic parameters
mitral valve leaflet AV, aortic valve; MV, mitral valve; RHD, rheumatic
such as vena contracta width, proximal isovelocity surface
heart disease
area, and effective regurgitant orifice area,which have
been formulated to categorize the severity of regurgitant/
BORDERLINE RHD stenotic lesion, have not been incorporated in the WHF
This category applies to individuals aged ≤20 years, criteria.
since these patients are the least likely to have developed Pansystolic/pandiastolic jet has been accepted as
echocardiographic features to fulfil the ‘definite RHD’ pathological regurgitation characteristic of RHD, but is
76 criteria (level 2+ evidence). 6 Inclusion of this category not sufficient enough to specify the etiology. Jet length,
KG-11.indd 76 02-11-2018 13:47:56

the traditional quantification method,also has significant MANAGEMENT OF BORDERLINE RHD CHAPTER
interobserver variability. 9-10 Jet length may be altered
11
In low risk zones, minor echocardiographic features
by the loading status and systemic blood pressure suggestive of ‘borderline RHD’ may be cautiously ignored
leading to improper disease stratification, though this as normal variant, whereas in high risk zones,even in the

might be negligible in individuals undergoing screening absence of positive clinical profile, these findings have to
echocardiograms, who would be essentially stable. be carefully interpreted. Though there are no guidelines
for use of secondary prophylaxis in this group of patients,
TARGETS FOR SCREENING the decision is at the discretion of the treating cardiologist.
Screening echocardiography is more meaningful in Some prefer to initiate penicillin prophylaxis while others
individuals with high pretest probability for RHD. It is of prefer to follow-up these patients closely.14,15
a
more value in endemic zones and should especially be
undertaken in fields of having high probability such as in CONCLUSION
di
schools and in areas of low socio-economic class where Subclinical RHD is an initial end of a spectrum of disease
overcrowding is common.11,12 process, which remains underdiagnosed and hence
In
untreated. With screening echocardiography, this cohort
THE NATURAL HISTORY OF can be diagnosed in and treatment initiated at an earlier
SUBCLINICAL RHD
of
age as compare to clinically detected RHD, thereby
It takes years for a subclinical case to develop overt RHD. rheumatic process can be halted and adverse morbidity
The time taken for conversion depends on the risk of and mortality can be avoided significantly. The role and
ty
cost effectiveness of screening echocardiography and the
recurrent infections and lack of secondary prophylaxis.
implications it has on the already overburdened health
This appears to be the reason behind the difference
18 cie
in age of presentation between developed (third –
fourth decade) and developing (second- third decade)
system in our setting and the role of secondary penicillin
prophylaxis in “borderline RHD” patients’ needs to be
validated.
countries. The repeated episodes of ARF increase the risk
20 o
of complications at an earlier age.
The importance of early diagnosis of RHD in subclinical REFERENCES
S
stage lies in the fact that early initiation of prophylaxis 1. Longo-Mbenza B, Bayekula M, Ngiyulu R, et al. Survey
favorably affects the natural course of the disease. of rheumatic heart disease in school children of Kinshasa
al
Late diagnosis of RHD, usually when associated with town. Int J Cardiol. 1998;63(3):287-94.
complications, is a major cause of RHD-related morbidity 2. Bach JF, Chalons S, Forier E, et al. 10- Year educational
ic
programme aimed at rheumatic fever in two French

and mortality. Important reasons for the same include
Caribbean islands. Lancet. 1996;347(9002):644-8.
lack of awareness among the public and difficulties in
3. Saxena A, Ramakrishnan S, Roy A, et al. Prevalence and
og
availing effective modes of surgical management in outcome of subclinical rheumatic heart disease in India:
underdeveloped countries. Performing a controlled The RHEUMATIC (Rheumatic Heart Echo Utilisation and
trial to evaluate the role of penicillin prophylaxis in Monitoring Actuarial Trends in Indian Children) study.
ol
subclinical RHD would be ethically unfeasible, as it is Heart. 2011;97(24):2018-22.

would necessitate withholding prophylaxis to individuals 4. Zühlke L, Mayosi BM. Echocardiographic screening for
di
with WHF-identified ‘definite RHD’.13 The easy availability subclinical rheumatic heart disease remains a research tool
of benzathine penicillin along with its low cost and pending studies of impact on prognosis. Curr Cardiol Rep.
ar
demonstrated benefits for future ARF mandates its use in 2013;15(3):343.

subclinical RHD. Similarly, there is also no evidence for 5. Wilson BRN, Steer A, Ferreira B, et al. World Heart
Federation criteria for echocardiographic diagnosis of
C
institution of secondary prophylaxis in ‘borderline RHD’,

rheumatic heart disease—an evidence-based guideline.
opening up a window for future trials.14,15
Nat Rev Cardiol. 2012;9(5):297-309.
6. Va s a n R S, Sh r i va s t ava S, Vi jaya ku ma r M , e t a l .
MANAGEMENT OF DEFINITE RHD Echocardiographic evaluation of patients with acute
Individuals labeled ‘definite RHD’ on screening echo- rheumatic fever and rheumatic carditis. Circulation. 1996;
94:73-82.
cardiogram,as per WHF criteria, should be considered to
7. Reid CL, Anton-Culver H, Yunis C, et al. Prevalence
have RHD regardless of the clinical profile, and secondary
and clinical correlates of isolated mitral, isolated aortic
prophylaxis should be initiated. Though no literature regurgitation, and both in adults aged 21 to 35 years (from
is available to estimate the degree of future ARF risk the CARDIA study). Am J Cardiol. 2002;99(6):830-4.
accurately in a subclinical case, enough data is available to 8. Webb R, Gentles T, Stirling J, et al. Echocardiographic
support that clinical cases with mild involvement benefit findings in a low risk population for rheumatic heart
the most by secondary prophylaxis.16,17 disease (RHD): implications for screening [Abstract ;
77
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SECTION page 283]. XVIII Lancefield International Symposium 13. Selamet Tierney ES, Graham DA, McElhinney DB, et
[online], http://www.lancefield2011.it/images/stories/ al. Echocardiographic predictors of mitral stenosis-
2 9.
pdf/riassunti_definitivo_lancefield.pdf (2011).
Chauvaud S, Fuzellier JF, Berrebi A, et al. Long-term
related death or intervention in infants. Am. Heart J.
2008;56(2):384-90.
(29 years) results of reconstructive surgery in rheumatic 14. Wilkins GT, Weyman AE, Abascal VM, et al. Percutaneous
mitral valve insufficiency. Circulation. 2001;104(12 Suppl balloon dilatation of the mitral valve: an analysis of
1):12-5. echocardiographic variables related to outcome and the
10. Scottish Intercollegiate Guidelines Network.SIGN 50: a mechanism of dilatation. Br. Heart J. 1998;60:299-308.
guideline developer’s handbook. Scottish Intercollegiate 15. Moore P. Valvular heart disease: severe congenital mitral
Guidelines Network [online] http://www.sign.ac.uk/ stenosis in infants. Circulation. 1994;89:2099-106.
guidelines/ full text/50/annexb.html (2011). 16. Tompkins DG, Boxerbaum B, Liebman J, et al. Long-
11. Webb RH, Wilson NJ, Lennon DR, et al. Optimising term prognosis of rheumatic fever patients receiving
a
echocardiographic screening for rheumatic heart disease regular intramuscular benzathine penicillin. Circulation.
di
in New Zealand: not all valve disease is rheumatic. Cardiol 1972;45(3):543-51.
Young. 2011;21(4):436-43. 17. Kassem AS, el-Walili TM, Zaher SR, et al. Reversibility of
In
12. Reeves BM, Kado J, Brook M, et al. High prevalence of mitral regurgitation following rheumatic fever: clinical
rheumatic heart disease in Fiji detected by echocardio- profile and echocardiographic evaluation. Indian J Pediatr.
graphy screening. J. Paediatr Child Health. 2011;47(7):473-8. 1995;62(6):717-23.
of
ty
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20 o S
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di
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CHAPTER 12
Natural History of Mitral and
Aortic Valve Regurgitation
a
di
INTRODUCTION past century in developed nations, now major causes of
Incidence of rheumatic fever (RF) and rheumatic heart MR in Western countries are degenerative, representing
In
disease (RHD) has drastically reduced in developed 60–70% of cases, followed by ischemic (20%), endocarditis
countries since mid-twentieth century; however, they are (2–5%) and rheumatic etiology being reduced to just
still a major public health problem among children and 2–5%. 5,6 Due to the limitations in severity assessment,
of
young adults in developing countries. Around 30% to 50% natural history of organic MR has been poorly defined.
of all patients with rheumatic fever develop rheumatic Pre-echocardiography studies have shown extremely wide
heart disease.1 RHD is a major cardiac problem in India. range in 5-year survival rates from 27% to 97%, probably
ty
In an echocardiographic screening study in school related to variations in assessed severity.7 Due to scarcity
children aged 5–15 years living in rural areas of north India of studies regarding natural history of rheumatic MR in
RHD was 20.4/1000.2

18 cie
prevalence of echocardiography—Doppler diagnosed
About 25% of all patients with RHD have isolated

pre-echocardiography era, the best natural history data
available are from studies of patients with mitral valve
prolapse (MVP) and flail mitral leaflet. It is assumed that
20 o
mitral stenosis (MS), and about 40% have combined MS
these findings may be applied to MR of other causes,
and mitral regurgitation (MR). Multivalvular involvement
S
including rheumatic.
is seen in 38% of patients, with the aortic valve affected in
about 35% and the tricuspid valve in about 6%. Isolated
Rate of Progression of MR
al
MR accounts for 10–15% of chronic RHD patients. The

pulmonic valve is rarely affected. The interval between Valvular lesions tend to progress resulting in worsening
the initial episode of RF and clinical evidence valvular
ic
hemodynamic consequences which ultimately leads

involvement is variable, ranging from a few years to more to clinical deterioration. This relentless progression of
than 20 years.3
og
valvular lesions and their subsequent clinical sequelae is

Unlike stenotic valvular lesions in whom symptoms the rationale for regular monitoring of these patients. In
are early to appear, chronic valvular regurgitant lesions
MR, the severity of regurgitation is an essential determinant
remain asymptomatic till very late, till left ventricular (LV)
ol
of hemodynamic load8 and of LV remodelling.9 It also

dysfunction sets in. As aptly said by Sir William Withey
determines the clinical outcomes, with subsets having
Gull that “Diseases are but parts of a course of natural
di
history”, understanding the natural history of valvular mild MR tend to have a more benign course with excellent
lesions is necessary to plan timely interventions and to survival,10 while those with severe MR often develop LV
ar
caution the patient regarding prognosis.4 Natural history dysfunction and congestive heart failure, and have poor
of RHD can no longer be observed in present era due to survival.11,12
C
ethical considerations and has been extrapolated from Enriquez-Sarano et al. did a prospective study of
older studies or from observations of patients who for MR, assessed using transthoracic echocardiography
various reasons were not subjected to surgical therapy. to define quantitatively the degree and progression of
Isolated organic pulmonary and tricuspid regurgitation MR.13 They studied the hypothesis that the regurgitant
are very rare and are mostly secondary to pulmonary volume (RVol) of MR increases progressively over time,
artery hypertension (PAH) that follows severe valvular and also examined the determinants of the sequelae of
involvement of aortic and mitral valves. This article this progression. Total of 74 patients were prospectively
describes in brief the natural history of isolated mitral and studied with two quantitative Doppler echocardiographic
aortic regurgitant lesions. assessment of MR done on an average 1.5 years apart.
Predominant etiology of MR was mitral valve prolapse
NATURAL HISTORY OF MITRAL (MVP, n = 64) while 10 patients had restricted motion.
REGURGITATION The average rate of progression of RVol, regurgitant
RHD is still the most common cause of MR in developing fraction (RF) and effective regurgitant orifice (ERO) was
world. However, due to gradual decline in RHD over the 7.4 mL/year, 2.9%/year and 5.9 mm2/year respectively.
KG-12.indd 79 02-11-2018 13:47:48

SECTION Patients who had restricted motion as etiology of MR diabetes, atrial fibrillation (AF) and the ejection fraction,
have significantly slow progression as compared to those ERO was the only parameter which independently
2 with stable MVP. New flail leaflet significantly accelerated
the progression of MR as compared to stable MVP. The
predicted survival. ERO was also a powerful predictor of
the risk of cardiac events. The five-year rates of cardiac
degree of regurgitation is determined by the ERO, the events, defined as death from cardiac cause, congestive
transvalvular gradient and the duration of regurgitation. heart failure (CHF) and new onset AF were significantly
In this study the main determinant of progression of higher among those with ERO of 40 mm2 or more (62 ± 8%)
MR was an increase in ERO. There was also a regression as compared to those with ERO between 20 to 39 mm2 (40
of MR in 11% of the study group. Contrary to the ERO, ± 7%) and ERO less than 20 mm2 (15 ± 4%). The RVol also
which was the major determinant of progression of MR, predicted the rate of five-year cardiac events, those with
hemodynamic variables like major reduction in blood RVol of less than 30 mL/beat, 30-59 mL/beat and 60 mL/
a
pressure, peripheral vascular resistance and wall stress beat or more had rate of five-year cardiac events at 17 ±
di
were the main contributors for regression of MR. 4%, 32 ± 6% and 55 ± 7% respectively. This study showed
that those with ERO of 40 mm2 or more and RVol of 60 mL/
In
Outcome of Asymptomatic Severe MR beat or more have a significantly high risk of cardiac events
Patients with organic MR who are symptomatic or have and of mortality, and these subsets of patients should be
developed left ventricular systolic dysfunction are at considered for surgery, even when asymptomatic, while
of
high-risk12,14 and warrant immediate surgical correction.15 others can be safely followed up medically.
Chronic severe MR may remain asymptomatic for many Left ventricular ejection fraction (LVEF) and progressive
years.16 The clinical outcome and criteria to define high- LV dilation are strong predictors of late survival in patients
ty
risk subgroups of patients with asymptomatic MR is with chronic asymptomatic severe MR. Patients with
not well defined. Identifying such high-risk subgroup is LVEF ≥ 60% have excellent long-term survival, however
18 cie
important to offer timely intervention and reduce both
mortality and morbidity. Most of the data is from studies
development of LV dysfunction (LVEF <60%) and LV
dilation (LVIDs > 45 mm) carry poor prognosis.21,22 Patient
from patients with flail leaflets with severe MR (Table 1). who underwent surgical correction with preoperative
20 o
The clinical outcome of asymptomatic MR was studied LVEF ≥ 60% had 10-year survival of 72 ± 4% as compared
S
in a prospective study involving 456 patients followed to 53 ± 9% and 32 ± 12% with preoperative LVEF of 50-60%
for 11.7 years with echocardiographic quantification of and <50% respectively.22 In a study of 739 patients with
MR.17 The majority of patients were elderly males in their MR due to flail leaflets a lower threshold of LVIDs ≥ 40
al
sixth decade with MVP as the major etiology. The mean mm was associated with poor outcomes not only in those
survival was 96 ± 1% at 1 year and 78 ± 3 by five years. who were conservatively managed but also in those who
ic
The severity of MR assessed by ERO strongly predicted underwent surgical correction. In conservatively managed
the likelihood of survival. The five-year survival rate was patients 10-year survival with LVIDs <40 mm was 64 ± 5%
og
highest among those with an ERO of less than 20 mm2 (91 as compared to just 48 ± 10% in those with LVIDs ≥ 40
± 3%), and lowest among those with ERO of 40 mm2 and mm.23 The AHA/ACC guidelines endorse a threshold of
more (58 ± 9%). While those with ERO between 20 to 39 LVIDs ≥ 40 mm for surgical correction whereas European
ol
mm2 had a five-year survival rate of 66 ± 6%. The observed guidelines maintain a threshold of ≥ 45 mm.24
survival rate was no different than the overall population Development of new onset AF and PAH both carry
di
for those with ERO less than 20 mm2 (91 ± 3 vs. 86%) but poor long-term prognosis and are indicators of early
was significantly reduced in those with ERO of 40 mm2 or surgical correction25,26. Eight-year post-operative survival
ar
more (58 ± 9 vs. 78%). Increasing age, diabetes and a larger is significantly poor at 58.6% in patients who had
ERO all predicted the survival. After adjusting for age, sex, preoperative PAH with pulmonary artery systolic pressure
C
Table 1: Clinical outcome of asymptomatic organic mitral regurgitation under medical management
Study Number of patients Etiology of MR Severity of MR Yearly mortality Yearly cardiac events
Enriquez-Sarano et al.17 198 Organic Severe 9% 15%
18
Rosenhek et al. 132 Degenerative Severe 1% 6%
14
Avierinos et al. 153 MVP Moderate to severe 6% 14%
19
Ling et al. 229 Flail leaflets Severe 4.1% 10–11%
20
Grigioni et al. 360 Degenerative Severe 6% 10–11%
11
Rosen et al. 31 Organic Severe - 10%
Abbreviations: MR, mitral regurgitation, MVP, mitral valve prolapse.
80
KG-12.indd 80 02-11-2018 13:47:49

(PASP) ≥50 mm Hg as against 86.6% in those who had a CHAPTER
Table 2: Parameters associated with poor long-term prognosis in
preoperative PASP <50 mm Hg.26 In those asymptomatic patients with asymptomatic severe mitral regurgitation.
severe MR patients without PAH, a subset of patients who
develop exercise induced significant increase inPASP to
Parameter Reference 12
ERO ≥ 40 mm2 Enriquez-Sarano M et al.17

more than 60 mm Hg carry poor prognosis.27
Left atrial (LA) enlargement occurs as a consequence LVEF < 60% Enriquez-Sarano M et al.22
of volume overload in organic MR. Le Tourneau et al. LVIDs > 40 mm Enriquez-Sarano M et al.22
conducted a prospective study of 492 patients with organic New onset AF Badhwar V et al.25
severe MR in sinus rhythm to analyse prognostic role of
PASP ≥ 50 mm Hg Le Tourneau T et al.26
LA volume28. Patients with LA volume indexed to body
surface area (LA index) ≥60 mL/m 2 had a lower 5-year Exercise induced PASP > 60 mm Hg Magne J et al.27
a
survival at 53 ± 8.6% as compared to those with LA index LA index ≥60 mL/m2 Le Tourneau T et al.28
di
40 to 59 mL/m2 (84 ± 4.8%) and <40 mL/m2 (90 ± 3%). Five- Abbreviations: ERO, effective regurgitant orifice, LVEF, left ventricular
year risk of cardiac events which included cardiac death, ejection fraction, LVIDs, left ventricular end systolic dimension, AF,
In
AF or CHF, were significantly higher in patients with LA atrial fibrillation, PASP, pulmonary artery systolic pressures, LA index,
left atrial volume indexed to body surface area.
index ≥60 mL/m2 (63 ± 8%) as compared to those with LA
index 40 to 59 mL/m2 (31 ± 6%) and <40 mL/m2(9.7 ± 3%).
Ling et al. conducted a clinical follow-up study of 229
of
Rosenhack et al. conducted a study of 132 asympto-
patients with isolated MR due to flail leaflet.19 The overall
matic severe degenerative MR patients, who were
mortality rate of patients treated medically was 6.3%
prospectively followed for up to 6 years.18 Asymptomatic
ty
yearly, which was significantly higher than the general
MR patients had the same survival as that of total
population. Old age, presence of symptoms and LV
cumulative study population, showing that asymptomatic
18 cie
severe MR does not affect the survival. Twenty-four (18%)
patients over 6 years (3%/year) progressed to symptomatic
dysfunction were all associated with increased mortality.
Patients in New York Heart Association (NYHA) functional
class I (asymptomatic) or II (mildly symptomatic) had
status. Only five (4%) patients developed asymptomatic mortality rate of 4.1% yearly, as compared to very high
20 o
LV dysfunction during the study period. Asymptomatic 34% yearly mortality rate in those in NYHA class III or
progressive LV dilation, reaching the stage of surgical
S
IV. Those with preserved LVEF of ≥ 60% had a linearized

threshold of LV end-systolic diameter (LVIDs) of more than yearly mortality rate of 5.3% as against 11.3% in those with
45 mm was reached in four (3%) patients. PAH and new reduced LVEF of <60%. Cardiac complications of CHF, AF,
al
onset AF developed in 2.5% each during the study duration thromboembolism and infective endocarditis occurred
on 6 years. Overall survival free of any indication of surgery with linearized yearly rates of 8.2% yearly, 2.2% yearly,
ic
was 92%, 78% and 65% at 2 years, 4 years and 6 years 1.9% yearly and 1.5% yearly, respectively.
respectively. The most common indication for surgery was Summarising, patients with asymptomatic severe MR
og
development of new symptoms and in majority, symptom have excellent outcomes and should be carefully followed
onset preceded development of LV dysfunction. This study medically till either they become symptomatic or reach
showed that patients with asymptomatic severe MR have currently proposed criteria for surgery. Those who are
ol
excellent outcomes when carefully followed medically symptomatic and/or have developed LV dysfunction
till either they become symptomatic or reach currently should undergo early surgical correction, preferably mitral
di
proposed criteria for surgery with respect to LV size, LV valve repair.

function, PAH or development of new onset AF.
ar
Table 2 lists various parameters which carries poor NATURAL HISTORY OF AORTIC
long-term prognosis in patients with asymptomatic severe
REGURGITATION
C
MR, which can be used for selecting patients for early

surgical correction. The most common cause of chronic aortic regurgitation
(AR) in developed countries is bicuspid aortic valve and
sclerodegenerative aortic valve disease, however, in
Outcome of Symptomatic Severe MR developing nations including India, RHD is still the major
Unlike asymptomatic severe MR which has a more benign etiology of AR. Natural course of the disease in most patients
course, there is a rapid clinical deterioration associated with AR is chronic with slowly progressive LV volume and
with poor outcomes once symptoms appear. Surgical pressure overload, resulting in compensatory eccentric LV
correction alleviates the symptoms in severe chronic MR, hypertrophy and dilation.30 These compensatory changes
however, when done in already symptomatic patients, keep the patient relatively asymptomatic for a very long
residual postoperative LV dysfunction persists, leading to time, however eventually decompensation occurs leading
poor long-term prognosis.22,29 to fall in LVEF and development of heart failure symptoms.
81
KG-12.indd 81 02-11-2018 13:47:49

SECTION Both the onset of symptoms and development of LV year. In asymptomatic patients, out of the baseline LV
dysfunction are ominous and carry a poor prognosis.31-33 parameters only the baseline LVEF and LVIDs corrected
2 Current guidelines recommend surgical correction
in patients with symptomatic AR and those with LV
for BSA (LVIDs/BSA) were independent predictors of
mortality. Asymptomatic individuals with LVEF ≥55% had
dysfunction,15 however, patients with asymptomatic severe a 10-year survival and linearized annual mortality rate of
AR with normal LV function pose a unique problem in that 83 ± 5% and 2%/year respectively, as against low 10-year
the appropriate timing of surgical intervention in these survival of 53 ± 13% and high linearized annual mortality
patients is still not well defined. Understanding the natural rate of 5.8%/year for asymptomatic patients with LVEF
history of chronic severe AR helps us for prognostication <55%. Asymptomatic individuals under conservative
and to plan timely interventions. Table 3 mentions natural treatment who had higher baseline LV dimensions with
history of severe chronic AR and factors influencing the LVIDs/BSA of ≥25mm/m2 had a low 10-year survival of
a
clinical outcomes. Table 4 briefly summarises few key 34 ± 10% as compared to 81 ± 5% when baseline LVIDs/
di
observational studies of asymptomatic severe AR. BSA was <25mm/m2. The respective linearized annual
Dujardin et al. followed 246 patients with conservatively mortality rate in these two groups was 7.8%/year and
In
managed severe to moderately severe AR over a period of 1.6%/year respectively. Apart from high mortality rate
7 ± 3 years.32 The overall 10-year survival in the whole in conservatively managed patients of severe AR, these
study population was 66 ± 5% which was significantly patients also showed a high cardiovascular morbidity. By
of
less than that in age and sex matched control population. 10 years 83 ± 6% patients developed some cardiovascular
The overall linearized annual mortality rate, was 4.7%/ event (a composite of death, surgery, CHF, new onset AF,
year. Symptoms were the major determinant of survival. endocarditis and vascular complications). CHF occurred
ty
Asymptomatic patients (NYHA I) had a 10-year survival in 47 ± 6% by 10 years with a rate of 6.2%/year. Higher
of 75 ± 5% and a linearized annual mortality rate of 3%/ baseline LV dimension, NYHA class, age and systolic
18 cie
year. In contrast those with significant symptoms (NYHA
III/IV) had just 28 ± 12% 5-year survival and a very high
blood pressure were all predictors of CHF. The incidence
of new onset AF and bacterial endocarditis were low at
linearized annual mortality rate of 24.6%/year. Those 0.9%/year and 0.2%/year respectively. Eventually 62 ±
20 o
with mild symptoms (NYHA II) had a 10-year survival of 4% patients required aortic valve surgery by 10 years at
S
59 ± 11% and a linearized annual mortality rate of 6.3%/ linearized annual rate of 14.6%/year.
al
Table 3: Natural history of severe aortic regurgitation and parameters influencing the prognosis
Baseline parameter Event Annual rate Reference
ic
Symptoms NYHA 1 Mortality 3%/year 32

NYHA II Mortality 6.3%/year
og
NYHA III/IV Mortality 24.6%/year

LVEF ≥55% Mortality 2%/year 32
ol
<55% Mortality 5.8%/year

$
Exercise change in LVEF No change Cardiac events 1%/year 34
di
>5% decrease Cardiac events$ 12%/year

Exercise ≤49% Cardiac events$ 8.8%/year 35
ar
LVEF
≥57% Cardiac events$ No events
C
2
LVIDs LVIDs/BSA of ≥25 mm/m Mortality 7.8%/year 32
2
LVIDs/BSA of <25 mm/m Mortality 1.6%/year
LVIDs ≥50 mm Cardiac events$ 19%/year 34
$
LVIDs <50 mm Cardiac events 6%/year
$
LVIDd ≥70 mm Cardiac events 10%/year 34
$
<70 mm Cardiac events 2%/year
CHF 6.2%/year 32
New AF 0.9%/year 32
Endocarditis 0.2%/year 32
Abbreviations: NYHA, New York Heart Association, LVEF, left ventricular ejection fraction, LVIDs, left ventricular end-systolic dimension, LVIDd,
left ventricular end-diastolic dimension, CHF, congestive heart failure, AF, atrial fibrillation, $, cumulative of cardiac death, symptoms or left
ventricular dysfunction.
82
KG-12.indd 82 02-11-2018 13:47:49

CHAPTER
Table 4: Various prospective observational studies of natural history of asymptomatic severe aortic regurgitation
Study Number Mean follow-
up (years)
Cardiac events$
(%/year)
Asymptomatic LV dysfunction
(%/year)
Mortality
12
Bonow et al.34 104 8 3.8 0.5 2

35
Borer et al. 104 7.3 6.2 0.9 4
36
Tornos et al. 101 4.6 3.0 1.3 0
40
Tarasoutchi et al. 75 10 4.7 0.1 0
41
Siemienczuk et al. 50 3.7 4.0 0.5 0
42
Scognamiglio et al. 30 4.7 2.1 2.1 0
a
43
Scognamiglio et al. 74 6 5.7 3.4 0
di
44
Evangelista et al. 31 7 3.6 NA 1
45
Ishii et al. 27 14.2 3.6 NA 0
In
Total 593 6.6 4.3 1.2 0.18%/year
Abbreviations: LV, left ventricle, $, cumulative of cardiac death, symptoms or left ventricular dysfunction.
of
Bonow et al. prospectively followed 104 patients of <60% independent predicted new symptom onset or
asymptomatic severe AR for a mean period of 8 years.34 development of LV dysfunction.36
ty
Most asymptomatic patients with chronic severe AR and In a prospective study of 160 patients of asymptomatic
normal LV systolic function had good prognosis with severe AR followed up for a median of 7.2 years,
18 cie
medical management. At 11 years 58 ± 9% of patients
remained asymptomatic with preserved LVEF, giving
an annual event rate of less than 5%/year. Baseline LV
cardiovascular mortality was no different between those
who underwent early surgery versus those who were
conservatively followed up till symptoms or significant
LV dilation developed. 37 The 10-year survival in the
20 o
dimensions and response of exercise on LVEF predicted
the likelihood of death, symptoms or LV dysfunction. conservative group was 83%. The chances of developing
S
Patients with LVIDs ≥50 mm had likelihood of death, significant LV enlargement, new symptoms or LV
symptoms or LV dysfunction at 19%/year as against 6%/ dysfunction were only 7.4%, 0.6% and 0.9% per 10 years,
al
year when baseline LVIDs was less than 50 mm. Similarly, respectively. This study did not show any significant
patients with left ventricular end diastolic dimension differences in long-term survival between patients who
ic
(LVIDd) of ≥70 mm had likelihood of death, symptoms underwent early valve surgery versus those who were
or LV dysfunction at 10%/year as compared to just 2%/ conservatively followed. A recent long-term postoperative
og
year for baseline LVIDd of less than 70 mm. Response of study demonstrated lower mortality when patients
LVEF to exercise also predicted the cardiac events of death, underwent early surgical correction after onset of mild
symptoms or LV dysfunction. Those patients who did not symptoms (NYHA II), mild LV dysfunction (LVEF = 45–
ol
show any change in LVEF on exercise had a low event rate 50%) or mild LV dilation (LVIDs of 50–55 mm) rather than
of 1%/year as against a high rate of 12%/Year in those who delaying surgery till severe symptoms or more severe LV
di
showed >5% decrease in LVEF on exercise. dysfunction develops.38 The 15-year survival in this early
Borer et al. prospectively followed 104 asymptomatic surgery group was 78 ± 7% as compared to 53 ± 6% in those
ar
patients of chronic severe AR.35 During mean follow-up who underwent delayed aortic valve replacement with
of 7.3 years 37.5% patients developed a cumulative of more symptoms (NYHA III/IV), poorer LV function (LVEF
<45%) and more severe LV dilation (LVIDs >55 mm). In
C
cardiovascular death, symptoms or LV dysfunction at a

linearized annual rate of 6.2%/year. LVIDd and exercise EF a yet another study the surgical outcome was worse with
were independent predictors for developing symptoms. poorer baseline LVEF. The 10-year survival after aortic
Patients with exercise LVEF ≤49% had highest risk of valve replacement in patients with normal baseline LVEF ≥
development of cardiac events (death, symptoms or LV 50% was 70 ± 3%, as compared to 41 ± 9% and 56 ± 5% with
LVEF <35% and LVEF 35–50% respectively.39
dysfunction) at 8.8%/Year, whereas those with exercise
LVEF ≥57% did not develop any cardiac events during the
study period.35 CONCLUSION
Tornos et al. studied natural history of 101 patients Unlike stenotic lesions the regurgitant lesions tend to
with asymptomatic chronic severe aortic regurgitation remain asymptomatic till significant LV dilation or LV
with normal ejection fraction for a mean duration of 4.6 dysfunction develops. Most patients of asymptomatic
years. Surgery was required in 12% patients at 5 years severe MR and severe AR have benign course and can
and 24% at 10 years. Baseline LVIDs >50 mm and LVEF be safely followed up till symptoms appear or significant
83
KG-12.indd 83 02-11-2018 13:47:50

SECTION
Table 5: Current guidelines for timing of surgery in patients of chronic severe mitral regurgitation and aortic regurgitation based on
observational studies of natural history of these lesions
2 Indications for intervention in severe primary mitral regurgitation
Recommendations Class Level Reference
Surgery is indicated in symptomatic patients I B 19, 22, 29

with LVEF >30%.
Surgery is indicated in asymptomatic patients with LV dysfunction (LVIDs ≥40 I B 21, 22, 23
mm and/or LVEF <60%).
Surgery should be considered in asymptomatic patients with preserved LV IIa B 25, 26
function (LVIDs <40 mm and LVEF >60%) and atrial fibrillation secondary to
a
mitral regurgitation or pulmonary hypertension (systolic pulmonary pressure
at rest >50 mm Hg).
di
Surgery should be considered in asymptomatic patients with preserved LVEF IIa C 28
(>60%) and LVIDs 40–44 mm when a durable repair is likely, surgical risk is
In
low, the repair is performed in a heart valve centre and at least one of the
following findings is present:
zz Flail leaflet or
2
zz Presence of significant left atrial dilatation (volume index ≥60 mL/m body
of
surface area) in sinus rhythm.
Indications for intervention in severe primary aortic regurgitation
ty
Recommendations Class Level Reference
AVR is indicated for symptomatic patients with severe AR regardless of LV I B 31, 32, 38, 39
systolic function
18 cie
AVR is indicated in asymptomatic patients with resting LVEF ≤50% I B 37, 38
AVR should be considered in asymptomatic patients with resting ejection IIa B 32, 34, 36, 38, 39
20 o
fraction >50% with severe LV dilatation: LVIDd
>70 mm or LVIDs >50 mm (or LVIDs >25 mm/m2 body surface area in patients
S
with small body size)

Abbeviations: LVEF, left Ventricular ejection fraction; LVIDs, left ventricular end-systolic dimension; AVR, aortic valve replacement; LVIDd, left
ventricular end-diastolic dimension
al
ic
guideline mentioned LV dilation develops. However, with 3. Essop MR, Nkomo VT. Rheumatic and nonrheumatic
development of symptoms and LV dysfunction the further valvular heart disease: Epidemiology, management, and
og
course is associated with rapid clinical deterioration, and prevention in Africa. Circulation. 2005;112(23):3584-91.
these patients should be offered urgent surgical correction 4. Gull WW. Introductory Address on the Study of Medicine.
Br Med J. 1874;2(718):425-9.
rather than waiting for development of advanced LV
5. Olson L, Subramanian R, Ackermann D, et al. Surgical
ol
dysfunction or significant NYHA III/IV symptoms.

pathology of the mitral valve: a study of 712 cases spanning
Understanding the natural history of these lesions helps
21 years. Mayo Clin Proc. 1987;62:22–34.
di
us in precisely identifying the at-risk patients and offer 6. Enriquez-Sarano M, Freeman WK, Tribouilloy CM, et al.
them timely intervention well within the short window functional anatomy of mitral regurgitation: echocardio-
ar
period between asymptomatic status and development of graphic assessmentand implications on outcome. J Am Coll
symptoms or significant LV dysfunction. All our current Cardiol. 1999;34(4):1129–36.
guidelines for management of these regurgitant lesions are 7. Horstkotte D, Loogen F, Kleikamp G, et al. The influence of
C
based out of these observational studies of natural history heart valve replacement on the natural history of isolated
of chronic severe regurgitant lesions (Table 5). mitral, aortic and multivalvular disease. Z Kardiol. 1983;72:
494–503.
8. Bentivoglio L, Uricchio J, Goldberg H. Clinical and
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al. Progression of mitral regurgitation: a prospective Impact of preoperative symptoms on survival after
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14. Avierinos JF, Gersh BJ, Melton LJ 3rd, et al. Natural history
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15. Nishimura RA, Otto CM, Bonow RO, et al; ACC/AHA
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Task Force Members.2014 AHA/ACC Guideline for the
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17. Enriquez-Sarano M, Avierinos JF, Messika-Zeitoun D, et al. criteria predictive of late survival following valve
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18. Rosenhek R, Rader F, Klaar U, et al. Outcome of watchful 34. Bonow RO, Lakatos E, Maron BJ, et al. Serial long-term
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outcome of mitral regurgitation due to flail leaflet. N Engl J 35. Borer JS, Hochreiter C, Herrold EM, et al. Prediction of
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20. Grigioni F, Enriquez-Sarano M, Ling LH, Bailey KR, Seward or minimallysymptomatic patients with chronic aortic
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JB, Tajik AJ, et al. Sudden death in mitral regurgitation due regurgitation and normal left ventricular performance.
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21. Wisenbaugh T, Skudicky D, Sareli P. Prediction of outcome 36. Tornos MP, Olona M, Permanyer-Miralda G, et al.
after valve replacement for rheumatic mitral regurgitation Clinical outcome of severe asymptomatic chronic aortic
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in the era of chordal preservation. Circulation. 1994;89: regurgitation: a long-term prospective follow-up study. Am
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22. E n r i q u e z -S a r a n o M , Ta j i k A J, S c h a f f H V, e t a l . 37. de Meester C, Gerber BL, Vancraeynest D, et al. Early
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Echocardiographic prediction of survival after surgical surgical intervention versus watchful waiting and outcomes
correction of organic mitral regurgitation. Circulation. 1994; for asymptomatic severe aortic regurgitation. J Thorac
90(2):830-7. Cardiovasc Surg. 2015;150(5):1100-8.
23. Tribouilloy C, Grigioni F, Avierinos JF, et al. MIDA 38. Tornos P, Sambola A, Permanyer-Miralda G, et al. Long-
Investigators. Survival implication of left ventricular end- term outcome of surgically treated aortic regurgitation:
systolic diameter in mitral regurgitation due to flail leaflets influence of guideline adherence toward early surgery.
a long-term follow-up multicenter study. J Am Coll Cardiol. J Am Coll Cardiol. 2006;47(5):1012-7.
2009;54(21):1961-8. 39. Chaliki HP, Mohty D, Avierinos JF, et al. Outcomes after
24. Baumgartner H, Falk V, Bax JJ, et al. ESC Scientific Document aortic valve replacement in patients with severe aortic
Group. 2017 ESC/EACTS Guidelines for the management of regurgitation and markedly reduced left ventricular
valvular heart disease. Eur Heart J. 2017;38(36):2739-91. function. Circulation. 2002;106(21):2687-93.
25. Badhwar V, Peterson ED, Jacobs JP, et al. Longitudinal 40. Tarasoutchi F, Grinberg M, Spina GS, et al. Ten-year clinical
outcome of isolated mitral repair in older patients: results laboratory follow-up after application of a symptom-based
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SECTION therapeutic strategy to patients with severe chronic aortic 43. Scognamiglio R, Rahimtoola SH, Fasoli G, et al. Nifedipine
regurgitation of predominant rheumatic etiology. J Am Coll in asymptomatic patients with severe aortic regurgitation
2 Cardiol. 2003;41(8):1316-24.
41. Siemienczuk D, Greenberg B, Morris C, et al. Chronic
and normal left ventricular function. N Engl J Med.
1994;331(11):689-94.
aortic insufficiency: factors associated with progression to 44. Evangelista A, Tornos P, Sambola A, et al. Long-term
aortic valve replacement. Ann Intern Med. 1989;110(8): vasodilator therapy in patients with severe aortic
587-92. regurgitation. N Engl J Med. 2005;353(13):1342-9.
42. Scognamiglio R, Fasoli G, Dalla Volta S. Progression of 45. Ishii K, Hirota Y, Suwa M, et al. Natural history and left
myocardial dysfunction in asymptomatic patients with ventricular response in chronic aortic regurgitation. Am J
severe aortic insufficiency. Clin Cardiol. 1986;9(4):151-6. Cardiol. 1996;78(3):357-61.
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KG-12.indd 86 02-11-2018 13:47:50

CHAPTER 13
Natural History of Rheumatic
Mitral Stenosis
Vivek Chaturvedi
a
di
INTRODUCTION upon due to class II/III symptoms. If sick patients (class
Mitral stenosis (MS) due to rheumatic heart disease (RHD) III/IV) were not operated, 1 year survival was 80%, 5 year
In
is still an important cause of morbidity and mortality in the survival was only 38%, and at 15 years less than 10% were
low and middle income countries. The epidemiology and alive. The outcomes are even worse if only symptomatic
patients are followed up. In the study by Olesen et al.3 of
of
natural history of rheumatic MS were elegantly established
in the first 70 years or so of the previous century by studies 271 symptomatic patients (60% in class III, 60% with AF)
mostly carried out in western countries at a time when with median age of 42 years, 70% were dead at an average
ty
definitive treatment of MS was not available or scarce. Also of 11 years and 83% at an average of 18 years. Congestive
the medical treatment in terms of secondary prophylaxis, heart failure was the cause of death in 62% while 22% died
18 cie
anticoagulation, diuretics and heart rate controlling
agents was infrequent. While rheumatic MS has virtually
disappeared from the developed nations, it is still prevalent
due to thromboembolic causes.
The natural history of MS from developing countries
is markedly different than that of developed countries.
in all age groups in developing countries. The natural In these countries, rheumatic MS is a disease of much
20 o
course of the disease is very variable in these countries, younger age group (although MS is detected and treated
S
depending on socio-economic/demographic profile and routinely at all ages, suggesting varying transitions within
access to medical care, and is not well documented. This the region) implying earlier disease onset as well as
gives rise to a peculiar situation whereby data on disease
al
rapid attrition in mitral valve area.4 The exact cause for

course is available from countries where MS has ceased this is not clear, but recurrent rheumatic fever definitely
to be a public health issue, and yet insufficient evidence
ic
contributes to it. The malignancy of disease is such that

exists to guide policy and practice in countries where it still
florid symptoms can occur within the first two decades of
og
is a public health problem! In this chapter while succinct

life, leading to the entity called ‘juvenile mitral stenosis’5.
data are provided for historical natural course of MS
This type of MS has high prevalence of congestive heart
(already well documented in several excellent books and
failure, pulmonary hypertension and sub-valvular disease
ol
articles), an attempt is also made to tabulate the outcome

of patients with rheumatic MS in the current era. leading to substantial morbidity and mortality. While
long-term outcome studies for untreated MS are lacking
di
NATURAL HISTORY OF MITRAL STENOSIS IN in developing nations, these outcomes are likely to be
THE ERA PRIOR TO DEFINITIVE THERAPY of similar nature as those from the developed countries.
ar
Mitral stenosis is still a common cause for congestive heart

Natural history of untreated rheumatic mitral stenosis is
failure and thromboembolism related hospital admissions
C
well documented in the western world. In these countries,

in many parts of India.
after an attack of rheumatic fever (RF) in young age, mitral
The natural history of MS is altered by the development
stenosis typically developed with a latency of 2–4 decades.
of atrial fibrillation. While there are obvious adverse
In the classic study by Rowe,1 of the 250 patents (about
half asymptomatic) followed for 20 years, 80% were dead hemodynamic consequences, development of AF also
at the end of study. Patients who were asymptomatic at denotes structural degeneration and worsening severity.
the beginning had a gradual attrition in their status, such Additionally, almost a quarter of mortality in MS is
that only a quarter remained asymptomatic at the end. In due to thromboembolism and embolic stroke. 3 The
another representative study,2 the average period from thromboembolic risk with MS varies, depending on
attack of RF to diagnosis was 16 years. At this point, half rhythm (sinus or AF), anticoagulation, and severity, from
were asymptomatic, a third were in NYHA class II, and 0% to 5.7 per 100 patient years.2 While AF is present in
8% had been operated upon. 25 years later, less than 10% almost one third to half of all MS patients (less in younger
remained asymptomatic, while 50% had been operated patients), the rate of embolism is about 12% over 3 years.6
KG-13.indd 87 02-11-2018 13:47:41

SECTION Natural History of Unselected Mitral Stenosis markedly different, 7% and 23% respectively in the PTMC
in Contemporary Era and conventional arm, in the two groups at 11 years.
2 Few studies from recent times have looked at the
In a retrospective single center study from Thailand12
between 1996 to 2013, patients aged 18 years and over with
progression of less than severe MS when managed
isolated rheumatic MS in sinus rhythm were followed up

conservatively in asymptomatic or mildly symptomatic
for a median period of 12 years. Of 185 patients in sinus
people. It is noteworthy that some of the individuals in
rhythm with mean age of 41 years, most had moderate
these studies would be classified as having severe MS,
(27%) or severe MS (64%) and a majority underwent
thresholds for which changed recently 7 from MVA of
PTMC or MVR at baseline or follow up. Long-term adverse
≤ 1.0 cm2 to ≤ 1.5 cm2.The progression of disease in mild or
outcomes were 43% and this included 1% death and 11%
moderate disease is variable, and varies by baseline valve
hospitalizations due to heart failure. Importantly, new
a
area, geographic location, recurrence of rheumatic fever,
age of manifestation, co-existent valvular lesions, and onset AF occurred in 38% patients and 7.6% had embolic
di
presence or onset of complications of mitral valve disease. stroke. Interestingly long-term adverse outcomes were not
Studies by Gordon8 and Sagie9 in 1990s on a small affected by baseline MVA. Kim et al.13 from Korea followed
In
group of middle aged patients (50-100) with mild MS up 292 individuals with MS in sinus rhythm with a mean
in USA showed average rate of progression of MS of age of 57 years for an average period of 6 years between
approximately 0.09 cm 2/year or a reduction of 0.2–0.3 2003 to 2013. About a third of these patients had severe
of
cm2 over a period of 3–4 years. In the study by Sagie et MS as per the new guidelines, i.e. MVA ≤1.5 cm2 while the
al.9 mild MS progressed to moderate in about 15% and mean MVA was 1.4 cm2. AF developed in 20.5% with an
to severe in about 5% of patients. The clinical status of annual rate of 3.5% per year. All cause death or systemic
ty
patients was not mentioned. Another study from Israel embolism occurred in 7.2% with an annual event rate of
looked at the progression of moderate MS (MVA 1.2-1.9 approx. 2% and overall mortality was 3%.
18 cie
cm2 as per authors). Rinkewich et al.10 followed 36 patients
with pure moderate MS and a mean age of 44 years (lower
While there is a paucity of studies from South Asia
or Africa, the existent data allows deriving reasonable
conclusions about natural history of MS in current era
than the US studies) for an average of ~ 6 years. Mean loss
20 o
of MVA was 0.04 cm2/year and MVA decreased from a from this part of the world. In sub-Saharan Africa, a study
mean of 1.53 to 1.41 cm2. About 40% patients did not have by Tadeleet al.14 looked at prevalence of rheumatic MS
S
any decrease in MVA over follow up while 28% had a fast in children aged < 16 years. Of 365 children with chronic
deterioration in MVA. While no patient was in functional RHD with mean age 10 years who presented to authors’
al
class III at baseline, about 22% developed it over follow institution from 2009 to 2012, 35% had MS with 10%
up period. Thus while the progression rate was lower having pure MS. While it was not seen typically below 5
ic
than the US, smaller MVA at baseline reflected in higher years of age, the prevalence of MS among all RHD in age
rate of development of symptomatic MS. In another group 5–10 years was 25%. This further increased to 52%
og
study from South Korea, 11 244 asymptomatic patients in children above 10 years. More than half of all MS in age
with moderate MS were either followed on medical groups 10–16 years was severe. The overall prevalence
management or underwent percutaneous transvenous of severe MS was 18%, which might be due to referral
ol
commissurotomy (PTMC). Medical follow-up arm had bias. This study suggests that in sub-Saharan Africa,
138 patients with a mean age of 54 years and a mean MVA unlike developed nations, the rate of progression of MS is
di
of 1.35 cm2, while 33% had atrial fibrillation at baseline. alarmingly high in children, possibly due to predisposing
About 44% of these patients followed conservatively factors and lack of adequate secondary prophylaxis.
ar
over a median period of 8 years (maximum 11 years) Assuming that rheumatic MS is quite uncommon before
remained free of symptoms and events (defined as a the age of 5 years, this translates to a progression rate of at
C
composite of cardiovascular mortality, cerebral infarction, least 0.2-0.3 cm2/year, or more than double of that seen in
systemic embolism, procedural mortality and urgent MV developed nations.
surgery) and 27% required PTMC or surgery over follow Another registry of children with RHD with age <15
up. Estimated actuarial cardiovascular (CV) mortality years from a tertiary hospital in Northern India15 enrolled
in this group was 15% at 11 years. On the other hand, of 451 children with RHD, of which 360 reported for follow
106 individuals who underwent ‘prophylactic’ PTMC, up. Of 79 patients followed up with predominant MS,
mean age was 48 years, mean MVA 1.35 cm2, and 25% had half had severe MS. During a follow up of an average 15
atrial fibrillation at baseline. About 75% of these patients months, MS had progressed in 9 cases, regressed in none
remained free of symptoms or events at follow up and the and remained same in 39 cases. 27 had undergone PTMC
restenosis rate was 16% at 11 years. Thus it appears that while 4 had undergone surgery. 5 patients with significant
PTMC, even if done in the early stages of asymptomatic MS died over 3 year follow up, 3 were postoperative; 5
but hemodynamically significant MS, alters the natural patients had neurologic events, one being a bleed post
course of disease. Notably, the embolism rate was also mitral valve replacement. While children presenting
88
KG-13.indd 88 02-11-2018 13:47:41

to a tertiary hospital are more likely to have severe and Clinical Course of MS Patients after Relief of CHAPTER
symptomatic MS, this data points to the ongoing high Severe Valvular Obstruction
morbidity and mortality (almost 2% per year) in this group
despite getting definitive treatment.
Starting with closed mitral valvotomy (CMV), the definitive 13
management of rheumatic MS has come a long way and

REMEDY registry for RHD has reported 5232 person
includes open mitral commissurotomy (OMC), mitral
years of follow up over 2 years worldwide.16 The prevalence
valve replacement (MVR) and PTMC. There is ample
of MS was low in ages <10 years but increased with age,
evidence that these treatments favorably change the
becoming 5–7% for pure MS and 16–22% for mixed
natural history of MS, more so in the younger intervened
mitral valve disease. With a median age of 28 years for
population. However, due to ongoing inflammation
3343 children and adults, the mortality rate was 17% and
or degenerative deterioration along with extracardiac
cumulative rate of death, CHF or stroke about 20%. It is
a
likely that a large proportion of these strokes and heart complications, the morbidity and mortality remains
elevated as compared to general population and this holds
di
failure are attributable to MS.
To summarize, in the contemporary era rheumatic MS true even for mitral valve replacement.
Several authors across the world have described the
In
is a different beast in developing countries as compared
to developed nations, which probably have their last long-term course of rheumatic MS after a successful
patients of RHD (except for clustered cases in indigenous PTMC (Table 1).16-23 In western or developed populations,
where severe MS presents in middle age (~50 years), after
of
populations). In developed nations, the patients are
typically middle aged, have slow but steady progression a successful intervention there is late failure of mitral
of MS. While it is unlikely that patients with mild MS valve in approximately one-third or more of the patients.
ty
will eventually require surgery, almost half of those with Also there is approximately 10% long-term cardiovascular
moderate MS require mitral valve intervention over 10 mortality. However, most of the surviving patients, with
18 cie
years. While atrial fibrillation may be more prevalent
with severe MS, it is also seen commonly with less than
severe MS. Atrial fibrillation develops at a rate of almost
or without re-intervention, remain in NYHA I or II class.
In countries like Korea,19 the presenting age is about a
decade younger. While the cardiovascular mortality is
3% per year and is an important cause of heart failure lesser, mitral intervention rates are similar to developed
20 o
hospitalization and systemic embolism. Overall mortality nations. In other Asian and developing countries, the
S
is low and in single digits. presenting age for severe MS is about 30 years. The long-
On the other hand, rheumatic MS afflicts much younger term outcomes are much better with low mortality as well
population in endemic areas of developing countries. as low intervention rates. Most of the patients remain
al
It is commonly seen among RHD cases in the first asymptomatic or mildly symptomatic. This is probably
decade of life. The progression is quite rapid with yearly due to lower age and lesser degeneration of mitral valve
ic
reductions in MVA of as much as 0.2–0.3 cm2/year leading and left atrium. In absence of data, it would be a matter
og
to development of severe MS within a few years. The of speculation as to how these patients would be fare in
reasons for this are multi-factorial but importantly include old age. The long-term outcomes of PTMC in children
lack of adequate secondary prophylaxis. Congestive heart are similar to those in young adults.21 While discussion
ol
failure is the main cause of morbidity and mortality in the on predictors of good outcomes in the long term is not
absence of adequate medical facilities. Mortality rates are possible in this chapter, factors such as age at presentation,
di
high, as much as 2–8% per year. symptomatic class, absolute gain in mitral valve area,
ar
Table 1: Long-term outcome studies with percutaneous commissurotomy (PTMC)

Study Population profile (N) Mean age Follow up duration NYHA class Stroke/ MV intervention Death
C
(years) (years) ( I/II) % embolism (%) (%)

France17 912, 49 20 96% N/A 38% 15% (9% CV)
40% in AF
Italy18 441, 46% in AF 56 12 95% 33% 9.1%
19
Korea 742, 41% in AF 41 12 N/A 4.4 41% 4.7% (CV)
Brazil20 1250, 13% in AF 36 15.6, uptil 23 years 87% N/A 18.3% 0.6
Saudi Arabia21 474, 14% in AF 33 8.5, uptil 18 years 100% 18% 2.5%
21
Saudi Arabia 57, 5% in AF 15 8.5, till 18 years 100% 24% 1.7%
22
Tunisia 110, 6% in AF 16 10 years 87% 13% 0
23
India 3500, 15% in AF 27 8 years 92% N/A 1.1% N/A
Abbreviations: AF, atrial fibrillation; CV, cardiovascular mortality; MV, mitral valve; NYHA, New York Heart Association
89
KG-13.indd 89 02-11-2018 13:47:42

SECTION
Table 2: Long-term outcome studies with surgical valvotomy or replacement
2 Study Population Mean age

(years)
Follow-up duration (years) NYHA class
( I/II) %
Stroke/
embolism
MV intervention
(%)
Death
India24 3480, 13% in AF 27 24 maximum 80% 1.6% 22% 4.3

25
USA 267, 54% in AF 44 14 years mean, uptil 20 years 24% over 10% at 10 34% at 10 years 33% CV over 20
20 years years years
Open Mitral Commissurotomy
India26 276, 49% in AF 30 6.5 years mean, uptil 11 years 3% 8% 13% at 10 years 0
27
Italy 300, 40% in AF 43 10 years, uptil 15 years 6% 6% 2% 1%
a
Mitral Valve Replacement
di
Italy27 240. 40% in AF 43 10 years, 15 years maximum 3% 16% 12% 6%
Abbreviations: AF, atrial fibrillation; CV, cardiovascular mortality; MV, mitral valve; NYHA, New York Heart Association
In
mitral valve morphology, and presence of atrial fibrillation CONCLUSION
do have an impact on event-free survival. The natural history of rheumatic mitral stenosis (MS)
of
The first effective therapy described for severe MS was
has changed over the past half century. The presentation
closed mitral valvotomy (CMV). Long-term outcomes
in developed western as well as Asian nations usually
after successful CMV have been variable (Table 2).24-27 As
happens in middle age. The progression is slow, and
ty
pointed out before, event free survival (survival without
almost half of all with moderate stenosis end up getting
mitral valve intervention and death and with good
mitral intervention over time. Among intervened patients,
18 cie
functional status) is dependent on the age of presentation
and surgery. Thus, while the outcomes reported from
Vellore, India 24 were excellent in younger age group,
long–term outcomes are punctuated with almost 40%
re-intervention rate, but the overall mortality is low and
the functional status of event-free survivors is good. The
outcomes of CMV were only fair in the long term in USA.25
20 o
prevalence of atrial fibrillation is high and does not exactly
On the other hand, with open mitral commissurotomy
S
correlate with severity of stenosis.

(OMC) the data26-27suggests excellent long-term outcomes
The situation is vastly different in developing countries
in both younger and middle aged individuals and superior
which have varying epidemiological transitions within the
al
event-free survival. The data are similar, though possibly

country itself. In several parts, rheumatic MS presents very
inferior for mitral valve replacement.27 Presumably this
early in life and progresses rapidly to severe stenosis. A
ic
is because of implantation of a prosthetic valve, mostly

metallic, and its accompanying unique problems. significant proportion of this progression can be ascribed
to lack of adequate secondary prophylaxis. This severe
og
The prevalence of atrial fibrillation is dependent

on age at presentation. While almost 40-50% of middle MS, in absence of facilities for relief of the obstruction,
aged adults with significant MS have MS at time of in is a significant cause of congestive cardiac failure and
ol
developing countries with younger population this is premature mortality. Prevalence of atrial fibrillation
much lesser. However, as this population ages, new onset is low, but lack of anticoagulation increases risk of
di
atrial fibrillation develops in about 7%.19 Incidence of systemic embolism. In places like India, however, severe
systemic embolism can be significant (5–15%) in this MS is detected and treated in all age groups, reflecting
ar
population post PTMC, despite anticoagulation. different transitional stages of the disease. However,
To summarize, relief of valvular obstruction, relief of obstruction in this younger population leads to
percutaneous or surgical, clearly changes the natural excellent long-term relief and low rates of re-intervention
C
course of disease in MS. This is true even for asymptomatic and cardiovascular death. Further long-term studies are
or mildly asymptomatic MS11 though benefits are larger in needed to better delineate the natural history of rheumatic
severely symptomatic cases. Over a period of 10–20 years, MS in the endemic regions.
almost a third in the developed countries and 10–20%
in younger populations in developing countries require REFERENCES
a repeat mitral intervention. Taken together, more than 1. Rowe JC, Bland EF, Sprague HB, et al. Course of mitral
90% are only mildly symptomatic or asymptomatic and stenosis without surgery: Ten and twenty perspectives. Ann
less than 10% have cardiovascular mortality. Relief of Intern Med. 1960;52:741-9.
obstruction, along with anticoagulation, also decreases 2. Horstkotte D, Niehues R, Strauer BE. Pathomorphological
probability of embolism which is one of the major cause of aspects, aetiology and natural history of acquired mitral
morbidity and mortality in MS. valve stenosis. Eur Heart J. 1991;12(Suppl B):55-60.
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3. Olesen KH. The natural history of 271 patients with mitral from 14 low- and middle-income countries: two-year CHAPTER
stenosis under medical treatment. Br Heart J.1962;24:349-57. follow-up of the global rheumatic heart disease registry
4. Chandrashekhar Y, Westaby S, Narula J. Mitral stenosis.
Lancet. 2009;374(9697):1271-83. 17.
(the REMEDY Study). Circulation. 2016;134(19):1456-66.
Bouleti C, Iung B, Laouénan C, et al. Late results of
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5. Roy SB, Bhatia ML, Lazaro EJ, et al. Juvenile mitral stenosis percutaneous mitral commissurotomy up to 20 years:

in India. Lancet. 1963;282(7319):1193-6. development and validation of a risk score predicting late
6. Chiang CW, Lo SK, Ko YS, et al. Predictors of systemic functional results from a series of 912 patients. Circulation.
embolism in patients with mitral stenosis. A prospective 2012;125(17):2119-27.
study. Ann Intern Med. 1998;128(11):885-9. 18. Tomai F, Gaspardone A, Versaci F, et al. Twenty year
7. Nishimura RA, Otto CM, Bonow RO, et al; ACC/AHA follow-up after successful percutaneous balloon mitral
Task Force Members. 2014 AHA/ACC Guideline for the valvuloplasty in a large contemporary series of patients
Management of Patients with Valvular Heart Disease: a with mitral stenosis. Int J Card. 2014;177(3):881-5.
a
report of the American College of Cardiology/American 19. Kim D, Chung H, Nam JH, et al. Predictors of long-
di
Heart Association Task Force on Practice Guidelines. term outcomes of percutaneous mitral valvuloplasty in
Circulation. 2014;129:e521-643. patients with rheumatic mitral stenosis. Yonsei Med J.
8. Gordon SP, Douglas PS, Come PC, et al. Two-dimensional 2018;59(2):273-8.
In
and Doppler echocardiographic determinants of the 20. Meneguz-Moreno RA, Costa JR Jr, Gomes NL, et al. Very
natural history of mitral valve narrowing in patients with long term follow-up after percutaneous balloon mitral
rheumatic mitral stenosis: implications for follow-up. J Am valvuloplasty. JACC Cardiovasc Interv. 2018.pii: S1936-
of
Coll Cardiol. 1992;19(5):968-73. 8798(18)31204-4 [Epub ahead of print]
9. Sagie A, Freitas N, Padial LR, et al. Doppler echocardio- 21. Fawzy ME, Stefadouros M, El Amraoui S, et al. Long-term
graphic assessment of long-term progression of mitral (up to 18 years) clinical and echocardiographic results of
ty
stenosis in 103 patients: valve area and right heart disease. J mitral balloon valvuloplasty in children in comparison with
Am Coll Cardiol. 1996;28(2):472-9. adult population. J Interv Cardiol. 2008;21(3):252-9.
18 cie
10. Rinkevich D, Lessick J, Mutlak D, et al. Natural history of
moderate mitral valve stenosis. Isr Med Assoc J. 2003;5:
15-8.
22. Gamra H, Betbout F, Ben Hamda K, et al. Balloon mitral
commissurotomy in juvenile rheumatic mitral stenosis: a
ten-year clinical and echocardiographic actuarial results.
11. Kang DH, Lee CH, Kim DH, et al. Early percutaneous Eur Heart J. 2003;24(14):1349-56.
20 o
mitral commissurotomy vs. conventional management 23. Arora R, Kalra GS, Singh S, et al. Percutaneous transvenous
S
in asymptomatic moderate mitral stenosis. Eur Heart J. mitral commissurotomy: immediate and long-term follow-
2012;33(12):1511-7. up results. Catheter Cardiovasc Interv. 2002;55(4):450-6.
12. Nachom P, Ratanasit N. Incidence and predictors of long-term 24. John S, Bashi VV, Jairaj PS, et al. Closed mitral valvotomy:
al
adverse outcomes in patients with rheumatic mitral stenosis early results and long-term follow-up of 3724 consecutive
in sinus rhythm. J Med Assoc Thai. 2016;99(4):374-80. patients. Circulation. 1983;68(5):891-6.
ic
13. Kim HJ, Cho GY, Kim YJ, et al. Development of atrial 25. Rihal CS, Schaff HV, Frye RL, et al. Long-term follow-up
fibrillation in patients with rheumatic mitral valve disease of patients undergoing closed transventricular mitral
og
in sinus rhythm. Int J Cardiovasc Imaging. 2015;31:735-42. commissurotomy: a useful surrogate for percutaneous
14. Tadele H, Mekonnen W, Tefera E. Rheumatic mitral balloon mitral valvuloplasty? J Am Coll Cardiol.
stenosis in children: more accelerated course in sub- 1992;20(4):781-6.
ol
Saharan patients. BMC Cardiovasc Disord. 2013;13:95. 26. Cotrufo M1, Renzulli A, Vitale N. Long-term follow-up of
15. Rheumatic Heart Disease in Children – AIIMS. Prospective open commissurotomy versus bileaflet valve replacement
for rheumatic mitral stenosis. Eur J Cardiothorac Surg.
di
Registry. ICMR, 2012-2015. Accessed at finalreport.icmr.

org.in/SQL_FR_ABS_PDF_Disp.aspx?Type=FR&Proj_ 1997;12:335-9.
No...1 on 23/07/2018 27. Choudhary SK, Dhareshwar J, Govil A, et al. Open mitral
ar
16. Zühlke L, Karthikeyan G, Engel ME, et al. Clinical outcomes commissurotomy in the current era: indications, technique,
in 3343 children and adults with rheumatic heart disease and results. Ann Thorac Surg. 2003;7:41-6.
C
91
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Percutaneous Transvenous
Mitral Commissurotomy:
CHAPTER 14
Tips and Tricks
a
di
INTRODUCTION — Pulmonary hypertension [pulmonary artery
Rheumatic mitral stenosis (MS) continues to be an systolic pressure (PASP)>50 mm Hg at rest or >60
In
important health issue in developing countries despite mm Hg with exercise]
— Thromboembolism/atrial fibrillation (AF)
its decreasing prevalence. Before the advent of balloon
Moderate MS in pregnancy.
of
mitral valvotomy (BMV) most patients were treated with
surgical mitral commissurotomy either open or closed.
In June 1982, Japanese cardiac surgeon Kanji Inoue, first Expanding Indications
ty
performed balloon mitral valvuloplasty using a pliant Mitral restenosis
natural rubber balloon. 1 Since then, various catheter- MS with left atrial (LA) clot (Ia, Ib and IIa)
18 cie
based techniques have been developed to perform
BMV, and has evolved as the procedure of choice for
symptomatic, pliable, severe rheumatic mitral stenosis.

Moderate MR (central jets)
Moderate MS (symptomatic)
Hybrid therapy in the setting of associated aortic
With the experienced operators at high-volume centers, regurgitation (AR), aortic stenosis (AS), coronary
20 o
successful BMV can be performed in most of mitral artery disease (CAD)
S
stenosis patients even in difficult challenging situations Lutembacher’s syndrome.

with least complications.
CONTRAINDICATIONS
al
ANATOMY AND PATHOPHYSIOLOGY Persistent LA body clot, interatrial septum clot or ball
ic
The mitral valve apparatus is a complex structure valve thrombus

consisting of annulus fibrosus, mitral leaflets, chordate More than moderate MR
og
tendinae, papillary muscles, posterior left atrial wall and Densely calcified valve or bicommissural calcification.
posterior wall of left ventricle (LV). The normal mitral
valve area is 4–6 cm 2. Rheumatic mitral involvement TECHNIQUE
ol
is the most common cause of MS. 2 The MS occurs as

a progressive late sequelae of mitral valvulitis (leaflet Pre-evaluation
di
thickening, commissural fusion, chordal shortening/ The first step for successful BMV starts with detailed
fusion and calcification in more advanced forms) due to preprocedural evaluation. All patients should undergo a
ar
acute rheumatic fever. The presence of significant pressure detailed clinical, roentogenographic, electrocardiographic
gradient between left atrium and LV is the hemodynamic and echocardiographic examinations. The presence of
C
hallmark of severe MS. This results in elevated pulmonary accentuated first heart sound (S1) and audible opening
capillary wedge pressure, pulmonary vascular resistance snap of mitral valve at apex indicates mitral valve pliability.
and right ventricular dysfunction. With further decrease
in mitral valve area less than 1.5 cm2, patients become Role of Echocardiography in BMV
severely symptomatic and develop complications.
Echocardiography forms the major role in evaluation
of patients with MS. It is essential for case selection,
INDICATIONS FOR BMV intraprocedural monitoring, postprocedural assessment
All symptomatic patients and follow-up. Valve area is calculated using planimetry
Asymptomatic MS and Doppler pressure half time methods. The aim is
— Severe MS [mitral valvular orifice area (MVOA) < to identify suitability of valve and high-risk features
1 cm2] that pre deter mine the p o or outcomes. Var ious
KG-14.indd 92 02-11-2018 13:47:29

echocardiographic scoring systems were developed septal dilator. TSP can be performed in anteroposterior CHAPTER
to assess suitability for BMV. Valve suitability is most (AP), right anterior oblique (RAO), left anterior oblique
commonly assessed using Wilkins scoring system which
includes leaflet mobility, valve thickening, subvalvular
(LAO), and lateral views according to the convenience
and preference of the operators (Figures 1A to D). It is
4

thickening and valvular calcification. A score of up to 8 is preferable to confirm the site for septal puncture in two
considered suitable for BMV, although it is performed in views.
patients with higher scores in our institute. Despite high
echo score, if one of the commissures is free from calcium, Landmarks for Trans-septal Procedure
favorable results can be achieved. About 36% of the
The target site for septal puncture is located at the
patients had echo score >8 in severe MS. Higher scores >8,
intersecting point of the vertical ‘mid-line’ (dividing
severe submitral disease and commissural calcification
a
interatrial septum into anterior and posterior halves) and
results in suboptimal procedural success and increased
the horizontal M-line (crossing the center of mitral annulus)
di
postprocedural acute mitral regurgitation. Other scores
(Figures 2A and B).4 However, it is only approximation
used are Lung-Cormiers score, real-time 3D echo score,
and the site often has to be modified in individual cases
In
Reid score, Chen et al. score, and Nobuyoshi score. Other
according the morphology. The horizontal and vertical
important features like severity of mitral regurgitation,
lines were initially described by Inoue using recirculation
left atrial and right atrial size, interatrial septum thickness
right atrial angiography.5 However, angiography-guided
of
and bulge, other valve diseases, presence of any clot, and
LA opacification in levophase following PA angiogram is
pulmonary hypertension must be looked before BMV.
reserved for difficult circumstances such as dextrocardia,
Transesophageal echocardiography is performed only in
kyphoscoliosis, or giant atrium. More commonly
ty
patients with atrial fibrillation or those with suspicion of
performed fluoroscopic method, a pigtail catheter
left atrial thrombus on transthoracic echocardiography.
positioned in the noncoronary sinus of Valsalva, touching
18 cie
Tip: Proper preprocedural evaluation, echocardiographic
valve assessment and patient selection remains the first
the aortic valve, is taken as anterior septal limit in the
frontal view. The medial left atrial silhouette is usually
step to success. considered to be the posterior limit of the septum. The
20 o
vertical line bisects the anterior and posterior septal limits
BMV TECHNIQUE
S
so determined. The horizontal line crossing the center of

the mitral annulus is determined from diastolic stop frame
Approach of the left ventriculogram. 4 However, for the practical
al
BMV is routinely performed through transvenous purposes, we assume it to be about half a vertebral body
approach using Inoue or Accura balloon; rarely through to one vertebral body lower than the pigtail parked in the
ic
the jugular venous approach. noncoronary sinus.

og
Techniques Technique of Trans-septal Puncture

Inoue technique-commonly used The right femoral vein is punctured and 0.032-inch
ol
Double balloon technique guidewire introduced and positioned in the mid-portion

Metallic commissurotomy of SVC. The Mullins sheath is advanced over the guidewire
di
Multitrack technique. into SVC and guidewire removed. The dilator is aspirated
and flushed. The Brockenbrough needles is advanced
Two important steps of BMV3 are:
ar
through the dilator under fluoroscopy and make sure that

1. Septal puncture to access the left atrium.
sharp tip of the needle remains 2–3 mm inside the dilator.
2. Crossing the stenosed mitral valve.
Under fluoroscopy (AP view) and right atrial pressure
C
monitoring, the entire assembly is withdrawn gradually.

Trans-septal Puncture During the initial descent from SVC to the right atrium,
Trans-septal puncture (TSP) is the most important and the needle is oriented at 3 o’clock and rotated clockwise
challenging step during BMV. The knowledge of the from 3 to 4 o’clock to 4 to 5 or 6 o’clock during subsequent
anatomy of the interatrial septum (IAS) is very essential withdrawal. Three leftward deflections are noted during
for safe septal puncture. The IAS is bounded posteriorly by descent: the first as catheter enters the right atrium, the
fold of pericardium between atria, above by superior vena second gradual one over the ascending aortic bulge,
cava (SVC), anterosuperiorly by the noncoronary sinus, and the third deflection as catheter tip clears the limbic
anteriorly by septal tricuspid annulus, anterioinferiorly edge and engages the fossa ovalis.6 To confirm the site of
by coronary sinus os, and inferiorly by the inferior puncture, the most reliable one is to tent the site of fossa
vena cava (IVC). The equipment for septal puncture ovalis with assembly and feel for the transmitted left atrial
includes Brockenbrough needle, Mullins sheath and the pulsations. If any doubt about the site, the septal flush or
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SECTION
2
A B
a
di
In
of
ty
C
18 cie D
20 o
Figures 1A to D: Septal puncture in various views. (A) Left anterior oblique (LAO) view; (B) Anteroposterior (AP) view; (C) Right anterior
oblique (RAO) view; (D) Lateral view
S
al
ic
og
ol
di
ar
A B
Figures 2A and B: Fluoroscopic landmarks for septal puncture
C
stain method,7 and transthoracic echo to track the plane enters LA. The LA entry is confirmed either by pressure
of the needle can be used. In the septal flush method, recording or by contrast injection or by oxymetry of
the needle is disengaged from the fossa ovalis by slightly blood. Expanding the indications for TSP, there has been
pointing anteriorly, and contrast flushed continuously in resurgence of interest in the development of technology
the cavity to outline the right atrial margin of the septum. that makes the procedure easier and safer like intracardiac
In the stain method, originally described by Mullins, 8 echocardiography, 9 3D-echocardiography, special
about 0.5 mL of undiluted contrast is injected against infrared emitting catheters, or excimer laser energy.
resistance after intentionally engaging the septum. Once
the site is identified, after engaging the septum with the Dilatation of IAS Puncture Site
dilator, the needle is advanced through the dilator and After septal puncture, a coiled tip guide wire is placed
popping sensation is usually experienced as the needle in LA. Later, the 14F septal dilator is introduced over the
94
KG-14.indd 94 02-11-2018 13:47:30

coiled guidewire and septum dilated after puncture site is technique followed by positioning of 0.025 coil wire CHAPTER
confirmed on echocardiogram. Difficulties in negotiating in LV.
balloon at atrial septum do occur and can be overcome by
upsizing the septal dilator size and changing the angle of
Meier’s technique : Crossing the MV and placing the
0.20 backup J-tipped wire in the left ventricular (LV)

4

entry. and then introduction of diagnostic Judkins right
coronary catheter over this wire. Then, positioning of
Selection of Balloon Catheter the preshaped 0.25 coil wire in the LV, followed by the
introduction of Inoue balloon over the wire.
The appropriate size of balloon and size for stepwise
Manjunath technique: Direct introduction of LA coiled
dilatation are chosen as given in Tables 1 and 2.
guidewire into LV through the Mullins sheath.
After each dilatation, check the LA pressure and
a
Methods of Crossing the Mitral Valve mitral valve gradient. If LA pressure has not fallen or
di
This is carried out in RAO view. For crossing the MV and the commissures not given way, upsize the balloon by
entering the LV, the LV entry stylet is used to maneuver the increasing the volume of the contrast and do further
In
balloon. Usually, the stylet is given a slight anterior curve dilatations until the transmitral pressure gradient reduces
to facilitate LV entry. The stylet is given 2–3 anticlockwise (Figures 3A and B).
rotations so that the balloon faces the LV. The balloon
Successful BMV: It is defined as:
of
facing the valve is identified by bobbing of the balloon and
50% or more increase in mitral valve area (MVA).
falls in aortic pressures as the balloon partially obstructs 2
Increase in MVA >1.5 cm .
the mitral valve. The following are the various methods
MR not more than grade II.
ty
described to cross mitral valve:
At least one of the commissures is visibly split.
Inoue method: Using the stylet to steer the Inoue
No major complications.
balloon across the MV:
— Changing stylet curvature
— Loop method.
18 cie
Swan-Ganz balloon assistance: MV can be crossed
20 o
by Swan-Ganz catheter using balloon floatation
S
Table 1: Calculating balloon reference size

al
Reference size (RS) (mm)

ic
Height (cm) (rounded to the nearest 0) × 1/10 plus 10

e.g. height = 147 cm
og
RS = 150 × 1/10 + 10 = 25 mm
Catheter selection based on patient height/valvular status
Valvular status Balloon catheter
ol
Pliable calcified/SL RS-matched (e.g. PTMC-26 for RS = 25 mm)

Under-sized (One size < RS-matched; A
di
e.g. PTMC-24 for RS = 25 mm)

Abbreviations: SL: presence of severe subvalvular lesions
ar
Table 2: Balloon sizing in stepwise dilatation

C
Valvular status Initial Increments

I. Pliable (RS-2) mm 1 mm (low and high-low-pressure
MR 0/1+ zone)
0.5 mm (high-pressure zone),
if increase in MR, or unilateral
commissural split
MR 2+ (RS-4) mm 1 mm (low-pressure zone)
0.5 mm (high-pressure zone)
II. Calcified/SL (RS-4) mm 1 mm (low-pressure zone)
Abbreviations: MR, mitral regurgitation, preexisting or increased;
B
RS-match, catheter with its nominal balloon size > RS; SL, sever
subvalvular lesions; Low-pressure zone, balloon diameter < 2 mm of Figures 3A and B: Simultaneous tracings of left atrial pressure and
nominal balloon size; High-pressure zone, balloon diameter within 2 left ventricular pressure in a patient with MS, preprocedure and after
mm of nominal balloon size serial balloon dilatations
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SECTION Complex Anatomy where BMV is Challenging the mitral valve is more appropriately performed with
over-the-wire method. Sometimes, even over-the-wire
2
At the level of trans-septal puncture:
— Abnormal septal profile
method may fail as the balloon introduced can prolapse
— Thick septum
back from LV to LA while maneuvering into LV over
— Bulging of IAS
the wire. In such cases, one should try the reverse loop
— Septal aneurysm
technique, especially when the septal puncture is low and
— Double atrial membrane
anterior. Generally, low puncture of the IAS and over-the-
— Dextrocardia
wire method of crossing the mitral valve will make BMV
— IVC anomaly
successful in giant LA (Figures 4A to F). The following are
the tips to successfully perform BMV in giant LA.
— Kyphoscoliosis.
a
At the level of crossing the mitral valve: Tips:
2
— Critical MS < 0.5 cm Use PA angio for levophase
di
— Small LA Increase the curvature of the puncture needle so that it
— Giant LA faces more posteriorly
In
— Giant RA and small LA Low puncture
— Thick IAS Reshape the stylet to cross the MV
— Severe submitral stenosis Over-the-wire technique
of
— Unfavorable IAS puncture site. Reverse loop of the balloon catheter
Gaint Left Atrium PERCUTANEOUS TRANSVENOUS MITRAL
ty
In the gaint LA, the interatrial septum (IAS) is shifted COMMISSUROTOMY (PTMC) IN LEFT ATRIUM
CLOT
18 cie
down and to the right and the operator is forced to make
septal puncture more caudally to the ‘M-line’ because the
septum begins its curvilinear shape more caudally. The
Traditionally, LA clot is a contraindication for performing
BMV as there is a high chance of embolism due to clot
20 o
IAS puncture is lower and anterior which will make the dislodgement while maneuvreing the Mullins sheath,
crossing of mitral valve also and unfavorable to maneuver guidewire, and balloon. BMV can be safely performed in
S
the balloon. PA angio with levophase opacification of some subsets of LA clot. Manjunath et al. have classified
the LA will help to delineate the IAS better and facilitate the LA thrombus according to their location in LA and
al
successful septal puncture. There is a difficulty to cross LA appendage (Figure 5).10 In the presence of LA clot,
MV by the usual stylet steering of the balloon. Crossing we anticoagulate the patients adequately for 8 to 12
ic
og
ol
di
ar
A B C
C
D E F
Figures 4A to F: (A) Transthoracic echocardiography (TTE) showing large LA; (B) Increasing curvature of puncture needle; (C) Low septal
puncture; (D) Reshaping the stylet; (E) Over-the-wire technique; (F) Reverse loop method to cross mitral valve
96
KG-14.indd 96 02-11-2018 13:47:31

CHAPTER

a
di
In
of
ty
18 cie
Figure 5: Manjunath et al. classification of left atrial thrombus
20 o S
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ic
og
A B C
ol
di
ar
C
D E F
Figures 6A to F: Over-the-wire technique. (A) LA angiogram showing clot in LAA; (B) Low septal puncture; (C) LA guidewire directed
towards the LV bypassing LA; (D) IAS dilated with dilator with guidewire in LV; (E) Accura balloon introduced over the wire into LV; (F) Balloon
dilatation
Abbreviations: LA, left atrium; LV, left ventricle; IAS, interatrial septum; LAA, left atrial appendage
weeks [international normalized ratio (INR)-2.5 to 3]. In The following precautions one should take during
cases of persistent clot despite anticoagulation, LA clot BMV in this setting:
of type Ia, Ib, and IIa are still suitable for BMV. Adequate Low septal puncture to facilitate crossing of the mitral valve
prior anticoagulation for 8 weeks prior is necesssary. The Over-the-wire technique for crossing the valve
patient’s INR on the day of procedure should be less than (Figures 6A to F)11
1.5. Case selection is the key. Septal dilatation done using septal dilator.
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KG-14.indd 97 02-11-2018 13:47:32

SECTION All exchanges and balloon dilatation should be Central jet on color flow
done over the wire to avoid the contact with clot by No commissural MR
2 the hardwares. 6 When two-thirds of the stretched
balloon crosses the IAS, balloon stretching tube is
Large LA
Commissures free from calcium.
withdrawn by 2–3 cm, so that the balloon navigates into

mitral valve into LV without dislodgement of coiled Severe Submitral Disease and PTMC
guidewire.
Severe submitral fusion is a relative contraindication for
BMV as the results may be suboptimal. The following
MANJUNATH’S CLASSIFICATION OF LA CLOT features identify the submitral fusion:
(FIGURES 5 AND 6) High LA pressure despite < moderate MS
a
Type Ia: LA appendage clot confined to appendage Disproportionate pulmonary arterial hypertension
Type Ib: LA appendage clot protruding to LA cavity
di
(PAH)
Type IIa: LA roof clot limited to plane above fossa Balloon impasse sign
ovalis
In
Difficulty in balloon reaching LV apex
Type IIb: Below plane of fossa ovalis
Frequent slipping of balloon during initial inflations.
Type III: Layered clot over IAS
Submitral fusion can be very severe in some cases.
Type IV: Mobile clot attached to LA free wall
of

Type V: Ball valve thrombus. In extreme submitral fusion, it may not be possible to
maneuvre the balloon across the submitral fusion during
Moderate MR and PTMC BMV (Figures 7A to H). In this case, submitral fusion was
ty
Mitral regurgitation (MR) in rheumatic MS is due to dilated with an 8-mm peripheral balloon to facilitate the
restriction of leaflet mobility. In a few of them, MR may passage of Accura balloon for successfully performing
18 cie
actually decrease because of better coaptation of the MV
leaflets following commissural release with BMV. While
BMV.
performing the balloon dilatation, one has to take care in Calcific MS and PTMC
20 o
going stepwise increase in the volume of the balloon for
In mitral stenosis with bicommissural calcification, BMV
S
inflation with 2 cc less than the routine. Echocardiographic

assistance is extremely important to assess the result and is contraindicated, because there is high probability of
proceed further. leaflet tear with resultant acute severe mitral regurgitation.
al
The following patients with ≥ moderate MR patients But, BMV can still be attempted in patients with
are benefited by BMV: unicommissural calcification (Figures 8A to H).12
ic
og
ol
di
ar
A B C D
C
E F G H
Figures 7A to H: (A) PLAX view showing severe submitral disease; (B) Choral level orifice narrower than commissural suggesting severe
submitral disease; (C) Commisural mitral orifice; (D) Post-Echo showing completely split medial commissure; (E) Balloon Impasse sign;
(F) Guidewire exteriorized; (G) Retrograde submitral valvuloplasty performed with peripheral balloon; (H) Submitral plasty facilitated
antegrade balloon passage and successful BMV
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CHAPTER

A B C
a
di
In
D E F
of
ty
18 cie
20 o S
G H
Figures 8A to H: (A) Dense calcification confined to the lateral commissure; (B) The Inoue balloon across the mitral valve (MV) with the distal
part of the balloon being inflated; (C) Both the proximal and distal part being inflated; (D) On further inflation, there is appearance of a waist,
al
with the balloon assuming ‘dumbbell’-like configuration; (E) The medial commissure is beginning to split on inflation; (F) On maximal balloon
inflation, the medial commissure seen to give way and the lateral commissure is unyielding; (G and H) Pre- and post-procedure echo showing
ic
severe calcified MV and medial commissure completely split after procedure

og
LUTEMBACHER’S—ASD/RHD SEVERE MS Dextrocardia and PTMC

WITH SEVERE SUBMITRAL DISEASE Distorted cardiac anatomy makes fluoroscopy-guided
ol
The BMV in Lutembacher’s syndrome is associated with transcatheter procedures difficult which become
lower complications as it does not require septal puncture. technically more challenging in the cases w ith
di
Crossing the mitral valve can be challenging despite the percutaneous mitral valvotomy (PMV), where the cardiac
malpositions substantially increase the complications
ar
presence of ASD. When ASD is very posterior, to facilitate

beginning from interatrial septal puncture to left ventricular
LV entry, we may need to take separate anterior septal
entry.13 We had a case of situs inversus with dextrocardia
puncture, as the balloon anchors in the septum and
C
associated with severe bicuspid aortic stenosis and

maneuvering the balloon will be better. We had a patient
rheumatic severe MS with pulmonary hypertension. The
with Lutembacher’s—ASD/RHD severe MS with severe
standard Inoue technique was modified by trans-septal
submitral disease, with ASD was located more posteriorly.
catheterization via the left femoral vein, image inversion on
We could not cross the MV; hence, separate low anterior the monitor, delineation of the interatrial septal anatomy
puncture was done to anchor the balloon across the via levophase pulmonary angiography, septal contrast
septum and MV was crossed. Severe submitral disease staining and pigtail catheter insertion in the noncoronary
did not allow Accura balloon entry into LV by the routine aortic sinus, interatrial septal puncture with the trans-septal
technique using stylet. Hence, an 8-mm peripheral balloon needle rotated to a 7 o’clock position,14 and wire crossed
dilatation of submitral fusion was performed (facilitated across aortic valve into aorta. Balloon aortic valvotomy was
the entry of Accura balloon into LV) followed by successful performed and left ventricular entry done with over-the-
BMV done using Accura balloon (Figures 9 and 10). wire technique and successful BMV performed.
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KG-14.indd 99 02-11-2018 13:47:33

SECTION
2
A B C D
Figures 9A to D: (A) Separate low interatrial septum (IAS) puncture as balloon entry difficult; (B) Over-the-wire technique difficulty to cross
MV due to severe submitral stenosis; (C) Guidewire exteriorised and retrograde submitral valvuloplasty performed with ATB 8 x 30 mm
balloon; (D) Submitral plasty facilitated antegrade balloon passage and successful BMV
a
di
In
of
ty
A B C
18 cie
20 o S
D E F
al
ic
og
ol
G H I
di
Figures 10A to I: (A) PA angiogram in levophase defining interatrial septum (IAS); (B) Septal puncture left anterior oblique (LAO) 30 view;
(C) Balloon catheter passed over wire into left atrium (LA) into left ventricle (LV) and aorta; (D) Snaring of wire from right femoral venous
ar
approach; (E) Balloon aortic valvuloplasty (BAV) performed using peripheral balloon, (F to I) Over-the-wire technique used to perform
successful BMV
C
Venous Anomalies and PTMC femoral venous approach (Figures 11A to F). 15,16 We
BMV is routinely performed succesfully through had another case of severe MS patient with absent right
femoral venous access; however, certain congenital SVC and aneurysmally dilated coronary sinus (CS). The
or acquired anomalies of the IVC or iliofemoral veins aneurysmally dilated CS caused distortion of anatomy
may preclude this option and necessitate the use of and septal bulge. As every time we tried to probe fossa
alternative access routes. The challenge is to perform ovalis, the assembly used to slip down to CS. This was
a safe septal puncture. We have encounterd cases of the area of concern as it could lead to CS perforation.
venous anomalies, interruption of IVC, and absent Septal stain method and echocardiographic assistance
right SVC with persistent left SVC with severe mitral was helpful in septal puncture in AP and RAO view.
stenosis which make BMV challenging. The transjugular Successful PTMC was performed using Accura balloon
approach for BMV is a useful alternative in patients dilatation using over-the-wire technique (Figures 12A
with venous anomalies that preclude the conventional to F).17
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CHAPTER

A B C
a
di
In
of
D E F
ty
Figures 11A to F: (A and B) Computed tomography (CT) and invasive venogram showing hepatic inferior vena cava (IVC) interruption and
continuation of azygous and hemiazygous veins; (C) Septal puncture using Brockenbrough needle by right jugular venous approach; (D)
18 cie
Balloon catheter maneuvered over the coiled wire into left ventricle (LV); (E) Accura balloon dilatation, (F) Post-procedure echo bicommisural
split with mitral valvular orifice area (MVOA)—1.9 cm2 16
20 o S
al
ic
og
A B C
ol
di
ar
C
D E F
Figures 12A to F: (A) Right subclavian venogram showing absent right superior vena cava (SVC) and right innominate vein draining into
left SVC which in turn drained into right atrium (RA) through an aneurysmally dilated coronary sinus; (B) Right anterior oblique (RAO) view
showing dye from Brokenbrough needle causing opacification of dilated coronary sinus and left SVC; (C) Septal stain; (D) Septal puncture
done in RAO view; (E and F) RAO view showing mitral valvotomy using Accura balloon, over-the-wire technique of BMV
Tips: Reshape stylet to ‘S’ shape

Endry’s/Pediatric Brockenbrough needle Right internal jugular vein approach in IVC anomaly
PA angio levophase—LA opacification
Pigtail in the noncoronary cusp (NCC) of aorta
Reduce the curvature of the puncture needle

Post-Mitral Valve Repair Stenosis and PTMC
Direction indicator of needle—7– 8 o’clock BMV can safely be performed for most patients after
Clockwise rotation on the stylet commissurotomy, either surgical or percutaneous. Two 101
KG-14.indd 101 02-11-2018 13:47:33

SECTION
2
A B C
a
di
In
of
D E F
ty
Figures 13A to F: (A) Septal puncture in right anterior oblique (RAO) view with mitral and tricuspid rings; (B) Difficult mitral ring negotiation
18 cie
using cobra catheter; (C) Mitral valve post negotiation; (D) Mitral valve crossed with coiled guidewire; (E) Passage of balloon catheter over the
wire in left ventricle (LV); (F) Successful balloon dilatation
20 o
major mechanisms are responsible for valvular restenosis: or lower) reduces radiation toxicity. Avoiding angulated
commissural refusion and progression of subvalvular
S
views, working in AP view and keeping intensifier as close

thickening/degeneration. Patients with mitral restenosis as possible to the patient also reduces radiation exposure.
caused by symmetrical commissural refusion obtain better Doses greater than 100 mGy should termination of
al
results from repeat procedures compared with patients pregnancy be considered on the basis of exposure.
with restenosis in whom the pathological mechanism of
ic
restenosis is mainly subvalvular and commissures are not PTMC in Kyphoscoliosis

bilaterally fused but rather unilaterally or bilaterally split
og
The presence of severe kyphoscoliosis increases the risk of

(Figures 13A to F).
inadverent perforation of neighboring cardiac structures
resulting in cardiac tamponade which occurred in our case
ol
PTMC During Pregnancy (Figures 15A to F). Angiography to delineate the LA and
Prophylactic BMV is offered to women with severe MS IAS profile and septal stain methods of septal puncture
di
who are planning pregnancy in the hope of preventing the facilitate septal puncture. Over-the-wire technique helps
expected clinical worsening in the second trimester and in crossing mitral valve in such cases. In some cases, it
ar
peripartum.18,19 However, BMV is performed in pregnant may be difficult to successfully perform BMV through
patients with moderate-to-severe asymptomatic or mildly femoral venous approach. Jugular approach facilitates to
C
symptomatic MS because of variable maternal and fetal successfully perform BMV in kyphoscoliosis.
outcomes reported in literature. 20,21 Pregnant patients
often present with exacerbation of symptoms of MS in
BMV in Juvenile MS
the second trimester as a result of the hemodynamic
burden imposed by physiologic circulatory changes of Special features of MS in children are fibrotic, rubbery
pregnancy. In symptomatic patients, BMV is usually valve with severe subvalvular disease. Calcification is rare
electively done at the end of the second or the beginning and AF is less common. Significant PAH is seen in majority
of the third trimester, at about 24–26 weeks of gestational of children. In our series of 12,550 cases, 4% were less than
age (Figures 14A to C). During BMV, Inoue balloon is the 10 years (youngest was 7 years old) and 14% were in the
preferrred technique because of shorter procedure time age range of 10–20 years. BMV in children appears to be
and low radiation exposure. External shielding and saving safe and effective similar to adult patients. In the long-
fluoroscopic images, avoiding high-dose cineradiography, term follow-up there was no significant difference in the
and reducing the frame rate of fluoroscopy (15 frames/sec incidence of restenosis and event-free survival.
102
KG-14.indd 102 02-11-2018 13:47:34

CHAPTER

a
A B C
Figures 14A to C: (A) Shielding of gravid abdomen with lead sheet; (B) Balloon catheter over the coiled wire in left atrium (LA);
di
(C) Accura balloon dilatation
In
of
ty
18 cie
A B C
20 o S
al
ic
og
ol
D E F
Figures 15A to F: (A) Demonstrating severe kyphoscoliosis; (B) Demonstrating two pigtails one in noncoronary cusp (NCC) and the other in
di
pericardial cavity (for pericardiocentesis to treat cardiac tamponade); (C) Septal puncture in right anterior oblique (RAO) view; (D) Balloon
catheter passed over the coiled guidewire in left ventricle (LV), balloon prolapsed back; (E) Reverse loop method to enter LV; (F) Successful
balloon dilatation
ar
Complications of BMV and autopsy 26 findings. Commissural calcification, 27

C
severe submitral disease, and balloon overinflation are

Death associated with increased risk of this complication. The
Mortality is usually 0.2–3%.22 The most common causes large regurgitant volume delivered to the relatively non-
of death include cardiac tamponade, acute MR, and compliant LA causes an acute increase in LA pressure and
cerebrovascular events. V-waves, resulting in acute pulmonary edema. Cardiac
output also is impaired, as the acuteness of the MR does
Acute Mitral Insufficiency not allow the LV to use its compensatory mechanism of
Although varying degree of MR occurs in up to 25% of preload reserve for pumping the excess volume.2D echo
patients undergoing percutaneous balloon valvotomy and color Doppler is useful in assessing the site of tear and
(PBV), only 3–8% develops severe MR.23,24 Acute mitral quantifying MR. Our SJICR data of 50 cases by Manjunath
insufficiency results from leaflet tear, annular tear, et al. out of 3,855 BMV procedures, 1.3% developed acute
chordal or papillary muscle rupture, as seen in surgical25 severe MR requiring emergency mitral valve replacement
103
KG-14.indd 103 02-11-2018 13:47:34

SECTION Table 3: Symptoms of acute severe mitral regurgitation28 the inferior vena cava-right atrial (IVC-RA) junction, left
atrium (LA) posterior wall and LA appendage]. Overall,
2
Symptoms No.(%)
mortality rate was 6.9% (2 patients).
Hypotension 37 (74%)
Hypoxia 32 (64%)
Orthopnea 7 (14%)
Embolism
Pulmonary edema 6 (12%) Clinically significant cerebral and systemic embolism
occurs in 0.5–1%.31 Shaw et al.32 found a higher incidence
(5%) of systemic embolism in elderly patients >70 years
Table 4: Causes of acute severe mitral regurgitation 28 of age. Risk factors include elderly, atrial fibrillation and
No.(%) presence of atrial thrombus.
a
Anterior mitral leaflet (AML) tear 36 (72%)
Atrial Septal Defect
di
Posterior mitral leaflet (PML) tear 5 (12.5%)
Paracommissural tear with annular involvement 7 (14%) Echocardiographic incidence of atrial septal defect
(ASD) occurs in 20–24%1 at the puncture site. Most close
In
Chordal tear 2 (5%)
spontaneously and hemodynamically significant shunts
are uncommon. Residual ASD is seen in 8.7% cases at 6
of
(MVR) (Tables 3 and 4).28 In-hospital mortality was 12%. months after BMV.33
Mortality was higher in those who underwent MVR >24
hours compared with those who underwent urgent MVR Others
ty
(<24 hours). The other complications include device-related
complications like broken wires, entrapment of
Cardiac Tamponade
18 cie
Potentially lethal complication is usually seen in <1%.29
The operators experience and increasing patient’s age
guidewires34 and failure of balloon to deflate are rarely
seen.
have beeen associated with increased risk of tamponade.30

20 o
CONCLUSION
During TSP, tamponade occurs owing to trauma to right
S
and left atrium, coronary sinus, IVC-RA junction, left BMV is safe and effective procedure across wide spectrum
ventricle and aortic root. In double balloon technique, of mitral stenosis. BMV in complex anatomy should be
done by experienced operators. PA angio with levophase
al
it may result from LV perforation by guidewires or the

balloons. Tamponade suspected when there is unexpected LA opacification helps in understanding of the septal
profile and facilitates septal puncture in technically
ic
hypotension, loss of pulsations on fluoroscopy, and

increase in cardiac silhouette. If delayed in treating difficult cases. Knowing different methods of crossing
the mitral valve is essential in technically challenging
og
patient, bradycardia with hypotension can cause cardiac

arrest. cases. Over-the-wire technique to cross the mitral valve
Management includes immediate pericardiocentesis, is useful in technically challenging situations like giant
ol
autotransfusion and IV fluids. If tamponade is noted LA, kyphoscoliosis, dextrocardia and LA thrombus (Type
on withdrawal of septal dilator or balloon, reinsert the Ia, Ib and IIa). Jugular approach helps in successfully
di
septal dilator or balloon to prevent further accumulation. performing BMV in the setting of IVC interruption/
Performing BMV successfully through another IAS anomalies and kyphoscoliosis. Echocardiography will
ar
puncture is required. Surgery (IVC–RA stitch, LA–RA be useful to guide septal puncture in technically difficult
stitch) may be required in refractory cases. Prevention of cases. Combination of submitral dilatation with smaller
tamponade requires a good knowledge of the fluoroscopic peripheral balloon, followed by mitral valvuloplasty
C
anatomy of the interatrial septum and adjacent structures, gives satisfactory results in patients with severe submitral
sound puncture technique, and gentle manipulation of disease using venoarterial loop. Complications do occur
the assembly while entering the LA and crossing the MV. during PTMC, especially in early learning curve and while
In our institute, out of 1,424 consecutive BMVs treating technically challenging cases.
performed, 29 patients developed hemopericardium
(2% of patients), in 6 patients (20.7%) there was minimal REFERENCES
effusion without tamponade and pericardiocentesis was
1. Inoue K, Owaki T, Nakamura T, et al. Clinical application
not done, and 23 patients (79.3%) underwent immediate of transvenous mitral commissurotomy by a new balloon
pericardiocentesis. Of these, 18 patients (78.2%) underwent catheter. J Thorac Cardiovasc Surg. 1984;87(3):394–402.
successful BMV in the same sitting), 4 patients (13.8%) 2. Horstkotte D, Niehues R, Strauer BE. Pathomorphological
required surgery to treat persistent pericardial collection aspects, aetiology and natural history of acquired mitral
[site of perforation in patients undergoing surgery were stenosis. Eur Heart J. 1991;12(Suppl B):5-60.
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3. Sinivas BC, Vijaykumar JR, Nagesh C, et al. Technically 19. Gupta A, Lokhandwala YY, Satoskar PR, et al. Balloon mitral CHAPTER
challenging percutaneous balloon mitral valvuloplasty. CSI valvotomy in pregnancy:maternal and fetal outcomes. J Am
Update. 2016;73:533-50.
4. Hung J, Lau K. Transseptal access in Inoue-balloon mitral
Coll Surg. 1998;187(4):409-15.
20. Hameed A, Karaalp IS, Tummala PP, et al. The effect of
4
valvuloplasty. Indian Heart J. 2006;58:463-5. valvular heart disease on maternal and fetal outcome of

5. Inoue K, Lau K W, Jung KS. Percutaneous transvenous pregnancy. J Am Coll Cardiol. 2001;37(3):893-9.
mitral commissurotomy. In: Grech ED, Ramsdale DR. 21. Silversides CK, Colman JM, Sermer M,et al. Cardiac risk
Practical Interventional Cardiology. 2nd edn. London,UK: in pregnant woman with rheumatic mitral stenosis. Am J
Martin Dunitz Ltd. 2002; pp. 373. Cardiol. 2003;91(11):1382-5.
6. Clugston R, Lau FY, Ruis C. Trans-septal Catheterisation 22. Arora R, Kalra GS, Murty GS, et al. Percutaneous transatrial
Update 1992. Cathet Cardiovasc Diagn. 1992;26(4):266-74. mitral commissurotomy: Immediate and intermittent
7. Hung JS. Atrial septal puncture technique in percutaneous results. J Am Coll Cardiol. 1994;23(6):1327-32.
a
transvenous mitral commissurotomy: mitral valvuloplasty 23. Kaul UA, Singh S, Kalra GS, et al. Mitral regurgitation
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using the Inoue balloon catheter technique. Cathet following percutaneous transvenous mitral commissuro-
Cardiovasc Diagn. 1992;26(4):275-84. tomy; a single-centre experience. J Heart Valve Dis.
8. Mullins CE. Transseptal left heart catheterisation 2000;9(2):262-6; discussion 266-8.
In
experience with a new technique in 520 pediatric and adult 24. Herrmann HC, Lima JA, Feldman T, et al. Mechanisms and
patients. Pediatr Cardiol. 1983;4(3):239-46. outcome of severe mitral regurgitation after Inoue balloon
9. Green NE, Hansgen AR, Carroll JD. Initial clinical valvuloplasty. North American Inoue Balloon Investigators.
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experience with intracardiac echocardiography in guiding J Am Coll Cardiol. 1993;22(3):783-9.
mitral balloon valvuloplasty : technique, safety, utility & 25. Hernandez R, Macaya C, Bañuelos C, et al. Predictors,
limitations. Catheter Cardiovasc Interv. 2004;63(3):385-94. mechanisms and outcome of severe mitral regurgitation
ty
10. Manjunath CN, Srinivasa KH, Ravindranath KS, et al. complicating percutaneous mitral valvotomy with Inoue
Balloon mitral valvotomy in patients with mitral stenosis balloon. Am J Cardiol. 1992;70(13):1169-74.
2009;74(4):653-61.
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and left atrial thrombus. Catheter Cardiovasc Interv.
11. Manjunath CN, Srinivasa KH, Patil CB, et al. Balloon mitral
26. Deshpande J, Vaideeswar P, Sivaraman A, et al. Balloon
mitral valvotomy: an autopsy study. Int J Cardiol.
1995;52(1):67-76.
valvuloplasty: our experience with a modified technique 27. Cannan CR, Nishimura RA, Reeder GS, et al. Echocardio-
20 o
of crossing the mitral valve in difficult cases. Cathet graphic assessment of commissural calcium: a simple
S
Cardiovasc Diagn. 1998;44(1):23–6. predictor of outcome after percutaneous balloon mitral

12. Shankarappa RK, Ramesh D, Satish K, et al. Balloon mitral mitral valvotomy. J Am Coll Cardiol. 1997;29(1):175-80.
valvotomy for calcific mitral stenosis . J Am Coll Cardiol 28. Nanjappa MC, Ananthakrishna R, Hemanna Setty SK, et al.
al
Intv. 2009;2(3):263-4. Acute severe mitral regurgitation following balloon mitral

13. Santosh KS, Ramesh T, Mukesh JJ, et al. Percutaneous mitral valvotomy: echocardiographic features, operative findings,
ic
valvotomy in a case of situs inversus totalis and juvenile and outcome in 50 surgical cases. Catheter Cardiovascular
rheumatic critical mitral stenosis: case report. J Clin Med. Interv. 2013;81(4):603-8.
og
2016;8(4):351–5. 29. Zeng Z, Fang Y, Fu H. Clinical analysis of percutaneous

14. Namboodiri N, Harikrishnan SP, Ajitkumar V, Tharakan balloon mitral valvotomy in 1063 patients. Hua Xi Yi Ke Da
JA. Percutaneous mitral commissurotomy in a case of Xue Xue Bao. 1999;30(1):85-7.
ol
mirror-image dextrocardia and rheumatic mitral stenosis. J 30. Joseph G, Chandy ST, Krishnaswami S, et al. Mechanisms of
Invasive Cardiol. 2008;20(1):E33-5. cardiac perforation leading to tamponade in balloon mitral
di
15. John J, Vipin K, George J, et al. Transjugular balloon valvuloplasty. Cathet Cardiovasc Diagn. 1997;42(2):138-46.
mitral valvotomy in a patient with inferior vena-caval 31. Fawzy M. Percutaneous mitral balloon valvotomy. Catheter
interruption. J Am Coll Cardiol Intv. 2012;5(2):243-4. Cardiovasc Interv. 2007;69(2):313-21.
ar
16. Shankarappa RK, Math RS, Chikkaswamy SB, Rai MK, 32. Shaw TR, Sutaria N, Prendergast GB. Clinical and
Karur S, Dwarakprasad R, et al. Transjugular percutaneous hemodynamic profiles of young, middle aged, and elderly
C
transvenous mitral commissurotomy (PTMC) using patients with mitral stenosis undergoing mitral balloon
conventional PTMC equipment in rheumatic mitral valvotomy. Heart. 2003;89(12):1430-6.
stenosis with interruption of inferior vena cava. J Invasive 33. Manjunath CN, Panneerselvam A , Srinivasa KH, et al.
Cardiol. 2012;24(12):675–8. Incidence and predictors of atrial septal defect after
17. Srinivas BC, Singla V, Reddy B, Nagesh CM, Nanjappa percutaneous transvenous mitral commissurotomy - a
MC. Percutaneous transseptal mitral commissurotomy transesophageal echocardiographic study of 209 cases.
in a patient with absent right superior vena cava and Echocardiography. 2013;30(2):127-30.
aneurysmally dilated coronary sinus. Cardiovasc Interv 34. Panneerselvam A , Prabhavathi B, Nanjappa MC.
Ther. 2013;28(4):419-21. Entrapment of guide wire – a preventable complication
18. Bhatla N, Lal S, Behera G, et al. Cardiac disease in of balloon mitral valvotomy. J Clinic Experiment Cardiol.
pregnancy. Int J Gynaecol Obstet. 2003;82(2):153-9. 2011;2:120.
105
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CHAPTER 15
Clinical Diagnosis of Tricuspid
Valve Disease
a
di
INTRODUCTION The tricuspid annulus (TA) diameter varies from 25
Tricuspid valve (TV) is the largest among the four cardiac to 39 mm based on the site of measurement. In situations
In
valves. Though tricuspid valve diseases are common, of tricuspid annular dilatation, the septal leaflet remains
it is not so in isolation. Clinically, and in the literature, fixed between the fibrous trigones. The TA usually dilates
along the anterior and posterior leaflet attachments. The
of
this disorder receives less attention as compared to the
primary left-sided disease. It is frequently labeled as ‘the annulus becomes more planar with decreased high-low
forgotten valve’ since surgical correction is often ignored. distance (<4 mm).6
ty
Appropriate treatment of the TV disease, may improve the
long-term functional outcome.1 In this chapter, we try to PHYSIOLOGY
18 cie
discuss the clinical recognition of TV disease.
CLINICAL ANATOMY OF TRICUSPID VALVE

Right heart is a low pressure system with TV peak inflow
velocities lower than 1.0 m/s. Peak and mean gradient
across the tricuspid orifice in diastole is less than 2 mm Hg.
20 o
The TV complex includes fibrous annulus, three leaflets, The TV is not optimally designed for increased right
chordae tendineae, papillary muscles, and adjacent ventricular pressure or volume. From a dynamic point of
S
myocardium.2 The normal TV area is 7-9 cm2, and it is the view, there is approximately 19% reduction in annular
largest cardiac valve. circumference (≈33% reduction in annular area) with
al
The TV is oriented at around 45° to the sagittal plane, atrial systole. 6 The diastolic valve opening along with
and has anterosuperior, inferior, and septal margins. 3 expansion of the annular orifice provides for unimpeded
ic
The three corresponding leaflets are the anterior, inflow. Although systolic narrowing of the orifice is
posterior, and septal. The anterior leaflet is semicircular intended to result in effective valve closure; some degree of
og
in shape and extends from the infundibulum anteriorly valvular regurgitation with color Doppler imaging is quite
to the inferolateral wall of right ventricle posteriorly. common. Thus, the two-dimensional echocardiography
The posterior leaflet extends from the septum to the has demonstrated that nearly 50–60% of young adults
ol
inferolateral wall. The septal leaflet attaches medially exhibit mild tricuspid regurgitation (TR).
above the interventricular septum. The anterior leaflet Being low-pressure system, the degree of TR is also
di
is the largest and the septal leaflet is the smallest of the influenced by right ventricular preload, afterload, and
three leaflets. The septal leaflet is inserted about 10 mm or right ventricular systolic function.
ar
less more apically compared to septal insertion of mitral Dilatation of TV annulus is generally accepted to be the
leaflets. basis of functional TR. The normal maximum TV diameter
C
The tricuspid subvalvular apparatus consists of three is 21 mm/m2. The critical diameter above which TR is
corresponding papillary muscles and chordae tendineae. common is estimated to be 27 mm/m2. In patients with TR,
The anterior papillary muscle is the most prominent one the tricuspid annular circumference is larger (14 ± 1 cm
and has chordal attachments to the anterior and posterior versus 12 ± 1 cm in normal individuals). The percentage
leaflets. Posterior papillary muscle provides chordae to the decrease in annular diameter is less (10% versus 19% in
posterior and septal leaflets. normal population).6
The septal leaflet is least mobile than the other leaflets. A continued pressure overload since birth results
The annulus is elliptical in shape. It is saddle in shape with in right ventricular (RV) hypertrophy with relatively
posteroseptal and anterolateral segments close to apex competent TV until RV dysfunction ensues compared to
and the anteroseptal and posterolateral segments close acquired causes where overload is on the thin-walled RV.
to the right atrium (RA).4,5 In healthy subjects, the mean This explains relatively less common TR in pulmonary
maximal annular circumference and area are 12 ± 1 cm stenosis than pulmonary hypertension secondary to
and 11 ± 2 cm2, respectively. mitral stenosis (MS).7
KG-15.indd 106 02-11-2018 13:47:20

ETIOLOGY OF TRICUSPID VALVE The TV regurgitation is generally categorized based on CHAPTER
ABNORMALITIES pulmonary artery pressure (PAP), into:
Two major abnormalities involving TV are tricuspid
TR with normal PAP or primary (organic, intrinsic, low
pressure). It is due to valve pathology per se.

15
stenosis (TS) and TR resulting from various causes.

16,17
TR with increased PAP or secondary (functional).
Tricuspid atresia, a congenital abnormality involving
This categorization is useful since the pathogenesis,
TV, is completely different hemodynamically and in
etiology, symptoms, physical signs, and management
presentation. So, it will not be discussed further in this
differs among the two types.
chapter.
Clinically, secondary, or functional TR, is the most
common TV abnormality.
TRICUSPID STENOSIS
a
The etiology of TS can be classified as primary or Etiologies of Tricuspid Regurgitation
di
secondary.
Primary
In
Rheumatic: The TR is present in most patients with
Primary

RHD, and more than one-third of the patients with MS

Rheumatic heart disease: The rheumatic heart disease have moderate-to-severe TR. However, it is most often
(RHD) is the most common cause of TS. Though
of
secondary. In 14%, TR was found to be primary.18
rheumatic fever causes pancarditis, endocardial Myxomatous: Tricuspid valve prolapse (TVP) is
involvement alone results in permanent damage. often associated with mitral valve prolapse (MVP).
ty
Necropsy studies show rheumatic TV valve involvement Isolated TVP is rare.19 Considering various studies, the
in 15–30% of all RHD patients.8,9 But clinically, TS is average prevalence is 37% among those with MVP. So,

virtually never occurs.7
Congenital TS10,11
18 cie
seen in 5% of RHD. Isolated rheumatic TV stenosis pathologically, it is present in up to 1% of population.
Combined MVP and TVP are more prevalent in
females with a female to male ratio of 3:1.20,21
Carcinoid syndrome: The TR is the most common Marfan’s syndrome: The TV is the least commonly
20 o

manifestation, but it is also associated with stenosis to involved valve in Marfan’s syndrome. The TVP is the
S
lesser extent. manifestation of Marfan’s syndrome. Studies have

Drugs (fenfluramine, methysergide, cabergoline, found prevalence of 4% in Marfan’s syndrome.22
pergolide): Mechanism is similar to carcinoid
al
Inf e c t i v e e n d o c a rd i t i s : R ight-side d infe ctive

syndrome12 endocarditis (RSIE) is relatively rare, encompassing
Whipple’s disease13
ic

only 5–10% of IE cases. The RSIE is strongly associated
Active infective endocarditis (IE) with intravenous drug use (IVDU), medical device
Right ventricular tumors
og

implantation, including pacemakers and defibrillators,
RV implantable devices: Fibrosis with subsequent TS vascular access for dialysis, and uncorrected congenital
has been reported.14,15 heart disease (CHD).23
ol
Prosthetic TV stenosis: Bioprosthetic TS stenosis has Iatrogenic [implantable cardioverter-defibrillator

been reported in chronic kidney disease (CKD) and (ICD) lead -induced injury]: Implantable device leads
post-IE.16,17
di
that cross the TV may cause acute or chronic TR,

which can be progressive. The mechanisms of ICD-
ar
Secondary associated TR are multifactorial.

These include24,25: Adverse effects of chronic RV pacing
Extrinsic compression.
on RV geometry and systolic function
C
Direct impingement of device on leaflet impairing

Pseudo-TS motion
The TV is normal, but flow is obstructed across TV. Foreign body inflammation and fibrosis of the leaflets
Right atrial myxoma.
Development of endocarditis.
In a retrospective study of 239 patients undergoing
device implantation with lead crossing the TV, 38%
TRICUSPID REGURGITATION of patients developed significant lead-associated TR
A small degree of TR is present in approximately 70% of within 1 to 1.5 years.26,27
normal adults. On echocardiography, this ‘normal’ or Immunological disorders : [systemic lupus
physiological degree of regurgitation is localized to a small erythematosus (SLE), antiphospholipid antibody
region adjacent to valve closure, often does not extend syndrome]: Libman-Sacks endocarditis is the cause
throughout systole, and has a low signal strength. of valvular heart disease in SLE and antiphospholipid
107
KG-15.indd 107 02-11-2018 13:47:20

SECTION syndrome (APS). However, it most commonly involves — Type C: Restricted anterior leaflet movement, can
mitral and aortic valves. Primary TV involvement is rare, lead to right ventricular outflow tract obstruction
2
but can be secondary to pulmonary hypertension.28
Carcinoid syndrome: Valvulopathy is the major
(RVOT) obstruction
— Type D: Near complete atrialization of RV or
cardiac abnormality in carcinoid syndrome. Valvular otherwise known as Uhl’s anomaly.

involvement is seen in 50–70% of patients with the Great Ormand Street score (GOSE score): First
carcinoid syndrome.29 The TV is the most commonly described by Celermajer et al., an echocardiographic
affected valve. The mechanism of carcinoid syndrome scoring system for neonates, and also known as
is thought to be activation of the 5HT2B serotonin Celermajer index.39
receptors. This is a G-protein-coupled receptor, which It is the ratio of the combined area of the RA and
leads to activation of multiple intracellular pathways atrialized RV to that of the functional RV and left heart.
a
involved in mitogenesis. Upregulation of transforming As the ratio increases, the prognosis worsens.
di
growth factor-beta (TGFB) has been proposed to be a — Grade 1 < 0.5 (estimated mortality)
mechanism, leading to increased extracellular matrix — Grade 2 = 0.5 to 0.99
In
and subsequent valvulopathy. In a series of 74 cases, — Grade 3 = 1.0 to 1.49
involvement of tricuspid and pulmonary valves was — Grade 4 >1.5.
seen in 97% and 88% of the cases, respectively. In only In a study of 220 cases by Celermajer et al. survival
of
7% of patients, left-sided valvular involvement was for all live-born patients at 1 and 10 year was 67% and
seen.30 59%, respectively. Grade of severity at presentation,
Radiation31 fetal presentation, and presence of RVOT obstruction
ty
Blunt trauma: Blunt trauma includes a group of were the important predictors of mortality.
lesions resulting from nonpenetrating chest trauma. Surgical grading of ebstein’s anomaly: It has been
18 cie
Aortic valve is the frequently involved valve followed
by the mitral and the tricuspid valves. 32 Clinical
manifestations and presentation depends on the
proposed based on operative findings and is based on
anterior TV mobility and size of atrialized RV.
— Type I: Anterior septal leaflet is larger and mobile
extent of TV injury. In a study of traumatic TR by and the septal and posterior leaflets are apically
20 o
van Son et al. the median duration between trauma displaced dysplastic or absent. The atrialized RV
S
and surgery was 17 years ranging from 1 month to varies from small to large.
37 years.33 The clinical feature may range from acute — Type II: All there leaflets are present, but they are
heart failure to slow, progressive deterioration.34,35 relatively small and displaced in spiral fashion.
al
The exact mechanism of TV injury is not known. The The atrialized ventricle is relatively large.
best postulated theory is extensive tricuspid ‘blowout’ — Type III: The anterior leaflet has restricted motion
ic
injury secondary to severe and sudden impact during and the chordae are short, fused, and tethered.
og
end-diastole, as occurs in steering injury with strong The anterior leaflet frequently gets attached to
deceleration force as seen in motor vehicle accidents. papillary muscle directly. The posterior and
Congenital—Ebstein’s anomaly (cleft, hypoplasia septal leaflets are grossly dysplastic and cannot be
ol
or dysplasia of TV): The estimated risk of Ebstein’s reconstructed. The atrialized RV is large.
anomaly in the general population is 1 in 20,000 — Type IV: The anterior leaflet is severely deformed
di
live births with no predilection for either gender.36 and displaced into RVOT. The posterior leaflet
The genetic predisposition for Ebstein’s anomaly is is dysplastic or absent. The septal leaflet
ar
considered heterogeneous.37 Lithium intake during is represented by a ridge of fibrous material

early pregnancy is an important known risk factor with descending towards apex from membranous
28-fold increased risk. septum. There is near complete atrialization of
C
In Ebstein’s anomaly, the septal and posterior RV.

leaflet has a distinct apical displacement more The clinical presentation of Ebstein’s anomaly
than 10 mm compared to mitral valve. This leads to varies widely. In general, symptoms are related to
displacement of TA downward and reduction of the the degree of anatomic abnormality (i.e. the degree
functional RV cavity and atrialization of remainder of of displacement and the functional status of the TV
RV. The atrialized ventricular wall thins out and RA leaflets, presence of interatrial communication, and
enlarges. severity of right ventricular dilation and dysfunction).
Various classification systems have been proposed Clinical presentations:
for Ebstein’s anomaly. — In case of severe cardiomegaly, Ebstein’s anomaly
Carpentier’s classification (1988)38 can be fatal in utero.40

— Type A: RV Volume is adequate — Children and adults with significant tricuspid
— Type B: Large atrialized RV but anterior leaflet leaflet displacement may have severe TR and
108 mobility is preserved cyanosis.
KG-15.indd 108 02-11-2018 13:47:20

— Adults with mild apical displacement and mild Secondary CHAPTER
TR usually are asymptomatic or may present with
15
Pressure overload: Pulmonary hypertension of any
arrhythmia or paradoxical embolic event.
cause lead to TR. The RHD with severe MS is the
In a review of 220 patients with Ebstein anomaly,
common cause of functional TR. Sagie et al. reported

early age at presentation was frequently associated
severe TR in 12% and moderate TR in 19% in series of
with other cardiac lesions, particularly atrial septal
318 patients.46
defect (ASD) and pulmonar y stenosis, which
predisposes to cyanosis from right-to-left shunting. 41
Volume overload: RV dilatation.
The clinical presentation varied with age at diagnosis:
fetuses, an abnormal routine prenatal scan (86%); Pathophysiology
neonates, cyanosis (74%); Infants, heart failure (43%);
The TR leads to reflux of blood into RA during systole
a
children, murmur (63%); and adolescents and adults,
arrhythmia (42%). and significant increase in RA pressure. The RV filling
di
Cyanosis: Transient cyanosis seen in infancy, which is voluminous during diastole, since the regurgitant
reappears a decade or later, is a distinctive feature of fraction adds to venous return from peripheries. The
In
Ebstein’s anomaly. In neonates, cyanosis is present rapidity of filling also increases due to increased RA
due to right-to-left shunt. As the pulmonary vascular pressure.
resistance decreases, cyanosis disappears. Cyanosis
of
reappears later due to RV dysfunction and elevated RA
TR with Normal Pulmonary Artery Pressures
pressure.
Arrhythmia in Ebstein’s anomaly In this scenario, the RV is subjected to pure volume
ty
Accessory pathways: The presence of accessory overload. The RV and RA are relatively compliant and
pathways is more frequent in Ebstein’s anomaly than the volume and velocity of regurgitation is relatively less.
18 cie
the general population. They are localized in the TA.
Posterior, posteroseptal, and posterolateral pathways
are more common as described in various studies.
Hence, venous congestion is relatively modest, unless the
TR is enormous or severe RV volume overload results in
RV dysfunction.
Mahaim pathway also has been described. This can
20 o
lead to atrioventricular re-entrant tachycardia (AVRT).
TR with Elevated Pulmonary Artery Pressure
S
Supraventricular tachycardias develop in about 25–

30% of patients.42 In patients with elevated pulmonary pressure, RV is
Atrial fibrillation (AF) and atrial flutter can lead to
al
hypertrophied and less compliant. The velocity of

conduction through accessory pathway and can cause regurgitation is more. Elevated pulmonary pressure per se
sudden death.
ic
leads to annular dilatation and worsening of TR. Organic

Ventricular tachycardia has been described in 1% of disease of TV disease can be associated with elevated
cases, probably arising from the atrialized RV.43
og
PAP as in cases of RHD. However, RV systolic pressure of

Endomyocardial fibrosis : Endomyocardial less than 50 mm Hg unlike leads to TR in the absence of
fibrosis affects both the right and left ventricles in
organic TV disease. So, associated organic TV disease
approximately 50% of patients, purely left in 40%,
ol
should be suspected in significant TR and modest

and the RV alone in the remaining 10%. The fibrosis
elevation in PAP.
involves the papillary muscles and chordae tendineae,
di
leading to atrioventricular valve (AV) distortion and

regurgitation.44 Respiratory Variation
ar
Atrial fibrillation : Severe secondary TR is also

The magnitude of TR increases during inspiration due
associated with AF, but whether the effects of TR, such
to increased venous return and preload. Respiratory
C
as right atrial enlargement, increase the likelihood of

AF or whether chronic AF increases the likelihood of variation in TR is most evident in standing and sitting
TR is not known.45 postures than supine posture. This is due to the fact that
Ischemic heart disease affecting the RV with papillary venous return is low in erect posture and the magnitude
muscle dysfunction or rupture. of increase in venous return is significant compared to
Other rare causes: supine, where baseline venous return is relatively more.
— Sarcoidosis Conditions where inspiratory increase does not cause
— Renal and ovarian tumors significant change:
— Atrial myxoma or cardiac tumor Massive TR: Preload is maximum and may not increase
— Postendomyocardial biopsies (especially in heart any more with inspiration.

transplant recipients) RV dysfunction: Dysfunctional RV may not be able to
— Metabolic or enzymatic abnormalities (Fabry’s increase stroke volume any more.

disease). Atrial fibrillation: Since there is beat to beat variation.
109
KG-15.indd 109 02-11-2018 13:47:21

SECTION Effect of Atrial Fibrillation and anterior motion of lower right chest and right upper
quadrant of abdomen. It needs to be distinguished from
2
In AF, the loss of RA contraction may adversely affect
optimal leaflet coaptation and failure of annular narrowing. the abdominal aortic pulsation. The abdominal pulsation
This leads to increase in TR. is felt medially and directed anteriorly. Bimanual palpation
of liver can be helpful since hepatic pulsations tend to be

expansile in all directions.
SYMPTOMS OF TRICUSPID VALVE DISEASE
Generally, the symptoms of left heart disease predominate
in those with secondary TV disease. It includes dyspnea on Arterial Pulse
exertion, paroxysmal nocturnal dyspnea, and orthopnea There is no specific alteration in character of carotid pulse.
caused due to pulmonary venous hypertension (PVH). The The arterial pulse amplitude can be low if cardiac output
a
improvement in symptoms of PVH suggests worsening of is grossly reduced. However, jugular venous pulse (JVP)
pulmonary hypertension and symptoms specific to TV can be confused with arterial pulse. This is due to systolic
di
disease predominate. timing of venous upstroke and thickening of jugular veins
The symptoms specific to advanced TV disease are from chronic elevation of venous pressure.
In
related to:
1. Decreased cardiac output (e.g. fatigue, exercise Jugular Venous Pulse
intolerance)
of
2. Right atrial hypertension (e.g. liver congestion resulting Tricuspid Stenosis
in right upper quadrant discomfort), or gut congestion The TS results in characteristic changes in the jugular
with symptoms of dyspepsia, indigestion, or fluid venous pulse in the form of leisurely V to Y descent and
ty
retention with pedal edema, ascites. prominent ‘a’-wave. The ‘a’ wave can be so prominent
Ascites and pedal edema are multifactorial and are that it can reach as high as 30 mm Hg, almost equal to RV
likely due to: 18 cie
Increased venous hypertension that results in
systolic pressure. The ‘x’ descent is usually normal. Rapid
‘y’ descent almost rules out the presence of significant TS.
increased capillary hydrostatic pressure. The JVP can be normal in mild TS or even in moderate TS
20 o
Decreased renal perfusion pressure leading to fluid on diuretics.
S
retention by kidneys.
Hypoalbuminemia due to cardiac cirrhosis; protein-
losing enteropathy from gut congestion.
al
As the severity of TR increases, the X descent gets

It may be emphasized that significant TV disease may
attenuated and ultimately disappears. A positive venous
not be associated with any symptoms until a late stage of the
ic
pulse wave becomes prominent which is called C-V

disease involving progressive RV dysfunction. In advanced
wave or S wave caused due to regurgitation jet. This is
stages, the symptoms attributable to liver congestion and
og
soon followed by steep descent, i.e. Y descent, which

fibrosis (cardiac cirrhosis) may be observed.47
represents sudden decompression of atrium into RV when
TV opens. The C-V wave occurs simultaneously with
PHYSICAL SIGNS
ol
carotid upstroke. However, the contour is more rounded

General Appearance and sustained compared to brisk up- and down-stroke of
di
arterial pulse.
These include signs related to TV disease and those
Other causes for prominent ‘v’ wave in JVP are (also cause
secondary to chronic venous congestion, i.e. dependent
ar
rapid ‘y’ descent):

edema, bilateral pitting pedal edema, abdominal wall
ASDt
edema, ascites. Signs secondary to prominent venous
ASD with MR (Lutembacher’s syndrome)
C
pulsation, i.e. head bob (side to side, no-no type), proptosis,

Ventricular septal defect (VSD) communicating left
anterior motion of eyes, and engorged neck. Femoral
ventricle to right atrium (Gerbode defect)
venous pulsation can be well felt in severe high-pressure
Constrictive pericarditis.
TR. Mild icterus can be seen due to hepatic congestion.
The JVP can remain normal despite severe TR if the
Low output can lead to mild peripheral cyanosis. In long-
RA is hugely dilated and compliant. This is the case in
standing TR, muscle wasting and weight loss develop,
Ebstein’s anomaly, where JVP will elevate only in the later
which is termed as cardiac cachexia.
stages of disease with severe RV dysfunction.
An important finding is hepatomegaly with pulsatile
liver in presystole in TS due to reversed blood flow during
atrial contraction against stenotic orifice (presystolic Effects of Respiration
pulsation) and systole in TR due to reversed systolic The magnitude of TR increases during inspiration due to
blood flow in great veins (systolic pulsation). The right increased venous return and preload. This results in larger
lobe of liver may be enlarged and produce a rightward V wave and steeper Y descent. In mild TR or in those with
110
KG-15.indd 110 02-11-2018 13:47:21

compliant RA, this may be the only sign of presence of TR This is due to prolonged excursion of large anterior leaflet CHAPTER
and JVP can otherwise be normal. while closure of TV. This can be appreciated as split S1.
In massive TR and RV dysfunction, this rise in JVP may
not be significant, as discussed before.
The loud T1 component of Ebstein’s anomaly is called
sail sound, because the large anterior tricuspid leaflet is
15

similar to a large sail of ship flapping in the breeze.48
Effects of Atrial Fibrillation The T1 can also be loud in TS. There is no significant
change in S1 in TR. It may be attenuated, normal or
The AF poses difficulty in the assessment of JVP. There is
increased.
absence of ‘a’ wave in JVP. So, ‘v’ wave is the only positive
wave, which may simulate the prominent ‘c-v’ wave of TR.
Respiratory variation may not be evident since JVP varies Second Heart Sound
a
from beat to beat based on cycle length. The character of S2 depends on etiology. The P2 component
of S2 is increased in pulmonary hypertension. In other
di
Maneuvers to Augment JVP etiologies, it is normal. In RV dysfunction, RV ejection can
be prolonged and there is no significant variation with
In
Any act that increases venous return leads to increase in
respiration. This may lead to wide fixed split of S2.
JVP. Leg elevation, squatting, mild exercise, Phase IV of
Valsalva maneuver, Muller maneuver, and hepatojugular
Third and Fourth Heart Sound
of
reflex (Pasteur Randot maneuver) increase ‘v’ wave.
The presence of S3 is common in the setting of TR. It
represents either increase flow across TV during diastole
Inspection
ty
or RV failure or both. The S4 can be present in setting of
The precordial movements depend on the presence or acute onset severe TR, as in infective endocarditis, RV
absence of pulmonary hypertension.
18 cie
In TR with normal PAP, there is a parasternal retraction
wave during late systole. A brisk early systolic outward
myocardial infarction (MI), and papillary muscle rupture.
The RVS4 can also be heard in severe hypertrophy due
to pulmonary hypertension. Both S3 and S4 are usually
motion is seen which is not sustained. In rest of systole, the localized to left lower parasternal area and increase
20 o
RV pulls away from the chest wall. In TR with pulmonary with respiration. In case of severe RV hypertrophy and
S
hypertension, left parasternal impulse is sustained. When dilatation, apex can be formed by RV. In such cases, S3 and
RV is significantly enlarged, left parasternal outward S4 can be also heard in the apex.
motion is seen and the LV apex retracts in early systole.
al
This may give rise to rocking or seesaw motion of chest

Opening Snap
wall.
ic
Opening snap (OS) is present in TS. The opening snap is

generated by abrupt halting of tricuspid leaflets during
Palpation
og
opening in early diastole. Since it is almost always

Palpable left parasternal impulse reflects the level of associated with MS, it is difficult to be differentiated from
pulmonary hypertension, RV size, and severity of TR. It is OS of MS. Maximum intensity in left lower parasternal area
ol
sustained in pulmonary hypertension and brisk in normal and increase in inspiration may give an evidence of the
PAP. Hypertrophied RV also produces a palpable epigastric presence of TS.
di
impulse. It is felt from the tip of the thumb when palpated The OS can also be heard in TR in the absence of TS
in epigastric region. The RV S3 and S4 can be palpable in and freely mobile valve leaflets; however, it is uncommon.
ar
left lower parasternal area. Other causes include Ebstein’s anomaly, ASD, and partial
anamolous pulmonary venous connection (PAPVC).48
C
Percussion
Percussion of right heart border is the only examination Systolic Clicks
finding that provides evidence for RA enlargement. This is Pulmonary ejection click can be heard over second left
one of the most important findings that can point towards intercostal space in pulmonary hypertension. It is the
Ebstein’s anomaly. only right-sided auscultatory finding that decreases in
inspiration. But inspiratory decrease may not be evident in
Auscultation setting of pulmonary hypertension.
The TVP can cause systolic click in the mid-to-late
First Heart Sound systole. It has been recorded in phonocardiogram,
The S1 usually is generated due to closure of mitral but unlikely to be detected clinically. However, click
valve (M1). The TV closes immediately after mitral valve prominent in left lower parasternal area and increasing
closure that is rarely heard as split S1, i.e. M1-T1. The T1 in intensity and later during inspiration can give a clue for
component of S1 can be accentuated in Ebstein’s anomaly. TVP. 111
KG-15.indd 111 02-11-2018 13:47:21

SECTION Murmurs This can be made out in area several centimeters
away from the area of maximum intensity and in standing
2
Tricuspid Stenosis
A mid-to-late diastolic murmur, medium-pitched is heard or sitting posture. The mechanism has been explained
best with the bell of the stethoscope. In sinus rhythm, previously. The respiration should be smooth and mildly
the murmur tends to be presystolic and the midsystolic deep in intensity. Forced respiration can cause inadvertent
component is present only in severe cases. In AF, the Valsalva maneuver and decrease in venous return and
murmur is mid-diastolic with decrescendo character in need to be avoided. Some of them advocate holding
late systole particularly in longer cycles. The murmur breath in deep inspiration while auscultate for variation in
is usually localized to the left lower sternal border. The murmur. But this leads to decrease in venous return and
murmur increases with inspiration and any maneuver need to be avoided. The grade of murmur increases for
a
that increases venous return to right heart, as discussed one to two beats during inspiration.
previously.49 As mentioned earlier, in severe TR with very loud
di
The mid-diastolic murmur in left parasternal area is murmur, severe RV dysfunction and in AF this inspiratory
also found in states of increased flow across the TV in the increase may not be significant.49
In
absence of TS. These include ASD, PAPVC, ruptured sinus
of Valsalva (RSOV) to RA, Gerbode defect, Lutembacher’s EFFECT OF VARIOUS MANEUVERS
syndrome.
of
Differentiating TS from Murmur of MS: Increased Murmur Intensity
TS murmur increases with inspiration, whereas in MS
Inspiration
ty
it decreases. Hepatojugular reflux maneuver
TS murmur increases in right lateral decubitus position,
Leg elevation
18 cie
as opposed to left lateral decubitus position of MS.
TS murmur is scratchy, superficial than MS murmur.

Squatting
Muller’s maneuver
Mild exercise
20 o
Volume overload
The murmur of TR is highly variable. This can be made Phase IV of Valsalva maneuver (intensity increases
S

out if the examiner specifically looks for the presence within 1 to 2 seconds of release).
of murmur. The classic murmur of TR is a holosystolic
al
murmur, increases with inspiration and is best heard

Decreased Murmur Intensity
in the left 4th and 5th intercostals space and extends
ic
to S2. But it can wane off commonly in late systole and Expiration
can be short particularly in cases of normal PAP. In such Standing/sitting
og
cases, murmur might be appreciated only in inspiration. Phase II of Valsava maneuver

However, in case of TVP, murmur is heard in the mid-to- Vasodilators: nitroglycerin
late systole following a click. Volume depletion (diuresis).
ol

The murmur of TR is rarely loud. It is usually of grade

II-III/VI in intensity. The intensity is particularly lower
di
Differentiating from Murmur of MR49

in those with normal PAP. The loud murmur indicates
large volume of regurgitation, but the converse is not true. The murmur of TR increases with inspiration, whereas
ar
Severe TR can be silent. the MR murmur remains same or decreases in

The frequency of TR murmur is usually medium intensity.
C
pitched, but can be rough. So, it is always better to look The intensity of TR murmur is maximum in left
for TR murmur with both the bell and diaphragm of parasternal area, and is barely heard in apex. Even
stethoscope. in cases of significant RV enlargement, where apex is
The murmur radiates both to right and left side for formed by RV, the murmur is louder in left parasternal
a short distance. Radiation to right parasternal space is area. There is no radiation to axilla, against the MR
quiet common. In patients with emphysema and thick murmur.
chest wall, TR murmurcan be best heard in xiphoid and In AF, TR murmur intensity increases in longer cycles,
subxiphoid areas. but there is no significant variation in MR murmur.
The increase in murmur of TR was first reported by When both mitral and TR is present together,
Rivero Carvallo in 1964; hence, known as Carvallo’s sign. the intensity of murmur wanes and increases as
The increase is subtle and the increase is often by less than the stethoscope is inched from apex to lower left
one grade in intensity. parasternal area and vice versa.
112
KG-15.indd 112 02-11-2018 13:47:21

Table 1: Difference between TR with increased pulmonary artery other associated valvular involvement. Symptoms and CHAPTER
pressure and normal pulmonary artery pressure signs per se due to TV disease may determine the severity of
Increased PA pressure Normal PA pressure the disease or dominant lesion. However, they contribute
to significant morbidity in these patients. Strong suspicion
15
JVP: C-V wave More prominent Less prominent

Parasternal impulse Sustained Brisk and ill sustained
and careful examination is important in diagnosing the
TV disease. Systematic evaluation including analysis of
P2 Loud Normal
symptomatology and clinical examination along with
Murmur:
evidence from ancillary investigations including ECG
Intensity Louder Soft
and chest X-ray helps in diagnosing the TV disease before
Duration Longer: Pansystolic Short: Early to proceeding to formal echocardiographic evaluation.
midsystolic
a
Contour Even: Pansystolic Often tapers in late
systole REFERENCES
di
1. Bruce CJ, Connolly HM. Right-sided valve disease deserves
Diastolic Murmur a little more respect. Circulation. 2009;119(20):2726–34.
In
2. Huttin O, Voilliot D, Mandry D, et al. All you need to know
An early to mid-diastolic murmur may also be found in
about the tricuspid valve: Tricuspid valve imaging and
severe TR, due to increased diastolic flow across the TV. It
tricuspid regurgitation analysis. Arch Cardiovasc Dis.
of
is a low-pitched murmur and heard in the left 4th and 5th 2016;109(1):67–80.
parasternal space. 3. Martinez RM, O’Leary PW, Anderson RH. Anatomy and
The presence of steep Y descent in JVP, and absence echocardiography of the normal and abnormal tricuspid
ty
of opening snap may suggest absence of concomitant TS valve. Cardiol Young. 2006;16(Suppl 3):4–11.
(Table 1). 4. Miglioranza MH, Mih il S, Muraru D, et al. Dynamic
ELECTROCARDIOGRAM
18 cie changes in tricuspid annular diameter measurement in
relation to the echocardiographic view and timing during
the cardiac cycle. J Am Soc Echocardiogr. 2015;28(2):226–
No sign is specific for TV disease. A few markers of 35.
20 o
involvement include right ventricular hypertrophy and 5. Fukuda S, Saracino G, Matsumura Y, et al. Three-dimensional
S
‘strain’, right axis deviation, and right atrial enlargement. geometry of the tricuspid annulus in healthy subjects and
Tall and broad P waves as a result of right atrial enlargement, in patients with functional tricuspid regurgitation: a real-
also known as Himalayan P wave, are the characteristic time, 3-dimensional echocardiographic study. Circulation.
al
features of Ebstein’s anomaly. Right bundle-branch block 2006;114(1 Suppl):I492-8.

(RBBB) is often seen. Due to infrahisian conduction 6. Tei C, Pilgrim JP, Shah PM, et al. The tricuspid valve
ic
abnormalities and abnormal depolarization of atrialized annulus: study of size and motion in normal subjects and
RV, the morphology of terminal QRS complex is bizarre. in patients with tricuspid regurgitation. Circulation. 1982;
og
Evidence of pre-excitation may not be found be one-third 66(3):665–71.

7. Joseph S Alpert. Valvular heart disease. 3rd edition.
of patients with Ebstein’s anomaly and symptomatic
Liottppinc; pp. 377-97.
tachyarrhythmias. In these patients, the absence of RBBB
ol
8. Edwards WD, Peterson K, Edwards JE. Active valvulitis

pattern is a strong predictor of an accessory pathway.42 associated with chronic rheumatic valvular disease and
di
active myocarditis. Circulation. 1978;57(1):181–5.

CHEST X-RAY 9. Chopra P, Tandon HD. Pathology of chronic rheumatic
heart disease with particular reference to tricuspid value
ar
Cardiomegaly associated with prominent right heart

involvement. Acta Cardiol. 1977;32(6):423–34.
borders resulting from RA enlargement and prominent
10. Cohen ML, Spray T, Gutierrez F, et al. Congenital tricuspid
superior vena cava may be noted in both TR and TS.
C
valve stenosis with atrial septal defect and left anterior

Evidence of RV enlargement can be made out in AP and fascicular block. Clin Cardiol. 1990;13:497.
lateral view of X-ray. There are no specific findings to 11. Tennstedt C, Chaoui R, Körner H, et al. Spectrum of
suggest a diagnosis of TV disease. Evidence of pulmonary congenital heart defects and extracardiac malformations
hypertension in X-ray, may give clue to the presence of associated with chromosomal abnormalities: results of a
functional TR. Calcification of the TV is rarely, if ever, seven year necropsy study. Heart. 1999;82:34.
observed. Massive cardiomegaly is the feature of Ebstein’s 12. Andrejak M, Tribouilloy C. Drug-induced valvular heart
anomaly. disease: An update. Arch Cardiovasc Dis. 2013;106(5):
333–9.
13. Hansen A, Mereles D. Cardiac complications in Whipple’s
SUMMARY
disease. European J Echocardiogr. 2008;9(3):426-7.
The TV diseases are most commonly functional and most 14. Rosenberg Y, Myatt JP, Feldman M, et al. Down to the wire:
often associated with other valvular heart disease. So, the tricuspid stenosis in the setting of multiple pacing leads.
clinical signs and symptoms are often dominated by the Pacing Clin Electrophysiol. 2010;33:e49.
113
KG-15.indd 113 02-11-2018 13:47:21

SECTION 15. E s s a n d o h M , Zu l e t a -A l a rc o n A , We i s s R , e t a l . 32. Krasna MJ, Flancbaum L. Blunt cardiac trauma: clinical
Transesophageal echocardiographic diagnosis of severe manifestations and management. Semin Thorac Cardiovasc
2 functional tricuspid stenosis during infected implantable

cardioverter-defibrillator lead extraction. J Cardiothorac
Surg. 1992;4(3):195–202. [PubMed]
33. Bortolotti U, Scioti G, Milano A, et al. Post-traumatic
Vasc Anesth. 2015;29:412. tricuspid valve insufficiency. 2 cases of delayed clinical
16. Reddy G, Ahmed M, Alli O. Percutaneous valvuloplasty for manifestation. Tex Heart Inst J. 1997;24(3):223–5. [PMC free
severe bioprosthetic tricuspid valve stenosis in the setting article] [PubMed]]
of infective endocarditis. Catheter Cardiovasc Interv. 2015; 34. van Son JA, Danielson GK, Schaff HV, et al. Traumatic
85:925. tricuspid valve insufficiency. Experience in thirteen
17. Boyaci, Gokce V, Topaloglu S, et al. Goksel outcome of patients. J Thorac Cardiovasc Surg. 1994;108(5):893–
significant functional tricuspid regurgitation late after 8. [PubMed]
mitral valve replacement for predominant rheumatic mitral 35. Lupo PJ, Langlois PH, Mitchell LE. Epidemiology of Ebstein
a
stenosis. Angiology. 2007;58:336-42. anomaly: prevalence and patterns in Texas, 1999-2005. Am
di
18. Madelli TJ. Tricuspid valve prolapsed diagnosed by cross J Med Genet A. 2011;155A:1007.
sectional echocardiography. Chest. 1979;79:201. 36. Pradat P, Francannet C, Harris JA, et al. The epidemiology
of cardiovascular defects, part I: a study based on data from
In
19. Ogawa S. Evaluation of combined valvular prolapsed
syndrome by two-dimensional echocardiography. three large registries of congenital malformations. Pediatr
Circulation. 1982;65:174. Cardiol. 2003;24:195.
20. David J. Weinreich, James F. Burke, Isolated prolapse of the 37. Carpentier A , Chauvaud S, Mace L , et al. A new
of
tricuspid valve. J Am Coll Cardiol. 1985;6(2):475-81. reconstructive operation for Ebstein’s anomaly of the
21. Pyeritz R, Wappel MA. Mitral valve dysfunction in the tricuspid valve. J Thorac Cardiovasc Surg. 1988;96:92–101.
38. Celermajer DS, Bull C, Till JA, et al. Ebstein’s anomaly:
marfan syndrome. Clinical and echocardiographic study of
ty
presentation and outcome from fetus to adult. J Am Coll
prevalence and natural history. Am J Med. 1983;74:797-807.
Cardiol. 1994;23:170-6.
22. Hussain ST, Witten J, Shrestha NK, et al. Tricuspid valve
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endocarditis. Ann Cardiothorac Surg. 2017;6(3):255-61.
23. Al-Bawardy R, Krishnaswamy A, Bhargava M, et al.
Tricuspid regurgitation in patients with pacemakers
39. Benson DW, Silberbach GM, Kavanaugh-McHugh A, et al.
Mutations in the cardiac transcription factor NKX2.5 affect
diverse cardiac developmental pathways. J Clin Invest.
1999;104:1567.
20 o
and implantable cardiac defibrillators: a comprehensive
40. Celermajer DS, Bull C, Till JA, et al. Ebstein’s anomaly:
review. ClinCardiol. 2013;36:249.
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presentation and outcome from fetus to adult. J Am Coll

24. Vaturi M, Kusniec J, Shapira Y, et al. Right ventricular pacing
Cardiol. 1994;23:170.
increases tricuspid regurgitation grade regardless of the
41. Iturralde P, Nava S, Sálica G, et al. (2006) Electrocardio-
mechanical interference to the valve by the electrode. Eur J
al
graphic charateristics of patients with Ebstein’s anomaly

Echocardiogr. 2010;11:550.
before and after ablation of an accessory atrioventricular
25. Höke U, Auger D, Thijssen J, et al. Significant lead-induced
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pathway. J Cardiovasc Electrophysiol. 2002;17:1332–6.

tricuspid regurgitation is associated with poor prognosis at 42. Cherry C, DeBord S, Moustapha-Nadler N. Ebstein’s
long-term follow-up. Heart. 2014;100:960.
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anomaly: a complex congenital heart defect. AORN

26. Lin G, Brady PA . Device lead-induced tr icuspid J. 2009;89(6):1098-110.
regurgitation: does it matter? Heart. 2014;100:900. 43. Verma V, Zafar K. Tropical endomyocardial fibrosis: an
27. C a r d i a c v a l v e i n v o l v e m e n t i n s y s t e m i c l u p u s overview. Int J Res Med Sci. 2014;2(4):1267.
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erythematosus and primary antiphospholipid syndrome: 44. Yamasaki N, Kondo F, Kubo T, et al. Severe tricuspid
lack of correlation with antiphospholipid antibodies. Int J regurgitation in the aged: atrial remodeling associated with
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Cardiol. 1995;51(2):117-26. long-standing atrial fibrillation. J Cardiol. 2006;48:315.

28. Anderson AS, Krauss D, Lang R. Cardiovascular 45. Sagie A, Schwammenthal E, Newell JB, et al. Significant
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complications of malignant carcinoid disease. Am Heart J. tricuspid regurgitation is a marker for adverse outcome
1997;134:693–702. in patients undergoing percutaneous balloon mitral
29. Pelikka PA, Tajik AJ, Khandheria BK, et al. Carcinoid heart valvuloplasty. J Am Coll Cardiol. 1994;24(3):696-702.
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disease. Clinical and echocardiographic spectrum in 74 46. Wooley CF, Fontana ME, Kilman JW, et al. Tricuspid
patients. Circulation. 1993;87:1188-98. stenosis: atrial systolic murmur, tricuspid opening snap,
30. Madan R, Benson R, Sharma DN, et al. Radiation induced and right atrial pressure pulse. Am J Med. 1985;78:375-84.
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31. Zakynthinos EG, Vassilakopoulos T, Routsi C, et al. 48. Jonathan abrams. Essentials of cardiac physical diagnosis.
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114
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Atrial Fibrillation in Rheumatic
a
di
INTRODUCTION was present in a majority of patients (90%) irrespective of
Often, high morbidity and mortality are linked with atrial rhythm at presentation. Existence of myocytolysis is shown
In
fibrillation (AF).1 It is worth mentioning that AF is a critical to be a significant predictor of AF. Apart from histological
factor for diagnosing rheumatic heart disease (RHD) and factors, LA enlargement is linked to the occurrence of AF.
Kim et al.5 followed (median 72 months) 293 patients with
of
hinders the prognosis. It is found that,in patients with
rheumatic valve disease in sinus rhythm (SR) at the time of
RHD, particularly in patients with disease of mitral valve
evaluation and 20.5% of patients developed AF (3.5% per
(MV), the prevalence of AF increases with age. The marked
year). The factors associated with AF occurrence included
ty
increase of AF incidence with age is consistent with the
age, serum cholesterol, diameter of LA and mitral valve
epidemiology of AF without valvular disease. Among
area <1.52 cm2 on univariate analysis.
18 cie
patients with valvular heart disease and AF, it is the mitral
valve which is most commonly involved. AF is seen in
29% of patients with mitral stenosis (MS), 16% of patients
Fibrosis indicates structural remodeling and AF is
shown to be associated with considerable fibrosis in
a variety of mitral diseases. Examining samples of LA
20 o
with mitral regurgitation (MR), and 52% with combined
appendage collectedduring mitral valve replacement
MS and MR. However, AF is rare in patients of RHD with
S
revealed that older patients and patients with larger LA had

aortic valve disease (1%).2 Patients of MV disease with AF
recurrent AF. A higher extent of fibrosis was also observed
have higher New York Heart Association (NYHA) class, left
in such patients. In patients with AF, MS was correlated
al
ventricular (LV) and larger left atrial (LA) size as compared

with higher degree of fibrosis despite being in a lower age
to those without AF. AF significantly impacts the event-free
group and having less dilated LA when compared with
ic
survival, both prior to and following an intervention on the

MR. Since LA size and fibrosis are evidently connected to
MV.
lesser chances of preserving SR by intervention, significant
og
problems have to be anticipated in maintaining SR.

PATHOPHYSIOLOGY
For patients with valvular heart disease, we have minimal
ol
PULMONARY VEINS, ELECTRICAL

understanding of the various pathological processes
REMODELING AND STRETCH
leading to AF. The LA size is a better predictor of incidence
di
of AF. The incidence of AF is 3% when the LA diameter is Fibrosis may have a pivotal role in the pathogenesis
40 mm and 54% when the LA diameter is 40 mm. 3 of AF, yet factors that are not-structural should not be
ar
Raised LA pressures, especially in cases with rheumatic overlooked. The Bordeaux group has clearly indicated
the importance of pulmonary vein foci in AF initiation
mitral valve disease leads to inhomogeneous dilatation
C
and maintenance. On the other hand, pulmonary vein

and fibrosis4 of left atrium causing myocardial stretch,
firing is rarely described in MS patients presenting with
slowing velocities of conduction, increasing dispersion of
AF. 6 Although paroxysmal AF has been described in
refractoriness and automaticity. All of these factors result
patients with MS,7 AF tends to be more often persistent
in initiation and perpetuation of AF.
in these cases, a condition that is thought to be less
dependent on PV foci.
INFLAMMATION AND STRUCTURAL AF has been found to induce electrical remodeling (i.e.,
REMODELING slow conduction and reduced refractory periods) which
Disease-specific inflammation, such as that seen in serves as a functional substrate for AF. A comparison of
Aschoff bodies, may play a role during acute episodes of electrophysiological studies in patients with MS prior to
carditis. However, a recent histological study found that commissurotomy versus patients undergoing left-sided
Aschoff bodies are rare and not statistically connected to accessory pathway ablation has demonstrated an increase
AF in biopsies obtained during surgery. Interstitial fibrosis in the effective refractory periods with a decrease in
KG-16.indd 115 02-11-2018 13:47:13

SECTION conduction velocity in both atria.8 Additionally, MS was mitral valve disease. This is in contrast to patients with
found to be associated with lower voltages and recurring nonvalvular AF in whom the clots are mainly located in the
2 electrical scar in both atria.8The study could not determine
whether electrical remodeling preceded or followed
left atrial appendage (90%).16
In the absence of contraindications, anticoagulation
structural remodeling. However, the conjunction of both is essential in all patients with rheumatic AF. There
types of remodeling was associated with an increased AF is an ongoing debate regarding the use and timing of
inducibility.8 Atrial stretch induced by pressure overload is anticoagulation in patients with MS who are in sinus
another player in the development of AF. rhythm. The risk of systemic thromboembolism is this
LA pressure has been correlated with inducibility of AF subset is not correlated with the disease severity. However,
in studies evaluating results before and after percutaneous resolution of spontaneous echo contrast and a decrease in
commissurotomy.9 The conduction velocities and effective thromboembolic risk have been observed in these patients
a
refractory periods seem to be affected by the atrial stretch. after successful commissurotomy.17 Therefore, correction
di
Various studies have reported a consistent decrease of the underlying valvular lesion should be attempted
in conduction times following commissurotomy. 9,10 whenever feasible.
In
On the contrary, the effect of commissurotomy on
atrial refractory periods is relatively ambiguous.9 These MANAGEMENT
electrophysiological effects of commissurotomy were
Although the initial episodes of AF may be paroxysmal
of
primarily observed in patients with sinus rhythm rather
in patients with rheumatic valvular heart disease, they
than those with AF.9 These observations indicate that
invariably evolve into persistent AF. Symptoms result
electrical remodeling in atria is at least partially influenced
from rapid and irregular ventricular rates, heart failure
ty
by atrial stretch secondary to pressure overload. This
and systemic thromboembolism. The development of
might be a potential reversible remodeling factor that
symptoms is related to the duration of AF. While the
occurs.10
18 cie
may be addressed before extensive structural remodeling
The effects of AF on the patient, especially those with

underlying valvular disease should be corrected whenever
feasible, the management of AF includes either the control
of ventricular rate without attempts at rhythm control
MS has been analyzed . The ventricular rate almost solely
20 o
or restoration of sinus rhythm followed by aggressive
decides the effect.11 Duration of diastole decreases with
S
therapy to maintain sinus rhythm on follow-up. Since

increase in ventricular rate further causing the transmitral
thromboembolic complications are a major source of
gradient to increase which in turn leads to rise in LA
morbidity, anticoagulation is essential.
pressures and pulmonary venous pressure. The impact of
al
a decrease in atrial boost effect with development of AF

by itself has less impact in patients with significant MS. CORRECTION OF UNDERLYING DISORDER
ic
This is because atrial contraction per se does not lead to The underlying valvular disorder should be corrected, e.g.
og
an increase in flow across a stenotic mitral valve. In the commissurotomy in MS or surgical repair or replacement of
M-mode echocardiogram, this is reflected by the loss of A mitral or tricuspid valves in severe regurgitation. However,
wave.11 AF tend to persist after correction of the underlying
ol
disorder in patients with enlarged and dysfunctional atria.

THROMBOEMBOLISM AND In all patients, as a rule of thumb, reversible factors like
di
ANTICOAGULATION thyrotoxicosis and alcohol intake, must be addressed.

Atrial fibrillation is an important cause of systemic
ar
thromboembolism accounting for more than one third CONTROL OF VENTRICULAR RATE
of all strokes above the age of 65 years. In the absence The control of rapid ventricular rate is one of the chief
C
of structural heart disease, AF increases the risk of targets of treatment in patients with any form of AF when
stroke by 5 times. 12 In patients with mitral valvular instant restoration of sinus rhythm is not feasible. This
diseases, the incidence of AF increases by a factor of 17 strategy is the mainstay of therapy in patients with valvular
so that the lifetime recurrence rate of stroke should be heart disease who are not readily amenable for rhythm
as high as 30–75%.13 The presence of significant mitral control.
regurgitation (MR) is seems to be associated with lower Beta-blockers like propranolol, atenolol and meto-
occurrence of spontaneous echo contrast in the left prolol and calcium-channel antagonists with negative
atria14 on transesophageal echocardiographic studies and chronotropic action such as verapamil and diltiazem, are
hence with a lower risk of thromboembolism compared effective agents for control of rapid ventricular rate with
to MS. Hwang et al.15 demonstrated left atrial thrombi in a low incidence of adverse effects.18 Digitalis, which has
20% of patients with MS and in none of the patients with been commonly used for rate control, has been observed
significant MR. Thrombi have been found in the body to be ineffective during exercise as the electrophysiologic
as well as the appendage of left atrium in patients with action is mediated largely through increase in vagal tone
116
KG-16.indd 116 02-11-2018 13:47:13

on the AV node. Combining digoxin with a beta-blocker methods including both surgical and radiofrequency CHAPTER
that has intrinsic sympathomimetic activity has been catheter-based ablation have been fairly successful in
shown to control the ventricular rates at peak exercise
while minimizes the effects of these drugs when the
maintaining of sinus rhythm.26 Studies comparing these
nonpharmacologic methods with rate control need to be
16
Atrial Fibrillation in Rheumatic Heart Disease

ventricular rates are slowest, as is usually seen during conducted to aid in formulating the guidelines for the best
the night.18,19 In drug refractory cases or in the presence methods of management.
of contraindications or intolerance to beta-blockers and
calcium-channel blockers, catheter ablation of the AV CONCLUSION
junction and implantation of a rate-responsive ventricular
Atrial fibrillation has emerged as a major healthcare
permanent pacemaker may be considered.20
concern among the younger population, mostly in
a
geographical areas with prevalence of rheumatic heart
RHYTHM CONTROL diseases. AF significantly contributes to morbidity and
di
The clinical advantage of restoration and maintenance mortality and imposes a drain on the healthcare resources
of sinus rhythm following corrective procedures for of the society. The benefit of long-term anticoagulation
In
mitral valvular diseases has been shown in a few studies. is well recognized. It is not yet clear whether rate control
Vaturi et al demonstrated increased transmitral gradients or rhythm control is a better strategy in valvular AF.
and worsened functional class following mitral valve On comparison with patients having nonvalvularAF,
of
replacement in patients with AF compared to those in maintenance of sinus rhythm in patients with rheumatic
sinus rhythm.21 In a study by Leon et al, balloon mitral AF seems more beneficial, especially among the patients
valvotomy was observed to lead to inferior immediate- and undergoing mitral valve surgery.
ty
long-term outcomes in patients with AF. This was reflected However, the benefit of restoration and maintenance
in smaller postvalvotomy mitral valve areas (1.7 ± 0.7 vs. of sinus rhythm is rather vague in patients with rheumatic
18 cie
2 ± 0.7 cm2 ; p =0.0001) and reduced event-free survival
rates (freedom from death, redo valvotomy and mitral
valve surgery) at a mean follow-up time of 60 months
valvular disease who are hemodynamically stable and
those who do not require valvular surgery. Although minor
studies have shown benefit in terms of improvement in
20 o
(32% vs. 61%; p =0.0001). AF, by itself, does not negatively functional class, it remains to be seen if important clinical
affect the outcome, but rather is a marker for clinical and
S
endpoints are significantly altered.

morphologic features associated with inferior result after Phar macological methods of rhythm control
BMV.22 Nair et al has also shown inferior immediate and
have several downsides and it is essential to compare
al
long-term outcomes after BMV in patients with BMV with

nonpharmacological methods of rhythm control with rate
lesser post-BMV mitral valve area (1.3 ± 0.4 vs. 1.6 ± 0.4
control, especially in view of the advancements in these
ic
cm2, p = 0.032) and higher event rate on follow-up.27

modalities and their success rates in maintenance of sinus
Restoration and maintenance of sinus rhythm is
rhythm. Despite lack of large supportive evidence, it seems
og
difficult in patients with valvular AF due to the underlying

reasonable to attempt conversion to sinus rhythm in
valvular disease and large atria leading to the presence
rheumatic heart disease in patients undergoing corrective
of unhealthy substrate. Chemical or electrical methods
valve surgery. However, there still fails to be a consensus
ol
can be adopted to achieve cardioversion to sinus rhythm.

on the optimal approach of achieving SR.
However, drugs have been found to be less effective in
di
rhythm conversion in long standing AF. Antiarrhythmic

agents belonging to Vaughan-Williams classes IA, IC or III ACKNOWLEDGMENT
ar
are more effectual. The reported success rates of flecainide, We would like to acknowledge Aparna Gautham who has
propafenone and amiodarone are in the range of 60%.23.24 helped us in proof reading the manuscript.
Class III agents like intravenous ibutilide and intravenous
C
or oral dofetilide are most effective in recent onset AF or

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Prevention of Rheumatic Fever/
CHAPTER 17 Rheumatic Heart Disease
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INTRODUCTION about one million population in 9 states located in
Rheumatic fever (RF) is an autoimmune inflammatory Chandigarh, Vellore, Kochi, Indore, Jammu, Shimla,
In
response following sore throat caused by group A Wayanad, Dibrugarh, Jodhpur, and Mumbai gave a
streptococci (GAS) affecting heart, large joints, skin and prevalence of 10-161/100,000 (median 84/100,000) in
general population and 0.1 to 1.2/1000 (median 1.1/1000)
of
brain. It damages heart valves but spare other tissues. The
damage to the heart valves after resolution of RF is called in 5–14-year-old children by the school health surveys.7,8
rheumatic heart disease (RHD) and it shows worsening Most of the school surveys with echo evaluation using the
World Heart Federation (WHF) guidelines for the presence
ty
with each recurrence of RF, if subsequent GAS sore throats
are not prevented. of RHD have suggested a prevalence 10–20 times higher
counting the clinically silent RHD.9 The overall prevalence
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While 0.3% of patients during endemic and 3% patient
during epidemic conditions of GAS sore throat develop RF,
40–60% patients with previous RF or RHD show recurrence
estimated to be above 1.5–2/1000 in all age groups in India,
suggests that there are about 2–2.5 million patients of RHD
of RF on developing GAS sore throat again and therefore in the country.10,11
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need continuous prophylaxis with antibiotics. The RF
DIAGNOSIS OF RHEUMATIC FEVER
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recurrences typically demonstrate a mimetic effect, which

means a patient with previous carditis would develop RF is diagnosed with combination of clinical manifestations
carditis again, if RF recurs. While appropriate antibiotic and laboratory evidence of preceding streptococcal
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treatment of GAS pharyngitis prevents RF in most cases; infection. The Jones criteria, first published in 1944
but at least one-third of RF cases results from subclinical and have been revised periodically, are guidelines for
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pharyngitis where medical treatment is not sought.1-4 diagnosis of RF. The recent revision of Jones criteria
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presents two distinct decision paths depending on the

EPIDEMIOLOGY risk category of the population (Table 1).12 For high-risk
The RF/RHD remains a major neglected disease of populations (RF prevalence ≥ 2 per 100,000 school-aged
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marginalized communities. Global burden of GAS- children) monoarthritis and polyarthralgia are considered
related disease estimates Globally, there are at least 15.6 as major criteria provided other causes are excluded and
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million people with RHD, 1.9 million with past RF without monoarthralgia and erythrocyte sedimentation rate (ESR)
carditis, 4,70,000 new cases of RF and over 2,30,000 ≥30 mm/hr are accepted as minor criteria in this high risk
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deaths due to RHD annually as per global burden of population.

group A Streptococcus (GAS))-related disease estimates.
PREVENTION OF RHEUMATIC FEVER/
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Prevalence of RHD is high in northern and sub-Saharan

Africa, the Indian subcontinent, Latin America, the Middle RHEUMATIC HEART DISEASE
East, and amongst aboriginal Australians, Maoris, Pacific
island nations and pacific islanders from New Zealand. 5 Primordial Prevention
Globally, India contributes nearly 25–50% of newly Primordial prevention aims to prevent GAS pharyngitis in
diagnosed cases, deaths, hospitalizations, and burden of susceptible population through implementing actions and
RHD.4 measures that target environment, social and economic
However, critical appraisal of published literature conditions that are known to increase the risk of GAS
suggests that there has been a real decline in occurrence infection. Poverty, household-crowding, poor nutrition
of RF/RHD in some parts of India, which seem to largely and health knowledge, and limited healthcare facilities
correlate with improved public health facilities rather than are considered as predominant predisposing factors for
economic development alone.6 RF/RHD. These conditions result in persistence of GAS
Registry-based RF/RHD surveillance carried out by in the environment and through droplet dissemination it
Indian Council of Medical Research (ICMR) covering spreads from person to person. Poor nutritional status is
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SECTION
Table 1: Revised Jones criteria for diagnosis of rheumatic fever (RF) (American Heart Association/World Heart Federation)
2 Major Criteria:
1. Carditis (clinical and/or subclinical)
2. Polyarthritis
3. Chorea
4. Subcutaneous nodules
5. Erythema marginatum
For moderate and high risk population
(RF incidence ≥ 2 per 100,000 school-aged children or all age RHD prevalence of > 1 per 1000 population per year)
In addition to above:
Monoarthritis and polyarthralgia (when other causes are excluded)
Minor Criteria:
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1. Polyarthralgia
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2. Fever (≥38.5º C)
3. Raised ESR (≥60 mm/hr) and/or raised C-reactive protein (CRP) (≥3 mg/dL)
4. Prolonged PR interval
In
For moderate- and high-risk population
In addition to the above, monoarthralgia, ESR ≥30 mm/hr
Diagnosis (all patients with evidence of preceding GAS infection):
of
Initial RF: Presence of 2 major or 1 major and 2 minor criteria
Recurrent RF: presence of 2 major or 1 major and 2 minor or 3 minor criteria
Abbreviations: ESR, erythrocyte sedimentation rate; GAS, group A streptococcus; RHD, rheumatic heart disease
ty
* Based on the American Heart Association Scientific Statement12
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believed to compromise immune response and limited
access to medical treatment allows RF to remain endemic.
Therefore, the incidence of RF may be reduced by
1.
2.
Table 2: Diagnosis of streptococcal pharyngitis*
Acute sore throat with painful swallowing
Pyrexia, headache, vomiting
social and political measures to alleviate poverty and 3. Congested pharynx and tonsils with exudates
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overcrowding, and through basic health education to 4. Petechiae on soft palate
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5. Congested swollen uvula

prevent GAS spread through droplets following ‘cough 6. Enlarged tender cervical nodes
etiquettes’ like using a handkerchief and hand washing.11,13 Features favoring viral upper respiratory infection:
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Coryza, conjunctivitis, hoarse voice, cough, diarrhea, exanthema

Primary Prevention * Based on the American Heart Association Scientific Statement13
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Ideally, the primary prevention requires public awareness

regarding danger of RF from sore throat; identification of over the country. Further, GAS sore throats are subclinical
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sore throat as being due to GAS infection (Table 2) and in over two-thirds cases and therefore remain untreated.
penicillin injection to cure the infection.11 The American Till today, there are no genetic markers to reliably
identify susceptibility to RF in population to practice
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experience during RF resurgences suggests that oral

penicillin may not prevent RF and more so its compliance primary prevention.11 However, the primary prevention
may not be certain.14,15 for RF would become a reality if the antistreptococcal
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Measures aimed at preventing RF through the vaccine becomes available.

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prevention or eradication of pharyngeal GAS colonization

or the early recognition and antibiotic therapy for GAS Antistreptococcal Vaccine
pharyngitis are of uncertain effectiveness. Programs Several GAS protein and polysaccharide components have
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aimed at preventing GAS colonization through antibiotic been considered in developing antistreptococcal vaccine.
use are unsustainable on long term due to associated cost, M-protein has been considered to be the virulence
patient inconvenience, and risk of developing antibiotic factor of the GAS and has been tried in preparation of a
resistance.13,16 The recommendations for treatment of GAS vaccine. The M-protein is strain-specific; and since over
pharyngitis are given in Table 3. The antibiotic treatment 250 different strains have been identified based on emm
of GAS pharyngitis will prevent RF in majority, but not typing, it is essential that the vaccine must be polyvalent
all children receive therapy due to lack of knowledge in incorporating all the strains present in the community.17
parents regarding sore throat causing heart disease and The GAS has a strong tendency for mutation and the
therefore failing to get medical help. vaccine may not be effective if the infection is due to such
The Sledgehammer approach of treating each sore organism. There is heterogeneous distribution of strains
throat with antibiotics is logically not feasible since varying from place to place and from time to time in the
bacteriological facilities to identity GAS do not exist all same community.
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CHAPTER
Table 3: Antibiotic therapy for streptococcal sore throat (primary prevention of rheumatic fever)*
A. Penicillins:
Rating
17
1. Benzathine penicillin G : ≤27 kg 600000 U IM once, >27 kg 1200,000 U IM once

2. Amoxicillin: 50 mg/kg (maximum 1 g) daily orally in 2–3 divided dosage for 10 days IB
3. Penicillin V: ≤ 27 kg 250 mg 2–3 times daily,
> 27 kg 500 mg 2–3 times daily for 10 days
B. For patients allergic to penicillin:
1. Azithromycin: 12 mg/kg (maximum 500 kg) once a day for 5 days
II aB
2. Clindamycin: 20 mg/kg 3 divided dosage daily orally
3. Cephalexin/Cefadroxil: 20 mg/kg daily in 2–3 divided dosage
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Table 4: Secondary prophylaxis*
In
Rating
A. Penicillins:
of
Benzathine penicillin G:
zz ≤27 kg 600,000 units IM every 3–4 weeks,
IA
zz >27 kg 1200,000 units IM every 3-4 weeks**
Penicillin V: 250 mg twice daily IB
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B. For patients allergic to penicillin:
1. Sulfadiazine: 500 (≤27 kg) to 1000 (≥27 kg) mg once daily orally IB
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2. Macrolide or azalide orally can be given IC
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** For high-risk population 3 weekly dosing is preferred.
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Thus, the M-protein-based vaccine is not likely to be Strategy of secondary prophylaxis has been proven in
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effective in preventing GAS infection. The other vaccine randomized controlled trials for preventing RF recurrence.
targets tried include GAS C5, a peptidase, fibronectin- A Cochrane meta-analysis concluded that for prevention
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binding protein sfb 1, and the chimeric peptide J8 from the of RF recurrences intramuscular benzathine penicillin
conserved region of the M-protein.18 Till date, no effective was superior to oral penicillin (penicillin V) (87–96%
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antistreptococcal vaccine is available; and hence, primary reduction).21 The regular secondary prophylaxis prevents
prevention of RF at community level has to wait till such disease progression and reduces the severity of RHD is
time when it becomes available.10,11 proven without doubt.22,23
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The antibiotic regimen for secondary prophylaxis

is given in Table 4. Benzathine penicillin can be given
Secondary Prevention
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alone or with lignocaine to reduce injection site pain.

Secondary prevention of RF consist of preventing The benefits of secondary prophylaxis using benzathine
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infection of the upper respiratory tract with GAS and penicillin on long-term outweigh the rare risk of
the development of recurrent rheumatic fever using anaphylaxis and fatality. The allergic and anaphylactic
antibiotics continuously to cases who have had RF or well- reactions to benzathine penicillin are reported in 3.2
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documented RHD.4,19 and 0.2% patients, respectively; and deaths are extremely
Secondary prevention is best achieved through rare. 24,25 Table 5 gives the recommended duration of
comprehensive register-based control program, identifying secondary prophylaxis in RF/RHD cases.
all cases of RF or RHD, providing health education to
parents who should understand the importance of sore Secondary Prophylaxis during Special Situations
throat in causing heart disease and need to get antibiotics Pregnancy and Breastfeeding
for its treatment, to bring children for 3–4 weekly injections Penicillins and erythromycin are considered safe for use
of benzathine penicillin to prevent disease progression. in pregnancy.26 Penicillins are considered safe for use
The penicillin prophylaxis is necessary due to the fact during breastfeeding since their excretion into breast milk
that RF has a tendency for recurrence in those who had is in low concentrations. Erythromycin is also excreted
RF in past, each new attack causing further valve damage into breast milk in low concentrations and has been
making the disease worse than before.3,20 considered safe in breast feeding.26
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Table 5: Secondary prophylaxis duration*
2 A. Rheumatic heart disease:

Rating
IC
For 10 years or until 40 years of age or lifelong
B. Rheumatic fever with carditis with no residual valvular disease:

For 10 years or until 21 years of age (whichever is longer) IC
C. Rheumatic fever without carditis:
IC
For 5 year or until 21 years of age (whichever is longer)
a
Secondary Prophylaxis in Anticoagulated Patients Disease in India. Comprehensive Project Report (2000-
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2010) New Delhi: Indian Council of Medical Research.
Benzathine penicillin injections are safe in patients with
2015. pp. 1-160.
prosthetic mechanical heart valves who need life-long
In
8. Bharani A, Tandon R, Sharma N, et al. Prevalence of
anticoagulation therapy excepting when there is evidence rheumatic fever/rheumatic heart disease in India: lessons
of active bleeding or the International Normalized Ratio is from active surveillance and a passive registry. J Am Coll
over 4.5.19
of
Cardiol. 2010;55(10A Suppl 1):E1415.
9. Reményi B, Wilson N, Steer A, et al. World Heart Federation
CONCLUSION criteria for echocardiographic diagnosis of rheumatic heart
ty
disease—an evidence-based guideline. Nat Rev Cardiol.
The combination of primary prevention and long-term 2012;9(5):297-309.
secondary prophylaxis strategies makes the prevention and 10. Shah B, Sharma M, Kumar R, et al. Rheumatic heart
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eradication of RHD possible. WHF and its working group
on RF and RHD provide the platform for RHD control.
disease: progress and challenges in India. Indian J Pediatr.
2013;80(Suppl 1):S77-86.
Comprehensive RF/RHD control programs (register- 11. Kumar R, Tandon R. Rheumatic fever and rheumatic heart
20 o
based), benzathine penicillin access globally, developing disease: the last 50 years. Indian J Med Res. 2013;137(4):643-58.
public leadership for control programs, expanding 12. Gewitz MH, Baltimore RS, Tani LY, et al. Revision of the
S
training hubs and supporting vaccine development are Jones Criteria for the diagnosis of acute rheumatic fever in
five key strategic targets provided by WHF. 27 the era of Doppler echocardiography: a scientific statement
al
from the American Heart Association. Circulation.

2015;131(20):1806-18.
ACKNOWLEDGMENTS
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13. Gerber MA, Baltimore RS, Eaten CB, et al. Prevention of

We thank Shri Ajay Malviya, Department of Medicine, rheumatic fever and diagnosis and treatment of acute
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MGM Medical College, Indore, Madhya Pradesh, India, for streptococcal pharyngitis: a scientific statement from the
secretarial assistance. American Heart Association Rheumatic Fever, Endocarditis,
and Kawasaki Disease Committee of the Council on
Cardiovascular Disease in the Young, the Interdisciplinary
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of rheumatic fever: treatment of preceding streptococcal Care and Outcomes Research: endorsed by the American
infection. J Am Med Assoc. 1950;143(2):151-3. Academy of Pediatrics. Circulation. 2009;119(11):1541-51.
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2. Dajani AS. Current status of nonsuppurative complications 14. Veasy LG, Wiedmeier SE, Orsmond GS, et al. Resurgence
of group A streptococci. Pediatr Infect Dis J. 1991;10 of acute rheumatic fever in the intermountain area of the
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(10 Suppl):S25-7. Unites States. N Engl J Med. 1987;316(8):421-7.

3. Feinstein AR, Spagnuolo M. Mimetic features of rheumatic 15. Veasy LG. Lessons learned from the resurgence of rheumatic
fever recurrences. N Engl J Med. 1960;262:533-40. fever in the United States. In: Narula J, Virmani R, Reddy KS
4. World Health Organization. Rheumatic fever and (Eds). editors. Rheumatic fever. Washington DC: American
rheumatic heart disease. World Health Organ Tech Rep Ser. Registry of Pathology. Armed Forces Institute of Pathology;
2004;923:1-122. 1999. pp. 69-78.
5. Carapetis JR, Steer AC, Mulholland EK, et al. The global 16. RHD Australia (RF/RHD writing group) National Heart
burden of group A streptococcal diseases. Lancet Infect Dis. Foundation of Australia and the Cardiac Society of Australia
2005;5(11):685-94. and New Zealand. The Australian guideline for prevention,
6. Ramakrishnan S, Kothari SS, Juneja R, et al. Prevalence of diagnosis and management of acute rheumatic fever and
rheumatic heart disease: has it declined in India? Natl Med rheumatic heart disease (2nd edition); 2012.
J India. 2009;22(2):72-4. 17. Smeesters PR, McMillan DJ, Sr iprakash KS. The
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Community Control of Rheumatic Fever/Rheumatic Heart Trends Microbiol. 2010;18(6):275-82.
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18. McMillan DJ, Davies MR, Browning CL, et al. Prospecting 23. Taranta A, Kleinberg E, Feinstein AR, et al. Rheumatic fever CHAPTER
for new group A streptococcal vaccine candidates. Indian J in children and adolescents: a long-term epidemiologic
Med Res. 2004;19(Suppl):121-5.
19. Heart Foundation of New Zealand. New Zealand guidelines
study of subsequent prophylaxis, streptococcal infections,
and clinical sequelae, V: relation of the rheumatic fever
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for rheumatic fever: diagnosis, management and secondary

recurrence rate per streptococcal infection to preexisting
prevention of acute rheumatic fever and rheumatic heart clinical features of the patients. Part 5. Ann Intern Med.
disease: 2014 update. Available at: www.heartfoundation.org.nz 1964;60:58-67.
20. Dajani A, Taubert K, Ferrieri P, et al. Treatment of acute 24. International Rheumatic Fever Study Group. Allergic
streptococcal pharyngitis and prevention of rheumatic
reactions to long-term benzathine penicillin prophylaxis
fever: a statement for health professionals. Committee
for rheumatic fever. Lancet. 1991;337(8753):1308-10.
on Rheumatic Fever, Endocarditis and Kawasaki Disease
25. Markowitz M, Lue HC. Allergic reactions in rheumatic fever
of the Council on Cardiovascular disease in the young,
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patients on long-term benzathine penicillin G: the role of
the American Heart Association. Pediatrics. 1995;96:
skin testing for penicillin allergy. Pediatrics. 1996;97:981-3.
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21. Manyemba J, Mayosi BM. Penicillin for secondary 26. Briggs GG, Freeman RK, Yaffe SJ. Drugs in pregnancy and
prevention of rheumatic fever. Cochrane Database Syst Rev. lactation, 9th edition. Philadelphia: Lippincott Williams &
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22. Tompkins DG, Boxerbaum B, Liebman J. Long-term 27 Remenyi B, Carapetis J, Wyber R, et al. Position statement of
prognosis of rheumatic fever patients receiving regular the World Heart Federation on the prevention and control
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intramuscular benzathine penicillin. Circulation. of rheumatic heart disease. Nat Rev Cardiol. 2013;10(5):
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Valvular Heart
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Disease—Others
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Newer Valve Guidelines: What Suits Indians and What does not?
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Role of Two- and Three-dimensional Echocardiography in Valvular Lesions
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Pitfalls in Assessment of Valvular Heart Disease
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Nonrheumatic Mitral Regurgitation
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Bicuspid Aortic Valve in 2018: What we Must Know?
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Low-gradient Aortic Stenosis

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Infective Endocarditis: What is New?

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Prophylaxis for Infective Endocarditis in India

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Mechanical Prosthetic Valve Thrombosis

Ganesan Karthikeyan
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Percutaneous Valve Interventions beyond Transcatheter
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Aortic Valve Implantation
Vijay Kumar Trehan, Safal, Siddhant Trehan
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Newer Valve Guidelines:
What Suits Indians and
CHAPTER 18 What does not?
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“It is much more important to know what sort of a patient the individual, but the community as well. In developed
has a disease than what sort of a disease a patient has.” countries, VHD related to RHD has declined significantly
In
—William Osler and left-sided degenerative lesions in the elderly were the
most common etiology.5 The new guidelines published in
INTRODUCTION 2017 are primarily based on the data from the developed
of
countries. In addition, the percutaneous interventional
The burden of valvular heart disease (VHD) in India is
techniques [transcatheter aortic valve implantation
significantly high and is a major cause of concern. The
(TAVI), percutaneous mitral valve edge-to-edge repair) are
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spectrum of VHD varies from predominantly rheumatic
commonly performed in developed countries, while India
heart disease (RHD) in adolescents and adulthood, to
is still in the early phase of the learning curve.
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degenerative valve disease in the elderly. The universal
access to health care in India is not optimal and certain
modalities of treatment, such as transcatheter valve GENERAL CONSIDERATIONS IN EVALUATING
replacement, remains expensive. VALVULAR HEART DISEASE
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Clinical practice guidelines summarize available Preprocedure patient evaluation and risk stratification are
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evidence intended to help clinicians in selecting the appropriately described in the guidelines. The vital points
optimal strategy for an individual patient with a given to be kept in mind are emphasized below:
condition. The most recent guidelines for the management
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Accurate assessment of symptoms and its correlation
of VHD are from the European Society of Cardiology (ESC) to underlying VHD are important in the patient
and the European Association for Cardio-Thoracic Surgery
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management.
(EACTS), and the American Heart Association (AHA)/ 2D echocardiography is the key to assess the etiology,
American College of Cardiology (ACC).1,2 Management of

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severity and prognosis of patients with VHD. The

VHD in Indian population presents unique challenges as assessment of severity should not rely on a single
the pattern of VHD is distinct, as compared to the Western criterion, rather a combined approach including
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population. In addition, the population perception various criteria is recommended.

regarding VHD, cultural beliefs and socioeconomic Invasive investigations apart from preoperative
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conditions are also quite different. In this review, we coronar y angiography is limited to situations
summarize the salient features of the recent guidelines where noninvasive evaluation is inconclusive
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and relevance to Indian population. It is recommended (ventriculography and aortography to assess the
to go through the 2017 ESC/EACTS, and ACC/AHA severity of regurgitant lesions).
guidelines for the management of VHD beforehand, for The presence of comorbidities and general condition
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better understanding of the current review. require attention, especially in the elderly patients.
Exercise testing is useful to unmask the objective
VALVULAR HEART DISEASE: THE INDIAN occurrence of symptoms and determine the level of
PERSPECTIVE recommended physical activity.
In the era of transcatheter valve interventions, the focus of There are two important areas to be stressed upon
VHD in India is still predominantly RHD and it continues to during the evaluation of VHD in Indians. There is a rapid
be a major cause of morbidity and mortality.3 In one of the increase in the burden of coronary artery disease (CAD)
largest echocardiographic studies from India regarding the over the past few decades, and CAD occurs at a younger
pattern of VHD, RHD was the most common etiology. In age in Indians.6,7 During planned intervention or surgery
addition, multiple valves were involved in more than a third for VHD, the presence of untreated significant CAD
of all the cases.4 RHD is primarily affecting the younger has a negative impact on the immediate and long-term
generation during their period of maximum productivity. patient outcomes. Hence, it is important to determine
Consequently, RHD has a devastating impact not only on if concomitant coronary revascularization is indicated.
KG-18 (Sec-3).indd 127 02-11-2018 13:52:32

SECTION The threshold for the evaluation of CAD should be low, One of the mechanisms of mitral regurgitation (MR) in
with meticulous assessment of cardiovascular risk factors rheumatic MS is due to restriction of leaflet mobility.
3 including family history of premature CAD. The use of
stress tests to detect CAD in patients with significant VHD
Following BMV, there may be improvement in leaflet
excursion and consequently degree of MR. Hence,
Valvular Heart Disease—Others
is inappropriate because of their low diagnostic value in patients with moderate MR (central jet), it may
and possible risks. Coronary angiography is appropriate be reasonable to attempt BMV. In a small study by
in patients with intermediate to high probability of CAD. Desabandhu V et al. BMV was safe and provided
Alternatively, coronary computed tomography (CT) sustained symptomatic benefit in patients with severe
should be considered to exclude CAD in patients at low MS and moderate MR.11
risk. The presence of severe concomitant aortic valve
The concept of ‘Heart Team’ has been endorsed by disease is considered a contraindication for BMV.
a
both the European and ACC/AHA guidelines and is the Patients with aortic valve disease have an elevated left
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subject of interest in the management of cardiovascular ventricular end-diastolic pressure, and these patients
disease. This allows the patients to have a one-stop shop are less likely to tolerate mitral regurgitation following
In
wherein all the issues are taken care of by a specialist BMV. A carefully performed BMV, with active surgical
team working together. The main goal of ‘Heart Team’ is to back-up is reasonable in such a setting. If the BMV
provide a ‘patient-centric’ approach where the alternatives is successful, aortic valve surgery may be postponed
of
and outcomes of treatment options are discussed in detail, depending on the symptom status, left ventricular
to understand and meet the family expectations. In India, function and the rate of progression of aortic valve
this concept is currently not uniformly implemented. It is disease.
ty
recommended the approach of ‘Heart Team’ be adopted The most common scoring system to predict the
in all the major cardiac centers to deliver better quality of outcome of BMV is the Wilkin’s scoring system.12 Patients
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care. In dealing with VHD, there are two situations where
this concept should be mandatory: (a) Patients at high risk
of surgery (based on the EuroSCORE II and the Society of
with a score ≤ 8 have a favorable outcome following BMV.
This scoring system does not assess the commissural
calcium, and this is one of the major limitations. The
Thoracic Surgeons score) and (b) Surgery or intervention
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presence of bicommissural calcification is an absolute
is being planned in an asymptomatic subject with severe contraindication for BMV. However, BMV is still feasible
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VHD. in the presence of dense leaflet calcification, provided the

commissures are free of calcium. Further, BMV can be
SPECIFIC VALVULAR LESIONS
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performed successfully in the presence of unicommissural

calcification. 13 The modality of intervention (BMV vs
Mitral Valve Disease
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surgery) in patients with unfavorable anatomy is still

Mitral Stenosis a matter of debate. Based on the available literature in
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Indian patients and local resources, we recommend the

The most common cause of mitral stenosis (MS) is RHD.
following protocol for the management of patients with
The incidence of rheumatic MS has significantly declined
rheumatic MS (Figures 1 and 2).
in developed countries, but continues to be endemic in
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India and is a major public health concern. 8,9 Balloon

mitral valvotomy (BMV) is the most common intervention Mitral Regurgitation
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performed for acquired VHD in India, and has had a major Mitral regurgitation (MR) is a common valvular disorder,
impact on the management of rheumatic MS. and key to the management lies in understanding the
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Guidelines recommend intervention (BMV or surgery) etiology and pathophysiology. It is important to distinguish
in all patients with a valve area ≤1.5 cm2. However, in our acute from chronic, and primary from secondary MR. In
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practise, if symptoms are well tolerated, it is reasonable to primary MR, one or more of the components of mitral
closely follow-up the patient till the valve area is ≤ 1.0 cm2. valve apparatus are directly affected resulting in valve
The choice of treatment should be decided not only based incompetence. Although the most frequent etiology of
on the echocardiographic features, but should consider primary MR is a myxomatous mitral valve in developed
local expertise as well. Considering the vast experience countries, RHD is the most common etiology in India.4
and high-volume BMV centers in India, the following Acute MR is due to disruption of the mitral valve
deviations from guidelines may be reasonable: apparatus. The common causes include infective
The presence of left atrial thrombus has long been endocarditis, spontaneous chordal rupture and papillary
regarded as an absolute contraindication for BMV. As muscle rupture in the setting of myocardial infarction.
described by Manjunath CN et al., in selected patients Guidelines uniformly recommend urgent surgery for
of MS and left atrial thrombus (Type Ia, Ib and IIa), acute severe MR. 1,2 From an Indian perspective, two
BMV can be safely performed with a modified over- additional important causes for acute severe MR needs
the-wire technique.10 to be considered. First, the presence of rheumatic activity
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Figure 1: Management of patients with rheumatic mitral stenosis
Abbreviations: BMV, balloon mitral valvotomy; GDMT, guideline directed medical therapy;
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MVOA, mitral valve orifice area; PASP, pulmonary artery systolic pressure
{Surgery includes either mitral valve replacement or open mitral commissurotomy}
18 cie
contributing to acute MR, especially in adolescents and Secondary MR is commonly seen in ischemic and
early adulthood needs to be considered in the differential dilated cardiomyopathies. Although secondary MR
20 o
diagnosis. Majority of these patients are effectively is associated with an unfavorable prognosis, there is
S
managed with medical therapy. The second scenario no evidence of mortality benefit with intervention.
is the setting of acute severe MR following BMV. In this However, surgery should be considered in patients with
setting, early surgery (<24 hr) is recommended for optimal severe secondary MR and LVEF >30% during coronary
al
outcome.14 artery bypass grafting or LVEF <30% with a feasibility of

In chronic primary MR, it is important to assess the revascularization in the presence of viable myocardium.
ic
hemodynamic consequences on ventricular function, left The decision to intervene for secondary MR should be
atrium and pulmonary circulation. The key parameters to made before surgery, as intraoperative assessment under
og
be considered for intervention are: symptom status, left general anesthesia significantly reduces the severity of MR.
ventricular ejection fraction (LVEF) ≤60%, left ventricular In India, the impact of catheter intervention (percutaneous
end-systolic diameter ≥45 mm, pulmonary artery systolic
ol
edge-to-edge repair and valve implantation) for MR

pressure >50 mm Hg and new onset of atrial fibrillation. requires further evaluation.
The essential points from the guidelines relevant to our
di
practise are highlighted below:

The decision to intervene based solely on pulmonary Aortic Valve Disease
ar
artery systolic pressure should be confirmed by right

Aortic Stenosis
heart catheterization.
C
Mitral valve repair should be the preferred technique

Degenerative aortic valve disease is the most common
of intervention for primary MR when feasible. etiology of aortic stenosis requiring intervention. The
Surgery should be considered in all symptomatic
current focus is on transcatheter aortic valve intervention
patients with LVEF of >30%. (TAVI) in select group of patients with severe aortic
In asymptomatic subjects, surgery is indicated with the stenosis (AS). However, local expertise and resources for
onset of left ventricular dysfunction (left ventricular TAVI are limited to very few centers in India. In future,
end-systolic diameter ≥45 mm, LVEF ≤60%), new onset with widespread applicability of TAVI in routine clinical
atrial fibrillation or pulmonary artery systolic pressure practice, the ESC/EACTS and ACC/AHA guidelines
of >50 mm Hg at rest. will serve as a roadmap. The key take-home messages
In the presence of severe left ventricular systolic applicable to the Indian population are highlighted below:
dysfunction (EF <30%), mitral valve repair should be The hemodynamic subsets of AS should be defined
considered when the likelihood of success is high and based on the mean gradient, valve area, LVEF and
comorbidity low. stroke volume index.
129
KG-18 (Sec-3).indd 129 02-11-2018 13:52:34

SECTION
3
a
di
In
of
ty
18 cie
Figure 2: Algorithm for the choice of intervention in mitral stenosis
20 o
Abbreviations: BMV, balloon mitral valvotomy; LA, left atrium; MR, mitral regurgitation; PTTC, percutaneous transluminal tricuspid
commissurotomy; TR, tricuspid regurgitation; TS, tricuspid stenosis; TV, tricuspid valve)
S
*BMV after 8–12 weeks of therapeutic anticoagulation

{Surgery includes either mitral valve replacement or open mitral commissurotomy}
al
The most important indication for intervention in Aortic Regurgitation

severe AS is the symptoms related to AS (spontaneous
ic
Aortic regurgitation (AR) caused by inadequate coaptation

or on exercise testing).
of valve leaflets results from primary disease of the valve
In asymptomatic severe AS, intervention is indicated
og

cusps or alteration in the geometry of aortic root and
in the presence of systolic left ventricular dysfunction
ascending aorta. Primary affection of the valve cusps is due
(EF <50%), hypotensive response to exercise testing,
to degenerative tricuspid and bicuspid valves, infective
ol
Vmax >5.5 m/s, severe valve calcification and rate of

endocarditis, and RHD. In the evaluation of AR, attention
Vmax progression ≥0.3 m/s/year and pulmonary artery
needs to be focused on the aortic root and ascending
di
systolic pressure >60 mm Hg confirmed by invasive

aorta. It is important to classify the three phenotypes of
measurement.
ascending aorta as it will have surgical consequences
ar
The choice of intervention (surgery vs TAVI) should

be based on the available resources and individual (aortic root aneurysm, tubular ascending aneurysm and
characteristics after comprehensive evaluation by the isolated AR).
C
Acute AR mandates emergency surgery. Similar to MR,

‘Heart Team’. The key factors influencing the decision
are the surgical risk score (STS/EuroSCORE II), age acute rheumatic fever as an etiology for acute AR needs
of the patient, prior cardiac surgery, frailty, porcelain to be considered in the appropriate setting.
Presence of symptoms (spontaneous or on exercise
aorta, prior chest radiation and suitability of access for
TAVI. testing) is the strongest indication for surgery in severe
Surgery is recommended in patients at low risk (STS or AR.
In asymptomatic severe AR, surgery is indicated with
EuroSCORE II <4%).
TAVI is recommended in high surgical risk patients, resting LVEF of ≤50% and left ventricular end-systolic
as assessed by the ‘Heart Team’. Multislice CT is the diameter >50 mm (>25 mm/m2 body surface area).
preferred imaging modality to assess the size and In the presence of dilated aorta, accurate measurements
shape of aortic annulus and its relation to coronary of diameter are critical to guide the timing of surgery.
ostia, morphology of aortic valve cusps, dimensions of Surgery is indicated in Marfan’s syndrome with
the aorta, and feasibility of various access routes. maximal ascending aortic dimeter ≥50 mm or ≥45
130
KG-18 (Sec-3).indd 130 02-11-2018 13:52:39

mm in the presence of additional risk factors. In the anticoagulation should be continued postoperatively. CHAPTER
presence of bicuspid aortic valve with additional risk The use of nonvitamin K antagonist oral anticoagulants
factors or coarctation, surgery is indicated with a
maximal ascending aortic diameter ≥50 mm.
is contraindicated in moderate-to-severe mitral
stenosis, and in all patients with a mechanical valve.
18
Valve-sparing aortic surgery to be considered in select The choice of prosthetic valve (mechanical vs bio-
cases with surgical expertise. prosthesis) is determined based on the risk of bleeding
and the indication for long-term anticoagulation,
Tricuspid Valve Disease risk of structural valve deterioration, compliance
issues, life expectancy, and the desire of the informed
Tricuspid stenosis is uncommon, while significant
patient. In patients with a mechanical prosthesis,
tricuspid regurgitation is more often secondary. In the
oral anticoagulation with vitamin K antagonist
a
setting of RHD, tricuspid stenosis is often accompanied by
is recommended lifelong. The most devastating
tricuspid regurgitation and left-sided valvular lesions.
di
Surgery is indicated for patients with tricuspid stenosis
complication of a mechanical prosthetic valve is
thrombosis. Guidelines recommend urgent valve
while undergoing valve replacement for left-sided
In
replacement for obstructive and large (>10 mm)
pathology.
Percutaneous balloon valvuloplasty for tricuspid
thrombi. In India, most of the cases are managed
with fibrinolysis because of the risks associated with
stenosis can be performed following a successful BMV
of
reintervention and the higher cost of surgery.
or can be attempted if tricuspid stenosis is isolated.
Surgery for tricuspid regurgitation is based on the need
COMMON CASE SCENARIOS IN ROUTINE
ty
for left-sided valve surgery, the mechanism and severity
of tricuspid regurgitation (primary or secondary), size CLINICAL PRACTICE
18 cie
of the tricuspid annulus, right ventricular function,
and severity of pulmonary hypertension.
Surgery for tricuspid regurgitation is indicated in: (a)
Mitral Stenosis with Left Atrial Thrombus
A 32-year-old female is being evaluated for New York
symptomatic severe primary tricuspid regurgitation Heart Association (NYHA) class III dyspnea of 6 months
20 o
and (b) at the time of left-sided valve surgery (in the duration. Echocardiography reveals RHD, severe MS
S
presence of severe secondary tricuspid regurgitation (valve area of 0.9 cm 2, Wilkin’s score of 8), trivial MR,
or moderate regurgitation with tricuspid annular mild tricuspid regurgitation, pulmonary hypertension
dilatation and/or signs of right heart failure). (pulmonary artery systolic pressure of 64 mm Hg), and
al
atrial fibrillation with a Type Ib soft left atrial thrombus

(clot in left atrial appendage protruding into cavity).
OTHER CONSIDERATIONS
ic
Guidelines recommend surgery as the treatment,

Combined valvular and multivalvular heart diseases
and BMV is considered a contraindication.1 However,
og
are commonly encountered in RHD. There is a lack of

it is reasonable to consider therapeutic anticoagulation
data, with no evidence-based recommendations. In
for 8–12 weeks and reassess the left atrial thrombus with
the presence of stenosis and regurgitation on the same
ol
transesophageal echocardiography. BMV can be safely

valve, treatment should follow the recommendation
performed subsequently with a modification of the over-
concerning the predominant VHD. In the presence of
di
the-wire technique.10
balanced lesions (moderate stenosis and regurgitation
affecting the same valve), the management should be
ar
based on symptoms and hemodynamic consequences Rheumatic Aortic Stenosis with Left
rather than the indices of stenosis or regurgitation Ventricular Dysfunction
C
alone. Similarly, in multivalvular heart disease, it is A 45-year-old male, known case of RHD, status post BMV
vital to consider the interaction between different 10 years prior, is being treated for congestive cardiac
valve lesions. Proximal valvular lesion leads to failure. His comorbidities include diabetes mellitus on
underestimation of the severity of distal lesion (the insulin therapy, severe chronic obstructive lung disease
presence of mitral regurgitation will underestimate the and renal dysfunction (creatinine clearance of 55 mL/
severity of aortic stenosis). min). Evaluation reveals severe AS (mean gradient of 36
The presence of atrial fibrillation which is common mm Hg, LVEF of 30% with preserved contractile reserve),
in rheumatic mitral valvular disease, contributes mild MS (valve area of 1.8 cm2), mild MR, mild TR and
to substantial morbidity and mortality due to pulmonary hypertension (pulmonary artery systolic
increased risk of thromboembolism. During valve pressure of 50 mm Hg). The patient is in sinus rhythm, and
surgery, surgical ablation of atrial fibrillation and coronary angiogram is normal.
left atrial appendage excision should be considered. The patient is referred for surgical aortic valve
In the presence of risk factors for stroke, long-term replacement. In view of EuroSCORE II of 6.15%, surgery
131
KG-18 (Sec-3).indd 131 02-11-2018 13:52:40

SECTION is deemed high risk by the ‘Heart Team’. Data on TAVI is 3. Arora S, Ramm CJ, Bahekar AA, et al. Evaluating health of
limited for patients less than 75 years of age, and all the emerging economies through the eyes of heart valve disease
3 trials have enrolled degenerative tricuspid aortic valve

disease. In the given scenario, the indication for TAVI
in the transcatheter era. Glob Heart. 2017;12(4):301-4.
4. Manjunath CN, Srinivas P, Ravindranath KS et al. Incidence
and patterns of valvular heart disease in a tertiary care high-
may have to be expanded, and should be considered in

volume cardiac center: a single center experience. Indian
rheumatic AS who are not candidates for surgery.15
Heart J. 2014; 66(3):320-6.
5. Andell P, Li X, Martinsson A, et al. Epidemiology of valvular
Rheumatic Multivalvular Heart Disease heart disease in a Swedish nationwide hospitalbased
A 37-year-old male is admitted with NYHA class II dyspnea register study. Heart. 2017;103(21):1696-703.
6. Prabhakaran D, Jeemon P, Roy A. Cardiovascular diseases
of 12 months duration. Evaluation reveals RHD, severe MS
in India: current epidemiology and future directions.
a
(valve area of 1.0 cm2, Wilkin’s score of 9), mild MR, severe
Circulation. 2016;133(16):1605-20.
AR (left ventricular end-systolic diameter of 41 mm), mild
di
7. Iyengar SS, Gupta R, Ravi S, et al. Premature coronary artery
aortic stenosis (gradient of 43/27 mm Hg), mild tricuspid disease in India: coronary artery disease in the young
regurgitation, and pulmonary hypertension (pulmonary (CADY) registry. Indian Heart J. 2017; 69(2):211-6.
In
artery systolic pressure of 55 mm Hg). The LVEF is 60%. 8. Iung B, Vahanian A. Epidemiology of acquired valvular
In the presence of severe concomitant aortic valve disease, heart disease. Can J Cardiol. 2014;30(9):962–70.
BMV is contraindicated.1 In the given case, the symptoms are 9. Shah B, Sharma M, Kumar R, et al . Rheumatic heart disease:
of
likely due to severe MS. It is reasonable to perform BMV progress and challenges in India. Indian J Pediatr.2013;80
with active surgical backup. Following a successful BMV, Suppl 1:S77-86.
the symptoms should be reassessed and the need for aortic 10. Manjunath CN, Srinivasa KH, Ravindranath KS, et al.
ty
valve replacement can be considered later depending on the Balloon mitral valvotomy in patients with mitral stenosis
indication. An initial strategy of double valve replacement, and left atrial thrombus. Catheter Cardiovasc Interv.
18 cie
with a higher mortality rate can be avoided. 2009;74(4):653–61.
11. Desabandhu V, Peringadan NG, Krishnan MN. Safety
and efficacy of percutaneous balloon mitral valvotomy in
THE FUTURE
severe mitral stenosis with moderate mitral regurgitation: a
20 o
There have been specific Indian guidelines and consensus prospective study. Indian Heart J. 2016;68(6):783-7.
S
for the management of pediatric acute rheumatic fever, 12. Wilkins GT, Weyman AE, Abascal VM, et al. Percutaneous
hypertension, dyslipidemia, and ST elevation myocardial balloon dilatation of the mitral valve: an analysis of
infarction.16-19 The burden of VHD in India is alarmingly echocardiographic variables related to outcome and the
al
high and is a major health problem. Therefore, it is mechanism of dilatation. Br Heart J. 1988;60(4):299–308.
imperative that guidelines be set for the management of 13. Khandenahally Shankarappa R, Dwarakaprasad R, Karur S,
ic
VHD in Indians, with special focus on RHD and newer et al. Balloon mitral valvotomy for calcific mitral stenosis.
modalities of percutaneous intervention. JACC Cardiovasc Interv. 2009;2(3):263-4.
og
14. Nanjappa MC, Ananthakrishna R, Hemanna Setty SK, et al.

Acute severe mitral regurgitation following balloon mitral
CONCLUSION
valvotomy: echocardiographic features, operative findings,
The recent guidelines (2017 ESC/EACTS, and ACC/AHA)
ol
and outcome in 50 surgical cases. Catheter Cardiovasc

have a global impact and facilitate decision making in Interv. 2013;81(4):603-8.
daily practice for majority of the cases. The concept of
di
15. Gunasekaran S, Ganesapandi R, Sivaprakasam MC, et al.

‘Heart Team’ approach should be uniformly implemented SAPIEN 3 valve implantation in rheumatic aortic stenosis
in all the tertiary cardiac care centers in India, to plan on with a functioning mitral prosthesis: first case report from
ar
the best treatment strategy for a given patient. Based on India. AsiaIntervention. 2018;4:35-7.
clinical judgement, deviations from guidelines may be 16. Working Group on Pediatric Acute Rheumatic Fever and
C
appropriate in certain clinical circumstances depending Cardiology Chapter of Indian Academy of Pediatrics,
on the local available resources and the wishes of the well- Saxena A, Kumar RK, Gera RP, et al. Consensus guidelines
on pediatric acute rheumatic fever and rheumatic heart
informed patients.
disease. Indian Pediatr. 2008;45(7):565-73.
17. Association of Physicians of India. Indian guidelines on
REFERENCES hypertension (I.G.H.) - III. 2013. J Assoc Physicians India.
1. Baumgartner H, Falk V, Bax JJ, et al. 2017 ESC/EACTS 2013;61(2 Suppl):6-36.
Guidelines for the management of valvular heart disease. 18. Iyengar SS, Puri R, Narasingan SN, et al. Lipid Association
Eur Heart J. 2017;38(36):2739-91. of India Expert Consensus Statement on Management of
2. Nishimura RA, Otto CM, Bonow RO, et al. 2017 AHA/ Dyslipidemia in Indians 2016: Part 1. J Assoc Physicians
ACC Focused Update of the 2014 AHA/ACC Guideline India. 2016;64(3):7-52.
for the management of patients with valvular heart 19. Guha S, Sethi R, Ray S, Bahl VK, et al. Cardiological Society
disease. A report of the American College of Cardiology/ of India: Position statement for the management of ST
American Heart Association Task Force on Clinical Practice elevation myocardial infarction in India. Indian Heart J.
132 Guidelines. Circulation. 2017;135(25): e1159-95. 2017;69(Suppl 1):S63-97.
KG-18 (Sec-3).indd 132 02-11-2018 13:52:40

Role of Two- and Three-
dimensional Echocardiography
CHAPTER 19
in Valvular Lesions
a
di
INTRODUCTION transthoracic (2DTTE) and 2D-transesophageal echo-
Echocardiography has become an indispensable modality cardiography (2DTEE), diastolic doming with a
In
in the noninvasive assessment of cardiac valvular disease typical hockey stick appearance of the mitral leaflets,
entities. Many patient-related decisions in day-to-day commissural fusion with narrowing of the mitral orifice as
clinical practice are based on this technology and recourse well as thickening and shortening of the subvalvular mitral
of
to other modalities including cardiac catheterization has apparatus are noted. Because of enlargement of the left
been obviated in a large number of patients leading to cost atrium from mitral orifice obstruction with consequent low
savings and reduced morbidity.1-3 flow state, thrombi may form in the left atrial appendage
ty
and occasionally in the body of the left atrium. Most
commonly, severity of mitral stenosis is estimated by 2D
MITRAL STENOSIS AND REGURGITATION
(TABLES 1 TO 7 AND FIGURES 1 TO 6) 18 cie
The most common cause of mitral stenosis in developing
echo by planimetry of the mitral orifice at its flow-limiting
tip and noting increased velocities and pressure gradients
across the mitral valve by conventional Doppler methods.
countries is rheumatic involvement and presents on The pressure half-time method derived from Doppler
20 o
M-mode echo with a decreased diastolic slope, absence gradients has also been found useful in deriving mitral
S
of A wave in patients with normal sinus rhythm, posterior orifice area in patients with mitral stenosis. Pitfalls in using
mitral leaflet moving parallel to anterior leaflet, and 2D/echo Doppler techniques and how some of them can
multiple linear bright echoes due to calcification and be avoided are described in the accompanying Tables
al
collagen deposition. On real-time two-dimensional 1 to 7. Live/real-time three-/four-dimensional (3D/4D)

ic
Table 1: Causes of mitral stenosis

Rheumatic heart disease
og
Most common cause worldwide. Commissural fusion, thick MV leaflets with restricted mobility, thickened and shortened chordae
Severe mitral annular calcification
Age-related changes, chronic kidney disease
ol
Congenital
Double orifice MV, parachute MV (caused by either one papillary muscle, two fused papillary muscles, or chordae attached to one head of a
papillary muscle), congenitally thickened or dysplastic MV leaflets
di
Secondary to systemic disease (may result in thickened and restricted leaflets/chordae)

SLE, MPS, Fabry’s disease, carcinoid disease, endomyocardial fibrosis, Whipple’s disease
ar
Infective endocarditis (vegetations)/tumor (left atrial myxoma)/ball valve thrombus

When large may obstruct MV orifice
C
Radiation induced
Thick MV with stenosis may occur 10–20 years after radiation
Abbreviations: MV, mitral valve; MPS, mucopolysaccharidosis; SLE, systemic lupus erythematosus
Table 2: Diagnosis of mitral stenosis by echocardiography

M-mode findings
Decreased MV diastolic E–F slope, multiple linear echoes suggestive of thickening/calcification, posterior MV leaflet (PML) moves parallel to
anterior MV leaflet (AML), absence of mitral A-wave in patients in normal sinus rhythm
2D echo findings
Morphology of MV/subvalvular apparatus: Thickened (>4 mm), calcified (increased echogenicity), and deformed MV. Diastolic doming of
the AML, restricted movement of PML; fusion of commissures with reduced MV orifice area, shortened and thickened subvalvular structures
with increased echogenicity
3D echo findings
Same as 2D echo but more accurate
Abbreviations: Echo, echocardiography; MV, mitral valve; 2D, two-dimensional; 3D, three-dimensional
KG-19.indd 133 02-11-2018 13:52:16

SECTION TTE/TEE provides incremental value over 2D echo and is
Table 3: Assessment of mitral stenosis severity
currently considered the gold standard in the assessment
3 Severity Mild Moderate Severe of mitral stenosis severity.4 This is because the entire
mitral valve together with the surrounding structures can
MVA by direct 2D/3D TTE/TEE >1.5 1–1.5 <1
planimetry (cm²)a,b be captured in the 3D data set allowing examination from

multiple vantage points including en face visualization
Pressure half-time (PHT) method 100–150 150–220 >220
of the mitral orifice from both atrial and ventricular
by 2DTTE/TEE (ms)c
aspects. The cropping plane can be placed exactly
Mean pressure gradient by 2DTTE/ <5 5–10 >10 parallel to the mitral orifice at its tip providing the most
TEE (mm Hg)d accurate assessment of stenosis severity. The 3D echo also
Supportive finding: Pulmonary <30 30–50 >50 facilitates systematic and comprehensive step-by-step
a
artery systolic pressure (mm Hg) examination of the left atrium and appendage for thrombi;
and when present, they can be sectioned to evaluate the
di
PHT divided by 220 gives MV area
in cm2 since PHT of 220 ms equals presence, extent, and progression of echolucent areas
MVA of 1.0 cm2 related to lysis (liquefaction) and eventual clot dissolution.
In
a
In contrast, 2D echo provides only a thin slice of a cardiac
Planimetry is not affected by cardiac chamber compliance or
structure, such as the mitral valve, at any given time
associated valvular lesions. However, reflections from heavily calcified
MV or very high 2D gain may cause MV orifice to appear falsely making it difficult to ascertain whether the section taken
of
smaller. MVA is averaged from several beats in AF. is indeed parallel to the orifice tip potentially leading to
b
3DTTE/TEE is the gold standard for MV planimetry because the inaccuracies in orifice area measurement. This limitation
cutting plane can be placed exactly parallel to the MV orifice at the of 2D echo also precludes systematic and complete
ty
tip that may not be possible by 2DTTE/TEE because MV is not viewed
in three dimensions.
examination of the left atrium and appendage for thrombi
c
Changes in LV/LA compliance or pressure across MV will affect PHT which can be easily missed, especially if they are small.
d
18 cie
(significant AR, diastolic heart failure, restrictive cardiomyopathy,
constrictive pericarditis, following MV valvuloplasty).
Tachycardia, significant MR and anemia can increase the gradient
Regarding mitral regurgitation, 2D echo/Doppler
provides a reasonably reliable semi-quantitative
assessment of severity. Mitral regurgitation jet area by
leading to overestimation of MS while low cardiac output states
color Doppler occupying more than 40% of the left area
20 o
decrease the gradient causing underestimation.
Abbreviations: AF, atrial fibrillation; AR, aortic regurgitation; LA, left
cavity is a good indicator of severe mitral incompetence
S
atrium; LV, left ventricle; MV, mitral valve; MVA, mitral valve area; provided careful attention is paid to the Nyquist limit and
MS, mitral stenosis; MR, mitral regurgitation; PHT, pressure half color gain as outlined in the Tables 1 to 7 in this section.
time; TTE, transthoracic echocardiography; TEE, transesophageal In most patients, eye balling is enough to judge the
al
echocardiography; 2D, two-dimensional; 3D, three-dimensional.

Source: Reproduced with modification and permission from Nanda NC,
proportion of mitral regurgitation color Doppler signals
occupying the left atrium which is a distinct advantage
ic
Karakus G, Degirmencioglu A; Manual of Echocardiography, Jaypee

Brothers, New Delhi, India; 2016. since complicated measurements are avoided. Eccentric
og
Table 4: Assessment of mitral valve morphology in mitral stenosis (Wilkins score) by 2DTTE/TEE
Grade Mobility Thickening¹ Calcification Subvalvular thickening
ol
1 Highly mobile MV with only MV near normal in thickness A single area of increased Minimal thickening just below
leaflet tips restricted (4–5 mm) echo brightness MV
di
2 MV mid and base portions Mid leaflets normal, Scattered areas of brightness Thickening of chordal
have normal mobility considerable thickening of confined to leaflet margins structures extending to one-
margins (5–8 mm) third of chordal length
ar
3 MV continues to move Thickening extending Brightness extending into the Thickening extends to distal
forward in diastole, mainly through the entire MV (5–8 mid-portions of MV third of chordae
C
from base mm)

4 No or minimal forward Considerable thickening of Extensive brightness Extensive thickening and
movement of MV in diastole MV (>8–10 mm) throughout much of MV shortening of all chordal
structures extending down to
papillary muscles
Abbreviations: LA, left atrium; LAA, left atrial appendage; MV, mitral valve; MR, mitral regurgitation; MVBV, mitral balloon valvuloplasty; TTE,
transthoracic echocardiography; TEE, transesophageal echocardiography; 3D, three-dimensional
Note: Sum of four parameters (Wilkins score) <9 is associated with good MV balloon valvuloplasty (BV) results, score 9–11 indeterminate results,
score >11 suboptimal results and score of 16 is a contraindication for MVBV. Wilkins score does not take into account MV commissural thickening/
calcification which if significant results in poor outcome (commissural tear with severe MR). Also, does not take into account presence of
thrombus in LA body (contraindication for MVBV) or LAA (relative contraindication) and other comorbidities.
MV, commissures and chordae often better visualized by 3DTTE/TEE.
¹ MV thickening may be more objectively done by comparing MV thickness to posterior aortic wall thickness. Normal ratio <1.4, up to 2.0 mild, 2
to 5 moderate, and >5 severe MV thickening
Source: Reproduced with modification and permission from Nanda NC, Karakus G, Degirmencioglu A. Manual of Echocardiography, Jaypee
Brothers, New Delhi, India; 2016.
134
KG-19.indd 134 02-11-2018 13:52:18

Table 5: Causes of primary mitral regurgitation CHAPTER
19
Rheumatic heart disease: Most common cause in developing
countries. Thickened and distorted MV. Often associated mitral
stenosis

Infective/marantic endocarditis/tumors: Most common cause in
developed countries. Destruction of MV tissue. Vegetations seen as
thickening or mobile masses involving MV
Myxomatous degeneration/MV prolapse (Marfan syndrome,
Ehler-Danlos syndrome, Barlow’s disease, fibroelastic disease):
Leaflets are thickened/redundant and prolapse beyond the annular
plane into left atrium. MV chordae may rupture.
Mitral annular calcification: Age-related changes, chronic kidney
a
disease
Calcification may involve MV base and body, tip usually free.
di
MR occurs because of MV leaflet malcoaptation and annulus
dysfunction.
In
MV or LV papillary muscle injury: Direct/indirect chest wall
Figure 2: Rheumatic mitral stenosis and regurgitation. Two-
trauma, LV infarction especially inferior wall
dimensional transthoracic echocardiography. Parasternal long-axis
Congenital: MV clefts, parachute mitral valve view. Shows thickened noncoapting mitral leaflets resulting in
severe mitral regurgitation (MR). The left atrium is severely enlarged.
of
Secondary to systemic disease: Collagen vascular disease,
carcinoid syndrome, hypereosinophilic syndrome. Thickened MV. Abbreviations as in Figure 1
Drug induced: Anorectic drugs, dopamine agonists, ergot Source: Reproduced with permission from Nanda, NC (Ed).
derivatives. Thickened MV. Comprehensive Textbook of Echocardiography, Jaypee Brothers
ty
Medical Publishers, New Delhi, India; 2013;1:865.
Abbreviations: LV, left ventricle; MR, mitral regurgitation; MV, mitral valve.
18 cie
Table 6: Causes of functional mitral regurgitation
Ischemic MR: MV leaflet tethering and displacement of coaptation
point into LV produced by LV remodeling and dilatation with
20 o
displacement of papillary muscles apically and laterally from
myocardial infarction. Results in reduced/malcoaptation of MV
S
with often asymmetric MR. MV annulus may be flattened. ‘Sea gull’

appearance of MV may result from a kink in the mid-portion of
anterior leaflet produced by a stretched strut chord.
al
Nonischemic MR: Dilated CMP, long-standing HT, restrictive

CMP, hypertrophic CMP (MR commonly pansystolic but may be
ic
nonpansystolic if it results from SAM). Mechanism same as above

but MR often symmetric as LV dilatation symmetric. AF results in
MR from dilated LA and MV annulus. RV pacing (especially apical)
og
creates LV dyssynchrony which may lead to MR.

Abbreviations: AF, atrial fibrillation; CMP, cardiomyopathy; HT, systemic
hypertension; LA, left atrium; LV, left ventricle; MR, mitral regurgitation;
ol
MV, mitral valve; RV, right ventricle; SAM, systolic anterior motion Figure 3: Rheumatic mitral stenosis. Live/real time three-dimensional
transthoracic echocardiography. Arrow head points to the tip of the
di
narrow MV orifice
Abbreviations as in previous Figures
Source: Reproduced with permission from Singh V, Nanda NC, Agrawal
ar
G, et al. Live three-dimensional echocardiographic assessment of

mitral stenosis. Echocardiography. 2003;20:743-50.
C
mitral regurgitation can also be graded successfully if

the area of the laminar flow signals moving and swirling
with the turbulent portion of the regurgitation is also
added when evaluating regurgitation severity. This is
an important consideration and one needs to realize
that when the eccentric jet impinges on the adjoining
leaflet or left atrial wall immediately after its exit from
the mitral valve, it loses its energy and the high velocity
mosaic colored turbulent flow signals are reduced to
Figure 1: Rheumatic mitral stenosis. Two-dimensional transthoracic
low velocity laminar red and blue signals; but they are
directed M-mode echocardiography. Note the flat mitral valve (MV)
diastolic slope and thickening still part of mitral regurgitation; and hence need to be
Abbreviations: AO, aortic valve; LA, left atrium; LV, left ventricle; RV, taken into account when assessing the regurgitation area.
right ventricle. However, quantitative assessment of mitral regurgitation 135
KG-19.indd 135 02-11-2018 13:52:22

SECTION
3
A B
a
di
In
of
C D
ty
Figures 4A to D: Rheumatic mitral stenosis and regurgitation. Live/real time three-dimensional color Doppler transthoracic
echocardiographic technique for assessment of mitral regurgitation vena contracta (VC) area. 3D color Doppler data set showing MR, (A)
18 cie
cropped from top to the level of the VC (arrowhead, B) and tilted to view it en face (C and D)
Other abbreviations as in previous Figures
Source: Reproduced with permission from Khanna D, Vengala S, Miller AP, Nanda NC, Lloyd SG, Ahmed S, et al. Quantification of mitral regurgitation
by live three-dimensional transthoracic echocardiographic measurements of vena contracta area. Echocardiography. 2004;21:737-43
20 o S
al
ic
og
ol
di
A B
ar
Figures 5A and B: Mitral valve prolapse with ruptured chordae tendinae. Live/real time three-dimensional transesophageal echocardiography.
(A) Arrowheads point to some of the ruptured chordae of P2 and P3 scallops of posterior mitral leaflet (PML). Both P2 and P3 scallops show
C
prominent prolapse; (B) Arrowhead shows a ruptured chord of severely prolapsing A2 segment of anterior mitral leaflet (AML) in another patient
Abbreviation: LAA, left atrial appendage
Other abbreviations as in previous figures
Source: Reproduced with permission from Manda J, Kesanolla S, Hsuing MC, Nanda NC, et al. Comparison of real time two-dimensional
with live/real time three-dimensional transesophageal echocardiography in the evaluation of mitral valve prolapse and chordae rupture.
Echocardiography. 2008;25(10):1131–7.
severity requires the use of 3D TTE/TEE. This is because can be quantified by multiplying the vena contracta area
the cropping plane in the 3D color Doppler data set with the velocity time integral of the regurgitation jet
can be positioned exactly parallel to the vena contracta obtained by conventional continuous wave Doppler. 5,6
and its size accurately planimetered in short axis. The With 2D echo, only one or two dimensions of the vena
vena contracta essentially represents the ‘hole’ in the contracta can be measured and even if one is able to view
mitral valve through which regurgitation occurs and it in short axis in an occasional patient, it is not possible
the larger the size, the more severe is the regurgitation. to decide whether the plane passing through it is parallel
136 Using the Doppler principle, the regurgitation volume or obliquely oriented compromising the validity of vena
KG-19.indd 136 02-11-2018 13:52:27

Table 7: Assessment of mitral regurgitation severity by echocardiography CHAPTER
MR severity (MR diagnosed by noting reverse color Mild Moderate Severe
Doppler flow signals moving from LV into LA)
Mitral valve morphology Flail MV with ruptured chordae, ruptured
19
papillary muscle, systolic noncoaptation of

MV leaflets, severe tenting of MV, systolic
expansion of LA (very useful criteria If present)
LV and LA size¹ Mostly normal Normal or mild Mostly dilated
dilatation
Mitral inflow¹ A-wave dominant Variable E-wave >1.5 m/sec
Pulmonary vein flow Mostly normal Normal or systolic Systolic flow reversal
blunting (very useful in OR for checking residual MR
a
severity)
MV/AO TVI >1.4
di
Maximum MR jet area using multiple planes/LA <20% 20–40 % >40%
area in the same frame²
In
(Most commonly used criterion in clinical
practice)
MR jet area by TEE (LA area not used as LA >10 (15)
posterior wall not fully visualized) cm2 commonly
of
used in OR and catheterization laboratory
MR jet intensity and contour by CW Doppler Faint/Partial or Dense/Parabolic Dense and triangular
parabolic or triangular
ty
Vena contracta width (cm) by 2D color Doppler <0.3 0.3–0.69 ≥0.7
(commonly used but 3DTTE more accurate)
PISA estimated EROA (cm²)³ by 2D color Doppler <0.2 0.2–0.39 ≥0.40
MR Fraction (%) by 2D color Doppler

2
18 cie
PISA estimated MR Vol (mL)³ by 2D color Doppler <30
<30
30–59
30–49
≥60
≥50
MR vena contracta by 3DTTE cm (quantitative <0.2 0.2–0.4 >0.4
20 o
method)
Abbreviations: AO, aortic; CW, continuous wave; EROA, effective regurgitant orifice area; LA, left atrium; LV, left ventricle; MV, mitral valve;
S
MR, mitral regurgitation; OR, operating room; PISA, proximal isovelocity surface area; Vol, volume; TTE, transthoracic echocardiography; TEE,
transesophageal echocardiography; VTI, velocity time integral; 2D, two-dimensional; 3D, three-dimensional
¹ Influenced by many other factors (LV diastolic function, atrial fibrillation, LA pressure, etc.)
al
² aKeep Nyquist limit between 50 and 60 cm/s and b adjust color gain so it is just below the level at which one observes artifactual stationary
echoes (random noise).c In eccentric MR, laminar blue/red signals swirling and moving with mosaic turbulent flow signals also represent MR and
ic
need to be taken into account to avoid underestimation of MR severity. Thus, area of laminar signals should be added to area of turbulent signals
to assess MR severity. Also, check if MR is pansystolic or not. Quantitation of nonpansystolic MR is similar to nonpansystolic TR and is described
under TR severity assessment (Section III, Table 3)
og
³The PISA method is based on the assumption it is hemispherical in shape which is mostly incorrect.
contracta area measurement. The 2D echo assessment

ol
of flow acceleration [proximal isovelocity surface area

(PISA) technique] has also been used to assess mitral
di
regurgitation severity but is limited by the assumption that

flow acceleration is hemispherical in shape which we now
ar
know is incorrect in the vast majority of patients.

The 3D echo assessment of mitral regurgitation volume
is especially important in patients with mitral valve prolapse
C
where even though the regurgitation may appear significant,

it may not be pansystolic and confined only to mid-to-late
systole or only late systole by color M-mode. In these cases,
the ratio of jet area to left atrium may appear high and the
vena contracta by 2D large in diameter and by 3D large in
area suggesting significant regurgitation, but the calculated
mitral regurgitation volume could be small leading to correct
characterization of severity. The 3D echo also supplements
Figure 6: Mitral valve prolapse. Live/real time three-dimensional 2D echo in patients with mitral valve prolapse and other
transesophageal echocardiography. Mitral valve quantification
analysis demonstrates the extent of A1 prolapse
pathologies, such as infective endocarditis, because of its
Abbreviations: AL, anterolateral; PM, posteromedial; P, posterior capability to provide en face views of the mitral valve. Prolapse
Other abbreviations as in previous figures of individual scallops and segments and number and sites of
chordae rupture, which are important considerations when
137
KG-19.indd 137 02-11-2018 13:52:29

SECTION contemplating mitral valve repair, are also much better gradients across the aortic valve and calculation of aortic
evaluated with 3D than 2D echo. valve orifice area utilizing the continuity equation represent
3 the main hallmarks of diagnosing hemodynamically
significant aortic stenosis and estimating its severity. Some
AORTIC STENOSIS AND REGURGITATION
(TABLES 8 TO 16 AND FIGURES 7 TO 11) pitfalls and caveats in their use are well known and described
in the accompanying Tables 8 to 16. It is important to
Unlike the mitral valve, the aortic valve area measurement
emphasize that aortic valve area derived from the continuity
by planimetry in aortic stenosis by 2D echo has not gained
equation may not also be reliable in a number of patients
popularity because of the difficulty to confidently visualize
because of many reasons including problems inherent
the aortic valve in short axis at the tip mainly because of
in measurement of left ventricular outflow tract diameter
the presence of calcification commonly noted in adult
leading to a false reading of severe stenosis in patients with
a
patients with degenerative disease. Even then, it should
obviously mild or moderate stenosis based on many other
not be discounted completely because it does help in an
di
parameters. Mean Doppler pressure gradients may also
occasional patient where the Doppler findings appear
not correlate with cardiac catheterization findings in some
completely discordant with the clinical findings. The 2D
In
patients because of pressure recovery phenomenon and
echo/Doppler findings of increased velocities and pressure
other unclear reasons.7,8 Pressure recovery phenomenon
becomes a particularly significant problem when the left
of
Table 8: Common causes of aortic stenosis ventricular outflow tract diameter is 2.0 cm or less, the
A. Elderly patients aortic sinotubular junction is < 3.0 cm in inner diameter
1. Calcific degeneration and the aortic valve shows prominent systolic doming.
2. Rheumatic valve disease
ty
Doppler gradients may be underestimated when the
B. Younger patients
transthoracic acoustic window is poor and the Doppler
1. Congenital abnormalities, most common bicuspid aortic
valve (AV) 18 cie
2. Rare congenital abnormalities such as unicuspid/
quadricuspid AV.
waveforms suboptimal in quality. In these cases, contrast
echocardiography is useful in enhancing continuous wave
Doppler signals and has helped detect severe aortic stenosis
which was otherwise missed with noncontrast Doppler.
20 o
Table 9: Estimation of aortic valve gradients and orifice area by
As a supplement to 2D echo, 3D echo-based planimetry
S
Echo/Doppler of the aortic valve has been shown to be helpful in

A. Maximum and mean AV gradients are estimated by converting characterizing aortic stenosis severity.9 Since the entire
extent of the aortic valve is contained in the 3D data
al
maximum and mean AV velocities (V) obtained with continuous

wave (CW) Doppler using the modified Bernoulli formula. set, its tip can be more easily identified and the valve
Gradient (G) = 4 x V2 (mm Hg).
orifice area planimetered accurately. The 3D echo also
ic
B. Aortic valve area (AVA) is calculated using the Doppler principle

flow volume = area x velocity) and continuity equation (flow provides incremental value over the 2D modality when
og
volume same in LVOT and aortic root). Volume of flow in LVOT aortic stenosis co-exists with sub- or supravalvular
is calculated by multiplying LVOT area (obtained from 2D echo stenosis because planimetry for determining severity
measured inner diameter assuming circular configuration) with
velocity time integral (VTI) obtained by pulsed-wave Doppler. can be performed separately at both levels. On the other
ol
The AV VTI is obtained by continuous-wave Doppler. AVA = hand, with 2D echo, the continuous wave Doppler beam
0.785 x (LVOT diameter)2 x LVOT VTI/AV VTI. Since VTI is related passing through both stenotic areas located in tandem
to velocities, it can be substituted by maximum velocities in this
di
will give only the maximum velocity/gradient but cannot

equation for convenience without significantly compromising
accuracy. assess stenosis severity at individual levels. Severe valve
ar
Abbreviations: AV, aortic valve; AVA, aortic valve area; LVOT, left
calcification and the fact that the quality of 3D echo is
ventricular outflow tract; VTI, velocity time integral; 2D, two- generally lower than 2D echo represent limitations of this
dimensional technique for aortic orifice planimetry. Bicuspid aortic
C
Table 10: Assessment of aortic stenosis severity by echocardiography

Parameters Aortic sclerosis Mild Moderate Severe
Maximum AV jet velocity (m/s) ≤2.5 2.6–2.9 3.0–4.0 >4.0
Mean AV pressure gradient (mm Hg) <20 20–40 >40
2
AVA by continuity equation and by 3DTTE/TEE (cm )¹ >1.5 1–1.5 <1
Indexed AVA by continuity equation (cm2/m2) >0.85 0.60–0.85 <0.6
Maximum LVOT/AV velocity ratio >0.50 0.25–0.50 <0.25
Abbreviations: AV, aortic valve; AVA, aortic valve area; AS, aortic stenosis, LVOT, left ventricular outflow tract; TEE, transthoracic echocardiography;
TTE, transesophageal echocardiography, 3D, three-dimensional
¹Aortic valve area calculated using the continuity equation may not be accurate (due to pressure recovery phenomenon and other factors),
especially when the left ventricular outflow tract (LVOT) diameter is narrow or borderline narrow (2.0 cm or less)
138
KG-19.indd 138 02-11-2018 13:52:30

Table 11: Pitfalls in two-dimensional echocardiography/Doppler assessment of aortic stenosis CHAPTER
19
Pitfall Avoiding pitfall
Misdiagnosis of severe AS due to contamination of AS jet with A. Timing: MR jet begins earlier with MV closure while AS jet begins later
coexisting MR jet by CW Doppler. with AV opening. Time of onset of AS jet will be exactly same as beginning

of LVOT velocity waveform in relation to QRS complex of EKG
B. Shape: MR jet is rounded. AS jet is more pointed.
Underestimating AS severity because of systemic hypertension Assess AV gradients after bringing down blood pressure
Overestimating AS severity due to inaccurately estimated AVA 3DTTE/2D/3DTEE direct planimetry of AV orifice at tip. Avoid post-
by continuity equation especially when LVOT diameter is narrow ventricular ectopic gradient. Average gradients from 10 beats in case of
or borderline narrow (2.0 cm or less) or aorta at sino-tubular atrial fibrillation
junction measures <3.0 cm It is best to measure LVOT width at
LV/AO junction since it does not change size during the cardiac
a
cycle.
di
Very high AV gradient despite absence of full blown severe AS Use 3DTTE/2D/3DTEE direct planimetry of AV orifice as mentioned above
clinically (including preservation of A2 by auscultation) and by
catheterization
In
Improper alignment of CW Doppler cursor parallel to eccentric Adjustment of transducer position and angle. Use color Doppler guidance
AS jet leading to underestimation of velocity/pressure gradient. for placing CW Doppler cursor, use multiple windows including right
parasternal. Check pressure gradient after giving echo contrast
of
Increased velocity by CW Doppler may be due to sub or supra- Planimetry by 3DTTE/TEE will localize stenosis severity at individual sites.
valvular AS or hypertrophic cardiomyopathy mimicking AS
or may co-exist with AS. CW Doppler will give the maximum
ty
gradient but cannot localize its origin.
Abbreviations: AS, aortic stenosis; AV, aortic valve; AVA, aortic valve area; CW, continuous wave; LV, left ventricle; LVOT, left ventricular outflow;
MV, mitral valve; MR, mitral regurgitation; TTE, transthoracic echocardiography; TEE, transesophageal echocardiography, 2D, two-dimensional;
3D, three-dimensional 18 cie
20 o
Table 12: Two other forms of aortic stenosis Table 13: Common causes of chronic aortic regurgitation
S
A. Low-flow low-gradient AS A. Rheumatic heart disease in developing countries

B. Degenerative AV diseases
zz AS severity may be underestimated due to severe low cardiac
C. Dilated aortic root/aorta (degeneration, systemic hypertension,
output (CO) states: Mitral stenosis, low LV ejection fraction/
al
Marfan syndrome) resulting in reduced, mal or non-coaptation

low stroke volume (SV).
2
of normal AV leaflets
zz CO = SV x heart rate. SV = LVOT area (π² x LVOT VTI cm) cm
D. Congenital abnormalities: most commonly bicuspid AV,
ic
Normal SV = 35 mL/m2 or more. Flow rate (FR) = SV/LVOT or quadricuspid AV, subvalvular membranous stenosis, tetralogy
AV ejection time measured from Doppler tracing. Normal FR of Fallot
≥200 mL/s
og
E. Infective endocarditis
zz In these cases, assess AV gradient/AVA after low-dose
intravenous dobutamine (begin at 2.5/5 mg/kg/min every

3–5 min up to maximum 20 mg/kg/min; provided SV/FR Table 14: Causes of acute aortic regurgitation
ol
increase by 15–20% or more. Projected AVA can be estimated

by joining FR points at baseline and peak dobutamine and A. Infective endocarditis
extrapolating the line to FR 250 mL/sec (250 mL/sec was B. Aortic dissection involving AV or aortic root
di
used instead of 200 mL/sec flow rate in this study). If SV/FR C. Direct or indirect trauma to AV or AO or as a complication of TAVR
increase less than 20% by Dobutamine, LV lacks contractile and aortic balloon valvotomy
D. Rupture of congenital fenestrated cusp
ar
reserve and AS severity indeterminate by Doppler (CT scan

may be useful, calcium score of 2,000 AU or more in men and Abbreviations: AO, aorta; AV, aortic valve; TAVR, transcatheter aortic
1,200 or more in women suggests severe AS). valve replacement
C
zz Dobutamine useful to distinguish true severe AS from
pseudosevere AS.
valves can be misdiagnosed as tricuspid by 2D echo
B. Low-gradient severe AS with normal LV function especially when the raphe is prominent and tricuspid
zz May occur in up to 15% of AS patients
aortic valves may be falsely categorized as bicuspid when
zz Mainly elderly women with small LV cavity and hypertrophy
the third cusp is not well visualized. In this regard, 3D echo
and severe diastolic dysfunction.
zz As above, low-dose dobutamine helpful to assess AS severity.
is useful in more confidently assessing the aortic valve
CT scan may also help. morphology since the 3D data sets can be systematically
zz Remember AVA by continuity equation as done routinely not and meticulously cropped to more comprehensively
always reliable. visualize the aortic leaflets.
Abbreviations: AS, aortic stenosis; AV, aortic valve; AVA, aortic valve There is also a subgroup of patients with severe
area; CT, computed tomography; LV, left ventricle; LVOT, left ventricular aortic stenosis who can be missed because they have low
outflow; VTI, velocity time integral pressure gradients on the basis of low cardiac output and
139
KG-19.indd 139 02-11-2018 13:52:31

SECTION
Table 15: Assessment of aortic regurgitation severity by echocardiography
3 Degree of severity
AR maximum jet width/
Mild Moderate Moderately severe Severe
inner <25 26–50 51–64 >65

LVOT width, both in the (≥75 on TEE)

same frame(%)¹
Jet area/LVOT area (%)² <5 5–20 21–59 ≥60
VC (cm) calculated by 2D <0.3 0.3–0.6 >0.6
color Doppler
VC area (cm2) calculated <0.2 0.2–0.4 0.4–0.6 >0.6
a
by 3DTTE color Doppler³
EROA by 2D color <0.1 0.1–0.29 ≥0.3
di
Doppler PISA (cm2)
RF (%) by color Doppler
In
PISA <30 30–49 ≥50
RV by color Doppler PISA <30 30–59 ≥60
(ml/beat)
of
PHT (msec) by CW >500 200–500 <200
Doppler4
ty
Pandiastolic flow reversal No No Prominent
in isthmus/proximal (Clinically useful criterion)
descending aorta
LV dilation No or mild
18 cie Mild-moderate Severe
(With end-diastolic velocity >20 cm/s)
Density and contour of Low density, faint or Higher density Similar to moderate,
20 o
AR jet incomplete contour compared to mild, high density, contour
more completely spherical to triangular
S
filled contour (very severe)

Flow convergence None/very small Intermediate Large with central jets/variable with
al
(not seen in considerable eccentric jets

number of patients)
ic
Other findings High frequency diastolic LV may be Perforation, flail cusp with diastolic
flutter of MV on M-mode hyperdynamic reduced/or non-coaptation of AV
may be present with leaflets may be noted.
og
any AR grade if AR jet Diastolic closure of MV is indicative of

directed toward MV acute severe AR in absence of heart
block
ol
Increased MV E/A ratio

Abbreviations: AR, aortic regurgitation; AV, aortic valve; EROA, effective orifice area; LV, left ventricle; LVOT, left ventricular outflow tract; MV, mitral
di
valve; PISA, proximal isovelocity surface area; PHT, pressure half-time; RF, regurgitant fraction; RV, regurgitant volume; TTE, transesophageal
echocardiography; VC, vena contracta; 3D, three-dimensional
¹Measurements made in parasternal long axis-axis view (Clinically useful and most commonly used criterion). If not available, may use apical
ar
5-chamber view. Measure jet width at point of exit of AR from AV (essentially the vena contracta). Adjust Nyquist limit and color gain as for MR
severity assessment (see MR tables)
² Measurements made in parasternal short axis view at high LVOT level. Less reliable than parasternal long axis view
C
³Useful parameter for quantitative assessment of AR.

4
Useful in acute more than in chronic AR.
poor left ventricular ejection fraction. Another subgroup of scans have also been used and a high calcium score has
severe aortic stenosis patients, mainly females with small, been shown to correlate with aortic stenosis severity.
hypertrophied left ventricles, may have normal ejection Thus, a multipronged approach which also includes
fraction and yet low pressure gradients because of poor clinical findings and in some cases cardiac catheterization
forward stroke volume and more importantly reduced may be necessary in assessing patients with suspected
flow rate. Low-dose dobutamine stress echocardiography aortic stenosis.
may be helpful in identifying these patients because of Regarding aortic regurgitation, 2D/echo Doppler
its ability to increase the stroke volume and flow rate and is most useful in the diagnosis and semi-quantitatively
hence the pressure gradients unless the ventricle lacks estimating its severity.10 Unlike mitral regurgitation, where
contractile reserve. Cardiac computed tomography (CT) one assesses jet area, in aortic regurgitation the width
140
KG-19.indd 140 02-11-2018 13:52:32

Table 16: Pitfalls in two-dimensional echocardiography/Doppler assessment of aortic regurgitation CHAPTER
Pitfall Avoiding pitfall
A narrow LVOT may overestimate AR severity as the ratio of
jet width to LVOT width may be high
zz Absence of pandiastolic reverse flow at the AO isthmus will exclude severe
AR
19
zz Keep pulse Doppler sample volume within reverse red color Doppler flow

signals since these signals may not occupy whole width of AO at that level
Misdiagnosis of mild/moderate anteriorly originating AR with Markedly increasing Nyquist limit scale may detect small/moderate
jet moving posteriorly along AV leaflets as severe AR or vice anterior origin and posterior course of AR jet along AV leaflets preventing
versa for posteriorly originating AR misdiagnosis. Pandiastolic reverse flow at aortic isthmus/proximal
descending aorta would be absent
Underestimating AR severity when AR jet is eccentric. Take into account color Doppler laminar flow signals which move/swirl
with turbulent AR signals. These signals also represent AR but have become
laminar because of reduced velocity resulting from high velocity AR jet
a
striking an adjacent structure shortly after its exit from AV.
di
Underestimating AR severity in cases of AO root or ascending Check AO isthmus/proximal descending AO for prominent pandiastolic
aorta aneurysm and in presence of vegetations. reverse flow
zz Increasing Nyquist limit which also changes the color filter Keep Nyquist limit between 50–60 cm/s and standardize color gain as for MR
In
(or reducing color gain) tends to decrease AR jet width (see MR tables)
leading to underestimation of AR severity
zz Lower Nyquist limit (or increasing color gain) will increase
of
jet width leading to overestimation.
Abbreviations: AO, aorta; AR, aortic regurgitation; AV, aortic valve; LVOT, left ventricular outflow tract
ty
18 cie
20 o S
al
ic
A B
og
Figures 7A and B: Aortic stenosis. Two-dimensional transthoracic echocardiography. Continuous wave Doppler interrogation in apical five
chamber view. Before contrast maximum/mean aortic valve (AV) pressure gradients (PG) were 54/28 mm Hg in this 68-year-old male patient
consistent with mild to moderate stenosis. After intravenous contrast administration, maximum/mean AV PG increased to 89/47 mm Hg
indicative of severe stenosis
ol
Abbreviation: RA, right atrium

di
(or height as it was referred to in the original work) of the TRICUSPID STENOSIS AND REGURGITATION
ar
regurgitant jet at the point of exit from the aortic valve (TABLES 17 TO 20 AND FIGURES 12 TO 15 )
(essentially the ‘hole’ or defect in the aortic valve or the
The 2D echo/Doppler criteria used for the assessment
C
vena contracta) is measured and related to the inner width

of the left ventricular outflow tract to grade severity. A jet of mitral stenosis have also been applied to the tricuspid
width/left ventricular outflow tract width ratio of 60% or valve for evaluating stenosis but with less success as the
more on 2DTTE represents severe aortic regurgitation. pressures on the right side are much lower than the left
As in mitral regurgitation, it is important to pay attention side making it somewhat difficult to differentiate normal
to the Nyquist limit and color gain when utilizing this from abnormal findings. Also, it is much more difficult
criterion. Another clinically useful parameter is pulsed to view the tricuspid valve in short axis as compared
Doppler interrogation of the aortic isthmus which will to the mitral valve for assessment of valve orifice area.
show prominent reverse pandiastolic flow signals in In addition, tricuspid stenosis is much less commonly
cases of severe aortic regurgitation. Similar to mitral seen than mitral stenosis and hence has been much
regurgitation, quantitation of aortic regurgitation requires less well studied. A flat diastolic E-F slope on M-mode
planimetry of the vena contracta area in short axis using echo is a good sign of tricuspid stenosis. Higher than
3D echo.11 normal pressure gradients across the tricuspid valve by
141
KG-19.indd 141 02-11-2018 13:52:33

SECTION
3
A B
a
di
In
of
C D
ty
18 cie
E
20 o
Figures 8A to E: Limitation of measuring aortic valve area using the continuity equation. Two-dimensional transthoracic echocardiography.
Aortic valve area (AVA) by the continuity equation in this 66-year-old female patient with end stage renal disease measured 1.06 cm2 using
S
the velocity time integral (VTI) method and 1.02 (0.73 cm2 indexed) using peak velocity. These values are consistent with almost severe
stenosis, even though in reality this patient with normal AV structure and motion and insignificant pressure gradients (PG) has no significant
stenosis.
al
Abbreviation: LVO, left ventricle outflow

ic
Source: Reproduced with permission from Nanda NC (Ed). Interesting Cases in Echocardiography, Jaypee Brothers Medical Publishers, New Delhi,
India; 2017.pp.36-7
og
ol
di
ar
C
Figure 9: Aortic stenosis. Live/real time three-dimensional Figure 10: Aortic regurgitation. Two-dimensional transthoracic
transthoracic echocardiography. Arrow points to severe bicuspid echocardiography. Parasternal long axis view. Aortic regurgitation
AV stenosis. (AR) jet width at its exit from the AV/left ventricular outflow tract
Source: Reproduced with a permission from Nanda NC, Karakus G, (LVO) width taken at the same point calculates 15% indicative of
Degirmencioglu A. Manual of Echocardiography, 2nd Edition, New mild AR in this 53-year-old male patient with an early diastolic
Delhi, India, Jaypee Brothers Medical Publishers, New Delhi, India; murmur heard in the aortic area.
2018 (in press) Other abbreviations as in previous Figures
Source: Reproduced with permission from Nanda NC. Interesting Cases
in Echocardiography, Jaypee Brothers Medical Publishers, New Delhi,
India; 2017.p.41
142
KG-19.indd 142 02-11-2018 13:52:43

Table 17: Causes of organic tricuspid valve stenosis/regurgitation
CHAPTER
19
Rheumatic valve disease: Commissural fusion, thick TV leaflets
with restricted mobility, thickened and shortened chordae causing
stenosis. Deformed TV with reduced/mal coaptation in systole

leading to TR. TS and TR may co-exist.
Infective/marantic endocarditis, masses, thrombi: Vegetations
seen as thickening or mobile masses with TV leaflet destruction.
Mostly cause TR. Obstruction to TV may cause TS.
Myxomatous degeneration/TV prolapse: Leaflets are thickened,
redundant and prolapse beyond the annular plane into right atrium.
Chordae rupture may occur/TR.
TV or RV papillary muscle injury: (direct/indirect chest wall
a
trauma, pacemaker or ICD lead induced, during endomyocardial
biopsy, RV infarction)/TR.
di
Congenital: Ebstein’s anomaly (adherence of TV tissue to RV wall/
ventricular septum), TV atresia, TV clefts, TV dysplasia, Double orifice
In
Figure 11: Aortic regurgitation. Two-dimensional transthoracic TV, Unguarded TV orifice/TR
echocardiography. Suprasternal view. Pulsed Doppler interrogation
at the aortic isthmus shows prominent pandiastolic reverse flow Carcinoid syndrome: Thickened, restricted TV leaflets. Carcinoid
signals (arrow) indicative of severe AR. Arrowheads point to mild deposits on chamber/IVC walls TS/TR
of
artifactual mirroring of these signals on the opposite side of the Loeffler syndrome: Thickened TV, may respond to steroids. TS/TR
base line. Drug (anorectic drugs, dopamine agonists, ergot derivatives,
Abbreviations: ACH, aortic arch; DA, descending thoracic aorta ecstasy) or radiation-induced TS/TR
ty
Source: Reproduced with permission from Nanda NC. (Ed). Interesting
Abbreviations: ICD, intracardiac defibrillator; IVC, inferior vena cava;
Cases in Echocardiography, Jaypee Brothers Medical Publishers, New
RV, right ventricle; TR, tricuspid valve regurgitation; TS, tricuspid valve
Delhi, India; 2017.p.42.
18 cie stenosis; TV, tricuspid valve.
Table 18: Assessment of tricuspid stenosis severity

20 o
Normal Mild Moderate Severe
S
TV area (cm²) by 2D/3D TTE/TEE planimetry 7–9 <2

Mean gradient mm Hg <2 2-3 3-6 >7
al
Peak gradient mm Hg <4 >25

Peak velocity (m/s) <1 1-1.5 1.5–2.5 >2.5
ic
CW Doppler signal Steep deceleration Delayed deceleration, dense signal

TV PHT (T1/2) ≥ 190 ms
og
Abbreviations: CW, continuous wave; PHT, pressure half-time; TV, tricuspid valve; TTE, transthoracic echocardiography; TEE, transesophageal
echocardiography; 2D, two-dimensional; 3D, three-dimensional
Source: Reproduced with modification and permission from Nanda NC, Karakus G, Degirmencioglu A. Manual of Echocardiography, Jaypee
ol
Brothers, New Delhi; India, 2016.

di
Doppler with restricted mobility of leaflets also point to

Table 19: Causes of functional tricuspid regurgitation
the diagnosis. The 3D echo is well suited to evaluate the
Primary/secondary pulmonary hypertension: Causes RV/RA/TVA
ar
tricuspid valve because of its ability to view all the three

dilatation
leaflets in short axis at various levels including the flow
Cardiomyopathy of RV: Dilated, ischemic, arrhythmogenic RV
limiting tip. Thus, accurate planimetry of the tricuspid
C
dysplasia
valve orifice area can be done by 3D echo and the severity
Stenosis of pulmonic valve/pulmonary artery: May cause RV/TVA
dilatation of stenosis confidently categorized. The 3D echo is also
helpful in assessing the subvalvular apparatus.12
Left-sided pathologies: LV dysfunction or mitral/aortic stenosis or
regurgitation resulting in pulmonary hypertension Unlike mitral and aortic regurgitation where the time-
Left-to-right shunt: Atrial septal defect, ventricular septal defect, honored cardiac catheterization and angiography served
anomalous pulmonary venous return as a gold standard, no satisfactory invasive standard
Chronic atrial fibrillation: Resulting in LA/RA dilatation exists for evaluating tricuspid regurgitation severity. The
Isolated TV annular dilatation peripherally inserted angiographic catheter in the right
ventricle needed for dye injection necessarily passes
Abbreviations: LA, left atrium; LV, left ventricle; RA, right atrium; RV,
right ventricle; TV, tricuspid valve; TVA, tricuspid valve annulus. through the tricuspid valve which by itself can make the
valve incompetent complicating severity assessment.
143
KG-19.indd 143 02-11-2018 13:52:45

SECTION
Table 20: Assessment of tricuspid regurgitation severity by echocardiography
3 TR severity (TR diagnosed by noting reverse

color Doppler flow signals moving into RA from
RV)
Mild Moderate Severe
Tricuspid valve morphology Systolic noncoaptation of TV, visualization of

chordae prolapsing into RA (very useful If present)
RV and RA size¹ Mostly normal Normal or mild Mostly dilated (RV, apical 4-chamber view, at the
dilatation base >42 mm, midlevel >35 mm, longitudinal
dimension >86 mm, RA area >18 cm², RA major
dimension >53 mm and minor dimension >44 mm)
IVC diameter (cm)¹ Normal 2.1–2.5 >2.5
a
Maximum TV annulus diameter in diastole ≥38 mm
di
Percent shortening of TV annulus <25%
Tricuspid inflow¹ A-wave Variable E-wave >1.0 m/sec
In
dominant
Hepatic vein (vertical) flow Systolic flow reversal (useful If present although
occasionally seen with moderate TR)
of
Extension of TR jet into coronary sinus None None Useful if present
Maximum TR jet area/RA area in the same <20 % 20–34 % >34%
frame by TTE (Useful and most commonly used
ty
parameter in clinical practice)2
Maximum color Doppler TR jet area by TEE <5 5–10 >10
18 cie
(cm²) (commonly used parameter in OR and
catheterization lab)2,3
TR jet intensity and contour by CW Doppler Faint/Partial or Dense/parabolic Dense and triangular
parabolic or triangular
20 o
Vena contracta width (cm) by color Doppler <0.3 0.3-0.69 ≥0.7
S
(commonly used but less reliable than 3DTTE)

PISA radius (cm) by color Doppler ≤0.5 0.6-0.9 >0.9
al
PISA estimated EROA (cm²) by color Doppler <0.2 0.2-0.39 ≥0.40

PISA estimated TR Vol (mL) by color Doppler <30 30-44 ≥45
ic
(provides quantitative assessment of TR

severity)
og
3D vena contracta area by 3DTTE cm² (provides ≤0.5 0.5-0.75 >0.75

quantitative assessment of TR severity) (>1.0 torrential TR)
ol
Abbreviations: CW, continuous wave; EROA, effective regurgitant orifice area; IVC, inferior vena cava; OR, operating room; PISA, proximal
isovelocity surface area; RA, right atrium; RV, right ventricle; TV, tricuspid valve; TR, tricuspid regurgitation; TTE, transthoracic echocardiography;
TEE, transesophageal echocardiography; Vol, volume; 3D, three-dimensional
di
¹ Influenced by many other factors (RV diastolic function, atrial fibrillation, RA pressure, etc.)
² Keep Nyquist limit between 50 and 60 cm/s and adjust color gain so it is just below the level at which one observes artifactual stationary echoes
ar
(random noise). Check if TR is pansystolic or mid/mid-to-late systolic. If latter, calculate TR volume by multiplying TR vena contracta area by
3DTTE with TR velocity time integral (VTI) from continuous-wave Doppler. In eccentric TR laminar blue/red signals swirling and moving with
mosaic turbulent flow signals also represent TR and need to be added to turbulent TR jet to avoid underestimation of TR severity. Use multiple
C
planes to find maximum TR jet

³ RA area not taken into account as RA posterior wall not completely visualized by TEE.
Because of this problem, color Doppler findings in tricuspid regurgitation severity by color Doppler. 13 Just
surgical patients who underwent tricuspid valve repair or like the mitral and aortic valves, quantitative assessment is
replacement and those who did not based on surgical and performed by evaluating the tricuspid regurgitation vena
clinical findings were examined in our echo laboratory. A contracta by 3D color Doppler.14
tricuspid regurgitation jet area occupying more than 33% Similar to mitral valve prolapse, it is also important
of the right atrium or maximum tricuspid valve annulus to perform color M-mode in patients with tricuspid valve
diameter of 38 mm or more correlated with tricuspid prolapse and if regurgitation appears significant but is
surgical intervention and these numbers were lower in confined only to mid-to-late or late systole, assessment
those who did not need tricuspid valve intervention. These of tricuspid regurgitation volume by 3D echo would be
findings have been used to semi-quantitatively evaluate necessary to correctly grade its severity.
144
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CHAPTER
19

A B
a
di
C
In
Figures 12A to C: Normal and stenotic and regurgitant tricuspid Figure 14: Severe tricuspid regurgitation. Two-dimensional
valve. Live/real time three-dimensional transthoracic echocardio- transthoracic echocardiography. Subcostal view showing flow
graphy. (A) En face views showing all three tricuspid valve (TV) signals (red) moving into a vertical hepatic vein (HV, arrow) during
leaflets in the open position. The opening is large with no evidence systole. Inferior vena cava (IVC ) is markedly dilated.
of
of stenosis; (B and C). En face views in another patient with mild Abbreviation: L, liver. Other abbreviations as in previous figures.
rheumatic TV stenosis but severe tricuspid regurgitation (TR). The
tricuspid orifice area (B) measured 2.4 cm2 in diastole. Systolic frame
ty
(C) shows non-coaptation of TV leaflets in the same patient as B. This
measured 0.4 cm2 in area and resulted in severe TR as assessed by
two-dimensional color Doppler echocardiography
18 cie
Abbreviations: A, anterior tricuspid leaflet; P, posterior/inferior tricuspid
leaflet; S, septal tricuspid leaflet. Other abbreviations as in previous figures
Source: Reproduced with permission from Pothineni K, Duncan K,
Yelamanchili P, et al. Live/real time three-dimensional transthoracic
20 o
echocardiographic (Nanda NC, Patel V, Fan P) assessment of tricuspid
valve pathology: incremental value over the two-dimensional
S
technique. Echocardiography. 2007;24(5):541–52.

al
ic
og
Figure 15: Tricuspid valve prolapse. Two-dimensional transthoracic

directed color M-mode echocardiography. Shows mid-to-late
systolic tricuspid regurgitation (arrowhead). C points to TV closure
ol

di
Table 21: Common causes and types of pulmonary stenosis

ar
A. Congenital pulmonary stenosis (PS) is most common.

zz Bicuspid pulmonary valve (PV ), commonly seen with
tetralogy of Fallot
C
zz Atretic PV
Figure 13: Severe tricuspid regurgitation. Two-dimensional zz Both bicuspid and atretic PV associated with poststenotic
transthoracic echocardiography. The arrows point to laminar red non- pulmonary artery dilatation
turbulent color flow signals moving towards the TV, these are seen zz Dysplastic PV with narrow annulus (No poststenotic
moving in the same phase as the mosaic colored turbulent TR signals dilatation)
and represent part of TR. These non-turbulent, laminar signals should
B. Isolated congenital valvular PS may be associated with:
be added to mosaic turbulent signals when assessing TR jet area zz Subpulmonic stenosis
Abbreviation: F, flow acceleration. Other abbreviations as in previous zz Infundibular stenosis
figures. zz Hour-glass right ventricle (RV ) body stenosis. Double
chamber RV
PULMONARY STENOSIS AND zz Supravalvular stenosis
zz Stenosis of main pulmonary artery (PA) and/or branches

REGURGITATION (TABLES 21 TO 25 AND
C. Acquired PS:
FIGURES 16A TO D) zz Carcinoid syndrome
zz Infective endocarditis
Pulmonary stenosis at various levels is more commonly
zz Connective tissue disease
seen in children than adults. Although a thickened 145
KG-19.indd 145 02-11-2018 13:52:52

SECTION pulmonary valve with restricted mobility by 2D echo
Table 22: Assessment of severity of pulmonary stenosis by
echocardiography points to diagnosis of stenosis, estimation of severity is
3 Parameter Mild Moderate Severe
performed by continuous wave Doppler interrogation.
Peak gradients across the pulmonary valve are commonly
Peak PS jet velocity (m/s) <3 3–4 >4
used to categorize grades of severity. The close proximity

Peak PS gradient (mm Hg) <36 36–64 >64 of the left lung to pulmonary valve makes it difficult to
identify all the three leaflets of the valve by 2D echo so that
planimetry to assess the valve orifice area is not possible
Table 23: Assessment of level of pulmonary stenosis by in most adults. The 3D echo may have the potential to
echocardiography do this as in a recent preliminary study, the third leaflet
zz Color Doppler useful to find location by showing beginning of of the pulmonary valve could be identified by 3DTTE in
a
turbulent flow all patients in whom two leaflets could be detected by 2D
zz Poststenotic dilatation of main pulmonary artery (PA) more likely
di
with valvular stenosis TTE.15
zz Systolic dagger-shaped Doppler tracing suggests subvalvular Because of the absence of an invasive gold standard
stenosis
In
to categorize pulmonary regurgitation severity similar to
zz 3DTTE helps visualize and assess the site of stenosis and
what is mentioned above regarding tricuspid regurgitation
quantitatively measures the orifice area by planimetry. Especially
useful when stenosis at multiple levels are present where CW severity, the color Doppler criteria used for estimating
of
Doppler is unable to assess severity at individual sites since it aortic regurgitation severity have been used to grade
gives only the maximum gradient. pulmonary regurgitation severity. In addition, extension
zz 3DTEE is helpful in cases of poor transthoracic window
of the pulmonary regurgitation jet to within 1 cm of the
ty
tricuspid valve is also a reliable sign of severe pulmonary
regurgitation. As with regurgitation involving other valves,
Table 24: Common causes of pulmonary regurgitation
zz
18 cie
Pulmonary valve annulus dilatation due to:
—z Primary or secondary pulmonary hypertension (PH)
—z Idiopathic pulmonary artery (PA) dilation

quantitation of pulmonary regurgitation requires en face
views of the vena contracta and planimetry by 3D color
Doppler.16
20 o
—z Connective tissue disease
Congenital absence or malformation of PV

zz
CONCLUSION
S
zz PV prolapse
zz Traumatic PR (after balloon valvuloplasty, surgical correction of A clinically useful comprehensive evaluation of all the
tetralogy of Fallot, carcinoid syndrome, infective endocarditis, four cardiac valves can be performed for both stenosis and
al
rheumatic disease)
regurgitation using all the available modalities residing
ic
Table 25: Assessment of pulmonary regurgitation severity by echocardiography

og
Parameter Mild Moderate Severe

Pulmonary jet width/RVOT inner width ratio in the same ≤25% 26–64% >65%
frame (most commonly used method in clinical practice)1
ol
PR jet length extension Within 1 cm of TV2

PR index (PR duration/total diastole) <0.77
di
Pulsed wave Doppler Holodiastolic reverse flow in the branch PAs3

CW Doppler PHT <100 ms
ar
PR VC area by 3DTTE (cm2) (quantitative method) >1.15 cm2

PR volume (mL) (quantitative method) <15 15–50 (51–115, >115 mL
C
moderately severe)
Other findings -PV diastolic coaptation defect,
dilated RV, PA annulus and RV dysfunction
may be present.
Abbreviations: CW, continuous wave; PA, pulmonary artery; PR, pulmonary regurgitation; RV, right ventricle; RVEF, right ventricular ejection
fraction; RVOT, right ventricular outflow tract; TV, tricuspid valve; VC, vena contracta
1
Measured using maximum width of color Doppler signals (obtained using as many planes as possible) at origin of PR from PV (essentially the
vena contracta). Because of difficulty in assessing PR severity by cardiac catheterization where the contrast dye is injected into the PA with the
catheter passing through the PV which by itself may cause PR, the echocardiographic color Doppler criteria used for AR severity are also used
for PR severity. The same pitfalls and their avoidance listed for AR, MR and TR severity assessment including level of Nyquist limit and adjustment
of color gain apply also to PR.
2
Requires widening the color Doppler sector to visualize both TV and PV.
3
Best modality to assess PR severity in children.
146
KG-19.indd 146 02-11-2018 13:52:53

CHAPTER
19

A B C D
Figures 16A to D: Pulmonary regurgitation. Live/real time three-dimensional transthoracic echocardiography. (A) Shows pulmonary
regurgitation (PR) jet (arrow) with the cropping plane (blue line) at the level of the vena contracta (VC) and aligned parallel to it; (B) En face
a
view of the VC (arrow), which measures 0.92 cm2 by planimetry. This is consistent with grade 3/4 PR; (C and D) Some of VC examples in
patients with PR. Note the complex geometric shapes
di
Source: Reproduced with permission from Pothineni KR, Wells BJ, Hsiung MC, Nanda NC, Yelamanchili P, Suwanjutah T et al. Live/real time three-
dimensional transthoracic echocardiographic assessment of pulmonary regurgitation. Echocardiography. 2008;25:911-7.
In
in modern echocardiographic machines. This includes gradient. Catheterization & Cardiovascular interventions.
M-mode, 2D echo, conventional-pulsed and continuous- 2005;65:180-2.
of
wave Doppler, color Doppler, contrast echo and live/real- 9. Vengala S, Nanda NC, Dod H, Singh V, Agrawal G, Sinha
A et al. Usefulness of live three-dimensional transthoracic
time 3D/4D echocardiography. The role of the emerging
echocardiography in aortic valve stenosis evaluation. Am J
ty
technique of 2D/3D speckle tracking echocardiography in Geriatric Cardiol. 2004;13:279284.
the evaluation of valvular lesions is still in its infancy. 10. Perry G, Helmcke F, Byard C, Soto B, Nanda NC. Evaluation
REFERENCES
18 cie 11.
of aortic insufficiency by Doppler color flow mapping. J Am
Coll Cardiol. 1987;9:952-9.
Fang L, Hsiung MC, Miller AP, Nanda NC, Yin WH,
1. Nanda NC (Ed). Comprehensive Textbook of Echo-
Young MS, et al. Assessment of aortic regurgitation by
20 o
cardiography, Jaypee Brothers Medical Publishers, New live three-dimensional transthoracic echocardiographic
Delhi, India; 2013.
S
measurements of vena contracta area usefulness and

2. Nanda NC, Karakus G, Degirmencioglu, A, Manual of validation. Echocardiography. 2005;22:775-81.
Echocardiography, Jaypee Brothers Medical Publishers, 12. Pothineni KR, Duncan K, Yelamanchili P, Nanda NC, Patel V,
al
New Delhi, India; 2016. Fan P, et al. Live/real time three-dimensional transthoracic
3. Nanda N.C.(Ed) Interesting Cases in Echocardiography, echocardiographic assessment of tricuspid valve pathology:
ic
Jaypee Brothers Medical Publishers, New Delhi, India; Incremental value over the two-dimensional technique.
2017. Echocardiography. 2007;24:541-52.
og
4. Singh V, Nanda NC, Agrawal G, Vengala S, Dod H, Misra V, 13. Chopra HK, Nanda NC, Fan PH, Kapur K, Goyal R,
et al. Live three-dimensional echocardiographic assessment Daruwala D, et al. Can two-dimensional echocardiography
of mitral stenosis. Echocardiography. 2003;20:743-50. Doppler color flow mapping identify the need for tricuspid
ol
5. Helmcke F, Nanda NC, Hsiung MC, Soto B, Adey C, Goyal valve repair? . J Am Coll Cardiol. 1989;14:1266-74.
RG et al. Color Doppler assessment of mitral regurgitation 14. Velayudhan DE, Brown TM, Nanda NC, Patel V, Miller AP,
Mehmood F, et al. Quantification of tricuspid regurgitation
di
using orthog¬onal planes. Circulation. 1987;75:175-83.

by live three-dimensional transthoracic echocardiographic
6. Khanna D, Vengala S, Miller AP, Nanda NC, Lloyd SG,
measurements of vena contracta area. Echocardiography.
ar
Ahmed S, et al. Quantification of mitral regurgitation by

2006;23:793-800.
live three-dimensional transthoracic echocardiographic
15. Elsayed M, Hsiung MC, Nanda NC, Alratroot A, Turaga
measurements of vena contracta area. Echocardiography.
C
NSS. Three-Dimensional Transthoracic Echocardiographic

2004;21:737-43. Identification of Individual Cusps of the Pulmonary Valve:
7. Sakthi C, Yee H, Kotlewski A. Overestimation of aortic Potential Misidentification by the Two-Dimensional
valve gradient measured by Doppler echocardiography Technique. Echocardiography. 2018;35:855-9.
in patients with aortic stenosis. Catheterization & 16. Pothineni KR, Wells BJ, Hsiung MC, Nanda NC, Yelamanchili
Cardiovascular interventions. 2005;65:176-9. P, Suwanjutah T et al. Live/real time three-dimensional
8. Zoltan G. Turi, Md. Whom do you trust?: Misguided transthoracic echocardiographic assessment of pulmonary
faith in the catheter- or doppler-derived aortic valve regurgitation. Echocardiography. 2008;25:911-7.
147
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Pitfalls in Assessment of
CHAPTER 20 Valvular Heart Disease
a
di
INTRODUCTION involved in immunuoinflammatory process leading to
Cardiac valves provide unimpeded phase-dependent permanent valvular dysfunction.
In
and unidirectional blood flow in the circulation and are Echocardiography has become the cornerstone of
a fine example of the ingenuity of the nature with regard diagnosis of the VHD occasionally complimented by
cardiac catheterization and computed tomography
of
to capacity to withstand prolonged biomechanical stress
of constant movements. Valvular heart disease (VHD) (CT) imaging. Echocardiographic assessment of VHD
represents an important class of cardiovascular ailments is noninvasive, fast, readily available, and mostly
accurate. However, it is not always without pitfalls,
ty
both in developing and the developed world. Rheumatic
caveats, subjectivity, and doubts. This review deals with
heart disease (RHD) is still prevalent in vast segments
appropriate evaluation of VHD and the pitfalls commonly
18 cie
of Asia, Latin America, and Africa. Degenerative VHD
is the other epidemic of this century more often seen in
the Western world because of better longevity but fast
encountered during echocardiographic assessment.
catching up in the rest of the world. The latest estimates ASSESSMENT OF MITRAL REGURGITATION
20 o
put the total RHD burden in the range of 62 million to Significant MR is present in 2–3% of the population.6 The
S
78 million subjects worldwide, which could potentially RHD is the most common cause of MR in the developing
result in 1.4 million deaths per year from RHD and its countries.6 The MR could be as a result of structural valve
complications. 1,2 This estimate is far higher than that pathology or due to involvement of the support system
al
suggested in the most recent status paper.3 Other valvular of the mitral valve complex. Young patients are the most
disease includes congenital valvulopathy, infections, affected by RHD in the developing regions with pure
ic
connective tissue disorders, endocrinopathies, radiation, MR and mixed lesions being the most common valve
and valve disorders secondary to trauma. Degenerative
og
dysfunctions. Two different degenerative MR phenotypes

valve disease has become the most common cause of VHD are generally described: fibroelastic deficiency and
in the Western world, causing significant morbidity and diffuse myxomatous disease, also called Barlow disease.
ol
mortality. No longer considered a benign consequence Fibroelastic deficiency is mostly localized to one segment
of aging, valve thickening and calcification are the result and often involves ruptured chords with histologically
of an active process such as atherosclerosis. 4 Aortic
di
myxomatous degeneration and macroscopically

stenosis (AS) and mitral regurgitation (MR) are the two leaflet redundancy and thickening predominant on
ar
most common types of valvular disease in Europe and the flail segment. The valve remainder is usually thin
North America. Common risk factors are advancing age, and translucent. Barlow’s lesions are generalized with
diabetes, hypercholesterolemia, hypertension, metabolic redundancy/thickening of both leaflets, involving multiple
C
syndrome, and tobacco use. Valve degeneration occurs segments.

due to an osteoblastic differentiation process mediated Echocardiography plays a pivotal role in diagnosis,
by the low-density lipoprotein receptor-related signaling assessing severity and mechanism of regurgitation,
pathway to cause valve thickening.5 The mechanism of choice of therapy, and follow-up of these patients.
degenerative VHD involves an endochondral bone process Clinical examination misses >50% cases of MR and
that is expressed as cartilage in the mitral valves and bone in echocardiography remains the only bedside modality
the aortic valve. Myxomatous mitral valve lesions causing for its accurate diagnosis. Quantification of MR severity,
MR are believed to be caused by progressive thickening rather than inaccurate, eyeball grading of color Doppler
due to activated myofibroblasts. It is estimated that jets, has been encouraged. Quantitative parameters for
significant valve disease affects 2–3% of the population.6 severe MR include regurgitant fraction ≥50%, regurgitant
The RHD accounts for 64% of all valvulopathies in India.7 volume ≥60 mL, and effective regurgitant orifice area ≥0.4
In about 37% patients with RHD, more than one valve gets cm2. Newer 3D-based quantification methods effectively
KG-20.indd 148 02-11-2018 13:52:04

CHAPTER
20

a
di
In
Figure 1: Schematic diagram showing mitral Figure 2: Systolic blood flow movement in left heart by color
regurgitation during systole Doppler. Turbulent jet of mitral regurgitation is seen crossing the
Abbreviations: Ao, aorta; LA, left atrium; LV, left ventricle mitral valve (red ring) and spreading in the left atrium to a variable
extent depending upon the physical constraints
of
Abbreviation: LV, left ventricle
ty
18 cie
20 o S
al
ic
og
Figure 3: Regurgitant fraction (RF) is ratio of mitral stroke volume- Figure 4: Two jets of mitral regurgitation in transesophageal
aortic stroke volume/mitral stroke volume echocardiography (TEE) view
Abbreviations: LV, left ventricular; IVCT, isovolumic contraction time; Abbreviations: LA, left atrium; LV, left ventricle; MV, mitral valve;
IVRT, isovolumic relaxation time; ECG; electrocardiogram LAA: left atrial appendage
ol
di
overcome the limitations of 2D methods for assessing Mitral valve repair may also result in two orifices which
severity and mechanism of regurgitation and provide new leak to some extent. All these parameters are used to
judge severity of MR.8 Total LV SV can be obtained by 2D
ar
cut-off values for the estimation of severity of MR.

The basic principle of flow quantification in MR or 3D echocardiographic volumetry. Forward SV can be
hinges on the accurate measurement of flow velocity and obtained from LV outflow tract flow using the formula of:
C
the cross-sectional area of the regurgitant flow, the two volume = area × velocity-time intergral. Table 1 provides
criteria for volumetric severity of MR.9
multiplied providing flow rate, and flow rate integrated
over time providing flow volume (Figures 1 and 2). Sources of Variations during Assessment
Total amount of blood flow which goes to the left
The regurgitant volume (RV) depends upon the
atrium (LA) per beat is called regurgitant volume.
regurgitant orifice and the systolic pressure gradient
Re gurgitant volume nor malize d to total left
between LV and LA.
ventricular (LV) stroke volume (SV) is regurgitation The observed degree of MR depends on hemodynamic
fraction (Figure 3). conditions at the time of examination.9 Any increase in
The orifice through which regurgitant volume enters preload or afterload, and any decrease in myocardial
the LA is called effective regurgitant orifice area (EROA). contractility, causes LV dilatation, enlargement of the
There can be more than one such orifices of different mitral annulus, and an increase in EROA. Vice versa
shapes and also of dynamic nature (Figure 4). also occurs especially after inducing anesthesia.
149
KG-20.indd 149 02-11-2018 13:52:07

SECTION Table 1: Regurgitant volume and regurgitant orifice area to assess
severity of organic mitral regurgitation [American College of
3 Cardiology/American Heart Association (ACC/AHA, 2014)]
Quantification of organic MR based upon regurgitant volume (RV)
z Absent: 0 RV
z Mild: RV ≤ 30 mL (ERO ≤20 mm2)
z Moderate: 31–59 (ERO 21–39 mm2)
z Severe: RV ≥60 mL (ERO > 40 mm2)
Abbreviation: ERO, effective regurgitant orifice
In acute MR, the atrium is noncompliant ; and
a
therefore, mechanical energy generated by the left
ventricle causes an increase in intra-atrial pressure.
di
Acute MR in RHD can occur in rheumatic carditis or
valve tear during balloon mitral valvuloplasty (Figures Figure 5: Schematic diagram displaying continuous-wave Doppler
In
5 and 6). spectrum of acute mitral regurgitation. Large V wave of left atrial
In chronic MR, the atrium is more compliant; and pressure cut-off the ascending limb obliquely
therefore, mechanical energy generated by the ventricle Abbreviations: MR, mitral regurgitation; LV, left ventricle; LA, left atrium
of
causes volume overload and atrial enlargement rather
than an increase in intra-atrial pressure (Figures 6
and 7).
ty
In severe MR, transthoracic echocardiography (TTE)
shows left atrial and ventricular enlargement. Without
18 cie
LV enlargement, it is not correct to diagnose significant
MR.
20 o
METHODS TO ASSESS SEVERITY OF
S
RHEUMATIC MITRAL REGURGITATION

There are several indirect clues to the severity of MR such
al
as LA and LV enlargement, dense continuous-wave (CW)

Doppler spectrum, pulmonary vein systolic flow reversal,
ic
increased mitral flow E wave velocity (>1.50 m/sec) in the

absence of mitral stenosis (MS), and en face view of the Figure 6: Different continuous-wave Doppler spectrum of chronic
og
mitral valve during systole in 3D. 9 However, in clinical versus acute mitral regurgitation
practice, the following methods are routinely used.
ol
Color Flow Jet Area in Left Atrium

Not long back, at default Nyquist limits, MR color jet area
di
in the LA was predominantly used to assess the severity

of MR. A color jet area <4 cm2 indicated mild MR and that
ar
≥8 cm2 suggested severe MR. Later on, jet area ≥10 cm2 was
considered evidence of severe MR (Figure 8). Nowadays,
C
color jet area is used to ballpark MR, but more refined

methods are used for estimating severity. Beyond doubt,
a small and thin jet area close to the mitral valve indicates
mild MR (Figure 9) and swirling jet is suggestive of severe
MR.8,9
There are a few caveats for color jet flow area as a
criterion for assessing MR severity:8,9
Figure 7: Large mitral E velocity and velocity-time integral
Most frequent but inaccurate way of assessing severe
suggestive of severe mitral regurgitation. Flow during diastole is the
MR. sum of forward stroke volume and regurgitant volume
Size and depth of the jet color area are frequently used
criteria for semiquantitation even though these are Color jet area is smaller in eccentric jets compared to
dependent upon many technical and hemodynamic central jets (Figure 12).
factors (Figures 10 and 11). In acute MR, color jet area is misleading.
150
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CHAPTER
20

a
di
In
Figure 8: Large color jet area and depth of presumably severe Figure 9: Mild mitral regurgitation by color jet area. The jet is shorter
mitral regurgitation without proximal isovelocity surface area (PISA) and narrower
Abbreviations: LA, left atrium, RA, right atrium; Abbreviations: LV, left ventricle; LA, left atrium
RV, right ventricle; LV, left ventricle
of
ty
18 cie
20 o S
al
ic
Figure 10: Two contrasting jet areas at nearly similar Nyquist limits. Figure 11: Left panel shows an apparently larger ERO with smaller
og
Even though ERO is bigger in right panel, its jet area is smaller color flow jet compared to that in right panel
Abbreviations: ERO, effective regurgitant orifice; RV, right ventricle; Abbreviations: ERO, effective regurgitant orifice;
RA, right atrium; LV, left ventricle; LA, left atrium RA, right atrium; LA, left atrium
ol
Jet area is usually low in the presence of elevated LA

di
pressure.
Color jet flow area is used to detect MR but not quantify
ar
it except in certain emergency situations.
Vena Contracta Width

C
Measurement of the vena contracta is useful as it describes

the smallest area of the blood flow jet as it exits a valve
(Figure 13). This corresponds to the effective orifice area
calculated for valves using the continuity equation.10
It is preferable to use a zoom mode to optimize
visualization of the vena contracta and facilitate its
measurement. The color flow sector should also be as
narrow as possible, with the least depth, to maximize
Figure 12: With similar vena contracta width, eccentric jet (right
panel) shows smaller jet area due to Koanda effect
lateral and temporal resolution, Nyquist limit of 30–70
Abbreviations: RV, right ventricle; LV, left ventricle; cm/sec and in views perpendicular to the commissures
RA, right atrium; LA, left atrium (Figures 14 and 15).
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Figure 13: Width of vena contracta in apical view (arrows) Figure 14: Commissural view showing a very large vena contracta.
Abbreviations: LA, left atrium; LV, left ventricle This view is not recommended for measuring vena contracta width
Abbreviations: LV, left ventricle; LA, left atrium
of
Limitations of Vena Contracta Width
No temporal information [as needed in mitral valve
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prolapse (MVP) and hypertrophic cardiomyopathy]
May need biplane or triplane measurement to get it
18 cie right in case of eccentric orifices.

Multiple jets are a problem.
Small errors can make a big difference.

20 o
In dynamic regurgitant orifice, vena contracta may
change with hemodynamic or during the cardiac cycle

S
The convergence zone is flatter with higher aliasing
velocities and become more elliptical with lower

al
aliasing velocities. The aliasing velocity is set between

20 and 40 cm/sec.
ic
Another limitation regards variation in the regurgitant
Figure 15: Best lateral resolution in parasternal long axis view for orifice during the cardiac cycle. This is particularly
measuring width of vena contracta as the jet is perpendicular to the
og
commissures (arrows)
important in MVP where the regurgitation is often
Abbreviations: RV, right ventricle; LV, left ventricle; LA, left atrium confined to the latter half of systole. The precise
location of the regurgitant orifice can be difficult to
ol
Vena contracta diameter measured from the parasternal judge, which may cause an error in the measurement
imaging window provides a more accurate estimate of of the proximal isovelocity surface area (PISA) radius.
di
Relation between a single vena contracta diameter and

actual office area compared with that measured from an
apical window, parallel to flow. actual regurgitant severity is poor when the regurgitant
ar
The largest diameter of a clearly defined vena contracta orifice shape is highly irregular. The 3D echo-derived
is measured if possible in two orthogonal planes and vena contracta measured in more than one axis when
C
averaged over several cardiac cycles.11 A color gain is seen en face is a better method.11
used that just eliminates random color speckles from Even though the measurement of the vena contracta
nonmoving regions. is less dependent on technical factors, small errors in
measurement can by multiplied due to the relatively small
Advantages of Vena Contracta values of the vena contracta width (VCW).
Simple measure of orifice area
valuable in eccentric jets as well Mitral Regurgitation Severity and Width of
Not dependent on pulse repetitive frequency Vena Contracta
No correction for angle or convergence walls Mild: <3 mm
Not affected by other valve involvement Moderate: 3.1–6.9 mm
If the orifice is fixed, then the size of the vena contracta Severe: ≥7 mm.
is independent of driving pressure and flow rate The above criteria are applicable only for holosystolic
Not affected by loading conditions. MR with preferably circular regurgitant orifice.
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Figure 16: Schema for proximal isovelocity surface area Figure 17: Multicolor hemispheres of PISA formed
(red hemispheres) in proximal flow convergence zone
Abbreviations: LV, left ventricle; LA, left atrium;
PISA, proximal isovelocity surface area
of
6.28 × radius2) and the aliasing velocity (Va) as 2πR2 ×
Va) (Figure 18).
ty
Assuming that the maximal PISA radius occurs at the
time of peak flow and peak velocity, the maximal ERO
18 cie is derived as: ERO = (6.28R2 × Va)/Vmax where Vmax is the
peak velocity of the jet by continuous-wave Doppler.
The transiting volume/beat can be estimated as ERO
20 o
multiplied by the velocity time integral (VTI) of the jet.
S
Since the PISA calculation provides an instantaneous

peak flow rate, ERO by this approach is the maximal
ERO and may be slightly larger than ERO calculated by
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other methods. If it is a regurgitant jet, ERO represents

regurgitant orifice area.
ic
Figure 18: Measuring PISA radius (10 mm) at aliasing velocity of 33 Measurement of PISA by color flow mapping requires
cm/sec and calculating flow rate and ERO of mitral regurgitation adjustment of the aliasing velocity such that a well-
og
Abbreviations: ERO, effective regurgitant orifice; LV, left ventricle; LA,

left atrium; PISA, proximal isovelocity surface area
defined hemisphere is shown. This is generally done
by shifting the baseline toward the direction of flow, or
by lowering the Nyquist limit, or both.13
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Proximal Isovelocity Surface Area Volumetric

The presence of flow convergence at default Nyquist
Measurements for Severity of Mitral

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limit of 50–60 cm/sec indicates significant MR.

Regurgitation
The proximal isovelocity surface area (PISA) is a Doppler
ar
Limitations of Proximal Isovelocity Surface

phenomenon to estimate orifice area.12
The PISA method is derived from the hydrodynamic
Area Method
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principle which states that, as blood approaches It is more accurate for central jets than for eccentric
a narrow orifice, its velocity increases forming jets.
concentric, roughly hemispheric shells of increasing The formula is applicable to a circular orifice. 13
velocity and decreasing surface area (Figures 16 However, quite often, the orifices are more often
and 17). elliptical or irregular or elongated along the coaptation
Color flow mapping offers the ability to image one of line (Figure 19).
these hemispheres that corresponds to the Nyquist If the image resolution allows the flow convergence to
limit of the instrument. Apical 4-chamber view is the be seen well (using zoom mode), and a Nyquist limit
most appropriate for visualization. can be chosen at which the flow convergence has a
If a Nyquist limit can be chosen at which the flow hemispheric shape, it is easy to identify the aliasing
convergence has a hemispheric shape, then the flow line of the hemisphere. However, it can be difficult to
rate (mL/s) through the orifice is calculated as the judge the precise location of the orifice and the flow
product of the surface area of the hemisphere (2πR2 or convergence shape.
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Figure 19: Irregular PISA shape not conforming to the hemispheric Figure 20: Modified PISA method to estimate ERO in those with
or hemiellipitical method normal systolic blood pressure and holosystolic mitral regurgitation
Abbreviation: PISA, proximal isovelocity surface area Abbreviations: ERO, effective regurgitant orifice; LV, left ventricle; LA,
left atrium; PISA, proximal isovelocity surface area
of
Any error introduced is squared, which can markedly
affect the resulting flow rate and ERO.
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In patients with normal blood pressure and MR, a
simplified formula can be used if aliasing velocity is
18 cie
brought to 40 cm/sec by shifting the baseline (Figures
20 and 21). The formula gives ERO or regurgitant
orifice area by R 2/2 wherein R is the radius of the
hemisphere.14
20 o
PISA method is much easier to apply in TEE images
S
than in transthoracic images.15 Scroll function must be

used to define a cardiac cycle, wherein PISA is seen the
best. In about 10–20% of the cases, PISA cannot be defined
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although vena contracta can be easily measured. Hence, a

compromise must be made.
ic
An ERO ≥40 mm 2 or a regurgitant volume ≥60 mL

og
indicates severe organic MR. Figure 21: Simplified method of estimating ERO from radius of PISA
at a Nyquist limit of 40 cm/sec. ERO = R2/2
Abbreviations: ERO, effective regurgitant orifice; LV, left ventricle;
Regurgitant Orifice Area by Real-time 3D AML, anterior mitral leaflet; LA, left atrium; PISA, proximal isovelocity
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surface area
Echocardiography (RT3DE)
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The size of the regurgitant jet, as it emerges from the lesion size.16,17 On the cropped images, the ratio of the
orifice, bears a consistent relation to the size of the orifice longest and shortest diameter of the orifice can also be
ar
itself. Color Doppler regurgitant orifice area by real-time measured to judge the shape of the hole. The 3D VCA
3D echocardiography (RT3DE), allowing for an unlimited measurement requires identification of the long axis of
plan orientation and in particular for an en face view of the flow in 2 orthogonal images, then identification of vena
C
mitral valve, provides a direct assessment of size and shape contracta cross-sectional area (Figures 22 and 23).
of regurgitant orifice, obviating the geometric assumptions 1. The RT3DE-derived regurgitant/left atrial volume
used in 2D echocardiography. Three-dimensional vena ratios provide a new method of assessing the severity
contracta area (VCA) which is a surrogate for regurgitant of MR.
orifice area measurement is feasible and obtainable in the 2. The advantage of 3D VCA over 2D vena contracta
majority of patients with mild or greater MR. diameter is more pronounced in eccentric jets and in
To measure 3D regurgitant orifice area, the 3D dataset moderate-to-severe MR.
is manually cropped by an image plane perpendicularly 3. Accurate 3D VCA measurement of small, central jets
oriented to the jet direction as far as the narrowest may be hampered by technical limitations, including
cross- sectional area of the jet (see Figures 59 and 60). image pixilation.
Orifice area is measured by manual planimetry of the 4. Lower 3D color Doppler frame rate may be a significant
color Doppler signal, tilting the image in an en face view limitation in the assessment of rapidly dynamic flow
154 and selecting the systolic frame with the most relevant events and correct VCA.
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Figure 22: Real-time 3D echocardiographic technique for Figure 23: Real-time 3D echocardiographic technique for
assessment of vena contracta area (EROA-3D). Note the elliptical assessment of vena contracta area (EROA-3D). Note the near
shape of the orifice in right panel spherical shape of the orifice in right panel
Abbreviations: EROA, effective regurgitant orifice area; 3D, three- Abbreviations: EROA, effective regurgitant orifice area; 3D, three-
of
dimensional dimensional; LV, left ventricle; LA, left atrium
5. T h e 2 D m e t h o d s, p a r t i c u l a r l y 2 D V C W a n d
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hemispherical PISA, systematically underestimate the
true regurgitant orifice area more so in asymmetric
shapes. 18 cie
6. Based on the VCA measurements obtained by RT3DE,
Kahlert et al. propose a larger cut-off value of 0.6 cm2
20 o
for the VCA compared to 0.4 cm2 for 2D-derived EROA
S
by the PISA method; and accordingly, 0.8 cm for mean

VCW (mean of 4- and 2-chamber views) instead of 0.7
cm for 4- chamber-based vena contracta for severe MR
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for all etiologies.18

7. The concept of the asymmetric VCA with new cut-off
ic
values particularly the 0.8 cm for mean VCW to define

severe MR has been adopted by the guidelines of the
og
European Society of Cardiology (ESC).19 Figure 24: Continuous-wave interrogation of mitral orifice in pure
8. Limitations that still remain to be overcome using mitral regurgitation (MR). Inset picture shows lack of mitral stenosis.
A peak mitral E velocity of 175 cm/sec is suggestive of severe MR
RT3DE color Doppler include a limited temporal
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and spatial resolution of 3D color Doppler datasets,

severe cases, systolic wave gets reversed or blunted.
translation artifacts, and complex dynamic changes of
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This sign lacks specificity because atrial fibrillation

VCA size and shape.
(AF) and diastolic dysfunction both can blunt systolic
ar
wave.
Pulsed-wave Doppler Velocity for Assessing
Severity of Mitral Regurgitation
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Continuous-wave Doppler Interrogation in Mitral

In the absence of MS, a peak mitral E velocity >1.5 Regurgitation
meter/sec suggests severe MR (Figure 24). However, MR velocity does not provide estimate of severity of
this may not be reliable in RHD because varying MR.
degree of MS may be present in a significant number Density of CW jet roughly correlates with severity of
of patients. MR.
A dominant mitral A wave practically rules out severe C W spectrum can display holosystolic versus
MR. nonholosystolic MR. Nonholosystolic jets have smaller
Mitral flow velocity-time integral/aortic time-velocity RV.
integral ratio >1.4 indicates severe MR. This ratio <1 In acute MR, CW spectrum of MR becomes triangular
indicates mild MR. with early systolic peaking (Figure 25).
Reduction in pulmonary venous systolic waveform True triangular CW spectrum can also occur due to
velocity occurs with increasing severity of MR. In severe LV systolic dysfunction (Figure 26).
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Figure 25: Continuous-wave Doppler spectrum of acute mitral Figure 26: Triangular CW spectrum of MR due to slow rise and fall
regurgitation. Left panel shows flail AML due to rheumatic carditis of LV pressure in systolic dysfunction
Abbreviation: AML, anterior mitral leaflet
of
In summary, evaluation of MR requires careful study pressure gradients, valve area planimetry, and pressure
of 2D/3D echocardiographic morphology of the mitral half-time. The TEE is employed to rule out left atrial
ty
valve complex, quantitation by measuring vena contracta thrombi before balloon mitral commissurotomy. The
and flow convergence method preferably by RT3DE and 3D echocardiography bridges the gap between novice
18 cie
use of supportive signs to corroborate the severity of
MR. Parameters used for the assessment of MR include
valve structure, cardiac remodeling, and color and
and expert with regard to accurately assessing severity.
From standpoint of therapeutic intervention, mitral valve
morphology can be classified into three groups: flexible
spectral Doppler. Quantitative measurements include valve and mild subvalvular disease (chordae ≥10 mm long)
20 o
effective regurgitant orifice area, regurgitant volume, (Group I), flexible valve and extensive subvalvular disease
S
and regurgitant fraction. An integrative approach is (chordae <10 mm long) (Group II), and calcified valves
recommended in overall grading of MR as mild, moderate, (Group III).
al
or severe since single parameters may be affected by

several factors. The assessment of LV function, left Echocardiographic Techniques to be Used in
ic
atrial volume, pulmonary artery pressures, associated Mitral Stenosis

functional tricuspid regurgitation (TR) and evidence of
2D transthoracic echocardiography (TTE) is most
og

early systolic dysfunction by global longitudinal strain are
commonly deployed and is usually sufficient to grade
important aspects of assessing MR. There is urgent need
MS severity and to define the morphology of the valve.
for automated software analysis to allow rapid, robust,
Transesophageal echocardiography (TEE) is used
ol

and user-independent flow quantification and the whole
when the valve cannot be adequately assessed with
dynamic flow information throughout the cardiac cycle.
TTE and to exclude intracardiac thrombi before a
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percutaneous or surgical intervention.

Assessing Mitral Regurgitation The 3D TTE/TEE adds value in a patient with MS
ar

in the Presence of Aortic Stenosis as it provides more detailed physiological and

This combination produces low-flow low-gradient AS. morphological information.
C
The LV function is preserved till late due to concentric Transthoracic stress echocardiography for patients
hypertrophy. with discrepancy between the resting Doppler
Planimetry of the aortic valve area (AVA) either by echocardiographic measurements and symptoms.
2D or 3D echocardiography is more reliable than the Effective orifice area is the area of the mitral orifice
Doppler methods. through which the blood flows in diastole (Figure 27).
The entire quantum of MR may not be organic; and It is usually slighter smaller than the anatomical area
hence, a relatively conservative approach should be due to viscous drag at the periphery of the orifice.
followed for mild-to-moderate MR.
Hemodynamics of Mitral Stenosis
ASSESSMENT OF MITRAL STENOSIS Normal mitral valve area (MVA) exceeds 4 cm2 and there
Mitral stenosis (MS) is studied by analysis of its is almost no pressure gradient between the LA and the LV
morphology and commissural calcification, transmitral during diastole. Blood flows without much resistance. As
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Figure 27: 3D reconstruction of the effective orifice area (red Figure 28: Depiction of pressure gradients in a patient with
arrows). Effective orifice area is smaller than the anatomical area rheumatic mitral stenosis (left panel). Right panel shows the
continuous-wave Doppler velocity pattern across the mitral valve
from which the pressure gradient is obtained by the modified
of
Bernoulli equation
Abbreviations: LA, left atrium; LV, left ventricle; CW, continuous wave
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18 cie
20 o S
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Figure 29: Parasternal long axis view showing three different shapes
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of the mitral orifice in open position. Pressure gradients are the

highest in the hole-in-diaphragm variety and least in funnel shape
Figure 30: Flow pattern across the mitral apparatus. Left atrium,
ol
2
mitral valve and the left ventricle all affect the resistance to flow
the valve area narrows to <2 cm , transmitral pandiastolic Abbreviations: LV, left ventricle; MV, mitral valve, LA, left atrium;
gradient develops with rise in the left atrial pressure LVOT, left ventricular outflow tract
di
(Figure 28). The MS becomes critical when the valve area

narrows <1 cm2 and mean gradient rapidly rises.20 Severity
ar
of MS is judged by: Table 2: Severity of mitral stenosis by estimating transmitral

gradients and mitral valve area
Transmitral pressure gradients
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Effective MVA Degree of mitral stenosis Mean gradient Mitral valve area
Pulmonary artery pressures.
Mild mitral stenosis <5 mm Hg >1.5 cm2
Hemodynamics of MS is determined by: Moderate mitral stenosis 5–10 mm Hg 1.0–1.5 cm2
Complex anatomical and pathophysiologic features of
Severe mitral stenosis > 10 mm Hg < 1.0 cm2
the valve apparatus (Figure 29). 21
Properties of the left ventricle, atrium, and pulmonary
vasculature (Figure 30). The American College of Cardiology/American Heart

The valve and the cardiac chambers have a functional Association (ACC/AHA) 2014 guidelines on management
reserve that becomes exhausted as the stenosis of VHD reclassified MS in a different way.9 Severe MS
worsens and/or the compensatory mechanisms of the was defined as a MVA of ≤1.5 cm2 with a mean diastolic
chambers fail. gradient of 5–10 mm Hg. Progressive mitral valve stenosis
Severity of MS is judged by estimating transmitral was a term coined for an MVA >1.5 cm2. Valve area ≤1.0
gradients and MVA as shown in Table 2.22 cm2 was termed very severe MS.
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Figure 31: Continuous-wave Doppler interrogation of the mitral Figure 32: Color Doppler guidance of CW interrogation of transmitral
orifice from apical view showing velocity profile flow. The jet direction should be parallel to the insonifying beam
Abbreviations: LV, left ventricle; RV, right ventricle; RA, right atrium; LA,
left atrium; CW, continuous wave
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20 o S
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Figure 33: Echocardiographic view showing nearly 30° angle Figure 34: Continuous-wave Doppler interrogation of the mitral
og
between the flow jet and the insonifying beam. The pressure from the apical window showing a peak gradient of 25 mm Hg
gradient may be underestimated while the mean gradient is only 11 mm Hg. Reduced left-sided
Abbreviations: LV, left ventricle; LA, left atrium atrioventricular compliance results in steep deceleration
ol
Assessment of Severity of Mitral Stenosis Color Doppler in apical view is useful to identify
di
Transmitral pressure gradient eccentric diastolic mitral jets that may be encountered
Estimation of the diastolic pressure gradient is derived in cases of severe deformity of valvular and subvalvular
ar

from the transmitral velocity flow curve using the apparatus. In these cases, the Doppler beam is guided
simplified Bernoulli equation, i.e. ΔP = 4V2 (Figure 31). by the highest flow velocity zone identified by color
C
This estimation is reliable, as shown by the good Doppler (Figures 32 and 33).
correlation with invasive measurements. Optimization of gain settings, beam orientation,
Use of continuous-wave Doppler is preferred to ensure and a good acoustic window are needed to obtain
maximal velocities are recorded. When pulsed-wave well-defined contours of the Doppler flow. Maximal
Doppler is used, the sample volume should be placed and mean mitral gradients are calculated by
at the level or just after leaflet tips. integrated software using the modified Bernoulli
Doppler gradient is assessed using the apical window equation.
in most cases as it allows for parallel alignment of the Mean gradient is the valid hemodynamic data for
insonifying beam and mitral inflow. severity. Maximal gradient is of limited value as it is
The ultrasound Doppler beam should be oriented to derived from peak mitral velocity, which is influenced
minimize the intercept angle with mitral flow to avoid by net left-sided atrioventricular compliance
underestimation of velocities. (Figure 34).
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Heart rate at which gradients are measured should arrhythmia. It is desirable to average 3–5 cardiac cycles CHAPTER
always be reported. for enhancing accuracy of estimation (Figure 38).
In patients with atrial fibrillation, mean gradient
should be calculated as the average of five cycles with

The transmitral mean pressure gradient commonly
increases during exercise, regardless of the severity
20

the least variation of R–R intervals and as close as of stenosis, in accordance with exercise duration and
possible to normal heart rate (Figure 35). exercise-induced changes in cardiac output. Exercise
Mitral gradient, although reliably assessed by Doppler Doppler parameters may help in deciding intervention in
method, is not the best marker of the severity of MS. asymptomatic patients or whenever there is discrepancy
Transmitral pressure gradients are reliable but depend between symptoms and resting hemodynamics.23
upon:
Severity of MS
Mitral Valve Area
a
Net left-sided atrioventricular compliance (mainly
The MVA can be estimated by four different techniques as
di
affects peak gradients)
shown in Table 3.24-28
Flow (Figure 36)
In
Diastolic filling period and heart rate
Associated MR (Figure 37). Mitral Valve Area Planimetry

Transmitral gradients and velocity-time integral can Planimetry using 2D echocardiography of the mitral
of
show significant beat-to-beat variability even in sinus orifice has the advantage of being a direct measurement
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20 o S
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ic
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Figure 35: Near equal RR intervals in atrial fibrillation for Figure 36: A patient with moderate mitral stenosis with mitral valve
measurement of transmitral gradients area of 1.18 cm2 showing very low mean gradient of 2 mm Hg due
to reduced flow. Sharp deceleration in 3rd cycle is due to reduced
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ventricular compliance
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ar
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Figure 37: Transmitral mean gradient of 15 mm Hg in the presence Figure 38: Beat-to-beat variation in continuous-wave Doppler
of moderate mitral regurgitation and mild mitral stenosis (valve area spectrum during sinus arrhythmia
2.0 cm2). Prolonged pressure half-time is due to increased left atrial
compliance
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SECTION Table 3: Mitral valve area estimation by four different techniques
3
Technique Method Remarks
Direct measurement measurement in short axis view Most reliable, operator dependent
Pressure half time P ½ =0.29 x Deceleration time Unreliable in conditions with elevated left ventricle
(P ½) *MVA= 220/ P ½ time end-diastolic pressure

Continuity equation assumption blood flow through different valves is equal In regurgitant lesions reliability decreases
MVA = D2LVOT × 0.785 × TVILVOT
TVIMV
Proximal isovelocity MVA = 2 × 3.14 r2 × V1 Very reliable, operator dependent
surface area (PISA)
Abbreviations: MVA, mitral valve area; TVI, time-velocity integral; LVOT, left ventricular outflow tract
a
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In
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20 o
Figure 39: Planimetery of the mitral valve area in mid-diastole in Figure 40: Zoomed view of the mitral orifice in mid-diastole.
S
short axis view Thickest leaflet curtains indicate the narrowest area
Abbreviations: 2D, two-dimensional; 3D, three-dimensional
It is recommended to perform several different
al

of MVA; and, unlike other methods, does not involve measurements, in particular in patients with AF and in
any hypothesis regarding flow conditions, cardiac those who have incomplete commissural fusion.
ic
chamber compliance, or associated valvular lesions. Another potential limitation is that the performance
Planimetr y has been shown to have the best
og

of planimetry requires technical expertise. The
correlation with anatomical valve area. For these
measurement plane must be optimally positioned
reasons, planimetry is considered as the gold standard
at the mitral orifice. This can be done by 3D-guided
measurement of MVA.29
ol
biplane imaging which allows the cursor to be placed

Planimetry measurement is obtained by direct tracing of
at the tip of the leaflets in desired mid-diastole
the mitral orifice in 2D or 3D format, including opened
di
(Figure 41).
commissures on a parasternal short-axis view (Figure 39).
Real-time 3D echo imaging is useful in optimizing the
Careful scanning from the apex to the base of the LV is
ar

positioning of the measurement plane and, therefore,
required to ensure that the valve area is measured at
the leaflet tips. improving reproducibility.30-32 It also improves the
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The measurement plane should be perpendicular to accuracy of planimetry measurement when performed
the mitral orifice, which has an elliptical shape. by less experienced echocardiographers (Figure 42).
Gain setting should be just sufficient to visualize the The 3D-TTE allows a 3D acquisition of the entire mitral
whole contour of the mitral orifice. Excessive gain valve, which can be sliced along any plane as desired
setting may cause underestimation of valve area, in (Figure 43).
particular when leaflet tips are dense or calcified. The 3D echocardiography and biplane imaging both
Image magnification, using the zoom mode, is useful have low temporal resolution as compared to standard
to better delineate the contour of the mitral orifice 2D echocardiography. If adequate time and multiple
(Figure 40). attempts are made to obtain valve area, 2D echo still
The optimal timing of the cardiac cycle to measure remains the preferred method in experienced hands.
planimetry is mid-diastole (some recommend early Planimetry using TTE (either 2D or 3D) is not feasible
diastole). This is best performed using the cine-loop in 5–10% of patients and 3D-TEE may represent an
mode on a frozen image.24 interesting alternative.
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Figure 41: Estimation of mitral valve area by biplane imaging. The Figure 42: 3D mitral valve area (red arrows) obtained from
cursor can be aligned perpendicular to the narrowest orifice (right multiplane reconstruction
panel)
Abbreviations: LA, left atrium; Ao, aorta; RV, right ventricle
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Figure 43: Real-time 3D-echo to obtain mitral valve area at the tip Figure 44: Inappropriate short axis view (right panel) for
og
of leaflets by slicing and dicing measurement of mitral valve area when seen in relation to the
shorter anteroposterior leaflet separation
Abbreviations: LA, left atrium; Ao, aorta; LV, left ventricle; AML, anterior
ol
It is recommended to measure the distance between mitral leaflet; PML, posterior mitral leaflet
the anterior and posterior mitral leaflets in the LV
di
parasternal long-axis view in its narrowest area.

When viewing the LV short axis, planimetry of the
ar
mitral valve is performed making sure that the level of

measurement is the level that has the smallest distance
between anterior and posterior leaflets, which is
C
closest to the smallest distance obtained from the LV

parasternal long-axis view; and thus serving as the
narrowest area possible by planimetry of the mitral
orifice (Figure 44).
Pressure Half-time Method for MVA

Pressure half-time (PHT) is the time interval in
milliseconds between the maximum mitral gradient
in early diastole and the time point where the gradient
is half the maximum initial value (Figure 45).33 The
ACC/AHA 2014 guidelines propose PHT of ≥150 msec Figure 45: Method to estimate pressure half-time
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Figure 46: Measurement of pressure half-time and hence mitral Figure 47: Bimodal deceleration slope transmitral flow. Latter part
valve area in multiple beats in the presence of atrial fibrillation. The (yellow) of the deceleration slope is used to estimate mitral valve area
area varies from 0.8 to 1.0 cm2
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Figure 48: Avoid pressure half-time measurement Figure 49: Postectopic beat (5th cardiac cycle) showing optimum
og
in short cardiac cycles deceleration slope for estimation of MVA
suggestive of severe MS and >220 msec indicative of In the rare patients with a concave shape of the tracing,
ol
very severe MS.9 PHT measurement may not be feasible.

The decline of the velocity of diastolic transmitral In patients with AF, tracing should avoid mitral flow
di
blood flow is inversely proportional to valve area (cm2), from short diastoles and average different cardiac
and MVA is derived using the empirical formula: 33 cycles (Figure 48). Similarly, in the presence of fast
ar
MVA = 220/PHT heart rate in sinus rhythm, postectopic beat with

longer diastole provides better assessment of MVA by
The PHT is obtained by tracing the deceleration
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the PHT method (Figure 49).

slope of the E-wave on Doppler spectral display
The PHT method is widely used because it is easy to
of transmitral flow and valve area is automatically
perform, but its limitations should be kept in mind
calculated by the integrated software of currently used
since different factors influence the relationship
echo machines (Figure 46).
between PHT and MVA (Figures 50 to 52). Left-sided
Quality of the contour of the Doppler flow, in particular
net atrioventricular compliance (NAVC) is the most
the deceleration slope is important. The deceleration
significant factor.34,35
slope is sometimes bimodal, the decline of mitral
PHT × effective orifice area
flow velocity being more rapid in early diastole than NAVC =
during the following part of the E-wave. In these cases, 11.6 × (peak transmitral gradient)–2
it is recommended that the deceleration slope in mid- Concomitant aortic valve disease can reduce left
diastole rather than the early deceleration slope be atrioventricular compliance and PHT becomes shorter
traced (Figure 47). (Figure 52).
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Figure 50: Mild mitral stenosis with mitral valve area of 1.7 cm2 and Figure 51: Mitral valve area by pressure half-time method in a
mean gradient of 3.6 mm Hg but pressure half-time of 260 msec. patient (with mean gradient of 18 mm Hg and effective orifice area
This is due to high-normal atrioventricular compliance of 0.8 cm2) is 1.45 cm2
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Figure 52: Short pressure half-time and higher mitral valve area in Figure 53: Elderly female with severe rheumatic mitral stenosis but
og
the presence of combined aortic valve disease18 mitral valve area by pressure half-time is 2.2 cm2. Associated left
ventricular diastolic dysfunction is the probable cause
The NAVC, derived by Doppler echocardiography,

ol
presence of AF, MR, or aortic regurgitation (AR). The MVA

has been shown to be an important physiological by the continuity equation can be obtained by dividing
determinant of pulmonary hypertension in patients
di
the Doppler SV (from either outflow tract) with the mitral

with MS.35 velocity-time integral (Figure 54).
Routine measurement of NAVC in all patients with MS
ar

is recommended because, in addition to clarifying the

Proximal Isovelocity Surface Area Method
inaccuracies of PHT in calculation of area out of the
C
4–6 mL/mm Hg range, it is also a predictor of the left The proximal isovelocity surface area (PISA) method is
atrial and pulmonary pressures, exercise capacity, and based on the continuity principle and assumes that blood
the need for mitral valve replacement. flow converging toward a flat orifice forms hemispheric
Impaired LV diastolic function is a likely explanation of isovelocity shells. It has been shown that the PISA method
the lower reliability of PHT to assess MVA in the elderly is accurate and reproducible. This method is useful in
(Figure 53). MS since the proximal convergence method can be easily
visualized and it may be the only method available in
Continuity Equation for Calculation of Mitral certain situations (Figure 55).36
Valve Area
Continuity equation is not recommended for routine Method
practice in obtaining MVA. It has many assumptions Measure the radius (R) of the hemisphere from the
which make it error-prone.24 It is also not reliable in the first aliasing velocity in the LA up to the beginning of
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Figure 54: Error introduced by measurement of the left ventricular Figure 55: Arrows point to proximal isovelocity surface area (PISA)
outflow tract (LVOT) in calculation of the mitral valve area (MVA) by in the left atrium in this apical 4-chamber view
the continuity equation. The LVOT is oval with maximum diameter
of 23 mm and minimum of 17 mm. Calculated area is 0.6 cm2 when
of
LVOT of 17 mm is used which significantly underestimates the valve
area (0.93 cm2). Estimate of stroke volume is the major factor
Abbreviation: VTI, velocity time integral
ty
narrowest portion of the color jet within the valve in

zoomed mode. 18 cie
Use an appropriate aliasing velocity (by baseline shift)
which clearly shows hemispheric shape of the PISA.
20 o
Estimate the mitral volume flow rate by multiplying
the area of the hemisphere (6.28 × R2) with aliasing
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velocity. This further needs to be corrected for mitral

leaflet angles/180.
al
Divide the mitral flow rate thus obtained by the

continuous-wave Doppler peak transmitral velocity to
ic
obtain MVA. Figure 56: Aliasing velocity of 30 cm/sec in TEE long axis view
Most systems have in-built capability to obtain these showing adequate PISA (arrows)
og
data. Abbreviations: LA, left atrium; LV, left ventricle

The PISA method provides an assessment of the
physiologic or effective orifice area at the vena of MS severity in routine practice. Simple equation
ol
contracta, as opposed to the anatomic orifice area using PISA, created by fixing the angle to 100° and the
measured by planimetry, which is generally somewhat aliasing velocity to 33 cm/s, to calculate MVA is the
di
larger. most practical method.

Use of very low aliasing velocity results in inadequate The use of color M-mode improves its accuracy,
ar
flow convergence shape, ambiguous surface contour enabling simultaneous measurement of flow and
and, therefore, difficulty in getting a reliable radius. velocity.
Hence, aliasing velocity should be between 30 and 40 The PISA method has the advantage of being applicable
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cm/sec (Figure 56). even in the presence of MR.

One limitation for a wider use of the PISA for the The 3D echocardiography with color Doppler
evaluation of the MVA in patients with MS is the interrogation can also be used to estimate MVA
requirement of an angle correction factor (angle α (Fig ure 57). Mu l t i p l a n e re c o n s t r u c t i o n ca n
between the mitral leaflets) which cannot be obtained be performed to obtain transverse section of the
using the machine’s built-in software and requires a transmitral jet in mid-diastole at the tips of mitral
manual measurement.36 leaflets and planimetry of the flow area can be
The angle formed by the mitral leaflet only slightly employed to obtain effective orifice area.
changes in between patients and use of a fixed angle
value of 100° provides an accurate estimation of the Miscellaneous Parameters of Severity of
valve area by the PISA method in patients with MS.36 Mitral Stenosis
This simplification would facilitate and extend the use Mitral valve resistance (ratio of mean gradient/
164 of the PISA as an additional method for the assessment diastolic flow rate) has been proposed as a flow-
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Figure 57: Technique of measuring effective mitral valve orifice area Figure 58: Interleaflet minimum distance
by 3D color Doppler interrogation using multiplanar reconstruction in mid-diastole in the mitral funnel
Abbreviation: LVOT, left ventricular outflow tract Abbreviations: LV, left ventricle; LA, left atrium
of
independent method of assessing severity. It correlates Table 4: Relationship of transvalvular velocities, Δ P and aortic
with the degree of pulmonary hypertension. However, valve area for judging severity
ty
it has limitations of assessing SV and is not routinely Severity of AS
used in clinical practice. Velocity (m/sec) Valve area (cm2)

18 cie
Estimation of pulmonary pressures (from tricuspid
and pulmonary regurgitation jets) is an indirect clue of
severity or rather the consequence of MS.
Mild
Moderate
2.6–3.0 (mean G < 25)
3.0–4.0 (MG 25–40)
>1.5
>1.0 to 1.5
Severe >4.0 (mean G > 40) ≤1.0
20 o
Shortest distance between the tips of the mitral leaflets
in early diastole in parasternal long axis view has been
S
found to correlate with severity of MS. A distance <10 The TR should be routinely followed by echocardio-
mm indicates severe stenosis (Figure 58) and <6 mm graphy after left-sided valve intervention.
al
indicates very severe MS.37

ASSESSMENT OF AORTIC VALVE
ic
Assessing MS in the Presence of Aortic Valve Complete assessment of the degree of AS requires:
Regurgitation Measurement of the transvalvular flow
og
Determination of the transvalvular pressure gradient

Despite significant AR, the left ventricle may not dilate;
Calculation of the AVA
and hence, the lack of ventricular dilatation is not the
Calculation of energy loss coefficient
ol
argument in favor of mild AR.

Calculation of valvuloarterial impedance (may not be
The PHT derived MVA overestimates area and
relevant in rheumatic AS).
di
underestimates its severity due to AR altering the

diastolic compliance of the left ventricle. Conventionally, severity of AS is judged by the above
parameters using criteria shown in Table 4.38,39
ar
Severe MS may result in low SV; and hence, quantitative

Recent ACC/AHA guidelines first published in 2014
parameters of AR may be underestimated.
and then updated in 2017, have labeled mild and moderate
Concentric hypertrophy in the presence of this
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AS as progressive AS. 9 These guidelines redefine truly
combination should point towards associated AS or
severe AS that having AVA <0.8 cm2.
systemic hypertension.
The SV is measured by multiplying LVOT cross-
Eccentric hypertrophy of the left ventricle is more often
sectional area by the velocity-time integral of the
seen when there is significant MR along with MS and
outflow. The SV should be indexed for body surface
AR.
area (Figure 59).
The LVOT diameter is measured from parasternal long
Mitral Stenosis with Tricuspid Regurgitation axis view in mid-systole from inner edge to inner edge
Always quantify TR by multiple methods along with and area is estimated by assuming it to be circular
estimation of pulmonary hypertension. (Figure 60). Accurate results can be obtained by
Tricuspid annular dimensions must be recorded. measuring cross-sectional area of the LVOT by 3DE.
Loading conditions and therapy at the time of Transaortic flow rate is calculated by dividing SV by
echocardiography should be documented. systolic ejection time

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Figure 59: Measurement of left ventricular outflow tract (LVOT) diameter from parasternal long
In
axis view and LVOT velocity-time integral from apical view using pulsed-wave Doppler with a small
sample volume placed just proximal to flow acceleration zone
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Figure 60: Aortic valve area by continuity equation is calculated as stroke volume divided by
ol
velocity-time integral across the aortic valve

Abbreviations: LVOT, left ventricular outflow tract; AV, atrioventricular; VTI, velocity time integral
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The AVA is calculated by dividing SV by aortic velocity- Optimization of Data Acquisition

ar
time integral (Figure 60). The most common windows utilized for recording peak
Valve resistance is calculated by dividing mean aortic systolic velocity are the apical, suprasternal,
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transaortic gradient by transaortic flow rate.40 and right parasternal. A comprehensive Doppler
Substituting the Doppler-derived SV by SV directly examination for AS requires that the ascending aorta
obtained with real-time 3D echocardiography, which be examined from all possible windows in order to
considerably simplifies the calculation, overcomes align the beam parallel to the jet (Figures 61 and 62).
many potential sources of error, and does not depend A potential source for error is mistakenly interpreting
on the quality of the parasternal acoustic window.41 the profile of MR for that of AS in apical windows.
Echo-2D underestimates the LVOT area which may However, AS signal begins after the isovolumic
explain the tendency of 2D-echo to estimate a smaller contraction and is slightly delayed (Figure 63).
AVA than 3D-echo. The continuous-wave spectrum profile can help in
Stroke volume index (SVI) and some pressure recovery differentiating mild AS from the severe one. As the
are the only independent predictors of the difference in severity increases, peak of Δ P gets delayed and occurs
AVA between invasive and noninvasive assessments.42 in later part of systole (Figures 64 and 65). However,
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Figure 61: Continuous-wave interrogation of aortic valve flow jet by apical window (left) and
suprasternal window (right). Note that the Δ P is higher by 14 mm Hg when measured from the
suprasternal window
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Figure 62: Incompletely formed aortic Doppler spectrum (upper Figure 63: Combined continuous-wave signals of mitral
panel) compared to the fully formed continuous-wave velocity regurgitation and aortic stenosis (AS). Note that the signal of AS is
ol
spectrum (lower panel) from apical windows. There is a difference of delayed

80 mm Hg in Δ P
di
ar
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Figure 64: Continuous-wave profiles of Figure 65: Comparison of continuous-wave Doppler spectrum of
varying degree of aortic valve stenosis mild versus severe aortic stenosis (AS)
Abbreviation: AS, aortic stenosis
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Figure 66: Echocardiographic images in a 32-year-old male with severe mitral and aortic stenosis.
Left upper panel shows early peaking continuous-wave spectrum across the aortic valve despite an
aortic valve area of 1.0 cm2 (right upper panel)
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Figure 67: Measurement of dimensionless index from the apical

window. Upper panel shows left ventricular outflow tract velocity Figure 68: In the presence of severe aortic regurgitation (AR),
ol
and the lower panel, aortic velocity profile dimensionless index is 0.21 despite left ventricular outflow tract
(LVOT) peak velocity of 118 cm/sec. This suggests significant aortic
stenosis in the presence of AR
di
the shape of the continuous-wave spectrum is often is some flow-dependency of the AVA by the continuity
ar
not reliable in rheumatic AS because of young age, equation.42

normal aortic compliance, reduced SV due to mitral Geometry of the aortic orifice, inflow and the size of
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valve disease, or due to functional MR (Figure 66). aorta all affect estimation of the AVA by the continuity
Whenever there is doubt about the quality of equation (Figure 69).
parasternal long axis measurement of the LVOT or there It has been suggested that the estimation of energy loss
is associated AR or MR (making continuity equation index (ELI) is a better guide for severity and prognosis
nonapplicable), it is prudent to use a dimensionless of AS than the AVA.43 Figure 70 shows the method to
index of ratio of LVOT peak velocity to transaortic peak estimate energy loss index. The ELI takes into account
velocity (Figures 67 and 68). An index of ≤0.25 usually the pressure recovery (Figure 71). The valves with the
denotes severe aortic valve stenosis. However, in greatest pressure recovery have the least energy loss.
low-flow situations, it may not differentiate true from Another method to assess hemodynamic burden of AS
pseudostenosis. is estimation of ventriculovalvular impedance (VVI).
The weakest aspect of area calculation is the variability The VVI is ratio of arterial systolic pressure + mean
in measurement of LVOT area, because it involves transaortic gradient divided by the SVI.44 More than
squaring the LVOT dimension. The other weak point 4.5 is significant VVI. The VVI takes into account the
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Figure 69: Diaphragm-like aortic valve orifice (arrow) and narrow Figure 70: Method of estimating energy loss index
ascending aorta; two common causes of higher transaortic velocity
and Δ P
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Figure 71: Just beyond the orifice, Δ P is maximum which gradually Figure 72: Systolic aortic pressure recovers in divergence zone with
decreases near sinotubular junction due to conversion of kinetic decrease in mean gradient (MG). Combination of systolic aortic
og
energy into pressure energy. If the flow distally is turbulent due to pressure and mean transaortic gradient represents the pressure load
dilated aorta, less pressure recovery occurs as some energy is lost to to be overcome by the left ventricle (LV) during ejection. When this
tissues as heat is divided by the stroke volume index, it is akin to total resistance
faced by the LV
ol
hemodynamic load on the left ventricle imposed by

di
systemic hypertension and also corrects for the lower

ΔP seen in patients with low flow (reduced SVI). It
ar
is possible to use VVI regardless of ejection fraction

(EF) (Figure 72). However, it may have limited role in
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patients with rheumatic AS who are usually younger

with normal blood pressure.
Percent stroke work loss, calculated as mean systolic
pressure gradient divided by mean ventricular systolic
pressure × 100% is also a good parameter of AS severity.
A simplified continuity equation which provides AVA
is a product of dimensionless index and LVOT cross-
sectional area (Figure 73).
If dynamic obstruction creates difficulty in estimating
LVOT stroke volume, the right ventricular outflow Figure 73: Modified continuity equation for estimating aortic valve
tract (RVOT) stroke volume can be used as the nume- area. Flow (Area × velocity) is constant across a stream if there is no
rator. sump or sink
Abbreviations: LV, left ventricle; Ao, aorta; LA, left atrium
169
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SECTION Low-gradient, Low-flow Rheumatic Aortic About 30% of all patients have AVA in the severe range
Valve Stenosis with low-flow or low-gradients or both.
3 Low-gradient, low-flow AS is characterized by AVA ≤1.0
Low-flow/low-gradient AS may truly have severe AS
with resultant myocardial failure (true AS) or may
cm2, mean gradient ≤30 mm Hg and SV index ≤35 mL/M2
have more moderate degrees of AS and unrelated

(Figures 74 to 76).
myocardial dysfunction.45,46
In patients with true AS, increased flow (as with
Types of Low-gradient Low-flow Severe AS dobutamine infusion) across a fixed valve orifice
Schematic diagram of low flow, low-gradient AS is shown results in increased transvalvular flow velocity and
Flow chart 1. gradients, without a change in calculated valve area
Low-gradient severe AS is infrequent in rheumatic (Figures 77 and 78).
a
etiology despite concomitant mitral valve disease and In the setting of pseudo-AS, the augmented flow results
di
severe pulmonary hypertension with and without normal in only a mild increase in transvalvular gradient and an
EF. Pure rheumatic AS behaves like any other AS except increase in valve area by ≥0.2 cm2.
In
that the issue of paradoxically low-flow–low gradient has As many as 30% of patients with low-flow and low-
not been discussed and described in any detail. gradient AS fail to augment SV by at least 20% with
Calculation of AVA by continuity equation is flow- dobutamine infusion; these patients are denoted as
of
dependent; and in the presence of low flow, one estimates having no contractile reserve.45,46 Such patients have
much smaller AVA due to boundary effects. higher operative mortality.
ty
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Figure 74: Low-gradient and low-flow aortic stenosis with mean gradient of 17 mm Hg and SV of 20 mL/M2
Abbreviations: LVOT, left ventricular outflow tract; AVA, aortic valve area
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Figure 75: Calculated aortic valve area of 0.5 cm2 in a patient with pseudosevere aortic stenosis (AS) with a peak transaortic velocity of 212
cm/sec. Continuous-wave Doppler pattern (left panel) shows early systolic peaking suggesting that the AS is not severe
170 Abbreviations: AVA, aortic valve area; AV, atrioventricular; LVOT, left ventricular outflow tract; SV, stroke volume; EF, ejection fraction
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Figure 76: Calculated aortic valve area of 0.6 cm2 in a 78-year-old female patient with severe aortic stenosis with a mean transaortic gradient
18 cie
of 26 mm Hg. Continuous-wave Doppler pattern (left upper panel) and pulse-wave across left ventricular outflow tract (lower panel) are
shown. Peak transaortic velocity was 3.23 m/sec
Abbreviation: AVA, aortic valve area
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Figure 77: Low flow (stroke volume index - 30 mL/m2) despite Figure 78: Baseline left ventricular outflow tract and transaortic
ar
adequate left ventricular outflow tract diameter velocities and calculated aortic valve area at baseline at heart rate
69/minute in a low-flow low-gradient aortic stenosis patient
C
Abbreviations: AV, atrioventricular; AVA, aortic valve area; LVOT, left

ventricular outflow tract
Majority of patients with low-gradient-low-flow AS Planimetry, when possible, can accurately tell about
have significant valve stenosis. anatomical area which in general is no bigger than 20%
The differentiation between true and pseudo-AS may when compared to the effective orifice area.
be improved by using other noninvasive parameters,
such as the projected valve area at a normal flow rate,
Paradoxical Low-flow AS with Preserved
an echocardiographic method that attempts to control
for the variable augmentation of transaortic flow Ejection Fraction
induced by dobutamine (Figure 79).47 As many as 35% of patients with severe AS (AVA <0.6
There is a good correlation between calcium and cm/m2) and preserved EF (>50%) have paradoxically
severity. Calcified valves usually have severe AS. low flow, defined as a SV index of <35 mL/m2.48
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SECTION Flow chart 1: Low-gradient AS True low-flow low-gradient AS must have an SVI ≤35
mL/M2 and peak transaortic velocity of <4 meter/sec.
3 Mean gradient <30 mm Hg
AVA < 1.0 cm2

A valve area <0.8 cm2 by Doppler represents true AS.
Morphology of the diseased valve must correspond to
the estimated Doppler parameters.
Reduced LVEF Severe MR Preserved LVEF Assessing Combined AS and MS

LV dilated Severe MS Reduced LV cavity
Always use planimetry to get valve area as far as
possible.
Abbreviations: LVEF, left ventricular ejection fraction; LV, left ventricle;
MR, mitral regurgitation; MS, mitral stenosis; AVA, aortic valve area Transmitral gradients are not affected much because
a
of compensatory tachycardia, but the combination
causes low-flow low-gradient AS
di
The combination results in markedly symptomatic
patients with excellent prognosis after intervention
In
The MVA derived by PHT method is unreliable.
ASSESSMENT OF AORTIC REGURGITATION
of
Aortic regurgitation (AR) is a common lesion and is
usually well tolerated. It causes both pressure and volume
ty
overload of the left ventricle. Severity of AR is assessed
both quantitatively and by indirect parameters of severity.
18 cie Volumetric Severity of Aortic Regurgitation
The following principles are applied for quantitation:
20 o
The total forward volume across a regurgitant orifice is
S
Figure 79: At 20 mg/kg/minute dobutamine infusion and heart rate the sum of systemic SV and regurgitant volume (R vol).
of 113/minute. There is 20% increase in stroke distance and 27% Regurgitant volume can be obtained by calculating the
increase in transaortic velocity without any change in aortic valve
difference between the total SV (regurgitant valve) and
al
area suggesting that it is true severe aortic stenosis despite a mean

gradient of 24 mm Hg at rest systemic SV (competent valve). R Vol = SV regurgitant
Abbreviations: AV, atrioventricular; AVA, aortic valve area; LVOT, left valve − SV competent valve.
ic
ventricular outflow tract In AR, the regurgitant volume corresponds to the
difference between the LVOT SV (total) and the mitral

og
The mechanism of the paradoxically low flow in the inflow volume (competent valve) (Figure 80).
face of preserved EF likely relates to high afterload, In both, effective regurgitant area is calculated as
ol
and the reduced SV in this setting is an early marker of R Vol divided by time-velocity integral (TVI) of the
intrinsic myocardial dysfunction. regurgitant jet velocity recorded by continuous-wave
di
Such cases can be identified by small LV cavity with Doppler (EROA = R Vol/TVI regurgitant jet).
marked hypertrophy. Regurgitant fraction (RF) is expressed as regurgitant
ar
Paradoxical low-low AS has variable prognosis. flow divided by total flow.

The 3D TTE or TEE planimetry of AVA may better Regurgitant volume can be obtained by combined
define the severity of AS in these patients. Doppler and 2D/3D volumetry of the LV.
C
Before a diagnosis of paradoxically low-flow low- In the presence of multivalvular regurgitation, it is not
gradient severe AS is made, the following conditions must possible to use this simple method.
be satisfied:
The patient should have normal or near normal LV
Color Flow Doppler Evaluation of Aortic
systolic function.
Aortic annulus size should be checked multiple
Regurgitation
times and even by 3D echocardiography. In an adult, It is a semiquantitative method to assess AR.
aortic annulus diameter <21 mm must be seen with Parasternal long and short axis views are used because
suspicion.The 3D cross-sectional area of the LVOT for of better axial resolution.
estimation of SV or 3D echocardiographic SV may be a Color jet area and length do not correlate with severity
better numerator. of AR and should not be used.
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Figure 80: Concept of aortic regurgitant volume. Systemic stroke vol- Figure 81: Parasternal long axis view in a patient with mitral
ume can be estimated at mitral orifice and total stroke volume in left stenosis and aortic regurgitation (AR). Note the central jet of AR
ventricular outflow tract. The difference provides the regurgitant volume
Abbreviations: Ao, aorta; LA, left atrium; LV, left ventricle
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Figure 83: Aortic regurgitation (AR) jet height is nearly two-thirds

ic
of the left ventricular outflow tract height indicating severe AR

Figure 82: Eccentric aortic regurgitation jet due to perforation
og
(arrow). The presence of diastolic mitral regurgitation indicates

markedly elevated left ventricular diastolic pressure
ol
Central jets are found in RHD (Figure 81), while eccen-

tric jets occur in prolapse or perforation (Figure 82).
di
Height of AR jet/LVOT height can be used as criterion

for judging severity of AR.49 A ratio >0.65 indicates
ar
severe AR (Figure 83).

Measuring jet height in LVOT is different from
measuring vena contracta. Jet height is measured in
C
divergence zone when jet is expanding. Jet expansion

may be erratic in eccentric flow jets.
Aortic Regurgitation Assessment

by Vena Contracta
For AR, imaging of the vena contracta—minimum width Figure 84: Arrows point to the vena contracta with convergence in
aorta and divergence in the left ventricular outflow tract
of the regurgitant jet as it traverses the aortic orifice
or the effective regurgitant area—is obtained from the
parasternal long-axis view (Figure 84).50 A narrow color sector scan coupled with the zoom mode
To properly identify the vena contracta, the three is recommended to improve measurement accuracy.
components of the regurgitant jet should be visualized Vena contracta represents the smallest flow diameter
(convergence zone, vena contracta, and divergence at the level of the aortic valve in the LVOT, immediately
zone). below the flow convergence region (Figure 84). 173
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3
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Figure 85: Eccentric jet of severe aortic regurgitation (arrow) in a Figure 86: 3D TTE color flow jet area of aortic regurgitation at its
patient with bicuspid aortic valve narrowest orifice. Note the irregular shape
Abbreviations: LV, left ventricle; LA, left atrium
of
Proximal Isovelocity Surface Area Flow
Convergence Method
ty
The assessment of the flow convergence zone is less often
performed in AR than in MR.
18 cie Imaging of the flow convergence zone is obtained from
the apical three- or five-chamber or parasternal long-

axis or upper right parasternal views (Figure 87).
20 o
The area of interest is zoomed, the sector size is
reduced as narrow as possible to maximize frame rate,

S
and the Nyquist limit is adjusted to obtain a clearly

visible, round, and measurable PISA radius.52
al
The color flow velocity scale is shifted towards the
direction of the jet. The PISA radius is measured from

ic
a stop frame as the distance between the regurgitant

Figure 87: Apical view showing proximal isovelocity surface area
orifice and the first aliasing in early diastole (closest to
(PISA) (arrows) with a hemispheric appearance
og
Abbreviations: LV, left ventricle; Ao, aorta; LA, left atrium the peak of regurgitant velocity).
When imaged from the apical window, the PISA
It provides thus an estimate of the size of the EROA and method significantly underestimates AR severity in the
ol

is smaller than the regurgitant jet width in the LVOT.50 presence of eccentric AR jets. In this situation, imaging
Using a Nyquist limit of 50–60 cm/sec, a VCW of <3 the flow convergence zone from the parasternal long
di

mm correlates with mild AR, whereas a width >6 mm axis improves the accuracy of the PISA method.
For central AR jets, the apical view remains the most
indicates severe AR.
ar
The measurement of the vena contracta is affected by appropriate.

The PISA method has several limitations. First, it is not
several factors as the presence of multiple jets. In this
C
situation, the respective widths of the vena contracta feasible in a significant percentage of patients with AR
are not additive. due to interposition of valve tissue and difficulty in
The concept of vena contracta is based on the correctly identifying the flow convergence zone.
assumption that the regurgitant orifice is almost Nonplanar flow convergence zones that invalidate the
circular. The orifice is, however, often elliptic or hemispheric assumption are potential causes of either
irregular, which changes the width of the vena contracta under- or overestimation of AR severity by the PISA
in different views (Figure 85). method (Figure 88).
The 3D color Doppler echo has been shown to be a Grading of the severity of AR classifies regurgitation
useful tool in the visualization of the actual shape of as:53

2
the regurgitant orifice and could be used to measure — Mild: EROA <10 mm and regurgitant volume <30
the vena contracta.51 With 3D echo, an EROA <20 mm2 mL

2
and an EROA >60 mm2 have been proposed to define — Moderate: EROA 10–29 mm and regurgitant
mild AR and severe AR, respectively (Figure 86). volume 30–59 mL

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Figure 88: TEE long axis view showing aortic regurgitation jet Figure 89: Color Doppler flow reversal in descending thoracic aorta
through eccentric orifice. Vena contracta is small but PISA is large Abbreviations: PA, pulmonary artery; LCCA, left common carotid
Abbreviations: LA, left atrium; Ao, aorta; RPA, right pulmonary artery artery; LSCA, left subclavian artery
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Figure 90: Pandiastolic flow reversal just below the left subclavian Figure 91: Pulse-wave Doppler interrogation of the descending
og
artery by pulse-wave Doppler. The late rise in diastolic velocity is thoracic aorta showing an end-diastolic velocity of 60 cm/sec in a
due to change in effective regurgitant orifice area pattern of pandiastolic flow reversal
ol
This can be further subdivided into mild-to- With milder degrees of regurgitation, there is a brief
moderate (EROA 10–19 mm2) and moderate-to- reversal of flow limited to early diastole. As the degree
di
severe (EROA 20–29 mm2) of the regurgitation increases, the duration and the
— Severe. An EROA ≥30 mm2 or a regurgitant volume velocity of the reversal flow increases.53
ar
of ≥60 mL indicates severe AR. It becomes sustained throughout diastole at velocities

exceeding 20 cm/sec in severe AR (Figure 91).54
Significant holodiastolic reversal in the abdominal
C
Diastolic Flow Reversal in the Descending aorta is also a sensitive sign of severe AR (Figure 92).
Aorta and Severity of Aortic Regurgitation However, in the case of reduced aortic compliance
The AR can lead to diastolic flow reversal in the aorta (advancing age) or in the presence of increased heart
(Figures 89 and 90) which can be assessed by several rate, the duration and velocity of flow reversal may be
Doppler techniques. increased.
The flow reversal is best imaged in the upper descending In severe acute AR, diastolic velocity decreases quickly
aorta at the aortic isthmus level using a suprasternal with no end-diastolic velocity due to equalization of
view by using pulse-wave Doppler (Figure 90). aortic and LV diastolic pressures.
The sample volume is placed just distal to the origin of
the left subclavican artery and it is aligned as much as Pressure Half-time of Aortic Regurgitation
possible along the major axis of the aorta. Signal
The Doppler filter is decreased to its lowest setting to The rate of deceleration of the diastolic regurgitant jet and
allow detection of low velocities (<10 cm/s). the derived PHT reflect both the degree of regurgitation 175
KG-20.indd 175 02-11-2018 13:53:21

SECTION
3
a
di
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Figure 92: Holodiastolic flow reversal in abdominal aorta Figure 93: Continuous-wave spectra of aortic regurgitation (AR). In
panel B, pressure half-time is much shorter due to severe AR
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Figure 94: Comparing mild aortic regurgitation (AR) (left panel) with Figure 95: Continuous-wave Doppler spectrum in acute aortic
severe AR (right panel). The right panel shows hardly any pressure regurgitation. Pressure half-time is <100 msec and end-diastolic
og
gradient in end-diastole indicating markedly left ventricular forward flow (arrows) is also seen due to left ventricular end-
elevated diastolic pressure diastolic pressure exceeding aortic diastolic pressure
and the ventricular end-diastolic pressures.54 As the degree In acute severe AR, PHT is markedly shortened,
ol

of AR increases, the aortic diastolic pressure decreases and the continuous-wave spectrum of AR may become
the LV end-diastolic pressure increases (Figure 93). triangular and diastolic forward flow may be seen in
di
The late diastolic jet velocity is thus reduced and end-diastole (Figure 95).
ar
the PHT shortened. A PHT of <200 ms is consistent with

severe AR, whereas a value of >500 ms suggests mild AR M-mode Color Flow Propagation Velocity
(Figure 94).
C
Although not commonly used, M-mode color flow

The PHT is dependent upon chamber compliance in
propagation velocity ≥80 cm/sec has been suggested as a
addition to chamber pressures. useful criterion to detect severe AR.55
For a given severity of AR, PHT may be further reduced
Estimation of AR severity is fraught with difficulties
by elevated LV diastolic pressures or prolonged in in patients with mixed valvular lesions, eccentric jets,
patients with increase in peripheral resistance or who and multiple AR jets as seen in bicuspid aortic valve and
have a dilated aorta with increased aortic compliance. paravalvular jets. Despite these limitations, minimum
It tends to normalize with chronic LV adaptation to AR.
information which needs to be provided while reporting
Hence, its sensitivity and specificity in detecting severe on a patient with AR and its severity is shown below:
AR is modest. Possible etiology should be mentioned after studying
Accurate measurement of PHT is also dependent the valve anatomy and function.
on obtaining an adequate spectral envelope of the Severity or grade of AR should be mentioned by an
regurgitant jet. integrated multiparametric approach using jet width,

176
KG-20.indd 176 02-11-2018 13:53:22

vena contracta, PHT, flow reversal in thoracic aorta, with proximal convergence: validation with concomitant CHAPTER
and PISA method whenever feasible. cardiac catheterization. Mayo Clin Proc. 1998;73:929-35.
Eccentricity of jet and its origin should be recorded.
Density of signal is not a useful criterion.
13. Fukuda S, Tran H, Greenberg NL, et al. Geometry of the
proximal isovelocity surface area in mitral regurgitation by
20
3-dimensional color Doppler echocardiography: difference

Size of aortic root and ascending aorta should be
between functional mitral regurgitation and prolapse
reported.
regurgitation. Am Heart J. 2008;155:231-8.
Consequences of AR which need to be reported are LV 14. Pu M, Prior DL, Fan X, et al. Calculation of mitral regurgitant
dimensions and volumes and EF. Global longitudinal orifice area with use of a simplified proximal convergence
strain is fast emerging as a useful prognostic factor. method: initial clinical application. J Am Soc Echocardiogr.
Right heart size, function and pulmonary pressures 2001;14:180-5.
along with indexed left atrial volume should form part 15. Tribouilloy C, Shen WF, Quéré JP, et al. Assessment of
a
of the report. severity of mitral regurgitation by measuring regurgitant jet
di
3DE EORA may become a useful index once the width at its origin with transesophageal Doppler color flow
technique is standardized.56,57 imaging. Circulation. 1992;85:1248-53.
16. Abudiab MM, Chao CJ, Liu S, et al. Quantitation of valve
In
regurgitation severity by three-dimensional vena contracta
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intracardiac hemodynamics for quantification of mitral 42. Kadem L, Rieu R, Dumesnil JG, et al. Flow-dependent
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stenosis. Am J Cardiol. 1987;60:327-32. changes in Doppler-derived aortic valve effective orifice
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31. Schlosshan D, Aggarwal G, Mathur G, et al. Real-time 3D 2009;54:1003-11.
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of rheumatic mitral valve stenosis. J Am Coll Cardiol.
Sugeng L, Weinert L, Lammertin G, et al. Accuracy of

dobutamine echocardiography in distinguishing severe
from nonsevere valvular aortic stenosis in patients with
depressed left ventricular function and low transvalvular
mitral valve area measurements using transthoracic gradients. Am J Cardiol. 1995;75:191.
20 o
rapid freehand 3-dimensional scanning: comparison 46. Monin JL, Monchi M, Gest V, et al. Aortic stenosis with severe
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with noninvasive and invasive measurements. J Am Soc left ventricular dysfunction and low transvalvular pressure
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33. Hatle L, Angelsen B, Tromsdal A. Noninvasive assessment of echocardiography. J Am Coll Cardiol. 2001;37:2101-7.
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35. Flachskampf F, Weyman A , Gillam L , et al. Aortic outcome in patients with paradoxical low-flow, low-
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mitral stenosis: clinical evidence, in-vitro simulation and Cardiovasc Imaging. 2013;6:175-83.
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ar
of mitral valve area by the proximal isovelocity surface area Cardiol. 1987;9:952-9.
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37. Raj BSVF, George P, Jose VJ. Mitral leaflet separation width of the vena contracta: A clinical color Doppler
index-A simple novel index to assess the severity of mitral imaging study. Circulation. 2000;102:558-64.
stenosis. Indian Heart J. 2008;60:563-6. 51. Fang L, Hsiung MC, Miller AP, et al. Assessment of aortic
38. Bonow RO, Carabello BA, Kanu C, et al. ACC/AHA regurgitation by live three-dimensional transthoracic
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on Practice Guidelines (writing committee to revise the Application of the proximal flow convergence method
1998 Guidelines for the Management of Patients with to calculate the effective regurgitant orifice area in aortic
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with the Society of Cardiovascular Anesthesiologists: 53. Tribouilloy C, Avinée P, Shen WF, et al. End-diastolic flow
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Doppler echocardiography: a new predictor of the aortic 56. Zoghbi WA , Enriquez-Sarano M, Foster E, et al. CHAPTER
regurgitant fraction. Br Heart J. 1991;65:37-40. Recommendations for evaluation of the severity of native
54. Samstad SO, Hegrenaes L, Skjaerpe T, et al. Half time
of the diastolic aortoventricular pressure difference by
valvular regurgitation with two-dimensional and Doppler
echocardiography. J Am Soc Echocardiogr. 2003;16:777-802.
20
continuous wave Doppler ultrasound: a measure of the 57. Ewe SH, Delgado V, van der Geest R, et al. Accuracy of three-

severity of AR? Br Heart J. 1989;61:336-43. dimensional versus two-dimensional echocardiography
55. O n b a s i l i O A , Te kt e n T, C e y ha n C , e t a l . A n e w for quantification of aortic regurgitation and validation
echocardiographic method for the assessment of the severity by three-dimensional three-directional velocity-
of aortic regurgitation: color M-mode flow propagation encoded magnetic resonance imaging. Am J Cardiol.
velocity. J Am Soc Echocardiogr. 2002;15:1453-60. 2013;112(4):560-6.
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Nonrheumatic Mitral
CHAPTER 21
Regurgitation
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INTRODUCTION Table 1: Etiology of primary and secondary mitral regurgitation
Mitral regurgitation (MR) is the most common valvular Primary MR (leaflet Mechanisms of MR
In
heart disease. Nonrheumatic MR is a term that abnormality)
encompasses various etiologies such as floppy mitral Myxomatous changes Prolapse, flail, ruptured or elongated
chordae
of
valve, fibroelastic deficiency with chordal rupture,
infective endocarditis, annular calcification, congenital Degenerative changes Calcification, thickening
causes, myocardial ischemia with papillary muscle Infectious Endocarditis , perforations, aneurysm
ty
necrosis and MR secondary to cardiomyopathies. Inflammatory/Infiltrative Collagen vascular disease, radiation,
The MR causes backward flow of blood from the drugs, amyloidosis, sarcoidosis
18 cie
left ventricle (LV) to the left atrium (LA) during systole
because of inadequate coaptation of the mitral leaflets.
The MR may be classified as primary MR and secondary
Congenital Cleft leaflet, dysplasia of the MV,
double orifice MV (DOMV), mitral
arcade
Trauma
MR.
20 o
Secondary MR
Primary MR occurs due to intrinsic disease of one or
(ventricular remodeling)
S
more components of the mitral valve apparatus. Secondary

Ischemic etiology Secondary to coronary artery disease
MR represents the valvular consequences of LV disease
Nonischemic
such as LV remodeling in idiopathic cardiomyopathy
al
cardiomyopathy
or regional wall motion abnormalities in ischemic
Annular dilation Atrial fibrillation, restrictive
cardiomyopathy which cause displacement of the papillary
ic
cardiomyopathy
muscles causing tethering and malcoaptation of the mitral Abbreviations: MR, mitral regurgitation; MV, mitral valve; DOMV,
valve leaflets (Table 1). Secondary MR is also described as
og
double orifice
functional MR and it is called ischemic MR, when it occurs
secondary to coronary artery disease (CAD).1 Carpentier type III MR is seen in mitral leaflets having
ol
reduced leaflet mobility and is subclassified as types

MITRAL VALVE ANATOMY IIIa and IIIb. In type IIIa, decreased leaflet mobility
di
is noted in both systole and diastole, commonly

Mitral Valve Apparatus seen in rheumatic valve disease or secondary to
ar
The mitral valve apparatus has several functional radiation therapy. In type IIIb, MR is due to ventricular
components as shown in Figure 1A.2 remodeling. The leaflet mobility is decreased during
Carpentier has classified the causes of MR into various systole, due to papillary muscle displacement, which
C
types. This is based on the mobility of the mitral valve leads to apical tethering and loss of coaptation of
leaflets (Figure 1B):3 leaflets.
Carpentier’s Classification ETIOLOGY

Carpentier type I MR is seen in mitral leaflets having The various causes and the mechanisms of MR are listed
normal mobility. The MR occurs due to mitral annular in Table 1.4
dilatation or because of a perforated leaflet, secondary Primary Mitral Regurgitation
to endocarditis.
Carpentier type II MR is seen in mitral leaflets having Floppy Mitral Valve/Mitral Valve Prolapse
increased mobility and it occurs secondary to leaflet or Mitral valve prolapse (MVP) is the leading cause of MR, in
chordal pathology such as prolapse or flail leaflet. developed countries and is seen in 2.4% of the population.5
KG-21.indd 180 02-11-2018 13:51:55

CHAPTER
21

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Figures 1A and B: Mitral valve anatomy. (A) Functional components of the mitral valve apparatus;
(B) Carpentier’s classification of mitral regurgitation
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The MVP due to degenerative disease has a spectrum PATHOPHYSIOLOGY
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of lesions that ranges from simple chordal rupture in a
normal valve causing prolapse of an isolated segment, to
multisegment prolapse involving one or both the leaflets
Primary Mitral Regurgitation
Mitral Valve Prolapse Spectrum
having abnormal excess tissue (Carpentier type-II).6 Thus,
20 o
In the MVP spectrum, the fibroelastic deficiency is usually
the spectrum involves:
S
seen in elderly (>60 years). These patients usually have

Fibroelastic deficiency
single chordal rupture and prolapse of an isolated scallop,
Barlow’s disease.
most commonly the P2. The associated MR jet in these
al
patients is usually eccentric and is directed opposite to

Syndromic Mitral Valve Prolapse the prolapsing scallop. Barlow’s disease is usually seen
ic
in younger patients (40-60 years). It is characterized by

The MVP may be associated with inherited connective
abnormal accumulation of mucopolysaccharides with
og
tissue diseases such as Marfan’s syndrome, Ehlers-Danlos

thickening of anterior and/or posterior leaflets and
syndrome, and osteogenesis imperfecta.7
chordae which become redundant and elongated which
may prolapse (Figure 2A) or flail (Figure 2C) and cause
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Secondary Mitral Regurgitation MR (Figure 2B). Tricuspid valve prolapse is seen in up to

40% of patients with MVP, whereas aortic valve prolapse is
di
Ischemic Mitral Regurgitation seen only in 1–2% of patients.

The MR secondary to myocardial infarction was described
ar
in 1968 by Dr George as ‘papillary muscle dysfunction Secondary Mitral Regurgitation

syndrome’. It is now described as ‘ischemic MR’.8 Normally, the closure and position of mitral leaflets is
C
It is a common complication of CAD, develops in determined by the balance between two opposing forces
approximately 50% of patients after an infarction and (Figure 4A):10
moderate regurgitation occurs in >10% of patients. It 1. The closing forces generated by the LV systolic
is associated with excess mortality regardless of the contraction which effectively close the valve
management.9 2. The tethering forces (chordae tendinae and papillary
It can be acute or chronic. The acute ischemic mitral muscles) which restrain the valve leaflets and avoid
regurgitation (IMR) occurs secondary to papillary muscle leaflet prolapse.
infarction and rupture, and patients usually present in Imbalance between these two forces (reduced closing
cardiogenic shock. In chronic IMR, mitral valve leaks forces and increased tethering forces) causes inadequate
secondary to left ventricular global or regional remodeling, closure of the mitral leaflets producing MR (Figures 3
but the leaflets and subvalvular apparatus are normal. and 4B).10
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SECTION
3
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A B C
Figures 2A to C: In a patient with myxomatous MVP. (A) PLAX view with PML prolapse; (B) 4C with PML prolapse and eccentric MR;
of
(C) 5C view with Flail AML
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Figure 3: Pathophysiologic factors and their interactions in

determining ischemic MR10
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Reduced closing forces, due to: orifice area (EROA). Changes in EROA can be seen in the
Reduction in LV contractility systolic phase and are important, more so when seen in
di
Systolic annular dysfunction early and late systole. This occurs as a result of dynamic
LV dyssynchrony. changes in transmitral pressure that causes valve closure.
ar
The EROA can also change, in response to changes in

Increased tethering forces
loading conditions which can cause transient episodes of
Local LV remodeling due to posterior infarction causes
increased MR.
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posterior, lateral, and apical displacement of the

posterior papillary muscle causing increased tethering
CLINICAL FEATURES
of posterior leaflet (Carpenteir type-IIIB) producing an
eccentric MR jet (Figure 4C). Patients with MVP may be asymptomatic. Some complain
Global LV dilatation due to dilated cardiomyopathy
of chest discomfort that is atypical for angina, sudden
leads to spherical LV causing displacement of both shortness of breath (due to chordal rupture and acute
papillary muscles and annular dilatation (Carpenteir MR) and palpitations (due to ventricular and atrial extra
type- IIIB/I) with a central MR jet (Figure 4D). systoles). Atrial fibrillation and atrial flutter can occur in
late stages of MVP.
Auscultatory findings for MVP include a mid-to-late
Dynamic Nature of Ischemic Mitral
systolic click that is followed by a high-pitched systolic
Regurgitation murmur heard at the apex. The murmur becomes
An important feature of IMR is its dynamic nature.10 The holosystolic with advanced MR and S3 may be heard with
degree of MR is usually defined by the effective regurgitant severe MR or associated LV dysfunction.
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CHAPTER
21

A B C
a
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In
of
D E F
Figures 4A to F: Pathophysiology of ischemic mitral regurgitation (MR). (A) Normal mitral leaflet closing position determined by the two
opposing forces, the closing forces and the tethering forces; (B) Imbalance between these two forces (reduced closing forces and increased
ty
tethering forces) causing inadequate closure of the mitral leaflets producing MR; (C) Local left ventricle (LV) pathological remodeling
resulting in increased tethering of posterior leaflet (arrow) with an asymmetric tenting area producing an eccentric MR jet; (D) Global LV
dilatation resulting in spherical LV causing displacement of both papillary muscles, the tenting area is symmetric (arrows) with a central
18 cie
regurgitant jet; Extent of mitral valve distortion; (E) Coaptation depth defined as the distance between leaflet coaptation and mitral annular
plane; (F) t: tenting area defined as the area enclosed between the annular plane and mitral leaflets
20 o
Dynamic Auscultation Mitral valve thickening of 5 mm or more is diagnostic
S
The click and murmur length vary in response to volume and is measured in diastole from the leading edge to the
trailing edge of the thickest area of the midportion of the
and loading changes. An increase in end-diastolic volume
al
leaflet. Doppler echocardiography provides information

which occurs with squatting or decreasing contractility or
about the presence and quantitation of MR and the
increasing afterload (with hand-grip) moves the click later
ic
pulmonary artery pressure. The 2D-transesophageal

in systole and shortens the length of the murmur, whereas
echocardiography (TEE) is done in nondiagnostic cases
a reduction in end-diastolic volume, that occurs with the
og
and for more accurate localization of lesions. The TEE in

Valsalva maneuver or standing, causes the click to occur
IMR helps in grading MR severity by pulsed Doppler flow
earlier and increases the length of the murmur.
patterns of pulmonary veins. With eccentric MR jets, there
Physical examination in IMR is unremarkable. The
ol
may be selective entrainment of one or more pulmonary

regurgitant murmur is usually mild, its intensity is not
veins lying in the path of flow. The TEE is usually needed
related to the severity of regurgitation and the auscultation
di
to demonstrate this phenomenon as only the right upper

may be normal. The presence of underlying IMR is usually
pulmonary vein can be reliably sampled in transthoracic
obtained by imaging.11
ar
imaging.
Three-dimensional echocardiography (3DE) provides
DIAGNOSIS
C
direct anatomic visualization of the MV apparatus and

Electrocardiographic changes in MVP include flattening size, shape, and orientation of MR jet. The 3D-TTE and
or inversion of the T wave in inferior leads with ventricular 3D-TEE is done in complex mitral valve lesions.
ectopy/tachyarrhythmia. Atrial fibrillation is seen in late
stages. QUANTITATION OF PRIMARY AND ISCHEMIC
MITRAL REGURGITATION (TABLE 2)
Two-dimensional (2D) Echocardiography Quantitative parameters, such as the EROA calculated
Two-dimensional transthoracic echocardiography by PISA or Doppler methods, measure the severity of
(2D-TTE) is the modality of choice. In the parasternal or MR independent of loading conditions and also help in
apical long-axis view, a diagnosis of MVP can be made prognostication. Semiquantitative approach using the
when one or both of the leaflets are displaced 2 mm or vena contracta width is useful particularly in the presence
more in systole above a line connecting the annular plane. of eccentric MR.4
183
KG-21.indd 183 02-11-2018 13:52:01

SECTION
Table 2: Left ventricle remodeling and jet characteristics in primary and ischemic mitral regurgitation
3 Cardiac remodeling and extent of mitral valve distortion4

Primary MR Secondary MR
Regional LV dysfunction Global LV dysfunction

LV remodeling Global, if severe chronic MR Primarily inferior wall Global dilation with increased
sphericity
Annulus Dilated, preserved dynamic Mild to no dilation, less dynamic Dilated, flattened, nondynamic
function
Tethering pattern None Asymmetric Symmetric
a
Systolic tenting None Increased Markedly increased
di
Papillary muscle Normal Increased posterior papillary Increased interpapillary muscle distance
distance intervalvular fibrosa distance
In
MR jet direction Eccentric or central eccentric Usually central
Jet characteristics with quantitation of MR4
Qualitative Doppler Mild Moderate Severe
of
Color flow jet area Small, central and narrow jet Variable Large central jet (>40% of LA) or
eccentric wall-hugging jet of variable size
ty
Flow convergence Not visible, transient or small Intermediate in size and duration Large, throughout systole
CWD jet Faint/partial/parabolic Dense but partial or parabolic Holosystolic/dense/triangular
Semiquantitative
VCW (cm) <0.3
18 cie Intermediate ≥0.7
Pulmonary vein flow Systolic dominance Normal or systolic blunting Minimal to no systolic flow/
20 o
systolic flow reversal
S
Mitral inflow A-wave dominant Variable E-wave dominant

Quantitative
al
EROA, 2D PISA (cm2) <0.20 0.20–0.29 0.30–0.39 ≥0.40

Primary MR
ic
Secondary MR <0.20 ≥0.20

RVol (mL) <30 30–44 45–59 ≥60
og
Primary MR
Secondary MR <30 ≥30
ol
RF (%) < 30 30–39 40–49 ≥50

Primary MR
di
Secondary MR < 50 ≥50

Abbreviations: CWD, continuous wave Doppler; VCW, vena contracta width; EROA, effective regurgitant orifice area; PISA, proximal isovelocity
ar
surface area; RF, regurgitation fraction
Mitral Valve Distortion in Ischemic Mitral Left Ventricular Function and Pathological
C
Regurgitation Remodeling (Table 2)

Annular dimension, coaptation depth, and tenting area Evaluate for end-diastolic and end-systolic volumes,
are assessed in long-axis view in the midsystolic phase sphericity index, LV ejection fraction (LVEF), distribution
of the cardiac cycle. The coaptation depth (Figure 4E) is of regional wall motion abnormalities, interpapillary
defined as the distance between leaflet coaptation and muscle distance, and LV dyssynchrony.
mitral annular plane. The tenting area (Figure 4F) is
defined as the area enclosed between the line drawn at
the annular plane and the mitral leaflets. It has a direct
Exercise Echocardiography
relation to the severity of MR, severity of LV dysfunction In patients who are sedentary or have equivocal symptoms,
and remodeling. Tenting volume derived from real-time exercise may unmask the underlying symptoms and
3-dimensional echocardiography is a better index of MV also establish the functional capacity in these patients.
remodeling than tenting area. Absence of usual increase in LVEF with exercise predicts
184
KG-21.indd 184 02-11-2018 13:52:01

worse postoperative LV function in primary MR. Increased Chronic Mitral Regurgitation CHAPTER
PA pressure during exercise (≥60 mm Hg) is important in
21
Treatment with vasodilators is useful in the acute
the management of asymptomatic severe primary MR.1,12 decompensated phase, and as a palliative measure in
The dynamic nature of IMR can be demonstrated by
patients with advanced disease who are inoperable.

an exercise Doppler echocardiogram. An increase in MR
Patients with heart failure (especially functional
and systolic pulmonary artery pressure are seen in 30%
MR) should be treated with one or more of the following
of patients. In some patients with moderate/severe MR
agents: angiotensin-converting enzyme (ACE) inhibitors
at rest, a decrease in EROA is noted with exercise. This
or angiotensin receptor blocker (ARB), beta-blockers,
increase or decrease in severity of MR is due to changes
spironolactone, ivabradine, sacubitril/valsartan, diuretics,
in LV remodeling and valvular deformation along with
and nitrates. Several of these agents may progressively
changes in LV and papillary muscle synchronicity. In
a
produce LV reverse remodeling and decrease in severity
patients with IMR, an increase in EROA (≥13 mm2) with
of MR.
di
exercise is associated with adverse outcomes.1,12
Cardiac resynchronization therapy: It may produce LV
In
Cardiac MRI remodeling and can reduce functional MR.
It should be considered in patients with functional
The cardiac magnetic resonance (CMR) imaging is
class III–IV symptoms despite optimization of medical
indicated in the quantitation of MR severity, when
of
therapy, reduced LV ejection fraction, and QRS duration
assessment by echocardiography is unsatisfactory or when
>120 ms.
there is a discrepancy between MR severity and clinical
The atrial fibrillation (AF) in MV disease predisposes to
findings and also in evaluation of obese patients. It can
ty
high risk of thromboembolism. Therefore, anticoagulation
provide incremental information about the mechanism of
therapy should be considered along with rate versus
MR and myocardial viability, which may have implications
18 cie
for surgical intervention and also provides quantitative
evaluation of chamber size, regurgitation volume and
rhythm optimization.
Percutaneous/Surgical Management
fraction.
20 o
The definitive treatment for severe or symptomatic MV
TREATMENT disease is surgery. The timing is vital to ensure good LV
S
function and prognostic improvement. Guidelines for

Medical Management management of mitral valve disease are defined by various
al
Acute Mitral Regurgitation stages of MR (Table 3). Intervention is recommended in

the following circumstances:13
ic
Patients with acute MR are usually hemodynamically

unstable and require urgent intervention. Nitrates,
Class-I Indications (MV Replacement)
og
diuretics, and sodium nitroprusside can be used to

stabilize them before surgery. Vasopressors and intra- Severe primary MR (Stage-D)
arterial aortic counter pulsation (IABP) may also be Symptomatic MR with ejection fraction (EF) >30%
ol
required in patients presenting with cardiogenic shock. (Stage-D)

di
Table 3: Stages of chronic mitral regurgitation13

Primary MR
ar
Grade A B C D
Definition At risk of MR Progressive MR Asymptomatic severe MR Symptomatic
C
C1: LVEF >60% and LVESD <40 mm severe MR

C2: LVEF ≤60% and LVESD ≥40 mm
Symptoms None z Decreased exercise tolerance
z Exertional dyspnea
Secondary MR (IMR)
Grade A B C D
Definition At risk of MR Progressive MR Asymptomatic Symptomatic
severe MR severe MR
Symptoms Symptoms secondary to myocardial ischemia or heart failure may be present z Symptoms of heart failure
(usually respond to coronary revascularization and appropriate medical (usually persist even after coronary
therapy) revascularization and optimization
of medical therapy)
z Decreased exercise tolerance
z Exertional dyspnea
185
KG-21.indd 185 02-11-2018 13:52:01

SECTION Symptomatic severe secondary MR (functional) with annulus (MA). The Cardioband device, Mitralign system,
persistent NYHA class-III to IV symptoms (Stage-D) and Accucinch system have been tested in trials.16,17
3 Asymptomatic MR with EF 30% to ≤60% or LVESD ≥40
mm (Stage-C2)
Percutaneous energy-mediated cinching approach: In this
approach, QuantumCor and ReCor devices are used to
Severe/Moderate MR undergoing CABG

apply heat energy to the MA, thereby causing scarring and
Class IIa Indications (MV Repair) shrinking of the annulus. This approach can also damage
or perforate neighboring cardiac structures.16
Asymptomatic patients with chronic severe primary
MR and preserved LV function (LVEF >60% and LVESD
<40 mm) (stage C1) Indirect Annuloplasty
Asymptomatic MR with preserved LV function and It basically mimics surgical placement of annuloplasty
a
new onset of AF or pulmonary hypertension (>50 mm rings. The device is placed in the coronary sinus to ‘cinch’
di
Hg at rest) (stage C1) the mitral valve leaflets by pulling together the tissue
Isolated MV repair can be considered for chronic just above the mitral annulus to approximate the mitral
In
severe secondary MR with persistent symptoms in leaflets and reduce the severity of MR. The various devices
spite of optimal medical therapy tried include MONARC (EVOLUTION trial), Carillon
In MR, where feasible, mitral valve repair is preferred Mitral Contour System (AMADEUS trial), and Viacor
of
rather than valve replacement. Outcome data for MV Percutaneous Transvenous Mitral Annuloplasty device.
repair are better than that for replacement. The 10-year These devices can cause potential left circumflex artery
event-free survival rate for MV repair is higher than compression.16,17
ty
that of MV replacement.6 If these devices can reduce MR, improve clinical
symptoms, and heart failure readmissions with a lower
TREATMENT IN PRIMARY MITRAL
REGURGITATION
18 cie risk than open surgery, then it will be a major step toward
patient care especially in high-risk patients.
Mitral Valve Repair

20 o
Left Ventricular Remodeling
It includes quadrangular/triangular resection of middle
S
scallop of posterior mitral leaflet (PML), chordal repair, The LV remodeling, reduces the anteroposterior
and ring annuloplasty. Patients with both leaflet prolapse dimension of the LV, which in turn decreases the septal-
and anterior mitral leaflet (AML) prolapse and fibrosed lateral annular distance and moves the LV papillary
al
leaflets are difficult to repair and may need mitral valve muscles closer to the leaflets and thereby reduce tethering
replacement with prosthetic valve.6 and MR. Two devices have been tested. In iCoapsys
ic
Percutaneous mitral repair with the MitraClip system technology pads are placed on both sides of the LV, and a
is approved (Class-IIb)13 for patients with degenerative cord passes through the LV cavity and applies tension on
og
mitral valve disease and who have a prohibitive risk for the MA and basal LV wall. With BACE (Basal Annuloplasty
surgery (EVEREST-2 trial).14 It creates a double MV orifice of the Cardia Externally) device, a silicone band is placed
around the atrioventricular groove, and built-in inflatable
ol
and reduces MR.

chambers are placed on the MA which reshape the MA
TREATMENT IN SECONDARY MITRAL and cause better leaflet coaptation.16
di
REGURGITATION
Valve Leaflet Procedures
ar
Revascularization (Percutaneous/Surgical)
In the COAPT roll-in experience, among high-risk
Patients w ith mild-to-moderate MR respond to
C
symptomatic heart failure patients with severe secondary

revascularization and appropriate medical therapy. In
MR, the MitraClip safely reduced MR and improved
patients with significant MR, surgical revascularization is
symptoms and quality of life through 2 years.18
associated with improved long-term event-free survival,
when compared to percutaneous coronary intervention
(PCI). Concomitant mitral annuloplasty should also be Surgical Treatment
considered in such patients.15 It includes:
Mitral valve repair using a restrictive annuloplasty
PERCUTANEOUS TECHNIQUES Mitral valve replacement with preservation of the
subvalvular apparatus.
Annular Modification Techniques
Direct Annuloplasty Mitral Valve Repair
Percutaneous mechanical cinching approach: In this A restrictive annuloplasty is done which addresses only the
186 approach, an attempt is made to directly reshape the mitral annular dilatation and flattening, but only annuloplasty
KG-21.indd 186 02-11-2018 13:52:01

can cause displacement of the posterior annulus anteriorly Systemic Lupus Erythematosus and Mitral CHAPTER
and hence augment posterior leaflet tethering as it Regurgitation26
increases its distance to the papillary muscle. This leads
to the development of recurrent MR (50%) on long-term
Nearly 50% patients have abnormal valves. The MV is 21
mainly affected and predominant functional abnormality

follow-up, with progressive left ventricular remodeling
is regurgitation. Valvular thickening and Libman-Sacks
and poor long-term survival.19,20
vegetations are found. These appear as valve masses
An adjunctive subvalvular procedure dur ing
usually <1 cm with irregular borders with firm attachment
annuloplasty improves the outcomes of repair. It includes
to the MV (on atrial side) and AV (on aortic side). The MR
anterior or posterior leaflet augmentation, papillary
is usually clinically silent. Infrequently, acute immune-
relocation and papillary muscle sling procedures. These
mediated valvulitis or infective endocarditis can cause
techniques have been associated with good early and late
a
cardioembolism and significant regurgitation.
results, with a recurrence/reoperation rate of less than
di
10%.21
Predictors for poor outcome in MV repair include Mitral Annular Calcification
In
coaptation distance of ≥1 cm, tenting area of >2.5–3 cm2, Mitral annular calcification (MAC) is a chronic
posterolateral angle >45 degree, interpapillary muscle degenerative process that can cause MR. It is usually
distance >20 mm, posterior papillary–fibrosa distance >40 seen with advanced age, in female sex, in patients with
of
mm, regional lateral wall motion abnormality, and systolic chronic kidney disease, in conditions that predispose to LV
sphericity index >0.7.11 hypertrophy including hypertension and aortic stenosis,
Several studies suggest that mitral valve repair is and in patients with prior chest irradiation. Assessment
ty
associated with a survival benefit in IMR. However, of mitral valve disease severity is usually challenging
recently the CTSN (Cardiothoracic Surgical Trials Network and may require combined imaging with TTE, TEE, and
replacement.22
18 cie
Investigators) trial has reactivated interest in mitral cardiac CT. Mitral valve replacement is associated with
high operative morbidity and mortality. Treatment with
transcatheter mitral valve implantation (TMVI) is a novel
therapeutic strategy for MAC. However, limitations include
20 o
Transcatheter Mitral Valve Replacement (TMVR)
prosthesis anchoring and stability, paravalvular leaks and
S
It is now an option in patients with prohibitive surgical left ventricular outflow tract (LVOT) obstruction.27
risk. It is associated with good clinical outcomes that
include decreased rehospitalization rates, improved
Submitral Aneurysm
al
functional class and favorable LV remodeling at 1 year of

follow-up.23 Submitral left ventricular aneurysm was described in
ic
1812 by Corvisart. It is seen commonly in African blacks.

They are thought to be true aneurysms caused by a
Other Causes of Primary Mitral Regurgitation
og
congenital defect in the posterior portion of the mitral

Congenital Mitral Regurgitation annulus and may produce symptoms (by causing MR),
Abnormalities in any one of the components of the MV, thromboembolism, compression of the left circumflex
ol
including leaflets, chordal apparatus, and papillary artery leading to ischemia or arrhythmias. Du Toit et al.
muscles, have been identified as mechanisms of congenital have classified the aneurysm into 3 types as—Type I,
di
MR. single localized neck; Type II, multiple necks; and Type
These include isolated anterior and/or posterior cleft III, involvement of the entire posterior mitral annulus.
ar
Treatment includes surgical repair of the aneurysm along

of the MV, dysplasia of the MV, double orifice MV (DOMV),
with mitral valve replacement.28
displacement of the MV of the Ebstein type, mitral arcade,
C
and papillary muscle ischemia or infarction resulting from

limited coronary supply due to anomalous left coronary Infective Endocarditis
artery from pulmonary artery.24 The main goal is to achieve The MVP is associated with increased risk of endocarditis.
a proper valve function. Surgical techniques include:25 It can cause valve perforation or chordal rupture and
MV annuloplasty: In annular dilation, posterior severe acute MR necessitating urgent surgery. Mitral valve
annular plication is done. aneurysm is a rare disorder occurs often in association
Isolated cleft closure with interrupted fine stitches with IE of the aortic valve. Possible mechanisms include
(single or figure-of-eight) with annular plication. regurgitant flow from the aortic valve and spread across
Aberrant orifice closure for DOMV adjacent structures such as the mitral–aortic intervalvular
Leaflet patch augmentation fibrous body. It can cause septic embolization or aneurysm
Chordae shortening or neochordae implantation for rupture. Acute severe MR and hemodynamic deterioration
elongated or ruptured chordae. can follow, necessitating urgent surgery.29
187
KG-21.indd 187 02-11-2018 13:52:01

SECTION Other Causes of Secondary Mitral 9. Smith PK, Puskas JD, Ascheim DD, et al. Surgical Treatment
Regurgitation of Moderate Ischemic Mitral Regurgitation (CSTN
3 Secondary MR without CAD

investigators). N Engl J Med. 2014;371(23):2178-88.
10. Agricola E, Oppizzi M, Pisani M, et al. Ischemic mitral
In dilated cardiomyopathy, annular dilatation with regurgitation: mechanisms and echocardiographic

decreased force and coordination of LV contraction classification. Eur J Echocardiogr. 2008;9(2):207–21.
11. Varma PK, Krishna N, Jose RL, et al. Ischemic mitral
causes MR. In hypertrophic cardiomyopathy, the LVOT
regurgitation. Ann Card Anaesth. 2017:20(4):432-9.
obstruction produces venturi effect and systolic anterior
12. Lung B. Management of ischaemic mitral regurgitation.
motion of MV. Pathological thickening and elongation of
Heart. 2003;89(4):459-64.
the MV is also commonly seen, both of which contribute
13. Nishimura RA, Otto CM, Bonow RO, et al. AHA/ACC
to MR. In restrictive cardiomyopathy secondary to
a
guideline for the management of patients with valvular
amyloidosis, MR is due to primary amyloid deposition in heart disease: A report of the American College of
di
valve. In Loeffler endocarditis, it is due to scarring and Cardiology/American Heart Association Task Force
fibrosis of chordae.30 on Practice Guidelines. J Am Coll Cardiol. 2014;63(22):
In
2438-88.
Prognosis 14. Glower DD, Kar S, Trento A, et al. Percutaneous mitral valve
repair for mitral regurgitation in high-risk patients: results
The outcome of patients with severe MR depends on
of
of the EVEREST II study. J Am Coll Cardiol. 2014;64(2):
symptoms at presentation and LV function. Independent
172-81.
determinants of survival are age, presence of diabetes,
15. Kang DH, Sun BJ, Kim DH, et al. Percutaneous versus
ty
and regurgitant orifice area, which provides a quantitative Surgical Revascularization in Patients With Ischemic Mitral
measure of severity of MR.29 The IMR is an independent Regurgitation. Circulation. 2011;124(suppl):156-62.
18 cie
predictor of cardiovascular death. It is associated with a
three-fold increase in the risk of heart failure. Severe MR
(EROA >20 mm2) and an exercise-induced increase of ≥13
16. Tobis JM, Abudayyeh I. Percutaneous Mitral Valve Repair
Devices beyond Mitra Clip. Cardiac Interventions Today.
2015:28-32.
mm2 of the EROA have worse prognosis.1 17. Kelley C, Lazkani M, Fara J, et al. Percutaneous mitral valve
20 o
repair: A new treatment for mitral regurgitation. Indian
S
REFERENCES Heart J. 2016;68(3):399-404.

18. Mack M, Abraham W, Lindenfeld JA, et al. TCT-138
1. Pierard LA, Carabello BA. Ischaemic mitral regurgitation:
Cardiovascular Outcomes Assessment of Mitra Clip
al
pathophysiology, outcomes and the conundrum of

Therapy in Heart Failure Patients with Functional Mitral
treatment. Eur Heart J. 2010;31(24):2996-3005.
Regurgitation (The COAPT Trial): Baseline Characteristics
ic
2. Enriquez-Sarano M, Freeman WK, Tribouilloy CM, et al.

and Preliminary 2-Year Outcomes of the Roll-In Cohort. J
Functional anatomy of mitral regurgitation: accuracy
Am Coll Cardiol. 2017;70(18):60-1.
og
and outcome implications of transesophageal

19. Mihos CG, Santana O. Mitral valve repair for ischemic
echocardiography. J Am Coll Cardiol. 1999;34(4):1129-36. mitral regurgitation: lessons from the Cardiothoracic
3. Carpentier A . Cardiac valve surger y–the “French Surgical Trials Network randomized study. J Thorac Dis.
ol
Correction”. J Thor Cardiovasc Surg. 1983;86(3):323-37. 2016;8(1):E94-9.

4. Zoghbi WA, Adams D, Bonow RO, et al. Recommendations 20. Kuwahara E, Otsuji Y, Iguro Y, et al. Mechanism of recurrent/
di
f o r No n i n v a s i v e Ev a l u a t i o n o f Na t i v e Va l v u l a r persistent ischemic/functional mitral regurgitation in the

Regurgitation. A Report from the American Society of chronic phase after surgical annuloplasty: importance of
ar
Echocardiography Developed in Collaboration with the augmented posterior leaflet tethering. Circulation. 2006;
Society for Cardiovascular Magnetic Resonance. J Am Soc 114:529-34.
Echocardiogr. 2017;30(4):305-71.
C
21. Mihos CG, Pineda AM, Santana O, et al. Targeting the

5. Freed LA, Levy D, Levine RA, et al. Prevalence and Papillary Muscles in Mitral Valve Repair for Ischemic Mitral
clinical outcome of mitral-valve prolapse. N Engl J Med. Regurgitation. Rev Cardiovasc Med. 2015;16(3):182-8.
1999;341:1-7. 22. Acker MA, Parides MK, Perrault LP, et al. Mitral-valve
6. Adams DH, Rosenhek R, Falk V, et al. Degenerative mitral repair versus replacement for severe ischemic mitral
valve regurgitation: best practice revolution. Eur Heart J. regurgitation. N Engl J Med. 2014;370:23-32.
2010;31(16):1958-67. 23. Lim DS, Reynolds MR, Feldman T, et al. Improved
7. Boudoulas KD, Pitsis AA, Boudoulas H, et al. Floppy Mitral functional status and quality of life in prohibitive surgical
Valve (FMV)—Mitral Valve Prolapse (MVP)-Mitral Valvular risk patients with degenerative mitral regurgitation after
Regurgitation and FMV/MVP Syndrome. Hellenic J Cardiol. trans catheter mitral valve repair. J Am Coll Cardiol. 2014;
2016; 57(2):73-85. 64(2):182-92.
8. Burch GE, De Pasquale NP, Philips JH, et al. The syndrome 24. Séguélaa PE, Houyel L , Acar P, et al. Congenital
of papillary muscle dysfunction. Am Heart J. 1968;75(3): malformations of the mitral valve. Arch Cardiovasc Dis.
399-415. 2011;104:465-79.
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25. Vida VL, Zanotto L, Carrozzini M, et al. Repair Techniques 28. Ruiz D, Domingo P, Canals E, et al. Annular submitral left CHAPTER
for Mitral Valve Insufficiency in Children. Semin Thorac ventricular aneurysm. Eur Heart J. 1992;13(3):424-5.
Cardiovasc Surg Pediatr Card Surg Annu. 2018;21:41-5.
26. Grimaldi A, De Gennaro L,Chiara Vermi A, et al. Cardiac
29. Tomsic A , Li WW, van Paridon M, et al. Infective
Endocarditis of the Aortic Valve with Anterior Mitral Valve
21

Valve Involvement in Systemic Diseases: A Review. Clin Leaflet Aneurysm. Tex Heart Inst J. 2016;43(4):345-9.
Cardiol.2013;36(3):117–24. 30. Foster E, Rao RK. Secondary Mitral Regurgitation. In:
27. Eleid MF, Foley TA. Severe Mitral Annular Calcification. Catherine M. Otto, Robert O Bonow (Eds). Valvular Heart
Multimodality Imaging for Therapeutic Strategies and Disease—A Companion to Braunwald’s Heart Disease.
Interventions. JACC Cardiovasc Imaging. 2016;9(11):1318-37. Philadelphia: Elsevier Saunders; 2014. pp. 297-309.
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KG-21.indd 189 02-11-2018 13:52:01

Bicuspid Aortic Valve in 2018:
CHAPTER 22 What we Must Know?
a
di
INTRODUCTION sinuses in paracrine fashion. The rudimentary arterial valve
Bicuspid aortic valve (BAV) is the most common congenital leaflets and sinuses are formed by creating ‘cavities’ in the
In
anomaly in the general population with a prevalence of fused distal parts of the proximal endocardial cushions.
0.5–2% and a male:female distribution of 3:1. 1 Adverse This cavitation results in a central lumen of each cushion
cardiovascular events related to bicuspid aortic valve pose that separates the three valve leaflets, with the peripheral
of
a huge burden. portion arterializing to form the wall of the supporting valve
sinuses. Valvulogenesis continues with elongation and
EMBRYOLOGY thinning of the endocardial cushions and forms the mature
ty
valve cusps made of three layers – the collagenous fibrosa,
Aortic and pulmonary valve development begins at
proteglycan-rich spongiosa, and elastin-rich ventricularis.
18 cie
approximately 31–35 days in the human embryo, from
the endocardial cushions in the outflow tract and
atrioventricular canal of the primitive heart tube.2 The
ANATOMY
endothelial cells overlying the primitive endocardial Bicuspid aortic valve (BAV) is classified into types 1, 2, and
20 o
cushions invade the cushion matrix and the cushions 3 based on the fusion of the coronary cusps and position of
the raphe.3 Type 1 is fusion of right and left coronary cusps,
S
expand and become cellularized. The conotruncal (superior

and inferior septal) cushions give rise to the right and left type 2 is fusion of right and noncoronary cusps, and type 3
coronary leaflets of the aortic valve and the right and left is fusion of left and noncoronary cusps (Figure 2). It can be
al
cusps of pulmonary valve (Figure 1). The right-posterior further described on whether the cusps are symmetrical,
intercalated cushion develops into the noncoronary cusp whether raphe is present or not and whether the raphe is
ic
of aortic valve and the left-anterior intercalated cushions partially or completely fused. A symmetrical BAV without
develop into the anterior cusp of the pulmonic valve. The raphe is called a ‘true BAV’ (Figure 3).
og
valve leaflets derive their mesenchyme primarily from the In BAV type 1, fusion of right coronary cusp (RCC) and
endocardium. The muscular wall of the proximal outflow left coronary cusp (LCC) results from persistent fusion of
tract contributes to the growth of the valve leaflets and the left and right leaflets which are normally formed by the
ol
di
ar
C
Figure 1: Development of the pulmonary valve with anterior, left and right cusps
and the aortic valve with left, right and non-coronary cusps from the conotruncal cushions
KG-22.indd 190 02-11-2018 13:51:45

CHAPTER
22

a
di
Figure 3: A “true” symmetrical bicuspid valve with no raphe
In
Figure 2: Types of bicuspid aortic valve .Type I has fusion of the right Abbreviations: R = right; L= left
coronary cusp (RCC) and left coronary cusp (LCC), Type II has fusion
of the RCC and non-coronary cusp (NCC) and Type III with fusion of
of
LCC and NCC
Abbreviations: R = right; L= left
ty
superior and inferior septal cushions. In type 2, fusion of
RCC and noncoronary cusp (NCC), and in type 3, fusion
18 cie
of LCC and NCC occurs. These result from fusion of the
posterior aortic interacted disc with either the inferior
(Type 2) or superior (Type 3) septal cushion.
Figure 4: Siever’s type 0 bicuspid aortic valve, with no raphe. The
20 o
Sievers and Schmidtke classification of BAV is used common lateral subtype with right and left cusps and the less
for planning aortic valve repair:4 types 0, 1, and 2. Type common antero-posterior subtype with anterior and posterior cusps
S
0 (no raphe); type 1 (1 raphe); and, type 2 (2 raphes). are shown

This is further divided based on the spatial position of
al
the cusps (type 0) (Figure 4) or raphes (types 1 and 2)

and valve function, graded as predominant insufficiency,
ic
predominant stenosis, balanced insufficiency and

stenosis, or no insufficiency and stenosis.
og
Sievers type 0: There is no raphe with 2 valve cusps (7%).

This is again divided into the more common lateral
ol
subtype with right and left cusps and the less common
anteroposterior subtype with anterior and posterior cusps.
di
The right and left main coronary ostia are closer to each
other in the lateral type and this may complicate aortic
ar
valve repair. Aortic insufficiency in this type is due to focal

Figure 5: Siever’s type 1 bicuspid aortic valve with a single raphe
or generalized valve prolapse. There is less aortic wall
and 2 valve cusps. 3 subtypes are also shown with fusion of the
shear stress in the ascending aorta. right and left coronary cusps, with fusion of the right and non-
C
Sievers type 1: This has a single raphe and 2 valve cusps coronary cusps and the type with fusion of the non-coronary and
left coronary cusps
(88%) and has 3 subtypes (Figure 5). The most common is
fusion of the right and left coronary cusps (71%); the less
between right and noncoronary cusps. The orifice area is
common with fusion of the right and noncoronary cusps restricted from the periphery to the center and most of the
(15%); and the rare type with fusion of the noncoronary patients present with early development of aortic stenosis.
and left coronary cusps (3%). The free edge of the conjoint Ascending aortopathy with dilatation of the convexity of
cusp exceeds that of the nonconjoint cusp, leading to the aorta is more common in this type.
prolapse of the conjoint cusp. Most patients with BAV disease have a left dominant
Sievers type 2: This has 2 raphes and 2 valve cusps and coronary circulation. The left main may be shorter than in
is the rarest of the three (Figure 6). The first raphe is normal in up to 90% of cases, an important consideration
between left and right coronary cusps and the second is for aortic valve surgery.
191
KG-22.indd 191 02-11-2018 13:51:48

SECTION AV. Aortopathy can be reversed by eliminating BAV. The
genetic theory states that aorta has an abnormal wall that
3 is inherited. Here, the aortic wall is vulnerable regardless
of the presence of BAV and favors more aggressive timing
and options of intervention on the aorta. Time-resolved

three-dimensional phase-contrast magnetic resonance
shows an abnormal helical flow in patients with BAV
(mainly ascending aorta) compared with a normal laminar
flow in tricuspid valve subjects. This flow is associated
with high wall shear stress.7 Increased jet eccentricity is
associated with greater aortic growth. Quantification of the
a
hemodynamic contribution to aortopathy could become
di
an ‘imaging biomarker’ for dissection risk-stratification.8
Pathological changes include medial degeneration,
Figure 6: Sievers type 2 bicuspid aortic valve has 2 raphes and 2
In
fragmentation loss of elastic fibers, focal loss of smooth
valve cusps, one raphe between left and right coronary cusps and
muscle cells, and increased proteoglycan deposition.9
the second between right and non-coronary cusps
Abnormal neural-crest cell migration has also been
of
postulated to result in BAV and aortopathy. The following
DYSFUNCTION OF BAV genetic abnormalities have been postulated: NOTCH1 gene
Aortic stenosis (AS) occurs in 75% and aortic regurgitation mutation can disrupt intercellular signaling during aortic
ty
(AR) in 15% of dysfunctional BAV.5 AR is more common valve development. ACTA2 mutation decreases vascular
in valves with tissue redundancy and prolapse, whereas smooth muscle cells α-2 production. The eNOS mutation
18 cie
stenosis is more prominent in valves without redundant
cusp tissue. Stenosis develops more rapidly if the
aortic cusps are asymmetric or in the anteroposterior
leads to abnormal valve and vascular development.
Downregulation of ubiquitin fusion degradation 1-like
gene leads to abnormal development of the outflow
tracts.10 Aortic involvement is characterized by deficiency
20 o
position. The asymmetrical systolic excursion causes
increased strain in systole, high stress in the raphae and of fibrillin 1, which leads to increased metalloproteinase
S
uneven systolic flow patterns. There can also be intrinsic activity with cystic medial necrosis, which results in aortic
morphological stenosis of the valve. These valves are degeneration. The dilatation occurs predominantly in
the ascending aorta in right-left coronary cusp fusion
al
prone for accelerated calcium deposition with the

development of fibrosis which is confined to the raphe and type (Figure 8A) and in the proximal arch in the right-
noncoronary cusp fusion type (Figure 8B).
ic
base of the cusp.

og
ANOMALIES OF AORTA GENETICS

6
Aortopathy is seen in 40% of patients. Complications The BAV is associated with genetic syndromes (Turner’s)
include aortic dilatation, aneurysm, dissection, rupture, and also with coarctation of aorta and hypoplastic left
ol
and death. Serious complications are rare. There are three heart syndrome. Approximately 10% of patients have first-
types of aortic dilatation in BAV1. Type 1 is dilatation of degree relatives with BAV, coarctation of aorta, ventricular
di
tubular ascending aorta primarily along convexity of aorta, septal defects, thoracic aortic aneurysms, and mitral valve
with mild-to-moderate root dilatation (Figure 7A). Type 2 disease.1 Chromosomal (Turner and DiGeorge syndrome)
ar
is arch dilatation with involvement of tubular ascending and Mendelian (NOTCH 1) causes account for a small
aorta, with relative sparing of root (Figure 7B). Type 3 number of BAV cases, but the genetic mechanisms for the
C
is isolated aortic root involvement with normal tubular sporadic cases are yet to be identified.
ascending aorta and arch dimensions (Figure 7C). The For aortopathy, autosomal dominant, X-linked, and
tubular ascending aortic dilatation is the most common familial modes of inheritance have been reported. Aortic
(60–70%), while sinus of Valsalva dilatation occurs in 25% involvement in BAV has been attributed variably to
and is more common in type 1 BAV and in males. Faster mutations in transforming growth factor-beta (TGF-B)
progression of root dilatation is seen in the tubular type, signaling pathway, mutations of NOTCH1, GATA5, FBN1,
whereas more severe AR is seen in the sinus dilatation NKX2-5, MATR3, and hemizygosity of TBX1.3
type. Root dilatation with AR is associated with higher risk
of dissection. NATURAL HISTORY
The heterogeneous clinical manifestations of BAV may
PATHOPHYSIOLOGY OF AORTOPATHY vary from severe AS or AR in a child, to aortic dissection
According to the hemodynamic theory, aortopathy is without significant valvar involvement in an adult to
due to altered hemodynamics generated by an abnormal incidental detection in the elderly. The prevalence of
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KG-22.indd 192 02-11-2018 13:51:49

CHAPTER
22

A B C
a
Figures 7A to C: (A) Dilatation of tubular ascending aorta primarily along convexity of aorta, with mild-to-moderate root dilatation (Type I);
di
(B) Arch dilatation with involvement of tubular ascending aorta, with relative sparing of root (Type II); (C) Isolated aortic-root involvement
with normal tubular ascending aorta and arch dimensions (Type III)
In
The prevalence of aortic dilatation is 56% in patients <30
years and 88% in patients >60 years of age. The prevalence
of
of aortic aneurysms is 20–40% in BAV. Coarctation has
been reported in 1–2% of BAV. Though BAV has 8 times
risk of aortic dissection than general population, the
ty
annual rate of aortic complications in BAV is 0.03% (0.4-
0.5% in those with aortic aneurysms and age >50 years).
18 cie About 50% of aortic dissections less than 40 years of age
is due to Marfan’s syndrome, while that due to BAV is
approximately 9%. Though aortic dilatation progresses
20 o
faster in BAV patients in comparison with tricuspid aortic
A B
S
valve patients with aneurysms, the incidence of aortic

Figures 8A and B: (A) The dilatation occurring predominantly in the dissection is equal in the two groups. Though AVR slows
ascending aorta in right-left coronary cusp fusion type; (B) The figure the progression of aortic dilatation in BAV, it does not
al
shows the dilatation of the proximal arch in the right-non-coronary

totally halt the progression of aortic dilatation or prevent
cusp fusion type
the occurrence of aortic dissection.
ic
Bacterial endocarditis affects approximately 2% of

right-noncoronary cusp fusion is higher in the young and BAV with male predilection and is complicated by abscess
og
is found in some studies, to be associated with accelerated formation more than tricuspid valves.9 However, there is
AS/AR. The presence of raphe is associated with a higher no survival difference noted in endocarditis of BAV and
prevalence of significant valvular dysfunction (AS/AR) trileaflet aortic valve.
ol
and increased rates of aortic valve surgery.11 But any A 25-year follow-up of BAV shows that the natural
particular valve phenotype is not always predictive of the history is similar to the normal population partly due to
di
development of valve dysfunction and the exact molecular the young age at diagnosis. In older post-AVR patients,
mechanism responsible for determining what predisposes survival is similar at 7 years, but it decreases at 15 years
ar
a particular BAV to be dysfunctional is yet to be elucidated. follow-up. Surgery results in 56% relative risk reduction of
Follow-up of asymptomatic patients showed that dissection and mortality.12
C
almost 42% had surgical or medical intervention at 15

years. Only 1 in 50 children had significant valve disease DIAGNOSIS
by adolescence. The AR is present in 47-64% of BAV Clinical findings are usually an ejection systolic murmur
patients with 13–30% having moderate-to-severe AR. heard loudest at the apex.13 There may be signs of AS/
The AR presents in younger patients (mean age 45 years) AR/coarctation of aorta. ECG may be normal or have
compared to AS (mean age 54 years). The AS presents left ventricular hypertrophy (Figure 9). The mainstay
in the fifth or sixth decade, 5–10 years earlier than of diagnosis is transthoracic echocardiography.
degenerative aortic valve disease. The rate of progression Transoesophageal echocardiography may be used in
of stenosis is also faster in BAV than trileaflet valve. Mixed patients with poor windows (Figure 10). The parasternal
AS and AR is uncommon in BAV (1–2%) and has similar short axis view permits direct visualization of the valve
outcomes as isolated AS or AR. Aortic valve replacement cusps. Instead of the normal triangular opening shape,
(AVR) results in similar survival as age-matched controls.12 there is ‘fish-mouth’ appearance, more akin to the mitral
193
KG-22.indd 193 02-11-2018 13:51:51

SECTION
3
a
di
In
of
ty
18 cie
Figure 9: ECG may show various signs of left ventricular hypertrophy
20 o S
al
ic
og
ol
di
ar
Figure 10: Transesopheal echocardiography image showing Figure 11: Aortic root angiogram showing doming of the aortic valve
bicuspid aortic valve in open position
C
valve. This is particularly marked in systole. Visualization INTERVENTION

of other cardiac abnormalities, such as vegetations, Less than 10% of patients will require intervention for
systolic dysfunction, and part of the aortic root, can be progressive AS or AR before the fifth decade of life.14 Options
made. During aortic root injection, the doming valve can are open surgical valvotomy or balloon valvuloplasty, both
be seen and the annulus measured (Figure 11). providing good temporary relief of stenosis.
Aortopathy cannot be fully assessed by echocardio-
graphy. Cardiac MRI and CT have been used to augment BALLOON VALVULOPLASTY
the diagnostic process. MRI will enable views of the valve The balloon valvuloplasty (BV) was first performed in
to be obtained without interference from calcification. It 1984 by Lababidi and colleagues.15 The aim is to relieve
also allows for excellent assessment of the aorta. AS without causing significant AR, and restoring normal
194
KG-22.indd 194 02-11-2018 13:51:54

ventricular function. With improved catheterization Children with a resting peak systolic gradient measured CHAPTER
techniques, BV has little mortality and minimal morbidity at catheter of >50 mm Hg.
and is the intervention of choice in most centers for severe
congenital AS.16
Children with a resting peak systolic gradient
measured at catheter of >40 mm Hg with symptoms of
22

angina or syncope or ischemic ST-T–wave changes on
Access electrocardiography at rest or with exercise.
The gradients recommended are in patients sedated
The classic approach is retrograde from the femoral artery.
during cardiac catheterization. Catheter gradients
Compromise of the femoral artery is a significant concern
in patients under general anesthesia may be lower.
in small kids, up to 61% in infants.17 Carotid approach has High-peak instantaneous gradients of transthoracic
excellent outcomes.18 Other approaches are umbilical echocardiography do not equate to peak-to-peak or
a
artery in newborns with critical AS,19 the axillary artery simultaneous gradients in the catheter laboratory.
approach,20 and the transvenous antegrade approach. 21
di
Class IIb recommendations are for asymptomatic
Transvenous antegrade access avoids femoral artery patients with a catheter-obtained peak systolic gradient
cannulation and offers more stable balloon position and
In
of <50 mm Hg in sedated or anesthetized, if a nonsedated
less inadvertent damage to the aortic valve. Incidence of Doppler study finds the mean valve gradient is >50 mm
postprocedural AR is less.21 But it is technically challenging Hg. Also, BV should be performed irrespective of the
of
and carries a risk of complications, such as cardiac gradient if systolic ventricular dysfunction is present.
perforation during transseptal puncture, left ventricular
wall perforation, and damage to the mitral valve.
Procedure of Balloon Valvuloplasty
ty
Sick newborns need monitoring of central venous and
Balloon Stability arterial pressure as well as urine output. They are electively
18 cie
Maneuvers to maximize balloon stability during balloon
inflation have evolved. Cardiac contractility of the left
ventilated. Prostaglandin infusion is useful to keep
ductus open and maintain systemic perfusion. Babies
ventricle (LV) will push an inflated balloon antegrade in cardiogenic shock need require ionotropic support.
20 o
to aorta, resulting in ineffective inflation of the balloon. Hypoglycemia should not be overlooked. The BV is
S
Excessive balloon motion during inflation may cause valve performed under general anesthesia. Deep sedation may
damage. To prevent this, double balloons were used.22 be considered in older patients undergoing nonemergent
The valve is crossed with two balloons from two separate BV. In neonates, infants, and critically ill patients, a 4F
al
retrograde arterial access sites. The balloon to annulus short sheath is placed at the access site and the valve is
diameter ratio is larger (up to 1.3:1) with this technique crossed with a 0.018-inch floppy-tipped wire advanced
ic
than a single balloon. This permits more aggressive through a 4F Judkins right catheter. Annulus is measured
dilatation without abolishing left ventricular output, thus from preprocedural transthoracic echocardiography. A
og
ensuring balloon stability. Use of two smaller-diameter low-profile Tyshak Mini balloon (NuMEDInc, Hopkinton,
balloons rather than one larger balloon reduces arterial NY, USA) is used to dilate the valve. A balloon 2 cm in
ol
complications. Availability of newer lower-profile balloons length and 1 mm less than the measured annular diameter
has made this irrelevant. is used. Balloon to annulus diameters of >1 leads high
incidence of postprocedural AR. 26 Gradients following
di
Adenosine was used to produce cardiac standstill with

good results.23 But the duration of asystole was long and dilatation may be estimated with a Multitrack Catheter
(NuMEDInc) or a 5F guide in a larger child. Rapid right
ar
variable. Rapid right ventricular pacing is a controlled

method to reduce ventricular stroke volume during ventricular pacing is usually not required in neonates as
balloon inflation.24 Pacing is done at 220 and 240 beats the heart rate is fast and stroke volume small.
C
per minute, reducing systemic blood pressure by 50% In older children, the valve is crossed with a 0.035-inch
during balloon inflation. Pacing of the LV using the guide straight-tipped guide and exchanged for a stiffer 0.035-
wire over which the balloon is advanced has also been inch J-tipped wire kept in the left ventricular apex. Pacing
is done to reduce systolic blood pressure. Aortogram may
described.25
be considered to assess the degree of postvalvuloplasty
AR. A balloon diameter to aortic valve annulus diameter
Indications for Balloon Valvuloplasty ratio of 0.9:1 is recommended. Dilemma may be faced
Class I recommendations for isolated AS are: in deciding to upsize (or not) the balloon with moderate
Critical AS in newborns, may be duct dependent, residual gradients. Increasing the balloon size leads to a
regardless of the gradient across the valve. lower residual gradient and, therefore, longer freedom
Infants and children with left ventricular dysfunction from AVR. This may also result in an increased amount of
(LVD) regardless of the gradient across the valve. AR which would negate the above benefit.
195
KG-22.indd 195 02-11-2018 13:51:54

SECTION Complications of Balloon Valvuloplasty after (BV) and surgical aortic valvotomy (SAV), it was
found that there was no difference between SAV and BV
3
Postprocedural AR
Femoral arterial compromise in hospital mortality or moderate AR at discharge. Also,
Thromboembolic events
there was no difference in long-term survival or freedom
Cardiac arrhythmias including complete heart block

from AVR. There was more reintervention in the BV
Damage to the mitral valve, in antegrade venous
group. First surgery is not curative and these patients
approach still have a reoperation risk as they age, with additional
Perforation of the ventricular myocardium.
comorbidities. The more complex the initial operation
Moderate-to-severe AR is an independent predictor for is, the more challenging the second operation may be,
earlier surgical reintervention following valvuloplasty.27 with an incremental operative risk. This is a more realistic
The incidence of AR is approximately 25%,27 with higher concern than the risk of aortic dissection.35
a
risk in older patients. There are reports of progressive
di
AR over time irrespective of the initial balloon size used SURGICAL AORTIC VALVULOPLASTY
and may be related to valve morphology. 28 Femoral The infant is assessed for a biventricular surgery. Absolute
In
arterial compromise is particularly common in neonates indications for surgical aortic valvuloplasty (SAV) are
and infants. Alternative arterial access has less chances the need for a single ventricle repair and the presence of
of arterial compromise, and may be useful in younger additional defects that require surgical intervention on their
of
infants.20 own merit: small aortic annulus, sub- or supra-valvar AS,
coarctation, etc. A relative indication is dysplastic aortic,
Outcome after Balloon Valvuloplasty with no clear leaflets or commissures. Follow-up over 3
ty
Although excellent gradient relief is obtained after BV, decades of 67 slightly older children, showed that congenital
AS in children can be controlled surgically until adulthood.36
18 cie
reintervention is required with eventual surgical repair or
replacement of the valve. Mean survival free from valve
reintervention at 5 years was 72%. A lower postdilation
Most patients will need eventual aortic valve repair,
replacement, or even cardiac transplantation. Severe
gradient and less postdilation AR leads to longer freedom residual AS/AR, left ventricular or dysfunction are
20 o
from AVR.27 Less than 50% required valve replacement at indications for AVR. This is deferred off as long as possible
S
20 years of follow-up. Lower postdilatation gradient and in children with small annuli, monitoring LV function. This
lower grade of AR were associated with longer freedom ensures an optimal patient-valve match for better valve
from AVR. Even mild postprocedural AR was associated longevity and interval between re-do surgery. Options for
al
with the need for valve replacement. This suggests that AVR are: mechanical prosthetic or bioprosthetic valves,
AR may worsen with time. Based on age at BV, patients Ross procedure and recently, transcutaneous aortic valve
ic
undergoing BV <1 month had a 10-year surgery-free implantation.

og
survival of 59%, whereas those >1 month had 70%

surgery-free survival.29 Another study30 showed balloon INDICATIONS OF SURGERY FOR AORTOPATHY
reinterventions were more common in newborns (16%) In asymptomatic patients with BAV, if the diameter of the
ol
than in those outside the newborn period (10%). This

aortic root or ascending aorta is >5.5 cm, then operative
multicentric study of 1,004 patients showed a surgery-free
intervention to repair or replace the aortic root (sinuses)
di
survival of 70% at 5 years and 50% at 10 years of follow-

or replace the ascending aorta is class I indication, level
up. Patients with functionally bicuspid valves had better
of evidence B.37 Cutoff is reduced to 50 mm in patients
ar
outcomes compared functionally unicuspid, dysplastic,

with a family history of dissection or in whom dilatation
true bicuspid, and true unicuspid valves.31
progression is >5 mm/year. When AVR is done in a BAV
One study evaluated outcomes in neonates undergoing
C
patient, aorta is to be repaired if it measures >45 mm.38

either surgical valvotomy or balloon valvuloplasty for
critical AS.32 Higher residual transvalvar gradients were
present in the surgical group, whereas significant AR was PREGNANCY AND BAV
seen more commonly in balloon valvuloplasty group. Severe AS and/or aortopathy at risk for complications
Time-related survival was 72% at 5 years, similar in both during pregnancy. The BV or SAV can be done during
groups. Freedom from reintervention was 48% at 5 years, pregnancy only when necessary. Women with moderate
with no difference seen between the groups. Results are and severe AS who become symptomatic in the antepartum
similar in older children and adults in spite of a perception period fail to increase LV twist. 39 Pregnancy hastens
that surgery is more appropriate in them.33 Another study indications for surgery postpartum by affecting the
showed that gradient reduction, AR and the need for ability of the LV to adapt to the fixed outflow obstruction.
reintervention were worse for BV.34 In a systematic review Women with BAV and ascending aorta diameter >4.5 cm
and meta-analysis 13 to compare survival in children should be counseled against the high risk of pregnancy.37
196
KG-22.indd 196 02-11-2018 13:51:55

Aortic dilatation is present in less than 10% pregnant a systematic review and meta-analysis. J Am Heart Assoc. CHAPTER
women with BAV, but the rate of progression of aneurysm 2016;5:pii: e003931.
increases during pregnancy.9 14. Roberts WC, Ko JM. Frequency of unicuspid,bicuspid and
tricuspid aortic valves by decade inadults having aortic
22
valve replacement for isolatedaortic stenosis. Circulation.

EXERCISE AND BAV
2005;111:920-5.
Patients with severe AS or AR with left ventricular 15. Lababidi Z, Wu JR, Walls JT. Percutaneous balloonaortic
dilation (left ventricular dimensions >65 mm) should not valvuloplasty: results in 23 patients. Am J Cardiol. 1984;53:
participate in competitive athletics. Those with or without 194-7.
aortic valve disease who have dilated aortic roots (>45 16. Borghi A, Agnoletti G, Valsecchi O, et al. Aortic balloon
mm) are advised only low-intensity competitive sports. dilatation for congenitalstenosis: Report of 90 cases (1986-
98). Heart. 1999;82(6);e10.
a
No restrictions exist for those with BAV with no significant
valve dysfunction or aortopathy (<40 mm).40 17. Rossi RI, Manica JL, Petraco R, et al. Balloon aortic
di
valvuloplasty for congenital aortic stenosis using the femoral
and the carotid artery approach: a 16-yearexperience from
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valve keep eluding us? Cardiol Rev. 2016;24:119-30.
force 3: valvular heart disease. J Am Coll Cardiol. 2005;45:
1334-40.
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CHAPTER 23 Low-gradient Aortic Stenosis
a
di
INTRODUCTION The therapeutic management of AS is essentially
Severe aortic stenosis (AS) is defined as when mean determined by:
In
Stenosis severity
gradient across aortic valve ≥40 mm Hg and the orifice
Patient’s symptomatic status
area ≤1.0 cm2.1,2 As the gradients are a squared function 2
LV function.
of flow, even a minimal decrease of flow across the aortic
of
valve will cause significant reduction in the pressure Low flow is defined in the guidelines as a stroke
gradients in the presence of severe AS. volume index <35 mL/m 2 and cardiac index <3.0 L/
min/m2 is present in up to one-third of patients with AS.
ty
Three main subtypes of LG AS (Low-gradient AS):2
Classical LF-LG AS can undergo low-dose dobutamine
1. Classical [low left ventricular ejection fraction (LVEF)]
stress echocardiography (DSE), whereas multidetector
low-flow, low-gradient (LF-LG) AS
18 cie
2. Paradoxical (preserved LVEF) LF-LG AS
3. Normal flow-LG (NF-LG) AS (Figure 1).
computed tomography (MDCT) calcium scoring of aortic
valve is preferred in those with paradoxical LF-LG or
normal flow (NF)-LG AS.2
Approximately 5–10% of patients with severe AS have
20 o
decreased left ventricular (LV) function leading to low-
TECHNICAL PITFALLS AND
S
flow low-gradient AS.2,3 The survival rate <50% at 3-year

follow-up on medical management, but perioperative
MEASUREMENT ERRORS
Echocardiographic interrogation in various views and
al
surgical risk is also high (6–33%) as compared to 3.2%

for aortic valve replacement (AVR). 4 Around 10–25% proper alignment the continuous-wave Doppler beam
with aortic flow jet to get the mean gradients across the
ic
of patients with severe AS with normal LV function

may exhibit LF-LG falling in the subtype of paradoxical aortic valve. In calcified aortic valve, the area calculation is
more prone for error as compared to mean gradients. The
og
LF-LG AS.2,4
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C
Figure 1: Subtypes of low-gradient aortic stenosis

Abbreviations: AVA, aortic valve area; MG, mean gradient; SVI, stroke volume index; LVEF, left ventricular ejection fraction
KG-23.indd 199 02-11-2018 13:51:37

SECTION AS severity may be overestimated in patients with small Stenosis Severity
body surface area (BSA), if not indexed for BSA.2
3 CLASSICAL (REDUCED LEFT VENTRICULAR
For evaluation of severity of valvular stenosis, DSE has
Class IIa (Level of Evidence: B) in guidelines.6,7
How the DSE protocol for LF-LG AS differs from that
EJECTION FRACTION) LOW-FLOW, LOW-

of CAD:
GRADIENT AORTIC STENOSIS Maximum target dose is lower: 20 µg/kg/min vs.
Definition and Pathophysiology 40 µg/kg/min

Duration of each dose stage is longer: 5–8 min vs 3 min
The low-flow state is due to LV systolic dysfunction, which
to allow stable, steady-state, hemodynamic condition.7
may be related to LV afterload mismatch due to severe
AS or the presence of cardiomyopathy, commonly due to
a
ischemic heart disease. Assessing LV Contractile and/or Flow Reserve
di
‘Classical’ LF-LG AS with LV dysfunction generally has
The term ‘flow reserve’ is used rather than ‘contractile
a dilated LV cavity and shares pathophysiology as well as
reserve’ because several mechanisms other than intrinsic
In
clinical features with heart failure with reduced ejection
myocardial contractility may contribute to the lack of
fraction.2,4
increase of flow across the valve during DSE. Patients
Stroke volume is frequently used as the gradient that
with increase in stroke volume <20% during DSE, or
of
depends on flow per beat. 1,4 Transvalvular flow rate is
dependent on stroke volume as well as duration of LV catheterization have no flow reserve1,4,6 and have higher
ejection, some investigators proposed to define low flow as operative mortality (22–33%) than those with flow reserve
ty
a mean transvalvular flow rate <200 mL/s.2,4 (5–8%) (Figure 2). Around one-third patients with low
The challenge is to distinguish LF-LG AS with low LVEF, LF-LG AS4,6 have no flow reserve and these patients
18 cie
LVEF from pseudosevere AS. In LF-LG true severe AS,
the primary culprit is the diseased valve, and the LV
dysfunction is a secondary or concomitant phenomenon.
have a higher prevalence of underlying multivessel CAD.6
Assessment of LV flow reserve is useful for estimation
of perioperative risk but does not predict recovery of LV
function, improvement in symptomatic class, and late
20 o
Conversely, the predominant factor in pseudosevere AS is
diseased myocardium, and severity of AS is overestimated survival after the surgery.4-6
S
due to incomplete opening of the valve in relation to the It is often impossible to differentiate true vs. pseudo-
LF state.3-5 46–79% of patients with low LVEF, LF-LG AS severe AS by DSE in patients with no significant increase
al
have concomitant coronary artery disease (CAD).3,6 in flow rate (15%) (Figure 3).2
ic
og
ol
di
ar
C
Figure 2: Clinical decision-making process in low left ventricular ejection fraction, low-flow, low gradient severe aortic stenosis
Abbreviations: LVEF, low left ventricular ejection fraction; P, pressure; EOA, effective orifice area; SAVR, surgical aortic valve replacement; CABG,
coronary artery bypass grafting; Rx, prescription; TAVR, transcatheter aortic valve replacement; CT CA, computed tomography coronary
angiography; AS, aortic stenosis; SV, stroke volume
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KG-23.indd 200 02-11-2018 13:51:38

CHAPTER
23

a
di
In
of
ty
Figure 3: Case of classic low-flow, low-gradient as with true-severe stenosis. The aortic valve area projected at proposed flow rate
(250 mL/s) was thus calculated to confirm severity of stenosis
Abbreviations: SV, stroke volume; MG, mean gradient, AVA, aortic valve area
18 cie
The Truly or Pseudo-Severe Aortic Stenosis (TOPAS) Factors associated with increased risk of mortality with
study was done to find out the projected valve area at flow or without AVR in patients with classical LF-LG AS:
20 o
rate of 250 mL/s which correlates better with AS severity New York Heart Association (NYHA) class ≥ III,
S
and underlying myocardial reserve as compared to DSE 6-min walk test distance <320 m
Duke activity score index <20

parameters.5,8
Multivessel CAD
al
The MDCT with modified Agatston method can be

LVEF: <35% at baseline or during DSE
used for assessment of valve calcium score with cut-off
LV longitudinal strain <9% during rest and <10% at DSE
ic
values of ≥1200 AU in females vs. ≥2000 AU in males.2,9

Absence of LV flow reserve
Calcification of aorta, coronary arteries, left ventricular
og
Moderate/severe tricuspid regurgitation

outflow tract (LVOT), and mitral annulus should be
Plasma BNP >550 pg/mL
excluded and the indexed calcium score for the given 3,5 6
Advanced myocardial fibrosis on cardiac MRI.
area of the aortic annulus should be calculated to avoid
ol
mismatch for large or small aortic annuli. Valve calcium

density scores ≥300 AU/cm2 in females and ≥500 AU/ Therapeutic Management
di
cm2 in males correlates with true severe AS.2,9 In patients True-severe AS on DSE [(Stage D2 in American College
with bicuspid valve, where valvular fibrosis contributes to of Cardiology/American Heart Association/(ACC/
ar
stenosis, MDCT may be falsely negative as fibrosis is not AHA) guidelines] should undergo AVR as a class IIa
detected by MDCT. recommendation.1,2 Patients who do not have LV flow
C
reserve on DSE have a class (IIb) for AVR as mortality is

higher and severity of stenosis is intermediate.1
Outcomes and Risk Stratification
Patient prosthesis mismatch is detrimental in patients
With conservative management, half of the patients with LV dysfunction which can be reduced to some extent
survive at 2 years; whereas the 30-day perioperative with transcatheter aortic valve replacement (TAVR).2,10
surgical valve replacement mortality ranges as high as However, additional studies are required as patients with
8–33%.2,3,5,6 Another powerful predictor of mortality in no LV flow reserve as well as those with very low LVEF were
patients with LF-LG AS regardless of treatment or the excluded from the PARTNER-I trial. 11 Palliative balloon
presence and/or absence of flow reserve is plasma brain valvuloplasty can be considered for relieving of symptoms.
natriuretic peptide (BNP) levels >550 pg/mL.1,3 Management of the associated CAD which is more
In LF-LG AS, fibrosis predominantly affects the frequent in these patients should be taken care off.2 The
subendocardial layer, which contains longitudinal fibers, LV dyssynchrony is present in up to two-thirds of patients
and affects longitudinal myocardial shortening.2,4 which further contributes to decline in LV function, 12
201
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SECTION
3
a
di
In
of
Figure 4: Approach to low-gradient aortic stenosis
ty
Abbreviations: AS, aortic stenosis; LF, low flow; LG, low gradient, MG, mean gradient; AVA, aortic valve area; LVEF, left ventricular ejection fraction;
MDCT, multidetector computed tomography; DSE, SAVR, surgical aortic valve replacement, TAVR, transcatheter aortic valve replacement; BAV,
balloon aortic valvuloplasty
18 cie
and should be considered for resynchronization therapy Calculation of valve area must be indexed in patients
20 o
according to current guidelines. with small body size as area of only <0.6 cm2/m2 indicates
severe stenosis.2,4
S
In patients with restrictive physiology, DSE should be

PARADOXICAL (PRESERVED LEFT
avoided. Exercise-stress echocardiography is preferred
VENTRICULAR EJECTION FRACTION) LOW-
al
rather than DSE in asymptomatic patients: (i) to assess

FLOW, LOW-GRADIENT AORTIC STENOSIS symptoms and (ii) to differentiate true vs. pseudo-severe
ic
AS. 14 Morphological assessment of the aortic valve

Definition and Pathophysiology
calcification and valve opening by echocardiography or
og
Paradoxical LF-LG AS is defined as aortic valve area (AVA) MDCT is the preferred approach in these patients.2
<1.0 cm2, indexed AVA <0.6 cm2/m2, mean gradient <40 mm
Hg, LVEF ≥50%, and presence of low flow (stroke volume Outcomes and Risk Stratification
ol
index <35 mL/m2).1,2,4 This was first described in 2007. 6 Prognosis in patients with paradoxical LF-LG AS is better
Pardoxical LF-LG AS and heart failure with preserved than those in classical LF-LG AS but is worse as compared
di
ejection fraction (EF) have a restrictive physiology, where to other forms of AS as those with high gradients or NF-LG
in spite of preserved EF, the LV pump function is reduced. or moderate AS.2,15,16
ar
Both are often associated with older age, systemic

Therapeutic Management
hypertension, female sex, and atrial fibrillation. There
C
is reduced longitudinal shortening in subendocardial The TAVR may be a better alternative to surgical aortic
valve replacement (SAVR) as these patients in PARTNER-I
layer due to advanced fibrosis.3 Other factors which may
Cohort A trial, showed better 1-year outcome with TAVR
contribute to a decrease in LV function and flow across the
but more data is required.2,11
aortic valve in the presence of preserved EF are significant
mitral valve disease (stenosis or regurgitation), high
NORMAL-FLOW, LOW-GRADIENT AORTIC
pulmonary artery (PA) pressure, or right ventricular
STENOSIS
(RV) dysfunction (Figure 1).2,11
Definition and Pathophysiology
Stenosis Severity The NF-LG AS is defined as an AVA <1.0 cm2, indexed AVA
The Doppler velocity index > 0.25 (ratio of LVOT to aortic <0.6 cm2/m2, mean gradient <40 mm Hg, preserved EF
velocity—time integrals) with reduced AVA raises the and normal transvalvular flow, i.e. stroke volume index
suspicion of paradoxical LF-LG AS.2,13 >35 mL/m2 (Figure 1). It is present in 15–40% of patients
202
KG-23.indd 202 02-11-2018 13:51:39

which may be due to discrepancies in guidelines for long-term outcome: a multicenter study using dobutamine CHAPTER
severity of AS.2,15,16 stress hemodynamics. Circulation. 2003;108:319 –24.
7. Pellikka PA , Nagueh SF, E lhendy A A , et al. ASE
recommendations for performance, interpretation
23
Outcomes and Risk Stratification and application of stress echocardiography. J Am Soc

Patients with NF-LG AS generally have less advanced Echocardiogr. 2007;20:1021-41.
disease and better outcomes than patients with severe or 8. Clavel MA, Burwash IG, Mundigler G, et al. Validation
paradoxical AS.2,16 of conventional and simplified methods to calculate
projected valve area at normal flow rate in patients with low
flow, low gradient aortic stenosis: the multicenter TOPAS
Stenosis Severity
(True or Pseudo Severe Aortic Stenosis) study. J Am Soc
The MDCT calcium scoring is the preferred imaging Echocardiogr. 2010;23:380–6.
a
modality in these patients as the transvalvular flow rate is 9. Enriquez-Sarano M, Vahanian A, Messika-Zeitoun D.
di
normal.2,4 Measurement of aortic valve calcification using multislice
computed tomography: correlation with haemodynamic
In
severity of aortic stenosis and clinical implication for
CONCLUSION
patients with low ejection fraction. Heart. 2011;97:721–6.
The low-gradient aortic stenosis includes three main 10. Kulik A, Burwash IG, Kapila V, et al. Long-term outcomes
subtypes : (i) classical (reduced LVEF) LF-LG, (ii)
of
after valve replacement for low-gradient aortic stenosis:
paradoxical (preserved LVEF) LF-LG, and (iii) NF-LG AS. Impact of prosthesis-patient mismatch. Circulation.
The first clinical challenge is to differentiate among the 2006;114(Suppl. 1):I5553-8.
11. Herrmann HC, Pibarot P, Hueter I, et al. Predictors of
ty
various subtypes and accordingly decide regarding the
intervention vs. conservative management (Figure 4). mortality and outcomes of therapy in low flow severe aortic
stenosis: A PARTNER trial analysis. Circulation. 2013;127:
REFERENCES
18 cie 12.
2316-26.
Garnier F, Eicher JC, Jazayeri S, et al. Usefulness and
1. Vahanian A, Alfieri O, Andreotti F, et al. Guidelines on the limitations of contractile reserve evaluation in patients with
20 o
management of valvular heart disease (version 2012): the lowflow, low-gradient aortic stenosis eligible for cardiac
Joint Task Force on the Management of Valvular Heart resynchronization therapy. Eur J Heart Fail. 2014;16:
S
Disease of the European Society of Cardiology (ESC) and 648-54.

the European Association for Cardio-Thoracic Surgery 13. Michelena HI, Margaryan E, Miller FA, et al. Inconsistent
al
(EACTS). Eur Heart J. 2012;33:2451–96. echocardiographic grading of aortic stenosis: is the left
2. Clavel MA, Magne J, Pibarot P. Low-gradient aortic stenosis. ventricular outflow tract important? Heart. 2013;99: 921–31.
14. Clavel MA, Ennezat PV, Marećhaux S, et al. Stress
ic
Eur Heart J. 2016; 37: 2645–57.

3. Connolly HM, Oh JK, Schaff HV, et al. Severe aortic stenosis echocardiography to assess stenosis severity and predict
outcome in patients with paradoxical low-flow, low-
og
with low transvalvular gradient and severe left ventricular

dysfunction. Result of aortic valve replacement in 52 gradient aortic stenosis and preserved LVEF. J Am Coll
patients. Circulation. 2000;101:1940–6. Cardiol Img. 2013;6:175–83.
4. Pibarot P, DVM, Dumesnil JG. Low-flow, low-gradient 15. Lancellotti P, Magne J, Donal E, et al. Clinical outcome in
ol
aortic stenosis with normal and depressed left ventricular asymptomatic severe aortic stenosis. Insights from the new
ejection fraction. JACC. 2012;60(19):1845–53. proposed aortic stenosis grading classification. J Am Coll
di
5. Clavel MA, Fuchs C, Burwash IG, et al. Predictors of Cardiol. 2012;59:235-43.

outcomes in low-flow, low gradient aortic stenosis: 16. Mehrotra P, Jansen K, Flynn AW, et al. Differential left
ar
results of the multicentre TOPAS Study. Circulation. ventricular remodelling and longitudinal function
2008;118:S234–42. distinguishes low flow from normal-flow preserved
6. Monin JL, Quere JP, Monchi M, et al. Low-gradient aortic ejection fraction low-gradient severe aortic stenosis. Eur
C
stenosis: operative risk stratification and predictors for Heart J. 2013;34:1906-14.
203
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Infective Endocarditis:
CHAPTER 24 What is New?
a
di
INTRODUCTION procedures and did not show strong association of IE
Infective endocarditis (IE) is an uncommon infection with invasive dental procedures.7-9 There was very low
In
with an incidence of 3–7 per 100,000 person-years in incidence of IE occurring after dental procedures and
epidemiological surveys. 1-3 Despite earlier diagnosis, hence giving antibiotics to all patients might lead to
antibiotic resistance and also expose the patients to
of
improvements in treatment and earlier surgical
intervention, one year outcome has not changed over 2 a risk of anaphylaxis. Moreover, human trials did not
decades; and, it still remains the fourth most common show efficacy in preventing bacteremia in nearly half the
patients. This data, generated over the last two decades,
ty
infection leading to mortality after sepsis, pneumonia, and
intra-abdominal abscess.4 led to significant changes in guidelines for IE across the
Atlantic by both the American and European cardiology
18 cie
There has been a change in epidemiology of the
organism causing IE and Staphylococcus aureus has
become the most common organism in most of the
societies in 2007–2009.10,11 They unequivocally suggested
that routine use of antibiotics prior to medical, dental,
industrialized countries. The reason for this is believed and surgical procedures is unwarranted, and agreed to
20 o
to be due to increasing incidence of healthcare contact limit the use of IE prophylaxis in selected patients (labeled
S
infections. Also, the clinical characteristics of the patients as ‘high risk’), who are undergoing invasive dental
have changed to increased age and higher incidence procedures involving mucosa and pulp. These patients
of prosthetic valve and device infections rather than were called high risk, because of IE associated with
al
rheumatic heart disease (RHD) in these countries.1,5,6 In unfavorable prognosis and poor response to therapy.10,11
addition to these epidemiological trends, there have been The UK authorities went a step further in 2008, and NICE
ic
multiple new developments in diagnosis, prognosis, and (National Institute of Health and Care Excellence) issued
treatment of this uncommon yet life-threatening infection. a controversial guideline to stop giving prophylaxis for
og
The previous guidelines were based on the experts’ any procedure in any patient.12 The Cardiological Society
opinion; but recently, there have been large studies of India (CSI), in its consensus statement recommends
antibiotic prophylaxis for dental procedures such as
ol
including randomized controlled trials for diagnosis and

management, including advanced imaging techniques. In gingival or periapical (root) procedures with perforation
view of these changing trends, clinical practice needs to of the mucosa; and also for infected gastrointestinal (GI)
di
be precise and target oriented for the benefit of the patient and urogenital tract procedures in patients with prosthetic
and society. Hence, we try to focus on what is new about heart valve IE.
ar
this infection.
IMPACT OF GUIDELINE CHANGE
C
PREVENTION Various country-wide data have shown variable reports

Penicillin, as antibiotic prophylaxis, was tried first after respective guideline publication. In France, a survey
after dental extraction in 1940s and it showed marked across three different time periods from 1991 to 2008
suppression of bacteremia. Based on this, the American showed the incidence of IE remaining same before and
Heart Association (AHA) recommended it to be used after the publication of guidelines, at 32–35 cases per
consistently for IE prophylaxis in patients of RHD and million population.13 Nearly similar data was published
congenital heart disease (CHD) in the 50s. These guidelines from the Rochester Epidemiology Project, which actually
were in force for next 50 years without any significant showed a fall of incidence from 3.6 per 100,000 person-
change with added stress to maintain good oral hygiene. years from 1999–2002 to 1.5 per 100,000 person-years in
Later, a series of reports revealed that routine daily 2011–2013.14 Similar data was published by the Canadian
activities, such as brushing, also lead to transient population surveys.15 In the UK, a very recent retrospective
bacteremia which is much higher than during dental analysis of hospital records showed a significant 80%
KG-24.indd 204 02-11-2018 13:51:17

reduction in prescription for prophylaxis of IE. Along with in cases of hospital-acquired or healthcare-related CHAPTER
this, there was a significant rise in cases of IE as per final infections and addition of new category of patients who
diagnosis in case records, though no change in mortality.16
During 2014 to 2017, the American College of
receive prosthetic material [cardiac implantable electronic
device (CIED, transcatheter aortic valve replacement
24

Cardiology (ACC)/American Heart Association (AHA) and (TAVR) (TAVR)].21,22 Bacteriology has also changed and
the European Society of Cardiology (ESC) streamlined S. aureus is the causative organism in nearly 30% cases.23
their guidelines and a pragmatic approach has led to a Expectedly, in-hospital mortality in these patients is also
very similar statement.17,18 They have identified high-risk very high as compared to community-acquired IE.21
patients who should receive antibiotic prophylaxis if Preventing hospital-acquired infection is, therefore,
dental procedure involves manipulation of gingival area or the first step in preventing IE in patients admitted for
periapical region or mucosa of oral cavity. Both have given health care. High-risk patients may be segregated and a few
a
them a class IIA indication. simple precautions, such as general antiseptic precautions
di
taken by attending health care providers24,25 and avoiding
They can be summarized as below:
multiple catheterizations and venous cannulations, have
Patients with a prosthetic valve or with prosthetic
In
shown marked reduction in bacteremia.26,27
material used for cardiac valve repair. This also
High propensity of IE for prosthetic material has led
applies to transcatheter-implanted prostheses and
researchers to look for barriers for bacterial adhesions
homografts.
of
Patients with previous IE.
on its surface.28 However, most of these have not resulted
Patients with untreated cyanotic CHD and those
in clinical benefit. An antibacterial coating of silver
compound on sewing ring of prosthetic valve (St Jude),
with CHD who have postoperative palliative shunts,
ty
did not translate in to expected clinical benefit and was
conduits, or other prostheses. After surgical repair with
associated with higher risk of valve thrombosis and
no residual defects, prophylaxis for the first six months
18 cie
after the procedure until endothelialization of the
prosthetic material has occurred.
paravalvular leak, leading to product recall within a few
years.29,30 There has been limited success in development
of a vaccine against Staphylococcus (5-component
Postcardiac transplant with valve regurgitation
vaccine) in animal model,31 although two vaccines tested
20 o
(recommended by ACC/AHA but not by ES C
in humans did not demonstrate benefit in clinical trials.32,33
guidelines).
S
It is interesting to note that ACC/AHA-focused update

in 2017 did not change any indication as compared to DIAGNOSIS
al
their recommendations in 2014, except changing the A quick and secure diagnosis is cornerstone on
level of evidence from B to C. 19 The ESC in their 2015 management of IE for subsequent therapy to reduce
ic
recommendations has already kept the level of evidence as attendant mortality. 34 Currently, modified Duke’s
C. Another interesting feature of NICE guidelines in 2015 is criteria are recommended for clinical diagnosis. The
og
the statement: “Antibiotic prophylaxis against infective Duke’s criteria include clinical, imaging (predominantly
endocarditis is not recommended routinely for people echocardiography), and pathological (blood/tissue
undergoing dental procedures” where word ‘routinely’ is culture) parameters with sensitivity of approximately
ol
added to the guidelines given in 2008.20 80%.35 But these criteria have been shown to have lesser
All national guidelines agree that none of the other sensitivity and specificity in patients with prosthetic valve
di
procedures involving skin, gastrointestinal, genitourinary, IE and pacing lead-associated IE.17

or respiratory tract require prophylaxis. They recommend
ar
proper dental hygiene and early treatment of infections for IMAGING

all other patients. This means that prophylaxis should be
Echocardiography remains cornerstone of imaging as it
C
extended to high-risk patients, but prevention should be

is rapid, straight forward, and diagnostic in many cases.
properly communicated to all patients with heart disease.
Transesophageal echocardiography (TEE) is superior to
However, it must be pointed out that patients who are
transthoracic echocardiography (TTE) in suspected native
immunosuppressed with noncardiac problems, who may
valve endocarditis (NVE) with sensitivity of 90–100%
have even higher risk of both, IE and poor outcome, have
and specificity of 90% for detection of vegetation. The
not been addressed by any of the guidelines.
sensitivity is lower in diagnosing early IE, prosthetic valve
endocarditis and pacemaker lead-induced IE, where the
PREVENTION OF HEALTH echocardiography can be negative or inconclusive in up to
CARE-ASSOCIATED IE 30% of cases.36,37
Epidemiology of IE has undergone a remarkable change in Recent diagnostic radiological investigations, such as
the Western world in the last two decades due to marked computed tomography (CT) scan, magnetice resonance
reduction in cases of RHD and unoperated CHD, increase imaging (MRI), fluorine-18–2-fluoro-2-deoxy-d-glucose
205
KG-24.indd 205 02-11-2018 13:51:17

SECTION positron emission tomography and computed tomography advancement.45 With application of these newer diagnostic
(FDG-PET/CT) and radio-labeled leukocyte single- techniques, newer atypical organisms are increasingly
3 photon emission computerized tomography (SPECT)
if included with Duke’s criteria, can improve diagnostic
being isolated from culture-negative IE. An approach
involving specific antibody-dependent serological tests
yield in these inconclusive cases in reaching a definitive may identify these organisms like Bartonella, Coxiella,
diagnosis in patients who fall in ‘possible’ group on the Mycobacterium, and Legionella. Polymerase chain
basis of Duke’s criteria. The ACC/AHA guidelines in reaction (PCR) technique, both general and specific, can
2014 have included CT imaging as adjunctive imaging also identify atypical organisms and fungi. A targeted
modality when anatomy is not clearly delineated by approach for these organisms in a step-wise manner
echocardiography, as Class II, Level of Evidence: B.17 The may yield positive results in majority of patients labeled
ESC guidelines in 2015 proposed a further modification as culture-negative IE. A recent large series has shown
a
in these criteria for diagnosis.18 They proposed to include: a yield of nearly 60% from a group of 759 consecutive
di
Identification of paravalvular lesion by cardiac CT to
culture-negative IE patients using these newer isolation
be included in major criteria. techniques, and Coxiella and Bartonella were identified to
In
If suspicion of prosthetic valve endocarditis (PVE),
be causative organisms in nearly half of this population.46
FDG-PET/CT should be considered (if implant >3
months) or radiolabeled leukocyte SPECT/CT should
PROGNOSTIC ASSESSMENT
of
be included in major criteria.
The identification of recent infarcts or infectious
In view of high mortality of patients with IE, early
aneurysms by imaging only should be included in recognition of high-risk patients may alter the clinical
ty
minor criteria. course and prognosis. Improved risk-scoring models for
These investigations are useful, but they do not replace IE would help to clarify the decision-making process.
18 cie
the clinical judgment. There are drawbacks, however.
Metabolic imaging cannot discriminate precisely between
sterile inflammation and infection, and is therefore of
A risk score model incorporating individual high-risk
characteristics as suggested by the ESC in 2015 18 is
mentioned in Table 1. Those with more than one of the
questionable use in the early postoperative period.38 False- following characteristics have a very high mortality,
20 o
positive findings for PET/CT imaging have been reported reaching up to 80%. Therefore, an endocarditis team
S
after cardiac surgery due to postpericardiotomy syndrome referral and early surgical intervention should be
and prosthetic valve thrombosis. They have also been considered in them.
Gaca et al.47 identified 13 risk factors to derive an IE
al
reported at the site of an aortic graft. Access to advanced

imaging is often limited, and there is a risk that logistical surgical risk score using the Society of Thoracic Surgeons’
hurdles may delay definitive surgical intervention. 39 database, including emergency status, cardiogenic shock,
ic
Hence, identifying the patient groups, which may have the hemodialysis, and ‘active endocarditis’. Other smaller
cohorts have incorporated more detailed parameters
og
most clinical benefit from advanced imaging, remains to

be established. of infection including valve type and organism. 48,49 The
Prosthesis, Age ≥70, Large Intracardiac Destruction,
ol
MICROBIOLOGY
Table 1: Poor prognostic parameters in patients with infective
Bacteriology of IE has changed recently with emergence
di
endocarditis
of resistant organisms and implanted prosthetic material-
Patient characteristics
related IE. Incidence of infection by virulent strains of
ar
z Old age
Staphylococcus, particularly coagulase negative and z Prosthetic valve
methicillin-resistant strains now reaches 30–40% in recent z Multiple comorbidities

C
z Diabetes
reports, and is associated with extensive tissue damage
and high case fatality reaching up to 50%, particularly Complicated infective endocarditis
z Heart failure
in patients with prosthetic valve IE.40-43 In most of the z Renal failure
series, Streptococcus involving native valves account for z Neurological complications
20–25% of cases and coagulase negative Staphylococcus, z Septic shock
Enterococcus, and Haemophilus, Aggregatibacter, Microorganism

Cardiobacterium hominis, Eikenella corrodens, and z Staphylococcus aureus
z Fungi
Kingella (HACEK) group organisms account for 5-10% z Non-HACEK organisms
each.44
Echocardiographic complications
Despite advances in culture techniques and bacterial
Persistence of bacteremia demonstrated by blood cultures up
isolation, culture-negative IE remains a challenge,
to 48–72 hr postantibiotic use
a c c ou nt i ng f o r 1 0 – 2 0 % . Ma s s s p e c t ro s c o py f o r
Abbreviation: HACEK: Haemophilus, Aggregatibacter, Cardiobacterium
rapid bacterial identification is another diagnostic hominis, Eikenella corrodens, and Kingella
206
KG-24.indd 206 02-11-2018 13:51:17

Staphylococcus, Urgent Surgery, Sex (Female) (PALSUSE) and inhibited by minimal concentration of specific CHAPTER
score includes age ≥70 years, substantial intracardiac antibiotics in culture, have shown to achieve a cure
destruction, staphylococcal infection, urgent surgery,
female sex, and European System for Cardiac Operative
with shorter duration of specific antibiotic therapy
given for two weeks.54,55 However, a minority of patients
24

Risk Evaluation (EuroSCORE) >10 as predictors of in- may be suitable for such therapy. Patients who have
hospital mortality, with in-hospital mortality ranging from undergone surgical intervention may be offered a
0% in patients with a score of 0–45% in patients with a shorter course of antibiotic therapy, in whom there is
score >3.49 a documented culture conversion to negativity after
surgery.56,57
Oral therap y : Oral antibiotic therapy w ith a
MANAGEMENT
combination of rifampicin and ciprofloxacin in
a
Optimal management of IE may require a multidisciplinary the right-sided IE caused by methicillin-sensitive
approach involving the physician, surgeon, infectious Staphylococcus of native valve has shown excellent
di
disease expert, anesthetist, nephrologist, neurologist, results in intravenous drug abusers.58 An approach of
and cardiologist. A recent approach of constituting the initial intravenous, followed by oral antibiotic therapy
In
‘IE Team’ on the lines of ‘Heart Team’ of CAD may lead was tested in randomized Partial Oral Treatment of
to quick interfaculty consultation and rapid initiation of Endocarditis (POET) trial, which enrolled patients
definitive therapy. Recent reports have shown mortality with gram-positive (Streptococcus, Staphylococcus,
of
reduction as high as 50% as compared to historical and Enterococcus) IE to receive initial intravenous
controls over a period of 1–3 years in observational studies, antibiotic therapy for 10 days followed by oral therapy
utilizing multidisciplinary approach. 50,51 There may be vs. continued intravenous therapy with a composite
ty
some drawbacks of this specialized approach such as loss end-point of death, embolism, and recurrence of
of local expertise or transfer delays associated with referral IE.59 A switch over to oral therapy was non-inferior to
18 cie
to such center.38 A comprehensive study is required to
assess the impact of such an approach on mortality and
continued intravenous therapy.
Outpatient parenteral antibiotic therapy (OPAT):
cure rates particularly in complicated cases. In an attempt to reduce hospital stay, initial in-
20 o
hospital intravenous therapy followed by out-patient
S
or home-based intravenous therapy under strict

ANTIMICROBIAL THERAPY
medical/paramedical supervision may be offered
Bacterial Resistance to selected patients who have exhibited excellent
al
clinical response, have shown rapid culture negativity,

Unlike other systemic infections, antibiotic therapy of
and are not having heart failure, large vegetation,
IE is fraught with many problems. Antibiotic resistance,
ic
annular abscess, conduction abnormality, or renal

longer duration of therapy, prolonged hospital stay,
derangement.60-62
og
and antecedent mortality pose daunting challenges.

Antibacterial resistance is due to many factors, most
Specific Recommendations
important being development of biofilm by bacteria,
The recommendations for the use of antibiotics have
ol
particularly coagulase-negative Staphylococcus, hindering

the bacterial penetration.52 Investigative approaches to remained the same, but a few considerations should be
kept in mind:
di
break this barrier by pretreating implants with antibiotics

Rifampicin should be used only in foreign body
or chemicals, such as silver compounds, has not been
infection, such as PVE, after 3–5 days of antibiotic use
ar
proven effective in human trials despite showing promising

results in experimental laboratory studies. 29,30 A new (i.e. once the bacteremia has cleared). Rifampicin has
approach of a combination of monoclonal antibody-TRLI antagonistic effect with other antibiotics for replicating
C
bacteria and synergistic effect on dormant bacteria in

1068 and daptomycin appears promising and is currently
biofilms which are prevalent in PVE.
being tested in experimental studies.53
Aminoglycoside usage is now not recommended for
staphylococcal native valve IE; because the clinical

Emerging General Trends in Management benefit is not much but causes renal toxicity. If
Intravenous antibiotic therapy for 4–6 weeks in hospital is required for other causes, then it should be given in
standard of care in most patients of IE. Reducing hospital single dosage.
stay is new focus of attention and modalities to achieve this Daptomycin and fosfomycin is recommended
are currently being tested. In general, these approaches for staphylococcal infections and netilmicin for
are restricted to select uncomplicated patients. streptococcal; but due to their limited availability, they
Shorter hospital stay: Patients with infection by are second line. If using daptomycin, then it should be
selected species of Streptococcus or methicillin- given in high dose (>10 mg/kg daily dose) along with
sensitive Staphylococcus, which are highly sensitive other antibiotics for best results.
207
KG-24.indd 207 02-11-2018 13:51:17

SECTION Empirical treatment for both native as well as late negative in up to 30% of patients of CIED-IE (lead
prosthetic valve IE should cover Staphylococcus, involvement) who have received antibiotics previously.70
3 Streptococcus and Enterococcus. Early prosthetic valve
IE should cover methicillin-resistant Staphylococcus CONCLUSION
aureus (MRSA) (MRSA), Enterococcus and non-

The innovations of reducing the antibiotic prophylaxis
HACEK organisms.
to only highest risk individuals, inclusion of radiological
investigations, treatment conceptualization and inclusion
SURGICAL INDICATIONS of the cardiologist, microbiologist, surgeons, and infectious
Indications for surgery remain the same as previously disease specialist in decision making are going to improve
with uncontrolled heart failure being one of the most the overall prognosis of IE. The IE has always been difficult
a
common indications, besides uncontrolled infection and to treat and the modifications if included in clinical
complications of IE. Recent update from the ACC/AHA practice can improve the armamentarium against the
di
and ESC are now unanimous in indications for surgical microbes. Carefully designed randomized controlled trials
indications. However, the ESC has indicated timings for (RCTs) can fill knowledge gaps and help in streamlining
In
intervention as emergent (within 24 hr) or urgent (within a the management strategies in patients of IE.
few days) or elective (after 1–2 weeks of antibiotic therapy).
The AHA/ACC defines early surgery as during hospital
REFERENCES
of
admission for treatment of IE. The only randomized trial of
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65. Regueiro A, Linke A, Latib A, et al. Association between survival: insights from the Italian Clinical Service Database. CHAPTER
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outcome.Heart. 1999;81:82-7.

66. Johansen JB, Jørgensen OD, Møller M, et al. Infection
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2011;32:991–8. 70. Cautela J, Alessandrini S, Cammilleri S, et al. Diagnostic
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di
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of
ty
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Prophylaxis for Infective
CHAPTER 25 Endocarditis in India
a
di
INTRODUCTION CARDIAC CONDITIONS AT RISK FOR IE
Infective endocarditis (IE) is a microbial infection involving The initial recommendations for IE prophylaxis included
In
the endothelial lining of intracardiac structures such as a large spectrum of cardiac conditions and invasive
the heart valves. The exact global burden of infective procedures. 3 The recommendations have changed
of
endocarditis is not known. The situation in developing significantly in recent years.
countries like India is difficult to comprehend. The data in The 2007 recommendations of the American Heart
our set-up is largely obtained based on sporadic reporting Association (AHA) reduced the number of cardiac
ty
from some teaching institutions about their experiences. conditions for which prophylaxis is required, compared
About 25! 30% of cases are associated with recent health to the 1997 recommendations.4 They attributed the same
care exposure.1 In the recent years, the epidemiology and
18 cie
clinical characteristics of IE have evolved continuously
but neither the incidence nor the mortality rate of IE has
to lack of clinical trial evidence. They have recommended
IE prophylaxis only for cardiac conditions with highest
risk. The 2015 AHA scientific statement incorporated the
declined significantly in the developing world. With the same in their recommendations.5 In 2015, the European
20 o
increasing use of cardiac devices, such as pacemakers, Society of Cardiology (ESC) guidelines and 2017 ACC/
S
implantable cardioverter! defibrillators (ICD), ventricular AHA updates have also made a similar recommendation
assist devices (VAD), transcatheter valve systems, and with minor modifications. 6,7 The IE prophylaxis is
intravascular stents, device-related infections are reported recommended only for cardiac conditions with highest
al
with increasing frequency. In addition, increasing risk of IE, as enumerated in Table 1.

numbers of vascular interventions, usage of intravascular
ic
catheters for drug delivery, hemodynamic monitoring,

Rationale for the Change in
hemodialysis, intravenous drug abuse, etc. predispose
og
Recommendations4,6,7
to increased occurrence. Despite significant advances in
diagnosis and treatment of IE, 6-month mortality rates IE is much more likely to result from frequent
still approach 25% in the Western world. 1 Treatment is exposure to random bacteremia associated with daily
ol
often complicated by high prevalence of culture-negative activities than from bacteremia caused by a dental,
endocarditis and increase in cases caused by drug- gastrointestinal (GI) tract, or genitourinary (GU) tract
di
resistant organisms. Irrational and indiscriminate use of procedure.

antibiotics further adds to the difficulties in management.
ar
The need for proper, rational use of antibiotic prophylaxis Table 1: Patients with highest risk of developing infective
for prevention of IE is the need of the hour. The same has endocarditis4,6,7
C
to take into account the overall scenario of the developing z Patients with any prosthetic valve, including a transcatheter
countries like India. valve and homografts.
z Patients in whom prosthetic material was used for cardiac valve
repair such as annuloplasty rings and chords.
RATIONALE FOR PROPHYLAXIS AGAINST IE z Patients with a previous episode of infective endocarditis.
The principle of antibiotic prophylaxis for IE was z Patients with congenital heart disease (CHD): (a) any type of
developed on the basis of observational studies and animal cyanotic CHD. (b) Any type of CHD repaired with a prosthetic
models and is aimed at preventing the attachment of material, whether placed surgically or by percutaneous
bacteria onto the endocardium after transient bacteremia techniques, up to 6 months after the procedure or lifelong if
residual shunt or valvular regurgitation remains.
following invasive procedures. This concept has led to
z Cardiac transplant patients who develop valve regurgitation due
the recommendation for antibiotic prophylaxis in a large
to structurally abnormal valve*
number of patients with predisposing cardiac conditions
*Recommended by ACC/AHA but not by ESC due to lack of strong
undergoing a wide range of procedures.2 evidence.
KG-25.indd 212 02-11-2018 13:50:13

Table 2: Conditions with moderate risk for developing infective Table 3: Procedures and relative risk of infective endocarditis CHAPTER
endocarditis for which prophylaxis is no longer recommended by from the Swedish National Register Data13
ESC/AHA/ACC4,6,7
z Acquired valvular heart diseases including rheumatic, stenotic,
Procedure Relative risk 25
Bone marrow puncture 4.3

regurgitant lesions
Bronchoscopy 5.0
z Mitral valve prolapse with leaflet thickening/significant
regurgitation Colonoscopy 2.8
z Hypertrophic cardiomyopathy Gastroscopy 2.5
z Congenital heart disease other than the highest risk category Therapeutic transluminal endoscopies 3.3
(bicuspid aortic valve, ostium primum atrial septal defect, Dialysis 4.3
ventricular septal defect, patent ductus arteriosus, and
coarctation of aorta) Blood transfusions 5.5
a
Therapeutic ENT procedures 2.3
di
Genitourinary and obstetric procedures 3.0
Prophylaxis may prevent an exceedingly small number
of cases of IE, if any, in individuals who undergo a
In
dental, GI tract, or GU tract procedure. mucosa. These would include dental extraction, dental
The risk of antibiotic-associated adverse events (drug scaling, and endodontic procedures.
resistance, anaphylaxis) exceeds the benefit, if any, of They do not recommend routine prophylaxis for the
of
prophylactic antibiotic therapy. following procedures as there is no compelling evidence
Maintenance of optimal oral health and hygiene that bacteremia from these procedures causes IE:4,6
may reduce the incidence of bacteremia from daily Respiratory tract procedures,
ty
activities and is more important than prophylactic Gastrointestinal (GI) or genitourinary (GU) procedures,
antibiotics for a dental procedure to reduce the risk of

IE. 18 cie
There are many cardiac conditions (Table 2) with
including vaginal and cesarean delivery, or
Dermatological or musculoskeletal procedures.
However, antibiotic prophylaxis should be considered

risk of developing IE apart from the highest risk category
in patients undergoing a respiratory, GI, or GU procedure
20 o
for which prophylaxis is no longer recommended by the
to treat an established infection and surgical procedures
above guidelines. However, the risk of IE in these patients
S
involving infected skin or musculoskeletal tissue.6

is not negligible as noted in the following studies.8-12
A recent study from Spain showed a higher incidence A recent Swedish study (observational study) showed
al
of IE with viridians streptococci and cardiac complications that several invasive nondental medical procedures are
in patients with bicuspid aortic valve (BAV) and mitral associated with markedly increased risk for infective
ic
valve prolapse (MVP) when compared to the high risk for endocarditis (Table 3).13 The above study highlights the
IE group.8 fact that risk of IE with nondental invasive procedures
og
An analysis of the United Kingdom (UK) data collected is not negligible and may need reconsideration for
from 2000 to 2013 showed a significant increase in the prophylaxis. This observational study also mentions
incidence of IE in both high-risk and lower-risk patients that there is a higher relative risk of developing IE even
ol
in the UK starting in 2008 after the new guidelines. 9 after diagnostic cardiac procedures including coronary
Though this was partly attributed to confounding factors, angiography and also therapeutic procedures, such as
di
such as increase in patients exposed to health care percutaneous transluminal coronary angioplasty (PTCA),
and hospitalization, the increase in IE after the newer coronary artery bypass grafting (CABG), although the
ar
recommendations cannot be ignored. cause-and-effect relation could not be established.

The spectrum of IE differs in India from the Western Though the study included patients at high risk for IE
and others, it is not very clear whether the risk of IE was
C
world, where the patients affected in India are younger and

the rheumatic heart disease is a common predisposing increased significantly in patients without predisposing
condition for IE.10-12 cardiac conditions. However, these observations may
Given the spectrum of IE and the young productive not be sufficient enough to expand the indication for
population being affected in a developing nation like prophylaxis. Nevertheless, they certainly make us think
India, it appears reasonable to recommend IE prophylaxis about stricter adoption of aseptic practices during cardiac
for patients at moderate risk of developing IE as mentioned procedures, infection control measures, and systematic
in Table 2. approaches to reduce health care-associated bacteremia.
Recommended Procedures before Prophylaxis Prophylaxis before Cardiac Catheterization

The ESC and AHA recommend antibiotic prophylaxis for and Therapeutic Cardiac Procedures
dental procedures requiring manipulation of the gingival Cardiac procedures both percutaneous and surgical have
or periapical region of the teeth or perforation of the oral been shown to be associated with increased risk of IE. 213
KG-25.indd 213 02-11-2018 13:50:18

SECTION The ESC guidelines6 recommend antibiotic prophylaxis developing IE which are known to significantly reduce the
to prevent local and systemic infections before the risk of developing IE (Table 4).
3 following cardiac procedures:
Class I: Pacemaker, implantable cardioverter-
Antibiotic Regimens for IE Prophylaxis4,6
defibrillator (ICD) The main targets of antibiotic regimens recommended

Class IIa: Patients undergoing surgical or transcatheter
are oral streptococci. The antibiotics recommended for IE
implantation of a prosthetic valve, intravascular prevention have remained similar over the years (Table 5).
prosthetic, or other foreign material. Patients undergoing procedure to treat established
Patients undergoing percutaneous valvuloplasties i n f e c t i o n s h o u l d re c e i v e a g e nt s a c t i v e a ga i n s t
(aortic, mitral, and pulmonary) are also at risk of Staphylococcus for respiratory procedures, enterococci
developing IE. The risk could be more when there is
a
(i.e. ampicillin, amoxicillin, or vancomycin) for GI and GU
reuse of procedural hardware. Hence, it is reasonable procedures. For infected skin (including oral abscess) and
di
to consider IE prophylaxis in patients undergoing these musculoskeletal tissue, the agent should be active against
percutaneous cardiac procedures. The antibiotic effective Staphylococcus and beta-hemolytic streptococci.6
In
against Staphylococcus should be considered in these
settings (Cefazolin). SUMMARY
of
The recommendations and studies for IE prophylaxis
Nonspecific Prevention Measures have mostly been from the Western world. In developing
There are many nonspecific prevention measures to countries, widening the coverage to moderate risk patients
ty
be followed in patients with moderate and high risk of and nondental invasive procedures should be considered
z
18 cie
Table 4: Nonspecific prevention measures to be followed in high-risk and intermediate-risk patients6
Strict dental and cutaneous hygiene. Dental follow-up should be performed twice a year in high-risk patients and yearly in the others.
20 o
z Disinfection of wounds.
Eradication or decrease of chronic bacterial carriage: skin, urine.
S
z
z Curative antibiotics for any focus of bacterial infection.

z No self-medication with antibiotics.
al
z Strict infection control measures for any at-risk procedure.

z Discourage piercing and tattooing.
ic
z Limit the use of infusion catheters and invasive procedure when possible. Favor peripheral over central catheters, and systematic
replacement of the peripheral catheter every 3–4 days.
og
Table 5: Recommended antibiotic prophylaxis4,6,7

ol
Situation Antibiotic Single-dose 30–60 minutes before procedure

di
Adults Children
No allergy to penicillin or ampicillin Amoxicillin or Ampicillin 2 g orally or IV 50 mg/kg orally or IV
ar
Cephalexin or 2 g IV 50 mg/kg IV
Cefazolin or 1 g IV 50 mg/kg IV
C
Ceftriaxone 1 g IV 50 mg/kg IV
Cephalosporins should not be used in patients with anaphylaxis, angioedema, or urticaria after
intake of penicillin or ampicillin due to cross-sensitivity.
Allergy to penicillin or ampicillin Clindamycin 600 mg orally or IV 20 mg/kg orally or IV
Pacemaker, implantable Antistaphylococcal drug: Cefazolin is commonly recommended, or vancomycin
cardioverter–defibrillators,
transcatheter valve therapies
Respiratory tract procedures Antistaphylococcal drug: Cefazolin is commonly recommended, or vancomycin
Gastrointestinal or genitourinary Antibiotic effective against enterococci (i.e. ampicillin, amoxicillin, or vancomycin (if beta-lactam
procedures intolerant)
Dermatological, oral or Antibiotic active against staphylococci and beta-hemolytic streptococci
musculoskeletal procedures
214
KG-25.indd 214 02-11-2018 13:50:21

Table 6: Summary CHAPTER
25
z Many changes have taken place in the recommendations of infective endocarditis (IE) prophylaxis over last two decades.
z Antibiotic prophylaxis is recommended for cardiac conditions with high risk as recommended by most guidelines.
IE prophylaxis should be considered before implantation of pacemakers, automatic implantable cardio-defibrillators (AICDs), etc.

z
z IE prophylaxis before percutaneous valve procedures and cardiac surgeries should be considered.
z The risk of IE in nondental invasive procedures is not negligible and needs consideration of prophylaxis in the presence of infection with
appropriate drug.
z It appears reasonable to consider prophylaxis in patients with moderate risk cardiac lesions such as bicuspid aortic valve (BAV) and mitral
valve prolapse (MVP) with mitral regurgitation.
z Nonspecific preventive measures, such as maintaining good dental hygiene, wound disinfections, strict aseptic precautions during
procedures, infection control measures and systematic approaches to reduce health care-associated bacteremia, should be practised to
a
reduce the risk of IE.
di
given the complications associated with IE and the long 6. Habib G, Lancellotti P, Antunes MJ, et al. 2015 ESC
In
duration of treatment required to treat IE (Table 6). Guidelines for the management of infective endocarditis.
Eur Heart J. 2015;36(44):3075! 128.
7. Nishimura RA, Otto CM, Bonow RO, et al. 2017 AHA/
REFERENCES
of
ACC Focused Update of the 2014 AHA/ACC Guideline
1. Murdoch DR, Corey GR, Hoen B, et al. Clinical Presentation, for the Management of Patients With Valvular Heart
Etiology and Outcome of Infective Endocarditis in Disease: A Report of the American College of Cardiology/
ty
the 21st Century: The International Collaboration on American Heart Association Task Force on Clinical Practice
Endocarditis-Prospective Cohort Study. Arch Intern Med. Guidelines. J Am Coll Cardiol. 2017;70(2):252-89.
2009;169(5):463-73.
18 cie
2. Duval X, Leport C. Prophylaxis of infective endocarditis:
current tendencies, continuing controversies. Lancet Infect
8. Zegri-Reiriz I, de Alarcón A, Muñoz P, et al. Infective
Endocarditis in Patients With Bicuspid Aortic Valve or
Mitral Valve Prolapse. J Am Coll Cardiol. 2018 ;71(24):2731!
Dis. 2008;8(4):225-32. 40.
20 o
3. Dajani AS, Taubert KA, Wilson W, et al. Prevention of 9. Dayer MJ, Jones S, Prendergast B, et al. Incidence of
bacterial endocarditis: Recommendations by the American infective endocarditis in England, 2000-13: a secular
S
Heart Association. JAMA. 1997; 277(22):1794 ! 801. trend, inter r upte d time-s er ies analysis. Lancet.
4. Wilson W, Taubert KA, Gewitz M, et al. Prevention of 2015;385(9974):1219-28.
al
infective endocarditis: guidelines from the American 10. Tornos P, Lung B, Permanyer-Miralda G, et al. Infective
Heart Association: a guideline from the American Heart endocarditis in Europe: lessons from Euro heart survey.
Association Rheumatic Fever, Endocarditis, and Kawasaki Heart. 2005;91(5):571-5.
ic
Disease Committee, Council on Cardiovascular Disease in 11. Garg N, Kandpal B, Garg N, et al. Characteristics of infective
the Young, and the Council on Clinical Cardiology, Council endocarditis in a developing country- clinical profile and
og
on Cardiovascular Surgery and Anesthesia, and the Quality outcome in 192 Indian patients,1992-2001. Int J Cardiol.
of Care and Outcomes Research Interdisciplinary Working 2005;98(2):253-60.
Group. Circulation. 2007;116(15):1736-54. 12. Madhumitha R, Ramasubramanian V, P SenthurNambi,
ol
5. Baddour LM, Wilson WR, Bayer AS, et al. Infective et al. Profile of Infective Endocarditis: At a Tertiary Care
Endocarditis in Adults: Diagnosis, Antimicrobial Therapy, Referral Centre. JAPI 2018;66:60-5.
di
and Management of Complications: A Scientific Statement 13. Janszky I, Gémes K, Ahnve S, et al. Invasive Procedures
for Healthcare Professionals From the American Heart Associated With the Development of Infective Endocarditis.
ar
Association. Circulation. 2015;132(15):1435-86. J Am Coll Cardiol. 2018;71(24):2744-52.

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215
KG-25.indd 215 02-11-2018 13:50:22

Mechanical Prosthetic Valve
CHAPTER 26 Thrombosis
Ganesan Karthikeyan
a
di
When anticoagulation is inadequate, thrombus forms
on mechanical heart valves, leading to prosthetic valve
In
thrombosis (PVT). Thrombus on mechanical valves may
lead to systemic embolic events or may interfere with
valve leaflet motion leading to obstruction. Left-sided PVT
of
is a life-threatening condition, and poses a high risk of
death, stroke or bleeding even with treatment.1 This review
describes our current understanding of the diagnosis
ty
and management of PVT involving left-sided mechanical
prostheses. Discussion of tissue valve thrombosis, though
18 cie
increasingly recognized as being common, is beyond the
scope of this review. Likewise, the treatment of right-sided Figure 1: Pathogenesis of prosthetic valve thrombosis
PVT is well-established, and will not be discussed here.2
20 o
Mechanical heart valves are prone to thrombosis hospital showed that the rates could range between 2.1%
because of contact activation of the blood coagulation to 6.1% within 6 months after cardiac surgery, depending
S
cascade, and activation of platelets by the high shear on the anticoagulation protocol in the immediate post-
stresses created at the time of leaflet closure. 3 The risk operative period. 6 Estimates based on admissions for
al
of valve thrombosis and embolic events is high without PVT also suggest that rates may be similar. 7 The most
anticoagulation. Over a mean follow-up of 7 years, likely cause for the high rates of PVT in all the published
ic
Anderson et al. found that the linearized annual rates of series, is the poor quality of anticoagulation. For example,
thromboembolic events was 5.2 per 100 patient-years, in a in a prospective randomized trial of PVT treatment, 72%
og
small cohort of patients who were not on anticoagulation (79/110) of patients had inadequate anticoagulation at
after aortic valve replacement (AVR).4 Therefore, patients presentation.7
need to be on lifelong oral anticoagulation after receiving
ol
mechanical heart valves. However, despite being on oral

anticoagulants, optimal anticoagulation is not achieved
CLINICAL PRESENTATION AND DIAGNOSIS
di
or maintained in a large proportion of patients in low and OF LEFT-SIDED PVT

middle income countries (LMICs), predisposing them Patients usually present with recent onset of dyspnea
ar
to PVT, and embolic complications. Poor compliance, on exertion or other symptoms suggestive of valve
inadequate knowledge regarding food and drug dysfunction. Patients are predominantly in NYHA class
C
interactions affecting vitamin K antagonists (VKA), and III or IV at presentation. In a retrospective study of 110
infrequent INR monitoring are likely the most important patients with PVT, over 75% were in poor functional class.8
reasons behind the poor quality of anticoagulation in Over the years however, due to increasing physician
LMICs (Figure 1). awareness of PVT, and the performance of routine periodic
fluoroscopy, the proportion of patients with incidentally
INCIDENCE OF LEFT-SIDED PVT detected, asymptomatic PVT has increased. More recent
There are no good data on the incidence of left-sided PVT. data from the same tertiary care hospital indicate that the
One small retrospective study indicated that the rates proportion of patients presenting with severe symptoms
of PVT among patients on VKAs are about 4.9 per 100 has fallen to less than a quarter.7 Compared to patients
patient-years, and may be as high as 12.5 per 100 patient- with a first episode of PVT, more patients with recurrent
years among patients with a bi-leaflet valve in the mitral PVT tend to be severely symptomatic.9 Some patients may
position. 5 Another prospective study at a tertiary care have systemic embolism as the presenting event.
KG-26.indd 216 02-11-2018 13:50:02

The diagnosis of PVT relies on the demonstration CHAPTER
of restriction of leaflet motion on fluoroscopy, or
transthoracic echocardiography (TTE) along with elevated
transvalvular gradients, in a patient with recent onset (≤2
26
Mechanical Prosthetic Valve Thrombosis

weeks) of symptoms suggestive of valve dysfunction.7 In
the appropriate clinical setting, if both fluoroscopy and
TTE are abnormal, the diagnosis of PVT is confirmed. If
fluoroscopy is abnormal but TTE is normal, PVT is still
very likely, but may need confirmation by transesophageal
echocardiography (TEE), particularly for single-tilting
disc valves. 10 With the current generation of bileaflet
a
valves, TEE is not required for diagnosis if fluoroscopy is
Figure 2: Comparison of the risk of adverse outcomes with
di
abnormal. Abnormal transvalvular pressure gradients in fibrinolytic therapy and surgery for left-sided PVT
the presence of normal fluoroscopy findings may suggest
In
patient-prosthetic mismatch, or the presence of pannus. are poor.1,7 Most importantly; however, FT is associated
Abnormal gradients are rarely produced by PVT in the with very high rates of bleeding and systemic embolism
absence of leaflet motion restriction. (including stroke). Over 15% of patients either die or suffer
of
Some authors have suggested that TEE may be required a major bleed or stroke. 1,7 The risk of complications is
for making treatment decisions based on thrombus size.11 unpredictable and does not appear to be associated with
However, it is often difficult or impossible to accurately the duration of FT infusion.13
ty
measure thrombus size by TEE. Moreover, even in the study Urgent surgery, while the standard of care in wealthy
advocating the use of TEE, there was clear concordance countries, remains underused in LMICs because of several
18 cie
between NYHA class and the thrombus area,11 suggesting
that all the information provided by thrombus area
(a potentially poorly reproducible measure), can be
reasons. As most expenditure in these countries is out-
of-pocket, surgery is unaffordable for most patients. Poor
access to surgical centers with the required expertise to
20 o
obtained from functional class at presentation. Therefore, perform re-do operations, and the perception that surgery
clinical decisions regarding treatment can be made on poses an unduly high risk, are other barriers. The belief
S
the basis of the NYHA class at presentation. However, that urgent surgery is associated with high mortality stems
TEE is important to detect non-obstructive thrombus, from the generalization of the outcomes in patients with
al
particularly in patients presenting with embolic events in poor functional class to all patients. For example, in a large
the presence of a normally functioning prosthesis. retrospective study, 10 of 14 deaths reported with surgery
ic
occurred in patients in NYHA class IV.14 It is important

MANAGEMENT OF LEFT-SIDED PVT to recognize that unlike FT, surgery invariably results in
og
complete restoration of valve function. Moreover, the

There is insufficient high-quality evidence to guide
risk of bleeding and embolic complications may be less
management decisions in patients with left-sided PVT.
than with FT. A systematic review of observational studies
Recommendations are based on observational studies
ol
demonstrated that surgery was associated with a tenth of

and expert consensus. There are three options available
the risk of embolic complications and one-fourth of the
for managing patients with PVT: (1) intensification of
di
bleeding risk.1 Recurrent PVT was also much less frequent

anticoagulation, (2) fibrinolytic therapy (FT), and (3)
with surgery (Figure 2).
urgent surgery. By consensus, intensification of therapy
ar
More recently, one group of investigators have reported

is preferred for patients who are incidentally detected,
lower bleeding and embolism rates with slow infusions of
asymptomatic, or who have had a recent embolic stroke,
C
t-PA.15,16 However, these are observational data, and to

which precludes the use of both FT and surgery.
date there is no randomized trial evidence to suggest the
In LMICs, symptomatic patients with left-sided PVT
superiority of FT over surgery. One such trial is currently
usually receive FT. This is because, the commonly used
underway (SAFE-PVT, NCT01641549).
fibrinolytic agent (streptokinase), is inexpensive, widely
available, does not require any particular expertise
to administer, and most importantly, was believed to RECOMMENDATIONS FOR MANAGEMENT
be highly effective (based on data from case series). 12 Left-sided PV T is a common and life-threatening
Moreover, the literature on FT for PVT is plagued by the illness which is preventable by improving the quality
inconsistent use of clinically invalid outcome measures. As of anticoagulation. There is uncertainty regarding the
an example, it is meaningless to categorize valve opening relative benefits and harms of FT and urgent surgery.
with the occurrence of a stroke as a successful outcome. Therefore, current recommendations are based on
Subsequent prospective studies have suggested that rates consensus. Figure 3 presents a suggested algorithm for
of complete success with FT, particularly streptokinase, the treatment of symptomatic patients with left-sided PVT.
217
KG-26.indd 217 02-11-2018 13:50:05

SECTION
3
a
di
In
of
ty
18 cie
Figure 3: Suggested algorithm for the management of symptomatic left-sided PVT
* Urgent surgery is preferred if: (i) fibrinolytic therapy is contraindicated, (ii) patient has had a previous episode of thrombosis involving the same
valve, (iii) previous fibrinolytic therapy was unsuccessful or associated with complications, (iv) large (0.8cm 2) thrombus, (v) left atrial thrombus,
(vi) NYHA class IV.
20 o
†
If FT is unsuccessful or partially successful, patient should be referred for surgery.
S
Abbreviations: INR, International Normalised Ratio; t-PA, Tissue plasminogen activator; VKA, Vitamin K antagonist
REFERENCES 10. Montorsi P, De Bernardi F, Muratori M, et al. Role of

al
cine-fluoroscopy, transthoracic, and transesophageal

1. Karthikeyan G, Senguttuvan NB, Joseph J, et al. Urgent
echocardiography in patients with suspected prosthetic
surgery compared with fibrinolytic therapy for the
ic
heart valve thrombosis. Am J Cardiol. 2000;85:58-64.

treatment of left-sided prosthetic heart valve thrombosis:
a systematic review and meta-analysis of observational 11. Tong AT, Roudaut R, Ozkan M, et al. Transesophageal
og
studies. Eur Heart J. 2013;34:1557-66. e c h o c a rd i o g ra p hy i m p rov e s r i s k a s s e s s m e n t o f

2. Taherkhani M, Hashemi SR, Hekmat M, et al. Thrombolytic thrombolysis of prosthetic valve thrombosis: results of
therapy for right-sided mechanical pulmonic and Tricuspid the international PRO-TEE registry. J Am Coll Cardiol.
2004;43:77-84.
ol
Valves: The largest survival analysis to date. Tex Heart Inst J.

2015;42:543-7. 12. Lengyel M, Fuster V, Keltai M, et al. Guidelines for
3. Bluestein D, Chandran KB, Manning KB. Towards non- management of left-sided prosthetic valve thrombosis:
di
thrombogenic performance of blood recirculating devices. a role for thrombolytic therapy. Consensus Conference
Ann Biomedical Eng. 2010;38(3):1236-56. on Prosthetic Valve Thrombosis. J Am Coll Cardiol.
ar
4. Andersen P V, Alstrup P. L ong-term sur vival and 1997;30:1521-6.

complications in patients with mechanical aortic valves 13. Karthikeyan G, Mathew N, Math RS, et al. Timing of adverse
without anticoagulation. A follow-up study from 1 to 15 events during fibrinolytic therapy with streptokinase
C
years. Eur J Cardiothorac Surg. 1992;6(2):62-5. for left-sided prosthetic valve thrombosis. J Thromb
5. Bharat V. Mechanical heart valves : an insight into Thrombolysis. 2011;32(2):146-9.
thrombotic complications. Indian Heart J. 1999;51:59-63. 14. Roudaut R, Lafitte S, Roudaut MF, et al. Management of
6. Talwar S, Kapoor CK, Velayoudam D, et al. Anticoagulation
prosthetic heart valve obstruction: fibrinolysis versus
protocol and early prosthetic valve thrombosis. Indian
surgery. Early results and long-term follow-up in a
Heart J. 2004;56(3):225-8.
single-centre study of 263 cases. Arch Cardiovasc Dis.
7. Karthikeyan G, Math RS, Mathew N, et al. Accelerated
2009;102(4):269-77.
infusion of streptokinase for the treatment of left-sided
prosthetic valve thrombosis: a randomized controlled trial. 15. Ozkan M, Gunduz S, Biteker M, et al. Comparison of
Circulation. 2009;120:1108-14. different TEE-guided thrombolytic regimens for prosthetic
8. Gupta D, Kothari SS, Bahl VK, et al. Thrombolytic therapy valve thrombosis: the TROIA trial. JACC Cardiovascular
for prosthetic valve thrombosis: short- and long-term Imaging. 2013;6(2):206-16.
results. Am Heart J. 2000;140:906-16. 16. Ozkan M, Cakal B, Karakoyun S, et al. Thrombolytic therapy
9. Balasundaram RP, Karthikeyan G, Kothari SS, et al. for the treatment of prosthetic heart valve thrombosis in
Fibrinolytic treatment for recurrent left sided prosthetic pregnancy with low-dose, slow infusion of tissue-type
218 valve thrombosis. Heart. 2005;91(6):821-2. plasminogen activator. Circulation. 2013;128:532-40.
KG-26.indd 218 02-11-2018 13:50:11

Percutaneous Valve
Interventions beyond
CHAPTER 27 Transcatheter Aortic
Valve Implantation
Vijay Kumar Trehan, Safal, Siddhant Trehan
a
di
INTRODUCTION
Table 1: Transcatheter valve interventions beyond transcatheter
The interventional cardiologist started taking on the aortic valve implantation (TAVI)
In
stenosed cardiac valves by balloon dilatation nearly four (A) Mitral valve repair:
Edge-to-edge repair: MitraClip and PASCAL mitral valve (MV) repair
decades ago. The first valve to be handled was pulmonary
system
of
valve in 1982; subsequently, the other stenosed valves Annuloplasty
were also handled.1 Balloon dilatation provided durable a. Indirect annuloplasty: Carillon ring, ARTO, VenTouch
results in all valves except the stenosed aortic valve in b. Direct annuloplasty: Cardioband, Mitralign, IRIS Millipede
complete annuloplasty ring, Amend mitral annuloplasty ring,
ty
the elderly population, which had a very high recurrence Cerclage annuloplasty, QuantumCor, Mitraspan TASRA
rate. For nearly two decades, there was quiescence; the Subvalvular mitral valve repair
a. Chordal implantation: NeoChord DS1000 & TSD-5 MV repair
18 cie
interventionist had only a balloon to take on these stenosed
valves and nothing to offer to the regurgitant valves. In the
last decade or so, there have been great advancements
device
b. Basal ventriculoplasty: AccuCinch system
(B) Mitral valve replacement:
in both the techniques and technologies to handle the
20 o
a. Valve-in-valve (VIV) & Valve-in-ring (VIR) procedures
diseased valves. Even though the pulmonary valve was the b. Valve implantation in native calcified mitral annulus (MAC)
S
first to be implanted percutaneously,2 it was transcatheter c. Dedicated MV replacement for noncalcified annulus: CardiAQ,
aortic valve implantation (TAVI) that totally revolutionized Tiara, Tendyne, Intrepid, Caisson, HighLife, NaviGate, Cardiovalve,
MValve docking system
the interventional treatment of valvular heart disease. Of
al
late, the interventionist has started looking beyond TAVI (C) Tricuspid valve repair:
a. Edge-to-edge repair: Mitraclip in tricuspid position, PASCAL
to cater to other valves, especially atrioventricular (AV)
ic
system
valves (mitral and tricuspid) by either repairing the native b. Annuloplasty: TriAlign, TriCinch, TRAIPTA, Cardioband, IRIS
valve or implanting an artificial valve percutaneously c. CAVI: Dedicated TricValve, self-expanding valves, Sapien family of
og
valves within self-expanding stent (1 valve vs 2 valve technique)

[or even a combination of transcatheter (TC) repair
d. FORMA device
and replacement] (Table 1). The TC intervention has
(D) Tricuspid valve replacement:
ol
also found a niche usage in failing bioprosthesis, as an VIV, VIR & NaviGate (for native tricuspid valve)
alternative to high-risk re-do surgery.
(E) Developments in pulmonary valve interventions:
di
Major impediments to the development of mitral valve a. Pre-stenting, Sapien valve at pulmonary position, Russian-doll
technique
(MV) interventions include the following:3-5 b. Valve implantation in both pulmonary arteries and
ar
Complex and dynamic three-dimensional structure: self-expanding valves

Disease processes affecting any of the components of
C
MV apparatus [viz. annulus, leaflets, chordae, papillary issues need to be overcome in future to render the
muscles, left atrium (LA) and the left ventricle (LV)] maneuvering and positioning of these enormous
can lead to mitral regurgitation (MR). The annulus is devices (bulkier than the ones used for TAVI) easy.
not only a three-dimensional saddle-shaped structure
The retrograde transarterial approach will not only
but also one with a dynamic shape, whose area varies
encounter vascular access problems but crossing
up to 15% during the cardiac cycle. This makes it
the aortic valve downward into LV and then turning
extremely difficult for any rigid percutaneous implant
upward towards LA will be an extremely challenging
to seat itself in the native annulus (unless the annulus
is heavily calcified or converted to a two-dimensional task. Correct alignment and positioning of the artificial
structure by a prior ring or bioprosthetic valve). valve within the native valve may be difficult in both of
Access: The first transcatheter mitral valve (TC MV) the above approaches. The transapical (TA) approach is
was implanted through a transvenous transseptal a straight shot and provides great control on the device
approach that has a clear safety advantage. However, during delivery; hence, most TC mitral valves have
the complex navigation, steering and alignment been delivered through this approach. Nonetheless, it
KG-27.indd 219 02-11-2018 13:49:51

SECTION cannot be called percutaneous in the true sense of the of TC MV interventions. The 3D volume rendering
word, and the need for a surgeon to provide the access can provide a complete anatomical roadmap and help
3 takes away at least some of the attraction associated
with TC procedures. Moreover, TA access in secondary
plan the procedure. An undersized valve can embolize
and an oversized valve has a potential to induce left
MR and cardiomyopathy with low left ventricular ventricular outflow tract (LVOT) obstruction, which
ejection fraction (LVEF) can worsen the already is more likely in DMR where the LV and LVOT are not
depressed LV function, as it involves trauma to the LV large. In patients with a wide mitral inflow-to-LVOT
by large (>30F) system. Subvalvular entanglement may angle and when the predicted neo-LVOT area (by
occur with both arterial and TA access. 3D printing) is small, one may consider prophylactic
Diverse etiologies: Each component of the MV can interventricular septal ablation prior to transcatheter
be responsible for MR either individually or in mitral valve replacement (TMVR) to prevent LVOT
a
combination; hence, TC therapy (especially repair) obstruction. Specific techniques like laceration of the
di
needs to be individualized. There is no one-size- anterior mitral leaflet to prevent LVOT obstruction
that-fits-all. Primary MR could be degenerative (LAMPOON) procedure [in which the anterior mitral
In
(DMR–due to fibroelastic deficiency, myxomatous leaflet (AML) is lacerated percutaneously with the help
degeneration or mitral annular calcification), of a wire delivered through the femoral artery, which
rheumatic or endocarditis, where disease of valve perforates the base of AML and subsequently lacerates
of
structure per se, makes the ventricle sick. This has the AML by the help of radiofrequency (RF) energy]
to be corrected by mechanical solution for the valve is also being tested to reduce the incidence of LVOT
(repair or replacement–either surgically or by TC obstruction.6
ty
method). Secondary MR or functional MR (FMR)
is due to alterations in LV geometry secondary to MITRAL VALVE REPAIR
18 cie
LV dysfunction where the ventricle makes the valve
sick; and hence, the ventricle has to be treated either
medically or otherwise. Mechanical reduction of MR
The transcatheter mitral valve repair techniques are
broadly based on the established surgical principles of
MV repair including edge-to-edge leaflet repair (leaflet
is offered only if the above fails and the anatomy is
20 o
plication), direct and indirect annuloplasty, neochordae
suitable. Secondary MR can be symmetric, usually seen
S
placement and LV remodeling (basal ventriculoplasty). A

in dilated cardiomyopathy (DCMP) or asymmetric
number of TC MV repair devices are currently in clinical
seen in ischemic cardiomyopathy (ICMP). The FMR
can have variable LV systolic function. The FMR can use or in various phases of development.3,4,7-9
al
be due to: (i) severe LV systolic dysfunction with dilated

LV (DCMP/ICMP), (ii) mild LV systolic dysfunction due Edge-to-Edge Mitral Leaflet Repair
ic
to a localized scar or ischemia involving the papillary

MitraClip
og
muscle usually without significant LV dilatation, or (iii)

pure LA dilatation (without LV dilatation) due to atrial Based on the Alfieri technique of edge-to-edge repair,
fibrillation or hypertension with normal LV systolic MitraClip is currently the only percutaneous (PC)
MV repair technology to have achieved widespread
ol
function. Both DMR and FMR can co-exist. Diverse

etiologies involving multiple mechanisms require a clinical acceptance for central DMR. The endovascular
Valve Edge-to-Edge Repair Study II (EVEREST II) trial
di
tailored approach of interventions for MR. Also, FMR

can be with or without TR and with or without RV demonstrated that even though MitraClip was somewhat
less effective in reducing MR, as assessed on echo, it was
ar
failure, which may complicate the treatment. Patients

with LVEF below 20%, very large LV and tenting clinically effective and safer than surgery, which led to
of mitral leaflets are usually not taken for surgery. its US Food and Drug Administration (FDA) approval in
C
Recurrence of FMR after surgical repair is reported to 2013 for the limited indication of significant symptomatic
be up to 50% two years after surgery; recurrence after DMR ≥3+ in patients at prohibitive surgical risk. However,
TC repair in this situation may be even higher. It is in practice, more MitraClips are being deployed for FMR
not surprising that in routine clinical practice, only a than for DMR at least in Europe. The COAPT trial (Clinical
small number of FMR patients are referred for valve Outcomes Assessment of the MitraClip Percutaneous
treatment. Therapy for High Surgical Risk Patients Trial) is evaluating
Proximity to left circumflex artery, coronary sinus, the role of this device in FMR.
conduction system, LV outflow tract, and aortic The best procedural outcomes can be expected in
root: Each of these structures runs a risk of being patients with pathology in segment 2 [anterior (A2)-
compromised during MV interventions. Selection posterior (P2)], in the absence of calcification, MV area
of an appropriate device size using accurate pre- >4 cm2, posterior mitral leaflet (PML) length >10 mm,
procedure imaging as well as the use of advanced coaptation depth <11 mm with normal leaflet thickness
real-time intraprocedure imaging is an integral part and mobility. In flail MV, the flail size should ideally be
220
KG-27.indd 220 02-11-2018 13:49:51

<15mm and flail gap <10 mm. However, centers with it is important to be sure that both leaflets are grasped CHAPTER
greater experience are increasingly taking up cases with and inserted into the clip arms. The 3D echo in diastole is
less than the ideal anatomy that was accepted in the
EVEREST II trial.
useful for evaluating the geometry and size of the orifices
created and the two symmetrical isosceles triangles with
27
Percutaneous Valve Interventions beyond Transcatheter Aortic Valve Implantation

The procedure is carried out through transseptal route. the base towards the annulus and the apex towards the
The septal puncture should be superior and posterior in clip. Distortion of the valve or excessive tension on the
the fossa with a height ranging from 3.5 to 4.5 cm above leaflets must be avoided. The clip is released only after a
the mitral annular plane, depending on the type of disease satisfactory result (i.e. mechanically stable clip position,
(lower for FMR). Puncture should be higher in case of a significant reduction of MR, and no significant induction
medial lesion and lower in case of a lateral lesion. of mitral stenosis).
The clip delivery system consists of three major In the case of FMR, one central clip strategy should be
a
components: 24 F steerable guide catheter which is attempted; however, if the annulus is >35 mm, two-clip
di
delivered into the LA, through which 16 F clip delivery strategy (with medial first since it is easier to implant a
system with a steerable sleeve with a clip attached to second clip laterally) should be followed. In the case of
In
its distal end (for proper positioning and placement), DMR, the target of the first clip should be the lesion (flail/
is advanced into the LV. As the MitraClip is pulled back prolapse). A second clip is advised, even if significant
from LV to LA with its arms fully open and perpendicular residual MR is not present, in order to stabilize the first clip
of
to the commissural line, it will simultaneously and and guarantee longer durability. If necessary, more than
symmetrically catch both the leaflets avoiding distorting of two clips can be implanted.
the MV. The en face 3D reconstruction on transesophageal The MitraClip device has established safety track
ty
echocardiography (TEE) is very useful to catch the leaflets record in >65,000 patients (barring one incidence of
device recall due to failure of delivery system to detach
especially if the target is away from A2-P2 scallop. In
18 cie
these cases, a clockwise rotation if the target is lateral,
or a counterclockwise rotation if the target is medial, is
from the device). The 2nd generation MitraClip NT, which
was made of nitinol (which increased the angle from
85° to 120° with better grasping), replaced the original
required.
MitraClip. The 3rd generation MitraClip NTR has better
20 o
The leaflets once caught by the arms of the clip are
steerability, so that clipping can be done quickly with
then grasped with the grasper and the clip is closed
S
better precision and less chance of displacement during

which will coapt the leaflets and keep them like this
the procedure. In addition to an improved delivery system,
throughout the cardiac cycle converting the MV into
al
the MitraClip XTR has 3 mm longer clip arm length for

double orifice resulting in reduction of MR (Figure 1).
easier grasping and 5 mm wider grasping width, which
If the result is unsatisfactory on echo, the clip is opened,
ic
improves coaptation surface area by 44%, allowing more

leaflets are ungripped and the procedure is repeated
difficult anatomies to be handled; also, this is more
all over again which can be readjusted multiple times.
og
suitable for tricuspid regurgitation.

The grade of residual MR, any induced mitral stenosis, Further improvements in design are likely to allow
and morphological evaluation must be carried out expanded area of transseptal puncture due to longer
before and after each clip. It is important to conduct the
ol
catheter, improved torque response with easier delivery

evaluation in the same hemodynamic conditions and into LV, stable clip arm orientation while crossing, and
with the same ultrasound machine settings. In addition
di
the ability to leave the clip unlocked for the duration of

to echocardiography, LA pressure measurement is useful procedure, thereby making the device more user friendly.
to assess the result. From a morphological point of view,
ar
In about 5–10% cases, the MitraClip procedure may

fail primarily due to inadequate indications, technical
problems, or unfavorable anatomy with destruction of
C
the leaflets (injury to the leaflets with perforation), severe

adhesion of the clip with leaflets, or severe adhesion with
the subvalvular apparatus and/or chordae tendinae. The
MitraClip has to be removed surgically and in majority of
patients (due to severe leaflet damage) the valve is replaced
rather than repaired, with a low postoperative morbidity
and mortality. However, emergent cases who presented
in cardiogenic shock and severe MR are at extremely high
risk for in-hospital mortality. Postprocedure concerns
include single leaflet attachment, clip embolization,
acquired mitral stenosis, endocarditis, and recurrent MR
Figure 1: MitraClip device (left); Schematic representation of device due to annular dilatation. In addition, a MitraClip will
postdeployment (right) (Images from Company website) make future TC intervention (including TMVR) difficult. 221
KG-27.indd 221 02-11-2018 13:49:53

SECTION PASCAL Mitral Valve Repair System associated with reduction in FMR, and improvement in
functional capacity and quality of life. The device does not
3
The PASCAL device is an improvement in the edge-to-
edge repair technique. It consists of two paddles that require additional anticoagulation, and leaves the scope
independently grasp mitral leaflets and facilitate leaflet for other therapies [including cardiac resynchronization
coaptation around a central spacer (Figure 2). The paddle therapy (CRT)] open in future. The device received
dimensions are tailored to accommodate the larger Conformite Europeenne (CE) mark approval in 2011,
coaptation gaps akin to FMR patients. The device coaxiality based on the results of AMADEUS and TITAN trials. The
and success is independent of septal puncture height. The REDUCE FMR and CARILLON trials are currently further
30-day compassionate use results with this device in 23 evaluating the safety and clinical efficacy of this device.
patients were presented at EuroPCR 2017and showed 96% ARTO system: The ARTO (Latin for ‘to press together’)
technical success and no procedural mortality.
a
system for FMR involves placing the ends of two magnet-
tipped catheters; one in the great cardiac vein through the
di
Mitral Annulus Repair jugular approach, and the other at the posterolateral wall
of LA through a septal puncture from the femoral venous
In
Indirect (Pseudo) Annuloplasty approach. A hard tip of a guide wire is guided from the
Coronary sinus (CS) is believed by the interventionists to inner lumen of one catheter to the inner lumen of the
be exactly at the level and adjacent to the mitral annulus, other catheter (magnetically attached to each other at
of
but the surgical experience, especially in patients with their tips) by piercing through the LA wall and the wall of
heart failure with dilated heart, has shown that there is the great cardiac vein, thus creating a venovenous loop. An
often a separation by more than 1.25 cm in these cases. atrial septal anchor and a coronary sinus anchor are then
ty
The left circumflex (LCx) on the contrary follows the placed and cinched together (Figure 4). This cinching
CS more closely and has a significant potential to get
18 cie
compressed by a CS-based device, often referred to as
‘mitral yikes’. Moreover, the CS incompletely encircles the
mitral annulus and is likely to be less effective. Indirect
20 o
annuloplasty is much simpler, but is also much less
effective and less predictable
S
Carillon (Pseudoannuloplasty): The Carillon Mitral

Contour System for PC annuloplasty in FMR is based on
al
the time-tested principle of surgical mitral annuloplasty.

The device (consisting of two anchors connected by an
ic
adjustable shaping ribbon), is delivered into CS through

transjugular venous approach (not requiring a septal
og
puncture). With the distal anchor deployed deep in the

CS and proximal anchor near the CS ostium, cinching
ol
of the dilated mitral annulus is done by shortening the

length of the connecting ribbon (Figure 3). Clinical Figure 2: PASCAL mitral valve repair system
di
data demonstrates that usage of the Carillon implant is (Image from reference 8)
ar
C
Figure 3: Schematic representation of mitral annulus after Carillon device implantation (Images from company website)
222
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CHAPTER
27

a
di
In
Figure 4: ARTO system for direct transcatheter annuloplasty Figure 5: Angiographic image of Cardioband annuloplasty ring
(Image from reference 8) implanted using corkscrew-shaped anchors (Image taken from:
https://www.dicardiology.com/content/henry-ford-hospital-first-
michigan-perform-cardioband-mitral-valve-procedure)
of
reduces the anteroposterior (AP) diameter of the mitral resulting in decrease of MR. Unlike a MitraClip, the native
ty
annulus reducing the MR under real-time echo guidance. anatomy of MV is preserved keeping future options open;
The MitrAl ValvE RepaIr Clinical (MAVERIC) Trial with also, it does not induce any mitral stenosis (Figure 5).
18 cie
this device is currently recruiting symptomatic patients
of LV dysfunction [ejection fraction (EF) < 40%] who have
moderate-to-severe MR.
Typically, the patients who have loss of coaptation due
to annular dilatation with or without posterior leaflet
tethering are the patients who are likely to respond to the
20 o
Cardioband. A good quality TEE image in supine position
VenTouch system (Mardil extracardiac annuloplasty): The
is essential for the Cardioband procedure. Pre-procedure
S
VenTouch device is an external sleeve that is deployed over

CT scan is extremely important for assessment and
the heart via transapical access, with an inflatable saline
localization of quality of tissue including calcification at
pouch located on its inferoposterior aspect. The pouch
al
the mitral annulus, assessment of proximity of LCx to the

is injected with saline, which extrinsically pushes the
hinge point of PML, determination of preferred puncture
posterior aspect of the mitral valve annulus anteriorly and
ic
site and selection of device size. Cardioband cannot be

thus reduces the anteroposterior annular diameter. The
used in the presence of severe mitral annular calcification
volume of the inflatable saline pouch can be controlled
og
(MAC) or severe tethering of PML. The best results are

from a subcutaneous access port through a needle and
expected if annulus dilatation is due to LA dilatation in
syringe, thereby allowing controlled reduction of mitral
atrial fibrillation (AF) or hypertension.
ol
annular diameter.
Mitralign: The Mitralign system for annular reduction in
di
Direct (True) Annuloplasty FMR involves approaching the posterior mitral annulus
through LV. Two pairs of surgical pledgets are delivered at
The mitral annulus is directly targeted from atrial or
ar
the P1 and P3 site of the annulus. The paired pledgets are

ventricular side with the help of anchors with a band or
pulled together to decrease the annulus circumference,
suture placation, like in surgical repair.
and the achieved plication is locked in place (Figure 6).
C
Cardioband: The Cardioband system is a surgical-like Multiplane images from intercommissural (50–70°) and
PC annuloplasty device that is implanted in the beating long-axis (120–160°) views are employed for correct and
heart through a 25 F transseptal steerable sheath under facilitated placement of the 14 F deflectable guiding
fluoroscopic and TEE guidance. The Cardioband is catheter, which is the key step of the procedure, and
delivered to the posterior annulus through multiple assessment of the correct annular puncture site at the
anchors piercing through the hinge point of the posterior posterior annulus (P1 and P3 scallop regions). The
mitral leaflet into the LV myocardium taking care not to annular puncture and plication process can be monitored
injure the LCx coronary artery. A Fielder XT percutaneous using live 3D TEE, which permits real-time visualization
transluminal coronary angioplasty (PTCA) wire is parked in of annuloplasty and final assessment of plication results.
the LCx which, being radiopaque for a longer length, serves Colour Doppler is used for the evaluation of residual
as a good reference telling about the position of LCx. On MR. Anterior-posterior and septal-lateral dimensions
cinching the Cardioband, the mitral annulus is constricted for the determination of induced MV geometry changes
223
KG-27.indd 223 02-11-2018 13:50:01

SECTION
3
a
di
In
Figure 7: Iris complete annuloplasty ring (Image from reference 8)
Figure 6: Schematic representation of pledget delivery (above) and

plication during Mitralign implant (Images from company website)
of
can be obtained from intercommissural and 4-chamber/
ty
long-axis views, respectively. A severely dilated or small
ventricular might cause steering difficulties and prohibit
18 cie
safe placement of the Mitralign Bident catheter on the
ventricular side of the mitral annulus and thus create
difficulty in safe annular puncture The MAC) is a common
degenerative process associated with advancing age and
20 o
other comorbidities and is present in approximately 6%
S
of the general population. Pre-procedure contrast CT may

detect possible MAC, which may interfere in the annular
puncture.
al
IRIS Millipede complete annuloplasty ring: The IRIS device Figure 8: Amend mitral annuloplasty ring
ic
is a semi-rigid nitinol ring implanted in the MV annulus (Image from reference 8)

from the atrial side through a transseptal approach.
og
The ring can be adjusted and tailored to the need of septum. It is then directed to perforate across a short
the patient’s annulus (Figure 7). As the Iris system is segment of myocardium to re-enter a right heart chamber
implanted and manipulated on the atrial side, there is no (usually RA), where it is snared and exchanged for a suture
ol
risk of LV chordal interactions. An early feasibility study and tension fixation device. Annular tension is introduced
with this device is ongoing. The concept has also been through this ‘cerclage’ suture that traverses the coronary
di
extrapolated to TC tricuspid valve annuloplasty. sinus and basal septal myocardium improving leaflet
coaptation. The coronary sinus frequently crosses over
ar
Amend mitral annuloplasty ring: The Amend device

the circumflex or one of its branches; circumflex coronary
is a semi-rigid, D-shaped ring that emulates current
artery protection is provided using a relatively rigid spacer
surgical annuloplasty ring (Figure 8). The implantation
C
device, shaped somewhat like a piece of elbow macaroni.

procedure utilizes transapical surgical access, and the
device is deployed on the atrial aspect. After successful QuantumCor: It uses a radiofrequency (RF) system to
deployment and fixation, the ring reduces the AP diameter shrink collagen, resulting in remodeling of the annulus.
of the annulus. This improves AP leaflet coaptation and The RF energy is delivered to the annulus by electrodes
reduces the regurgitant orifice. The concept may also be through transseptal route.
useful in future to create a platform for mitral valve-in-ring
Mitraspan transapical segmental reduction annuloplasty
therapies.
(TASRA): The TASRA technique is based on the
Cerclage annuloplasty: Venous access is obtained through experimental concept of septal-lateral annular cinching
superior vena cava (SVC) and inferior vena cava (IVC) (SLAC). The SLAC concept was first described in adult
using a 9 F sheath. A guidewire traverses the coronary sheep with acute ischemic MR produced by LCx occlusion.
sinus and the proximal great cardiac vein into the first Using a 12 F sheath through a transapical (TA) access, a
septal perforator vein, towards basal interventricular polyester suture with pledgeted stainless steel anchors
224
KG-27.indd 224 02-11-2018 13:50:09

on the LV side is placed from the mid-anterior annulus delivery system. This releases the preformed ePTFE knot CHAPTER
to the posterior LV wall to achieve annular cinching. The on the atrial aspect of the posterior leaflet. This process
TA access allows a direct approach to critical locations for
device implantation, using short tools. Tissue crossing is
can be repeated multiple times to achieve the desired
degree of PML tethering.
27

done with a 0.018” wire.
Basal Ventriculoplasty
Subvalvular Mitral Valve Repair AccuCinch system: The AccuCinch device is implanted in
the subannular groove 10 to 20 mm below MV plane at
Chordal Implantation the base of LV using a transfemoral retrograde approach.
DS1000 (For localized P2 prolapse): The NeoChord Anchors are placed in the posterior mitral annulus and
DS1000 device is based on the principle of transapical connected with a ‘drawstring’. When the cord is tightened,
a
artificial chordae tendinae implantation in DMR with the mitral annulus is cinched (like drawstring of a curtain),
di
prolapsed or flail leaflets (where natural chordae have and mitral leaflets are drawn together to decrease the
become elongated/ruptured due to degenerative disease). regurgitant orifice area. The implant also decreases the
In
The device consists of a hand-held delivery instrument, circumference of posterior free wall of LV, which reduces
a cartridge in which expanded polytetrafluoroethylene LV radius and thereby LV wall stress. Papillary muscles
(ePTFE) suture is loaded, a needle, and a tethered leaflet get realigned and MV tenting reduces. Subsequently, the
of
capture verification monitor that enables confirmation of secondary effects of reverse LV remodeling occur, proper
capture of the free edge of mitral leaflet in the distal clamp coaptation of mitral leaflets is achieved, and FMR is
of delivery instrument prior to deploying the ePTFE suture reduced.
ty
and knot at the leaflet (Figure 9). The procedure is done
under real-time echo guidance and has the advantage Combination of TC MV Repair Techniques
18 cie
of assessing MR reduction under beating heart (vis-à-vis
cardioplegic conditions in conventional surgery). The
The TC annuloplasty in combination with MitraClip is
likely to be more effective than annuloplasty alone in
device has received CE mark approval. Its clinical safety
20 o
FMR. In this combined approach, annuloplasty is followed
and efficacy (versus open surgical repair) is being further
by MitraClip implant if required. As the Cardioband
S
assessed in the ongoing ReChord trial.

provides immediate reduction in MR, need for MitraClip
TSD-5 mitral valve repair device (Harpoon): The TSD- insertion can be assessed at the time of TC annuloplasty.
al
5 mitral valve repair device is an artificial chord-based However, when the Carillon system is used, one must
system that consists of a preformed ePTFE-knotted assess the need for add-on MitraClip after about 6 months
ic
suture delivered through a transapical 12 F access. Under of annuloplasty because MR reduction after Carillon is
fluoroscopic and TEE guidance, the device is advanced delayed. Theoretically, the Cardioband could also serve as
og
just below the posterior mitral leaflet and positioned on a support for TAVI devices in the mitral position for mitral
ventricular aspect of the leaflet with the help of a stabilizer. valve replacement (similar to valve-in-ring procedures).
This reduces the need to catch the prolapsing leaflet In a hypothetical treatment scenario, a combination of
ol
directly. Once the device position is confirmed on TEE, percutaneous annuloplasty, edge-to-edge repair, and
a needle is released by depressing the plunger on the chordae implantation can give a fully percutaneous repair.
di
MITRAL VALVE REPLACEMENT

ar
The challenges to TMVR have already been discussed

above. It will not be surprising to note, after the above
C
discussion, that valve-in-valve (VIV) and valve-in-ring

(VIR) (redo procedures) are today far ahead in terms of
clinical adoption and acceptance vis-à-vis native TMVR–
as the pre-implanted valve (or ring) provides a readymade
rigid scaffold for TMVR that bypasses many of the annular
geometric limitations. Post-TMVR concerns include
thrombosis, endocarditis, embolization, paravalvular
regurgitation, and need for anticoagulation.
Valve-in-valve Procedures
Figure 9 : Components of Neochord DS 1000 system The basic principle of TAVR involves implanting a
(Image from company website) sutureless valve in a pre-existing frame (annulus) and
225
KG-27.indd 225 02-11-2018 13:50:11

SECTION ensuring its stability by relative oversizing. With the success evident LVOT obstruction). In June 2017, the Sapien 3
of TAVR, there has been a natural effort to extrapolate this valve received US-FDA approval for VIV procedures at
3 principle to degenerative bioprosthetic valves. Owing to
the pre-existing frame that these valves provide, valve-in-
aortic and mitral position in high-risk patients.
Valve-in-ring Procedures
valve (VIV) procedures have been successfully performed

at the mitral and tricuspid positions (in addition to aortic). As in VIV interventions, valve-in-ring (VIR) procedures
While both self-expanding and balloon expandable are also based on the principle of using the pre-existing
VIV have been used at the aortic position, the balloon surgical ring as the scaffold to deploy the TC valve. The
expandable valves (most commonly Sapien family) VIR interventions are frequently more challenging than
have primarily been used for mitral and tricuspid VIV VIV, with higher incidence of paravalvular regurgitation
procedures.10-13 as well as procedure failure. The primary reason for this
a
Pre-procedure planning is a critical part of VIV is the numerous variations in shape and size of surgically
di
procedure and involves selection of valve type and size deployed rings.13,14
as well as assessment of likelihood of complications like Ring characteristics need to be especially taken into
In
LVOT obstruction and coronary artery pinching. Operator account while planning a VIR procedure. Both rings and
experience and comfort with a particular valve is a major bands are used for mitral (and tricuspid) annuloplasty.
factor in selection of valve type. Valve size selection However, unlike rings, mitral bands do not provide a stable
of
involves identification of predeployed surgical heart valve anchor for TC valve deployment. While semirigid mitral
and the stent internal diameter (ID), which can be got from rings can be more easily forced into a circular position
the manufacturer label. However, the true ID is not the by a balloon-expandable valve (e.g. Sapien family), rigid
ty
same as the stent ID because it is influenced by the type of rings tend to deform the valve. Hence, while the Sapien
leaflets (porcine or bovine) and the method of mounting valves may be best in semirigid rings, valves like Lotus and
18 cie
them. For instance, porcine leaflets mounted within the
stent reduce the true ID by 2 mm, while pericardial leaflets
mounted outside the stent frame do not affect the ID. For a
Direct Flow Medical (DFM) that can adapt and function
better in noncircular geometry may be preferable in rigid
rings.14 (Note: DFM valve is no longer available; Lotus valve
VIV procedure, the true ID is the measurement of interest.
20 o
has been recalled and is currently off the market – being
This information can easily be obtained from the VIV App
discussed here for conceptual purposes).
S
(from Dr Vinayak N Bapat). For any given true ID, each TC

While determining valve size, a delicate balance
heart valve has its own sizing algorithm, which takes into
between likelihood of LVOT obstruction (with excess
al
account factors like anatomic position of implant, pre-

oversizing) vis-à-vis device embolization (if undersized)
existing calcium and stenosis of the surgical heart valve,
needs to be struck. Unlike in VIV procedures, there is no
evidence of pannus growth, etc. These factors are also
ic
validated software to guide valve sizing. By and large, rings

incorporated in the aforementioned VIV App.11,12
over 32 mm are too large for VIR procedures with currently
og
Fluoroscopic landmarks must be defined for optimal

available devices.
deployment of the TC valve within the surgical valve.
The aortic annulus is used as a reference line during
TMVR in Mitral Annular Calcification
ol
TC valve positioning within a native aortic valve (TAVR

procedure). Similarly, during VIV interventions, level of The principle of delivering a TC valve in a pre-existing
di
the neoannulus of surgical valve has to be identified by anchor has also been extrapolated to native valves
correlating its structure to its fluoroscopic appearance. with MAC, which provides a rigid anchor for the TC
ar
This neoannulus is at the level of the sewing ring of valve. The ongoing MITRAL (Mitral Implantation of
surgical valve. Some surgical valves have a marker within TRAnscatheter vaLves) and SITRAL (Surgical Implantation
the sewing ring, while others have their stent frame visible;
C
of TRAnscatheter vaLve in MAC) trials are evaluating the

and for these, it is important to assess the relationship balloon-expandable Sapien valve in this setting.15,16
between the inflow and the level of sewing ring. In surgical
valves with no fluoroscopic marker in the frame or sewing
TMVR in Native (Non-calcified) Annulus
ring, the level has to be determined by TEE, balloon waist
during inflation, or multiple contrast injections through a (Dedicated TMVR)
pigtail.11 As already discussed above, TMVR in the pliable native
Transseptal route is frequently used for mitral position; mitral annulus is a very difficult proposition. It is not
transapical route is a viable alternative. Transjugular is the possible to use radial force of the valve for fixation at the
preferred approach for tricuspid valve. mitral level (in the absence of a surgical bioprosthesis or
As per the valve-in-valve international data (VIVID) surgical ring). Nevertheless, the ideal TMVR device, when
registry (worldwide data presented in TCT 2016), 88.8% of developed, may actually fare better than surgery because it
349 mitral VIV procedures were clinically successful (30- would offer subvalvular plus leaflet preservation, avoid any
226 day survival free from moderate or severe MR or clinically intraprocedure myocardial ischemia, and possibly reduce
KG-27.indd 226 02-11-2018 13:50:12

CHAPTER
27

a
di
In
Figure 10: CardiAQ first generation (left) and second generation Figure 11: Tiara transcatheter mitral valve
(right) transcatheter mitral valve
of
incidence of postoperative RV and septal dysfunction.
Several TMVR devices are in various stages of investigation
and some of these are summarized below.3,4,17-20
ty
CardiAQ Edwards TMV: The CardiAQ was the first TC
18 cie
heart valve to be implanted in native mitral annulus in
humans, which was done through transseptal route from
femoral venous access in 2012. In subsequent cases,
the valve, requiring 33 F access, has been deployed
20 o
transapically. While the first-generation valve was made
S
of porcine pericardium, the second-generation device

consists of three bovine pericardial leaflets mounted on
al
a self-expandable nitinol frame. The valve is circular,

and intended for supra-annular deployment to reduce
ic
the ventricular profile (and subsequent risk of LVOT

Figure 12: Tendyne transcatheter mitral valve
obstruction). The anchoring mechanism consists of two
(with tether and apical pad)
og
sets of circumferentially oriented opposing anchors,

which secure the device to the mitral annulus (Figure 10). is repositionable and retrievable even after complete
The ventricular anchors take support from the native
deployment (Figure 12). However, concerns have been
ol
leaflets. The RELIEF study is currently evaluating the

raised regarding effect of future ventricular remodeling on
clinical safety and performance of this valve in patients
the apical tether. In addition, while the transapical route
di
with DMR or FMR.

is a straight shot, circumvents any aortoiliac disease and
Tiara valve and transapical delivery system: The Tiara gives optimal control, large size transapical access may
ar
valve is a self-expanding trileaflet valve made of bovine further worsen LV function in heart failure patients. An
pericardium and a nitinol frame. The D-shaped valve is early feasibility study of 110 patients with the Tendyne
C
designed to conform to the D-shape of the mitral annulus

valve is currently recruiting subjects.
(Figure 11). The atrial portion has a full atrial skirt and helps
to seat the prosthesis in the atrial portion of mitral annulus. Medtronic intrepid TMV: The Intrepid device has a dual
There are two anterior and one posterior ventricular structure, consisting of a circular inner stent to house
anchors, which fix the valve onto the fibrous trigone and the valve and a conformable outer fixation ring to engage
posterior part of mitral annulus. The valve requires a 32 F the mitral anatomy. The outer fixation ring is designed to
delivery system and can only be deployed transapically. accommodate the variability of the native mitral annulus
The TIARA-I and TIARA-II studies are currently evaluating while isolating the inner valve assembly throughout the
clinical safety and efficacy of this valve. cardiac cycle (Figure 13). The device is designed for
Tendyne transapical TMV: The Tendyne self-expandable transapical access only. The first-in-human case was
nitinol double frame porcine pericardium trileaflet valve performed in 2014. The APOLLO trial is an ongoing first of
is unique in its concept of using an apical tether as its its kind randomized trial comparing TMVR (using Intrepid
anchoring mechanism. This dedicated transapical valve device) to surgical MVR.
227
KG-27.indd 227 02-11-2018 13:50:18

SECTION transfemoral TMVR system has a 28 F profile and began
recruitment for its European feasibility study (AHEAD)
3 in 2017. Other devices in various preclinical stages of
development include AccuFit, Cephea, Saturn TMVR, and
Abbott TMVR, to name a few.
Choosing the Ideal MV Therapy (Surgical vs TC

and Repair vs Replacement)
The most important factor in deciding the mode of therapy
is assessment of the surgical risk by an experienced heart
a
team. The Society of Thoracic Surgery (STS) scoring
system may not correctly assess the risk for it does not take
di
into account the frailty, hostile chest, and RV dysfunction,
which are very important risk factors. The other important
In
Figure 13: Intrepid transcatheter mitral valve
factor to decide about the treatment is anatomic suitability
by CT and echo.
Caisson TMVR system : The Caisson TMVR system
of
consists of two main components, an anchor and a valve High-risk patients who are inoperable: Patients with DMR
should undergo MitraClip and may participate in EXPAND
(Figure 14). The anchor is D-shaped and implanted onto
study. The FMR patients may also undergo MitraClip and
the mitral annulus such that tips of the ventricular feet
ty
can be a part of COAPT continued access trial. For patients
engage under the annulus, and the atrial holding features
with a bioprosthetic valve/surgical ring at mitral position,
engage with atrial surface of annulus. The valve consists
18 cie
of a self-expanding nitinol frame with three porcine
pericardial leaflets and is designed to nest in the anchor.
TMVR (VIV/VIR) with Sapien-3 may be considered.
High-to-intermediate risk patients who are operable:
Both the valve and anchor are fully retrievable. In contrast PASCAL Clip may be inserted and the patient enrolled in
20 o
to most transapical devices, this 31 F system is designed the PASCAL Clip trial. The patient may also be considered
S
for delivery using a transseptal approach. The PRELUDE is for TMVR early feasibility trials with one of the TMVR
an ongoing early feasibility study with the Caisson TMVR devices (like Tiara, Tendyne, CardiAQ, Intrepid, Caisson,
system. Highlife M3). In patients with a bioprosthetic valve
al
at mitral position or a mitral ring, a VIV or VIR TMVR

Highlife TMVR device: The Highlife device consists
with one of the TAVR valves, such as Sapien-3, may be
ic
of a ring (polymer tube with nitinol hooks) placed in

considered. Valve in MAC may be considered in patients
subannular position around the native valve leaflets; the
with MAC.
og
trileaflet bovine pericardial valve is placed inside this ring.

After the ring is placed through femoral artery approach, Operable patients: Surgery is treatment of choice for low-
the valve is deployed transapically like a VIR procedure. risk patients.
ol
Postdeployment, the native leaflets are trapped between Significant residual MR after mitral repair is bad. A good
the ring and the valve. The device is in early feasibility trial MV repair is better than replacement and a replacement is
di
stage. definitely better than a bad repair. Only surgical repair by

an experienced surgeon in carefully selected DMR gives a
MValve system: The MValve system is not a valve but a
ar
good repair and in the purest sense, there is no good TC

docking system designed to be compatible with a variety of
MV repair, especially if multiple targets (leaflet, annulus,
commercially available transcatheter valves. The docking
C
chordae and ventricle) are involved. When multiple

system is placed transapically; and subsequently, the
components of the mitral valve apparatus are involved,
valve can be anchored within this docking system. The
MV replacement is preferable by TC or surgical approach
first-in-human implantation was performed in 2015; the
depending upon other factors. The TC treatment should
early feasibility will be studied in dedicator of cytokinesis
be offered only in selected situations, especially if the
1 (DOCK 1) study.
patient does not want or has been refused surgery.
Other dedicated TMVR systems in early stages With localized central MR due to P2 prolapse, a large
of development/testing: The NaviGate valve is a self- MV area of >4 cm 2 and no or minimal calcification, a
expandable TMVR system consisting of a nitinol stent- MitraClip may be offered as a part of EXPAND study
frame with a truncated cone. The valve is anchored by or one may enter Edward CLASP Trial, especially if the
annular winglets. The 30 F system can be delivered by patient does not want surgery. The FMR patients may
transapical, transatrial, or transseptal approach. The first- be MitraClipped as a part of CAS study. Those with a
in-human valve was deployed in 2015. The Cardiovalve wide jet extending from one commissure to the other
228
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CHAPTER
27

a
di
In
of
Figure 14: Caisson transcatheter mitral valve (anchor and valve within anchor)
ty
commissure or with multiple jets, if there is mild-to-
18 cie
moderate calcification, may undergo TMVR with early
feasibility trials (Edward P3 TMVR Trial). If there is severe
MAC and low risk for LVOT obstruction (LVOT-to-mitral
20 o
inflow angle of < 45° & neo LVOT area of >100 mm2) valve
in MAC may be done.
S
As the risk of an individual patient increases, one leans

towards TC therapy; and as the anatomical complexity
al
of MV disease increases, one chooses replacement

(Figure 15). If we extrapolate findings of Cardiothoracic
ic
Surgical Trials Network (CTSN) in FMR, where recurrence

was high in certain patients (e.g. severe leaflet tethering,
og
markedly dilated ventricle >65mm and inferobasal

aneurysm), one should preferably replace the valve rather
than repairing in this group of patients. A combination of
ol
Figure 15: General scheme for repair/replacement by surgical or

TC repair therapies (e.g. Cardioband with MitraClip) as
transcatheter approach
well as a combination of TC repair with replacement (e.g.
di
VIR procedure within a Cardioband) may be considered in

select patients. PERCUTANEOUS THERAPIES FOR TRICUSPID
ar
In general, a repair approach is more respectful of VALVE

the physiology of the mitral valve complex. As shown As more and more data regarding the not-so-innocuous
C
in surgery, mitral replacement is associated with a outcomes of persistent tricuspid regurgitation (TR) in
nonphysiological inflow pattern from the LA to LV. This patients with left heart disease has emerged over the last
results in increased LV stress and a loss in LV efficiency. few years, efforts at PC treatment of functional TR have
This may not be trivial, in particular in patients suffering gained pace. The tricuspid valve (TV) presents with its
from heart failure with a low EF. Basal LV contraction own set of challenges that differ from the MV. The TV
is expected to be reduced by fixation of these large annulus is larger, elliptical, and more fragile. Patients
prostheses to the mitral annulus. The contribution of frequently have pacing leads traversing the TV and many
basal contraction to the cardiac output again plays a major have already undergone left-sided heart surgery. However,
role in heart failure patients with severely depressed EF. possibly the biggest challenge in TV interventions is that
Hence, MV repair (TC or surgical), despite its demand for these patients are referred only when refractory RV failure
higher clinical expertise, should be the first choice when has set in—and the outcomes of any intervention at this
anatomically feasible. late stage are suboptimal.
229
KG-27.indd 229 02-11-2018 13:50:27

SECTION The prevalence of TR in patients with left-sided heart more, with less dependency on TEE compared to mitral
disease is about 50%. The prognostic impact of TR in such Cardioband. The TRI-REPAIR study is currently ongoing
3 patients is directly related to its severity; with current
guidelines proposing correction of TR at the time of left
with Cardioband at the tricuspid position.
IRIS Millipede system: The IRIS Millipede system (also

heart surgery. Late occurring TR after mitral valve surgery

used for TC mitral annuloplasty) is a repositionable
affects up to 37% patients and is associated with worse
clinical outcomes. Treatment options are limited, as and retrievable complete ring, which can be implanted
operative mortality rates for redo surgery can be as high surgically or by TC approach on the atrial side of native
as 20%; TC TV repair/replacement has a niche use in TV annulus, in order to restore its shape and diameter. It is
this subgroup of patients. A third group includes patients an appealing technology, but there appears to be high risk
with isolated true TR; risk-benefit ratio of conventional of complete AV block since the complete ring compresses
a
surgery for this group is unclear and TC therapies may be the annulus at the attachment of septal tricuspid leaflet,
impinging on the base of triangle of Koch.
di
worth offering. PC therapies for TR under early clinical/
preclinical testing include the following:21-24 Caval valve implantation (CAVI) concept (Heterotopic
In
Mitralign system: Originally designed for MR, the therapy implantation): An alternative approach to PC treatment
has shown promise in functional TR as well (Mitralign of TV is to implant a TC prosthesis in IVC (single valve
device with modified delivery approach – TriAlign system). approach) or in both IVC and SVC (dual valve) to prevent
of
It is based on the established surgical principle of Kay, damage to liver and other organs. The single valve
which involves bicuspidization of TV using two pledgeted approach may be preferable in patients with advanced
sutures which are delivered over a radiofrequency wire to RV dysfunction as there is less increase in RV afterload.
ty
anatomically opposite sites of the TV annulus and then The Sapien XT has been deployed within a self-expanding
plicated using a plication lock device. The procedure stent in the vena cava, acting like a valve and preventing
18 cie
is time consuming and requires advanced 3-D TEE
guidance. The early feasibility SCOUT study has shown
backpressure effects of TR.
Self-expandable devices with little radial force are
encouraging 30-day results with this device. likely to be a superior alternative, as they do not require
20 o
pre-stenting of the landing zone. The TricValve is a
TriCinch device: Using a steerable catheter, a corkscrew
dedicated device for this purpose; the SVC device has
S
is deployed close to mid-part of anterior TV annulus.

a one-size valve diameter of 30 mm in the tubular part of
The delivery system is retrieved and a self-expanding
the stent, with a variable hip protrusion of up to 45 mm.
al
nitinol stent is introduced over the wire and coupled to

The IVC device is deployed with the jacketed valve part in
the implant. Under real-time echo guidance, the whole
the right atrium and a waist in the hiatus of the diaphragm,
ic
system is then tensioned to reshape the TV promoting

allowing hepatic veins to drain unobstructed into the IVC.
annular cinching and to increase the leaflet coaptation.
Pulsatile systolic blood flow reversal in the caval
og
Finally, the stent is deployed in the inferior vena cava

veins is a prerequisite for proper function of the caval
(IVC) to maintain the tension applied. The PREVENT trial
valves. Postprocedure caval V-waves are flattened, while
is currently ongoing with this device.
atrial V-waves increase. In the acute phase, mean caval
ol
TRAIPTA concept: A circumferential compressive implant pressures are only slightly reduced (2–3 mm Hg). In the
is delivered along the AV groove through femoral vein following weeks, the remodeling of RV due to reduced
di
approach after right atrial appendage puncture. The volume load initiates a fall in RA and caval vein pressures.
procedure can only be performed in cases with free Although the concept is appealing due to its simplicity,
ar
pericardial space, thereby excluding a significant subgroup it is worth noting that the TR per se is not reduced by this
with prior cardiac surgery. technique. The persistence of right atrial volume overload,
C
ventricularization of RA and increase of RV afterload are

Cardioband system: Mirroring what is done at mitral
potential limitations of this procedure. Unlike most other
position, the Cardioband has been successfully used for
TC techniques, CAVI is not based on any established
functional TR, through transfemoral approach, of course,
surgical principle. Its long-term impact on RA and RV
without a septal puncture, primarily anchoring the band
function is currently unknown. Ongoing trials with this
on anterior and posterior leaflets, sparing the septal leaflet
technology include the TRICAVAL and HOVER trials.
near the triangle of Koch to avoid the AV block. A Fielder
wire in the right coronary artery (RCA) serves as reference FORMA device: It is a simple procedure with few anatomic
and the anchors are kept within the C of the wire loop. limitations and can treat a wide range of patients with even
Cinching is done under normal hemodynamics to test the advanced disease, having severely dilated RA, RV and/or
reduction of TR, which, if not satisfactory, can be undone annulus. It can handle a wide variety of leaflet or chordal
to repeat the cinching again. Check angio of RCA is done geometry including patients with pacemaker lead(s). A
to rule out any injury to the RCA. Fluoroscopy is used spacer is positioned in the TR orifice and distally anchored
230
KG-27.indd 230 02-11-2018 13:50:27

to the RV, to create a platform for native leaflet coaptation. another refinement in technique, which has been shown CHAPTER
Proximal fixation is obtained in a small surgically prepared to reduce rates of stent fracture and future reintervention.
pocket in the subclavian fossa. Given the wide area of
noncoaptation in TR, relatively large and bulky devices
An early feasibility study with the self-expanding Harmony
valve is currently recruiting patients; the device has an
27

would be required to fill the gap of regurgitant orifice. hourglass design and can be used in patients with larger
This is among the few repair options that can be helpful in RVOT diameter.2,25
torrential TR where leaflet and annuloplasty devices may
not be effective. CONCLUSION
MitraClip in tricuspid position: In 2017, Nickenig et al. Many advances have been made in the realm of valvular
published their experience of using MitraClip device in heart interventions beyond TAVR, with MitraClip and
a
the tricuspid position in 64 patients, with acceptable safety valve-in-valve procedures having gained maximum
and some reduction in the degree of TR. MitraClip is more clinical acceptance. Conquering the noncalcified native
di
effective for TR if coaptation defect is <10 mm or is brought mitral annulus still seems at least a few years away.
to <10 mm after annuloplasty. MitraClip XTR system may As clinicians, we must be aware of ongoing trials that
In
be preferable at the tricuspid position owing to its larger are recruiting patients so that suitable patients can be
coaptation surface area. The PASCAL system is useful informed of the same, for the mutual benefit of both
for challenging tricuspid anatomy with larger coaptation
of
patient and science. It is important to note that outcomes
defects. are more favorable when the disease process is addressed
Tricuspid VIV and VIR procedures : Experience is early – hence allowing RV (in cases of TR and PR) or LV (in
ty
accumulating with the Sapien and Melody valves for cases with MR) dysfunction to set in/progress without even
VIV and VIR procedures in tricuspid position. Given the discussing PC treatment strategies with the patients may
18 cie
unfavorable acute angle between the IVC and TV while
using the femoral vein approach, the transjugular route
may be preferable. As of 2015, 156 patients had undergone
not be justified in this day and age. Also, while discussing
metallic versus bioprosthetic valve implantation prior
to surgery, patients should be informed that if and when
20 o
VIV or VIR procedures as per the VIVID registry – and the their bioprosthetic valve degenerates in future, VIV is
numbers have picked a significant pace since then. likely to be a feasible alternative to redo surgery.
S
NaviGate tricuspid valved stent: The NaviGate valved stent

is a dedicated tricuspid valve replacement system available REFERENCES
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in sizes up to 52 mm and can be deployed through the 1. Kan JS, White RI Jr, Mitchell SE, et al. Percutaneous balloon
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system. The device can be used in cases with torrential pulmonary valve stenosis. N Engl J Med. 1982;307(9):540-2.
TR (where most repair techniques are not feasible), 2. Chatterjee A, Bajaj NS, McMahon WS, et al. Transcatheter
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markedly dilated annulus or after failed TV annuloplasty. Pulmonary Valve Implantation: A Comprehensive
Attainment of complete seal at the TV position is difficult Systematic Review and Meta-Analyses of Observational
and incidence of paravalvular leak is high. Studies. J Am Heart Assoc. 2017;6(8). doi: 10.1161/
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JAHA.117.006432.
3. Regueiro A, Granada JF, Dagenais F, et al. Transcatheter
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Mitral Valve Replacement : Insights From Early Clinical

IMPLANTATION Experience and Future Challenges. J Am Coll Cardiol.
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percutaneously in 2000. However, the valve had an 4. Ramlawi B, Gammie JS. Mitral Valve Surgery: Current
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sizes [16 mm and 18 mm diameter that can be used up to Debakey Cardiovasc J. 2016;12:20-6.
5. Pai RG, Tanimoto M, Jintapakorn W, et al. Volume-rendered
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of 22 mm]. As a result, a large number of potential
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6. Bab a l ia ro s V C , G re e n b au m A B , Kha n JM , e t a l .
has partly overcome this limitation (useful for RVOT IntentionalPercutaneous Laceration of the Anterior
diameter up to 27 mm). In addition, use of Russian doll Mitral Leaflet toPrevent Outflow Obstruction During
technique (implantation of double or triple layer bare Transcatheter Mitral Valve Replacement: First-in-Human
metal stent prior to valve insertion) may facilitate use in Experience. JACC Cardiovasc Interv. 2017;10:798-809.
larger RVOTs. The use of two Melody valves implanted 7. D’ascenzo F, Moretti C, Marra WG, et al. Meta-analysis
in both pulmonary arteries has also been reported. 25,26 of the usefulness of Mitraclip in patients with functional
Routine use of pre-stenting prior to valve implantation is mitral regurgitation. Am J Cardiol. 2015;116(2):325-31.
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SECTION 8. Sharma R, Gafoor S. Percutaneous Mitral Valve Repair: The 18. Verheye S, Cheung A , Leon M, et al. The Tiara transcatheter
Next Wave. Cardiac Int Today. 2017;11(4):65-70. mitral valve implantation system. EuroIntervention.
3 9. Markham R, Kyranis S, Aroney N, et al. Transcatheter
mitral valve intervention: an emerging treatment for mitral
2015;11:71-2.
19. Perpetua EM, Reisman M. The Tendynetranscatheter mitral
regurgitation. Int Med J. 2018;48(4):382-90.
valve implantation system. EuroIntervention. 2015;11:78-9.

10. Rodés-Cabau J, Kalavrouziotis D. Transcatheter Mitral 20. Meredith I, Bapat V, Morriss J, et al. Intrepid transcatheter
Valve-in-Valve Replacement: The New Gold Standard for
mitral valve replacement system: technical and product
Treating Mitral Bioprosthesis Failure? JACC Cardiovasc
description. EuroIntervention. 2016;12:78-80.
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21. Taramasso M, Pozzoli A, Guidotti A, et al. Percutaneous
11. Bapat V. Technical pitfalls and tips for the valve-in-valve
procedure. Ann Cardiothorac Surg. 2017;6:541-52. tricuspid valve therapies: the new frontier. Eur Heart J.
12. Bapat V. Valve-in-valve apps: why and how they were 2017;38:639-47.
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developed and how to use them. EuroIntervention. 2014;10 22. BouletiC , Juliard JM, Himbert D, et al. Tricuspid valve and
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13. Dvir D, Webb J. Mitral valve-in-valve and valve- Archives of Cardiovascular Disease. 2016;109:55-66.
inring: technical aspects and procedural outcomes. 23. Besler C, Meduri CU, Lurz P. Transcatheter Treatment
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EuroIntervention.2016;12:93-6.doi:10.4244/EIJV12SYA25. of Functional Tricuspid Regurgitation Using the Trialign
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ugly. Euro Intervention. 2016;11:1092-4. doi: 10.4244/
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24. Latib A, Mangieri A. Transcatheter Tricuspid Valve Repair:
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15. Guerrero M, Dvir D, Himbert D, et al. Transcatheter Mitral 2017;69(14):1807-10.
Valve Replacement in Native Mitral Valve Disease With
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25. BiernackaEK, Rużyłło W, Demkow M. Percutaneous
Severe Mitral Annular Calcification: Results From the
pulmonary valve implantation – state of the art and Polish
First Multicenter Global Registry. JACC Cardiovasc Interv.
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(MITRAL) (ClinicalTrials website). 2016. Available
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26. Boudjemline Y, Legendre A, Ladouceur M, et al. Branch
at:https://clinicaltrials.gov/ct2/show/NCT02370511. pulmonary artery jailing with a bare metal stent to anchor
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17. Søndergaard L, De Backer O, Franzen OW, et al. Firstin- a transcatheter pulmonary valve in patients with patched
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Human Case of TransfemoralCardiAQ Mitral Valve large right ventricular outflow tract. Circ Cardiovasc Interv.
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In
of
Congenital Heart
T
Disease—Key Issues ty
18 cie
I
20 o S
Epidemiology of Congenital Heart Disease in India

al
Anita Saxena
O
Assessment of Congenital Heart Defects with Left-to-Right Shunts
ic
and Pulmonary Hypertension for Operability

R Krishna Kumar
og
Pregnancy and Congenital Heart Disease

Arima Nigam
N
ol
A Simplified Approach to the Management of Congenitally

Corrected Transposition of Great Arteries
di

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Epidemiology of Congenital
CHAPTER 28 Heart Disease in India
Anita Saxena
a
di
INTRODUCTION identified in less than 20% of CHD cases.4 In about 10% of
India is the second most populous country in the world cases, CHD may be associated with certain chromosomal
In
with a population reaching almost 1.3 billion and is and nonchromosomal syndromes. Common examples
one of the fastest growing major economies. The Indian include Down’s syndrome, where prevalence of CHD is
economy was the world’s seventh largest by nominal gross 45–50%.5
of
domestic product (GDP) and third largest by purchasing A number of risk factors have been attributed
power parity two years ago. India is now considered a new to the causation of CHD. Conventional risk factors
include maternal rubella infection (and other viral
ty
industrialized country. However, she continues to face
the challenges of poverty, malnutrition, and inadequate infections), maternal diabetes, family history of CHD,
exposure to medications in the first trimester and in
18 cie
public health care. As many as 2.2 to 2.5 million children
are born in India every year.1 In recent decades, notable
progress has been made in reducing the child mortality.
vitro fertilization pregnancies amongst others. Use of
antibiotics (trimethoprim-sulfonamide combination and
The proportion of deaths due to infectious causes, such as nitrofurantoin) in the first trimester and use of fertility
20 o
pneumonia, diarrhea, and neonatal sepsis, has decreased drugs to assist conception are known to be associated
with higher frequency of birth defects. Antibiotics could
S
and thereby the proportion of deaths from congenital

causes has increased. Of the congenital birth defects, be a significant factor in India as these drugs are freely
congenital heart disease (CHD) is the most frequently available over the counter in most parts of the country and
al
occurring disorder, responsible for 28% of all congenital inappropriate use of antibiotics is rampant. Paternal age at
birth defects.2 conception and high maternal body mass index have also
ic
The birth prevalence of CHD has generally been been blamed for CHD in the fetus.
accepted worldwide at 8-10/1000 live births for several In some studies, parental consanguinity has been
og
decades. 3 It seems logical to believe that the birth found to aggravate the underlying genetic risk for CHD
prevalence of CHD is similar across the various parts of as an autosomal recessive component. 6,7 Studies from
the world, there may only be some minor differences in the India, Saudi Arabia, and Egypt have also found significant
ol
type of CHD by country or race. correlation between consanguinity and risk of CHD.8-
10
With advances in cardiovascular medicine and surgery, Advanced maternal age is another risk factor for
di
majority of children born with CHD in high-income development of CHD.11,12 This may be due to the use of
countries reach adulthood. However, this is not true for assisted reproductive technology (ART) and increased
ar
affected children born in India and other developing incidence of maternal comorbidities such as diabetes,
countries as such advanced care is not available for all obesity, hypertension, and medication use. Advanced
C
those born with CHD. Considering birth prevalence as paternal age at conception has also found to be a risk
9/1000, the estimated number of children born with factor.
CHD would be 242,390 every year. This is a tremendous
challenge for the society, healthcare system and families. INCIDENCE AND PREVALENCE
Treatment of CHD is resource intensive and expensive and The occurrence of new cases of CHD has been labeled
this fact remains a major barrier to achieve good care of as incidence. As CHD is present since birth, incidence
children with CHD. So, the epidemiology of CHD in India is often referred to as ‘birth prevalence’ and is generally
is likely to be very different from the epidemiology of CHD expressed as number of cases of CHD per 1000 live births.
in high income and developed countries. Prevalence of CHD is defined as number of living patients
with CHD at a specific period of time. Various studies
RISK FACTORS in the past have reported a wide range in estimates of
The etiology of CHD is not known in over 85% of cases. birth prevalence, figures varying from 4–5 cases/1000
Despite a strong heritable basis, a genetic etiology is live births.3,13 In a systemic review and meta-analysis of
KG-28 (Sec-4).indd 235 02-11-2018 13:57:49

SECTION 114 papers and 24,091,867 live births, CHD was detected perhaps related to better diagnostic modalities. After
in 164,396 babies. The birth prevalence of CHD showed early 2000, most studies have reported a decline in birth
4 an increase over time and was 9.1/1000 live births [95%
confidence interval (CI): 9.0-9.2) after the year 1995.14
prevalence, which may be real, due to the various factors
enumerated above.
Congenital Heart Disease—Key Issues
Higher birth prevalence in Asia could in part be due

to high consanguinity rates in some study population, Incidence or Birth Prevalence of CHD in India
including one from India.8,15 The birth prevalence of severe
Most studies reported from India are not on incidence,
CHD has been more consistent, reported as 1.5-1.7/1000
but on prevalence. Some are conducted in the community
live births.3,13,14
and will be discussed in the section on prevalence of CHD.
Factors that may decrease the birth prevalence
Others are based on data from pediatric patients reporting
include increasing use of fetal echocardiography leading
a
to pregnancy termination in case a complex CHD is to hospitals, as outpatients or as inpatients, such studies
obviously have a large sampling bias and the reported
di
detected.16 In high-income countries, almost half to three-
fourths of critical CHD are detected during pregnancy.17,18 prevalence rates are much higher.20-24 The true incidence
or birth prevalence has been reported in four studies from
In
Many of these pregnancies are terminated once critical
CHD is detected. As much as 21% reduction in birth India, all of which are hospital based.25-28 The details of the
prevalence of CHD may be due to antenatal detection.16,19 findings are given in Table 1. In the two recent studies, all
newborns have undergone echocardiography. As can be
of
Other factors that may be responsible for decrease in
the birth prevalence of CHD include improvement in seen, the prevalence rates are quite variable. In the study
maternal health, e.g. better control of diabetes mellitus and by Khalil A et al. the diagnosis has been made by thorough
clinical examination in all 10,964 newborns.25 Suspected
ty
reduction in smoking and alcohol consumption during
pregnancy. There is growing evidence to suggest that newborns were further investigated by X-ray chest and
18 cie
folic acid supplementation may be effective in decreasing
the risk of CHD. According to the European Registration
of Congenital Anomalies and Twins (EUROCAT) data
ECG, and were followed up for a period of 6–18 months.
Out of the 96 babies suspected of having CHD, definite
CHD was diagnosed in 43. However, echocardiography
reported in the year 2009 and derived from European confirmed CHD only in 30. The study by Vaidyanathan B
20 o
network of population based registries for epidemiologic et al. was primarily done to develop a clinical strategy for
S
surveillance of congenital anomalies from 22 regions in diagnosis of CHD in newborns through a combination
Europe, a decline in birth prevalence of CHD was seen of clinical examination and pulse oximetry. 26 Major
from 2004 onwards.2 Severe CHD decreased by 14% from CHD was found in 17 of 5,487 newborns screened. All
al
1.95/1000 live births in 2000-2001 to 1.67/1000 live births babies had undergone echocardiography; however, two
in 2008-2009. A significant decline was also seen overall in of 17 major CHD cases were initially missed on the first
ic
birth prevalence of CHD from over 7/1000 to under 6/1000 echocardiography. It is not clear from their study whether
og
for the same period. of the 119 minor CHD at 6 weeks of follow-up, how many
Overall, data suggests that a rise in birth prevalence were real CHD, since some of small atrial septal defects
of CHD was seen until the beginning of the years in 2000, and patent ductus arteriosus may be normal variations
ol
di
Table 1: Birth prevalence of congenital heart disease in India

Author No. of babies Screening method No. of babies Echo Prevalence/1000 live
ar
screened with CHD confirmation births
Khalil A et al. 199425 10,964 Clinical examination only 43 30/43 3.9

C
Vaidyanathan B et al. 201026 5,487 Clinical Minor: All Minor CHD:

pulse oximetry 408 at birth 74.4 at birth
echocardiography 119 at 6 weeks 21.7 at 6 weeks
Major: 17 Major CHD: 3.1
Sawant SP et al. 201227 2,636 Clinical, echocardiography in 35 All 13.28
suspected cases only
Saxena A et al. 201628 20,307 Clinical All Significant: 8.07
pulse oximetry Significant: 164 (95% CI, 6.94-9.40/1000)
echocardiography Major: 71 Major CHD: 4.5/1000
Note:
Minor congenital heart disease: Atrial septal defect >5 mm, patent ductus arteriosus >2 mm with left ventricular volume overload, ventricular
septal defect with gradient of >30 mm Hg, aortic stenosis/pulmonic stenosis with gradients of <25 mm Hg and pulmonary artery branch stenosis
with gradients of <20 mm Hg.
Major congenital heart disease: Congenital heart disease that is likely to require early intervention.
Significant congenital heart disease: Includes minor and major congenital heart disease but pulmonary artery branch stenosis is not included.
236
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Table 2: Prevalence of congenital heart disease in India CHAPTER
28
Author Age group Setting Place of study Total no. Screening method No. with Prevalence per
(years) CHD 1000
Vashishtha et al. 199331 5–15 School Agra 8,449 Clinical 44 5.2

Thakur et al. 199532 5–16 School Shimla 15,080 Clinical 30 2.25
Chadha et al. 200133 <15 Community Delhi 11,833 Clinical 50 4.2
Misra et al. 200934 4–18 School Eastern Uttar 118,212 Clinical 42 1.3
Pradesh Echo for suspected
cases only
Kumari et al. 201335 5–16 School Dist. Prakasam, 4,213 Clinical and echo 39 9.2
Andhra in all
a
Pradesh
Saxena et al. 201336
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5–15 School Ballabgarh, 14,716 35 2.37
Haryana Clinical and echo
77 5.23
In
Bhardwaj et al. 201637 All age Community Himachal 1,882 Clinical 12 6.3
groups Pradesh (<18 years: echo for suspected 12.95 (in <18 years)
Mean age: 660) cases only
of
19.5 + 11.1
and can close after 6 weeks also. Similarly, pulmonary childhood.30 The prevalence of CHD is likely to be lower
ty
artery branch stenosis, which was also included as minor in India as compared to high-income countries. Most of
CHD in their series, is mostly physiologic and disappears diagnosed cases of CHD in adults have not yet undergone
18 cie
with time. Sawant SP et al. reported birth prevalence of
13.28/1000 in a cohort of 2,636 babies born in Bhabha
any intervention. The proportion of adults who had
undergone a cardiac surgery was only 14% in a public
Atomic Research Centre Hospital, Mumbai. 27 Only those hospital in New Delhi.29 This proportion may be somewhat
20 o
suspected to have CHD underwent echocardiography. higher in private hospitals catering to relatively affluent
S
However, a good follow-up and timely intervention, families. The prevalence of CHD in older children and
performed as per clinical requirement, gives credence to adults is likely to be much lower in India. Several studies
this study. The study by Saxena A et al. was also done in have reported the prevalence of CHD.31-37 As can be seen
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a general hospital setting and all 20,307 newborns were in Table 2, the prevalence of CHD has varied from 1.3 to
screened by echocardiography.28 In this study, insignificant 9.2/1000 population, five of seven studies available are
ic
CHD cases including those with pulmonary artery branch in schoolchildren. The wide variation is partly explained
stenosis were excluded. The birth prevalence of CHD by population studied and the diagnostic method used.
og
was more in keeping with the data available in literature Studies using echocardiography as a screening tool show
from other countries. It is important to note that all the a higher prevalence than those where clinical examination
four studies on birth prevalence in India are done in alone has been used. This is largely due to inclusion of
ol
hospital setting with its attendant sampling bias. Large, relatively milder forms of CHD. Since rheumatic heart
methodological, community-based studies are required. disease is also prevalent in India, especially during school
di
age, finding of a murmur by auscultation is not necessarily

Prevalence of CHD in India indicative of CHD. Unless confirmed by echocardiography,
ar
one can overestimate or underestimate the prevalence of

Prevalence should be calculated by taking the total number
CHD. The relative occurrence of individual CHD lesions
of cases born with CHD and then subtracting those that
C
reported in Indian and Western studies are summarized

would have died or cured, e.g. due to spontaneous closure
in Table 3.
of either a ventricular septal defect or a patent ductus
arteriosus. The total number of CHD cases keeps on
increasing, at least in countries where advanced care is PREVENTION
available to children with CHD. In several high-income Prevention of a disease is often far less expensive than
countries, where the birth rates are low and success rates treating it. Prevention of CHD may not be possible in a
of CHD intervention are high, the prevalence of CHD in majority since the cause of CHD is not known. However,
adults has either equaled or exceeded the prevalence by reducing the fertility rates, the number of children
of CHD in children.29 This is not the case for India since born with CHD will decrease. This strategy has been
the survival to adulthood is much lower for want of demonstrated to be successful in China, Vietnam, and
cardiac surgery. Considering that only 10–15% of children many other countries. If the fertility rate in India is
born with CHD undergo an intervention and that the reduced from the current of 2.2 to 1.1 per woman, the
natural survival rate for CHD overall is only 67% beyond incidence of CHD will reduce to 50% of current birth 237
KG-28 (Sec-4).indd 237 02-11-2018 13:57:50

SECTION Table 3: Demographics of India in comparison to China and United States of America
4
India China United States of America
Total Population* 1,311,050,527 1,371,220,000 321,418,000
Crude birth rate/1000* 20 12.07 13.2
Fertility rate/woman* 2.2 1.6 1.8

No. of children born annually 26,932,586 16,591,762 3,978,497
No. of children with CHD born each year 242,390 149,325 31,828
(estimated prevalence of CHD) (9/1000) (9/1000) (8/1000)
No. of children with critical CHD (estimated 43,092 26,547 6365
prevalence 1.6/1000)
a
Under 5 mortality/1000 live births** 53 13 7
Infant mortality /1000 live births 41 11 6
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Human development index*** 131 90 10
In
GDP per capita* 6104.6 14,450.7 56,115.7
Health expenditure (as a % of GDP)* Total: 4.7% Total: 5.5% Total: 17.1%
Government: 1.4% Government: 3.1% Government: 8.3%
of
Population per one cardiac center 16 million (Asia) 16 million (Asia) 120,000
6
Population served by one cardiac surgeon 12 million (2017) 25 million (Asia, 2013) 3.5 million (2013)6
Abbreviation: CHD, congenital heart disease
ty
*http://data.worldbank.org/indicator. Accessed on 28th May 2018
**https://data.unicef.org/country. Accessed on 28th May 2018
***http://hdr.undp.org/en/countries 2016. Accessed on 28th May 2018
18 cie
prevalence. Empowerment and education of women to childbearing age who are planning a pregnancy are
improve efforts for family planning can achieve reduction prescribed 400 ug of folic acid daily as a supplement
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in fertility rates. tablet which is continued till 14 weeks of pregnancy.
S
Specific measures for prevention of CHD include 3. Control of chronic conditions: Adequate control of
counseling of parents to avoid known risk factors for CHD. diabetes, hypertension and other chronic conditions is
Some of the important strategies for prevention of CHD important as these have been shown to be associated
al
are listed below: with CHD.

1. Immunization against rubella: According to a World 4. Complete cessation of smoking and alcohol: All
ic
Health Organization report, a single dose of rubella prospective mothers should be advised to stop smoking
vaccine gives more than 95% long-lasting immunity. and alcohol consumption. Passive smoking must also
og
If a woman gets infected with the rubella virus during be avoided.

early stages of pregnancy, there is a 90% chance of 5. Avoiding harmful medications. All medications,
ol
transmitting it to the fetus. The virus can cause hearing other than vitamin, iron, and calcium supplements
impairments, and eye and brain damage in newborns, (in recommended doses) are best avoided. If the
di
in addition to CHD (congenital rubella syndrome or mother suffers from some chronic conditions, such as
CRS). Of the 110,000 children born with CRS every diabetes, hypertension, and epilepsy, she should be
year globally, an estimated 40,000 cases occur in India prescribed only those drugs that have no or minimal
ar
alone. Rubella vaccine was not included in the vaccine effect on fetus.
schedule in India, till recently. Mass vaccination for 6. Genetic counseling: Prospective mothers or fathers who
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rubella in childhood should be aimed at. have had a previous child with CHD or have a relative
2. Fortification with folic acid: There is a growing with CHD should be referred for genetic counseling
evidence to suggest that folic acid supplementation when planning to get pregnant. Genetic counseling
may be effective not only in decreasing the risk of can advise parents of the likelihood of having a baby
neural tube defects, but also CHD. Several countries with CHD.
including Canada and the USA have a policy of 7. Other measures: Those planning to start a family should
folic acid fortification of flour.39 However, India has be educated about harmful effects of commonly used
no such policy. In a study from Canada, folic acid products such as organic solvents used in dry cleaning,
food fortification was associated with lower rates paint thinners, and nail polish removers. They should
of conotruncal defects, coarctation of the aorta, avoid contact with persons with symptoms of viral
ventricular septal defects, and atrial septal defects.40 infection.
The prevalence of severe nonconotruncal heart defects 8. Fetal echocardiography: Strictly speaking, fetal
238 was not reduced. In many other countries, women of echocardiography should not be considered as a tool
KG-28 (Sec-4).indd 238 02-11-2018 13:57:50

to prevent CHD. However, termination of pregnancy this time. The less affluent population relies primarily on CHAPTER
may be considered for complex CHD with adverse government-aided programs. Public hospitals are faced
long-time outcome despite cardiac surgery. Fetal
echocardiography should be performed between 18
with a very large number of patients and have waiting
lists ranging from months to years, especially as the
28

and 20 weeks of pregnancy as termination cannot be emergency cases get priority over stable patients. Children
resorted to beyond 20th week of pregnancy. undergoing surgery are often in advanced stages of heart
failure, have severe cyanosis, pulmonary vascular disease
CURRENT STATUS OF CHD CARE IN INDIA and associated malnutrition.46 The results of intervention
in such settings may have long-term squelae.
Advanced cardiac care is practically unavailable to over
The resources for treatment of CHD are not only
90% of babies born in developing countries, including
inadequate but also seriously maldistributed. The
a
India.41 A gross disparity exists between developing and
geographical distribution of these centers is very uneven
developed countries as far as care of children with CHD
di
and a number of centers have been established over the
is concerned (Table 3), primarily related to the economic
last 15 years or so in the southern states of India which
status of the country as measured by GDP. Whereas one
In
are economically better off and have better literacy
cardiac center caters to a population of 120,000 in North levels. Some of the most populous states of India (with
America; in Asia, 16 million population is served by one the highest birth rates and lower domestic product) in
center.42 In Africa, it is one center for 33 million population.
of
central and eastern parts do not have even one center
Similarly, the number of cardiac surgeons is also much that can provide optimal care for neonates and infants
more in North America and Europe (one cardiac surgeon with CHD. Therefore, a large number of children born in
per 3.5 million population) as compared to Asia (one
ty
India with CHD have practically no access to affordable
cardiac surgeon per 25 million population). 43 Of the treatment. Rapid population growth, lack of healthcare
180,000–200,000 children born with CHD each year in
18 cie
India, about one-fourth would need early intervention to
survive the first year of life. The magnitude of the problem
funding, competing priorities, inefficient and inadequately
equipped infrastructure, and a deficit of trained staff at all
levels of health care are some of the major roadblocks to
is further compounded by a large pool of older infants and cardiac care of children with CHD in the country.
20 o
children who may have survived despite no intervention. Predischarge screening of newborns by pulse oximetry
S
These facts indicate that hundreds of thousands of is practiced infrequently, especially in rural and semiurban
children die from CHD each year and many more are in centers. In contrast to high-income countries, the rate
desperate need of treatment. A number of cardiac care of antenatal detection of CHD is very low, though exact
al
centers have come up in India in the last 12 years or so, data is not available. This is despite the fact that routine
their total number approximates to 62, though only 9 of ultrasound in pregnancy is commonly performed. Front
ic
these can be considered high-volume centers (more than line health workers are not sensitized to the problem of
500 cardiac surgeries per year). As per data provided by
og
CHD. A number of physicians/pediatricians still believe

all large- and medium-volume centers and majority of that a child with CHD is doomed and will never be able
small-volume centers, a total of approximately 24,000 to lead a fruitful life even if intervened. This leads to delay
patients with CHD underwent cardiac surgery in the year
ol
between diagnosis and referral to a cardiac center.

2016. Of this total number, about 8,500 patients are infants Once the diagnosis of CHD is made, it may be difficult
under one year of age and about 1,600 are neonates, one
di
for families to travel to cities where cardiac care facilities

month of age or under. Considering the birth prevalence are available as pediatric cardiac centers are very sparsely
of serious CHD (requiring intervention in the first year of
ar
located in some parts of India. In most instances, families

life) as 1.6/1000 live births, about 43,000 babies are born are expected to pay for the treatment out of their pocket,
in India every year with serious CHD. Only 8,500 or 20% of which they can ill-afford. Insurance companies in
C
these receive optimal cardiac care. However, looking at the general do not cover for the cost of treatment of CHD in
positive side, this number is much better when compared India. Though several state government level programs,
with that published earlier. The estimated numbers of microfinance schemes, and charitable and philanthropic
cardiac surgeries for infants were only 1,200 in the year organizations exist for the benefit of economically weaker
1998.44 In another study published from India in the year sections of the society, awareness amongst public about
2005, it was estimated that <2% of total number of infants such programs is very low.
and newborns requiring heart surgery actually receive According to data collected from over 40 centers
optimal treatment.45 in India, about 35% of cardiac surgeries are funded by
Most of centers caring for CHD patients, especially families themselves. Most families find it hard to pay out of
those set up more recently, are in the private sector and their pocket, as cost of surgery may be more than family’s
may not be affordable for the majority of Indian population. annual income. This is especially true for complex CHD
Unfortunately, the number of government-aided centers operated in private hospitals since the stay in intensive
and public hospitals have not expanded much during care unit can be long. Government schemes, mostly at state
239
KG-28 (Sec-4).indd 239 02-11-2018 13:57:50

SECTION level, cover about 40% of all surgeries for CHD patients. level. Although one can have a specific program for children
Many hospitals partner with charitable nongovernment with CHD, a more comprehensive program which caters
4 organizations and multinational companies to assist
economically weaker families. About 20% of cardiac
to the well-being of children in general, and incorporates
a number of other common disorders is more likely to be
surgeries are funded by such organizations. Other sources sustainable. Periodic education programs to sensitize the
of funding include parents’ employer, donations, etc. practicing physicians and pediatricians are necessary. The
(<5%). Some of the charitable cardiac centers are providing front line health workers as well as community in general
absolutely free treatment; however, such centers generally should be made aware of the availability of advanced
have long waiting lists. care in India for children with CHD. The various national
Health-seeking behavior of the community and local programs which screen and fund treatment of CHD and
religious and sociocultural practices in India affect the other diseases in children should be advertised in print
a
level of care received by children with CHD. Parents often media and national television. This will greatly aid in early
di
do not seek medical care until the child develops advanced diagnosis also. Screening newborns with pulse oximetry
degree of disability as it is difficult and expensive to seek to diagnose critical CHD has been found to be useful in
In
treatment. It is usual in clinical practice to come across several studies in the past including one study from India.
older children and adults who have significant symptoms/ This should become a part of newborn care.48
cyanosis attending healthcare facility for the first time. Establishing more centers for cardiac care would
of
Gender bias, as prevalent in some societies, may put girls be ideal, but this is the most challenging task. The
at a disadvantage compared to boys. In a study from a investments required are huge. One not only needs
referral tertiary care center, girls were less likely to undergo sophisticated technology and infrastructure but also
ty
cardiac surgery for CHD than boys.47 A scar on the chest a motivated team of health professionals. Pediatric
may adversely affect the chances of a girl’s marriage. cardiac care is a team effort and includes cardiologists,
18 cie
Investment on health care is one of the lowest in India
when compared with several other countries, including
developing countries (Table 3). Of the total investment
surgeons, anesthesiologists, intensive care specialists,
and many other specialists. Currently, there are over 60
such centers in India; but as mentioned earlier, these are
on health, less than one-third is contributed by the not geographically well distributed. There should be at
20 o
government, rest is all private contribution. There is no least one center in each state unit, so that families do not
S
national level policy for CHD. However, as the burden of have to travel long distances to new cities with different
infectious diseases decline, future may see an increasing local environments and languages. Ideally, these centers
budget for noncommunicable diseases of children, should be supported by the government, either directly
al
helping the cause of CHD also. or through welfare schemes so that families belonging
to middle and lower strata on socioeconomic scale can
ic
also reap the benefits. This would also maintain a high

Strategies for Improvement of Cardiac Care
volume of cases, leading to professional satisfaction and
og
for Children with CHD motivation of the employed staff.

The care of children in high-income countries have Since establishing a state-of-the-art pediatric cardiac
improved tremendously with practically every child born care center is very resource intensive, an alternative strategy
ol
with CHD receiving optimal care and surviving to reach that has been often practiced in India is piggybacking
adulthood. It may not be feasible to follow the formulated pediatric cardiac program on a successful ongoing
di
guidelines in high-income countries, as India has limited adult cardiac program. This model optimizes resource
resources which need to be very optimally utilized so utilization. The cardiac catheterization laboratory,
ar
that benefit is provided to maximum number of children. operating rooms, and other laboratory services are shared
Significant strides have been made in trying to achieve for both pediatric and adult patients. In such ‘adult-
C
better care of these children in the last 20 years or so. program first’ models, the pediatric cardiac program
However, India being a huge country, largest democracy, is gradually expanded. Relatively simpler surgeries are
and with limited resources, it is surely an uphill task. performed initially. Later, a dedicated team is able to
Health is a state subject and the various states of India take on more demanding surgeries and interventions,
differ vastly in their economy, literacy levels, population, including those on neonates and infants. Such models
languages, cultural beliefs, and human development have been successfully employed in many hospitals,
indices. This regional diversity makes the task more including large multispecialty public hospitals. The
difficult as ‘one size fits all’ approach is not tenable. downside is that pediatric program may not take off
So far, little emphasis has been placed on preventive well as it drains much more resources than the adult
measures for CHD (detailed above); this needs to be cardiology program. Whatever be the model of care, a
stressed more as the investment required is much constant evaluation of its performance is mandatory. All
smaller. Mass immunization against rubella and folic acid efforts should be made to follow postintervention patients
fortification should be the starting point at the national meticulously. Collection of outcome data to assess the
240
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quality of program is very important for self-sustainability REFERENCES CHAPTER
and this data should be collected for early, mid-term and
28
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ol
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not differ much, the care available for these children is Heart Assoc.2013;2(3):e000064.
13. Hoffman JI, Kaplan S. The incidence of congenital heart
ar
vastly different. A large proportion of children with CHD go

undiagnosed and untreated in India. Prevention of CHD disease. J Am Coll Cardiol. 2002;39(12):1890-900.
is not entirely possible but universal immunization for 14. van der Linde D, Konings EE, Slager MA, et al. Birth
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prevalence of congenital heart disease worldwide: a

rubella, folic acid supplementation along with education
systematic review and meta-analysis. J Am Coll Cardiol.
and counseling of prospective parents is likely to reduce
2011;58(21):2241-7.
incidence to some extent. The care of children with CHD is 15. Naderi S. Congenital abnormalities in newborns of
a continuing challenge due to huge numbers and limited consanguineous and nonconsanguineous parents. Obstet
resources. A significant amount of progress has been made Gynecol. 1979;53(2):195-9.
in India for the management of children with CHD over the 16. Germanakis I, Sifakis S. The impact of fetal echocardiography
last 50 years or so, but it still remains grossly inadequate. on the prevalence of liveborn congenital heart disease.
Pediatr Cardiol. 2006;27(4):465-72.
17. Tomek V, Marek J, Jicínská H, et al. Fetal cardiology in
ACKNOWLEDGMENT the Czech Republic: current management of prenatally
Author would like to acknowledge all those who provided diagnosed congenital heart diseases and arrhythmias.
data of their centers for preparation of this chapter. Physiol Res. 2009;58(Suppl 2):S159-66.
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SECTION 18. Tegnander E, Williams W, Johansen OJ, et al. Prenatal 33. Chadha SL, Singh N, Shukla DK. Epidemiological study
detection of heart defects in a non-selected population of of congenital heart disease. Indian J Pediatr. 2001;68(6):
4 30,149 fetuses—detection rates and outcome. Ultrasound

Obstet Gynecol. 2006;27(3):252-65.
507-10.
34. Misra M, Mittal M, Verma AM, et al. Prevalence and pattern
of congenital heart disease in school children of eastern
19. Bull C. Current and potential impact of fetal diagnosis

on prevalence and spectrum of serious congenital heart Uttar Pradesh. Indian Heart J. 2009;61(1):58-60.
disease at term in the UK. British Pediatric Cardiac 35. Rama Kumari N, Bhaskara Raju I, Patnaik AN, et al.
Association. Lancet. 1999;354(9186):1242-7. Prevalence of rheumatic and congenital heart disease
20. Kapoor R, Gupta S. Prevalence of congenital heart disease, in school children of Andhra Pradesh, South India. J
Cardiovasc Dis Res. 2013;4(1):11-4.
Kanpur, India. Indian Pediatr. 2008;45(4):309-11.
36. Saxena A. Echocardiographic prevalence of congenital
21. Bhat NK, Dhar M, Kumar R, et al. Prevalence and pattern
cardiac malformations among 14,716 asymptomatic school
a
of congenital heart disease in Uttarakhand, India. Indian J
children in India. Presented at EuroEcho Imaging 2013.
Pediatr. 2013;80(4):281-5.
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37. Bhardwaj R, Kandoria A, Marwah R, et al. Prevalence of
22. Wanni KA, Shahzad N, Ashraf M, et al. Prevalence and congenital heart disease in rural population of Himachal - a
spectrum of congenital heart diseases in children. Heart
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population-based study. Indian Heart J. 2016;68(1):48-51.
India. 2014;2(3):76-9. 38. Pillutla P, Shetty KD, Foster E. Mortality associated with
23. Kiran B, Chintan S, Reddy C, et al. Study of prevalence of adult congenital heart disease: trends in the US population
congenital heart diseases in children in a rural tertiary care from 1979 to 2005. Am Heart J. 2009;158(5):874-9.
of
hospital. J Pediatr Res. 2016;3(12):887-90. 39. Ionescu-Ittu R, Marelli AJ, Mackie AS, Pilote L. Prevalence of
24. Abqari S, Gupta A, Shahab T, et al. Profile and risk factors severe congenital heart disease after folic acid fortification
for congenital heart defects: a study in a tertiary care of grain products: time trend analysis in Quebec, Canada.
ty
hospital. Ann Pediatr Cardiol. 2016;9(3):216-21. BMJ. 2009;338:b1673.
25. Khalil A, Aggarwal R, Thirupuram S, et al. Incidence of 40. Liu S, Joseph KS, Luo W, et al. Canadian Perinatal
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congenital heart disease among hospital live births in
India. Indian Pediatr. 1994;31(5):519-27.
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Effect of folic acid food fortification in canada on congenital
heart disease subtypes. Circulation. 2016;134(9):647-55.
26. Vaidyanathan B, Sathish G, Mohanan ST, et al. Clinical
41. Tcher venkov CI, Jacobs JP, Bernier PL , et al. The
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screening for congenital heart disease at birth: a prospective
improvement of care for paediatric and congenital cardiac
study in a community hospital in Kerala. Indian Pediatr.
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disease across the world: a challenge for the World Society

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outcome of congenital heart disease in Bhabha Atomic 42. Pezzella T. Worldwide maldistribution of access to cardiac
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286-91. 43. Hoffman JIE. The global burden of congenital heart disease.
28. Saxena A, Mehta A, Sharma M, et al. Birth prevalence of Cardiovasc J Afr. 2013;24(4):141-5.
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congenital heart disease: a cross sectional observational 44. Kumar RK, Shrivastava S. Pediatric heart care in India.
study from north India. Ann Pediatr Cardiol. 2016;9(3): Heart. 2008;94(8):984-90.
205-9. 45. Saxena A. Congenital heart disease in India: a status report.
ol
29. Webb G, Mulder BJ, Aboulhosn J, et al. The care of adults Indian J Pediatr. 2005;72(7):595-8.
with congenital heart disease across the globe: Current 46. Liu J. Challenges and progress of the pediatric cardiac
di
assessment and future perspective: a position statement surgery in Shanghai Children’s Medical Center: a 25-year
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Cardiovasc Surg Pediatr Card Surg Annu. 2009. pp. 12-18.
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Disease (ISACHD). Int J Cardiol. 2015;195:326-33.

47. Ramakrishnan S, Khera R, Jain S, et al. Gender differences
30. Sam ánek M. Children with congenital heart disease:
in the utilisation of surgery for congenital heart disease in
probability of natural sur vival. Pediatr Cardiol.
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India. Heart. 2011;97(23):1920-5.

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48. Saxena A, Mehta A, Ramakrishnan S, et al. Pulse oximetry
31. Vashishtha VM, Kalra A, Kalra K,et al. Prevalence of as a screening tool for detecting major congenital heart
congenital heart disease in school children. Indian Pediatr. defects in Indian newborns. Arch Dis Child Fetal Neonatal
1993;30(11):1337-40. Ed. 2015;100(5):F416-21.
32. Thakur JS, Negi PC, Ahluwalia SK, et al. Congenital heart 49. Pezzella AT. Cardiothoracic surgery residency program
disease among school children in Shimla hills. Indian Heart in Shanghai, China. Ann Afr Chir Thor Cardiovasc.
J.1995;47(3):232-5. 2009;4(2):81-99.
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Assessment of Congenital Heart
Defects with Left-to-Right Shunts
CHAPTER 29 and Pulmonary Hypertension for
Operability
R Krishna Kumar
a
di
INTRODUCTION The reduced availability of endogenous nitric oxide (NO)
Left-to-right shunts are traditionally classified as pre- and and increased production of vasoconstrictor prostanoids
In
post-tricuspid shunts. Pretricuspid shunts occur at the in response to high pulmonary blood flow result in
level of atria and include atrial septal defect (ASD) and impaired endothelium-mediated relaxation and increased
partial anomalous pulmonary venous return. Shunts at vasomotor tone.10,11 Studies in rats with an experimentally
of
the level of ventricles or great arteries are known as post- created aortocaval shunt have demonstrated changes
tricuspid shunts. They often have symptoms and failure in the morphology and vasoreactivity of the pulmonary
arterial wall with an increase in the thickness of the internal
ty
to thrive during infancy and may result in death from
heart failure and pneumonia if correction is delayed.1-4 elastic lamina and basement membrane and a widening of
the subendothelial space due to exposure to high blood
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Ventricular septal defects (VSDs) and patent ductus
arteriosus (PDA) are common examples of post-tricuspid
shunts. A proportion of infants with large post-tricuspid
flow. Protein quantification carried out using Western
blot analysis and scanning densitometry demonstrated
shunts, however, survives infancy without surgery and increased levels of endothelial nitric oxide synthase
20 o
may even show transient reduction in pulmonary blood (eNOS) and cyclooxygenase-2 (COX-2) in the pulmonary
S
flow. In the long-term, however, this process often arterial wall. Cyclic guanosine 3′,5′-monophosphate
becomes progressive leading to the development of (cGMP) levels measured by radioimmunoassay are
pulmonary vascular occlusive disease with right-to-left reduced accounting for the decreased biological activity
al
shunting and cyanosis. of endogenous nitric oxide. 12 The imbalance between

Eisenmenger in 18975 initially described a 32-year-old COX-2-mediated vasoconstrictor prostanoids and
ic
man with cyanosis and hemoptysis who was found after endogenous NO in response to high pulmonary blood flow
death to have a VSD. Paul Woods in 19586 coined the term results in increased pulmonary arterial vaso-reactivity.
og
Eisenmenger syndrome to describe situations where high Table 1 summarizes the various mechanisms responsible
pulmonary blood flow due to left-to-right shunts results in for development of increased PVR.
pulmonary vascular occlusive disease and shunt reversal. The response of the pulmonary vasculature to high
ol
Although patients with ASDs usually do not present in pulmonary blood flow is, however, not uniform and
early infancy, they may be associated with pulmonary does not occur in a predictable fashion.3,4 This results
di
vascular obstructive disease (PVOD) in adulthood. in difficulties in decision making regarding operability
For a variable period of time, after pulmonary vascular of these defects particularly in patients who present
ar
resistance (PVR) starts to increase, the changes in lung beyond infancy and early childhood. There appears to
vasculature may still be reversible following correction of be a spectrum in the development of pulmonary vascular
C
the defect (operable situation). Once PVOD is established, disease (PVD) with a subset of patients with high PVR
closure of the defect may actually worsen the natural and advanced pulmonary vascular occlusive disease in
history (inoperable situation). The question of operability early infancy at one end of the spectrum 13 and adults
most commonly arises in older children and adults with who remain operable with large left-to-right shunts at the
large post-tricuspid shunts and selected patients (mostly other.14
adults) with shunts at the atrial level (pretricuspid) who The two main factors that affect patient outcome after
develop increased PVR. The clinical and management closure of large left-to-right shunts have been identified
implications of elevated PVR in this group of patients as the age at repair and the preoperative PVR. 5,15-17
remains unclear and has been the subject of intense The rapid evolution of pediatric cardiac surgery and
debate.7 cardiology in recent decades has lead to early correction
The mechanism and histological changes of pulmonary in these patients in much of the developed world. The high
vascular occlusive disease in the setting of increased mortality associated with infant cardiac surgery during
pulmonary blood flow has been extensively described.8,9 the 1960s 4,12 has dramatically declined with excellent
KG-29.indd 243 02-11-2018 13:57:24

SECTION Table 1: Mechanisms that contribute to development of increased pulmonary vascular resistance in congenital heart defects associated
with increased pulmonary blood flow
4 Broad category Specific consequences
Loss of endothelial barrier function resulting z Degradation of extracellular matrix, release of growth factors, smooth muscle
from high flow and pressure hypertrophy and proliferation, extension of smooth muscle into peripheral pulmonary
arteries, smooth muscle migration with neo-intima formation
z Adherence and activation of platelets, activation of coagulation pathways and
thrombosis
Activation of the endothelin system Vasoconstriction and unfavorable vascular remodeling
Decreased production of prostacyclin Shift of balance in favor of arteriolar vasoconstriction
Decreased production of nitric oxide Shift of balance in favor of arteriolar vasoconstriction, reduction in antiproliferative stimuli
a
Increased turnover of serotonin Pulmonary arteriolar vasoconstriction
di
Altered expression of pulmonary potassium Accentuated response to hypoxia
channels
Mutations in bone morphogenetic protein May account for rapid development of PVD (PVD) in selected patients. Bone
In
receptor (type 2) and activin-like kinase (type 1) morphogenetic protein (BMP) receptor type 2 mutations have been identified in 6% of
patients associated with pulmonary arterial hypertension (PAH)
of
results now being achieved at minimal risk in early large population of untreated older children with CHD
infancy. However, progression to inoperability, a feared including several with simple shunt lesions (such as VSDs)
complication of large left-to-right shunts still remains a many of whom have varying degrees of elevation of PVR.
ty
reality particularly in low-resource environments of low- There is an urgent need to evolve management guidelines
and middle-income countries (LMICs). for these patients. The key question that needs to be
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There remains a striking paucity of management
guidelines regarding operability in patients with left-to-
answered relates to whether or not the lesion is operable
(or correctable if catheter intervention is feasible).
right shunts and pulmonary hypertension (PH) presenting
20 o
beyond infancy and early childhood. The rare infant who OBJECTIVES OF THE REVIEW
S
presents with left-to-right shunts and elevated PVR can To provide a framework for decision making on
also be challenging. Some hemodynamic information is
operability in common left-to-right shunts using
available from early studies of patients with large left-to-
al
clinical, noninvasive and invasive investigations.

right shunts in the catheterisation laboratory.3,4,18,19 These To suggest indications for diagnostic catheterization
were performed in the era when cardiac surgery was only
ic
for shunt lesions.

realistic in relatively older children. These studies were To identify the sources of error in hemodynamic
limited by small numbers of patients included and limited
og
assessment : shunt quantification, resistance

follow-up duration and could not generate unambiguous
calculations.
guidelines for decision making and could not establish
clear cut-offs for operability. Once infant heart surgery
ol
was well established in the 1980s, there was no impetus for CORRELATING PREOPERATIVE
refinement of these guidelines because almost all patients HEMODYNAMICS WITH LUNG BIOPSY
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were operated well before establishment of irreversible FINDINGS AND CLINICAL OUTCOMES
PVOD. The 1980s also saw the advent of two-dimensional Several studies have identified a period of reversibility
ar
and color echocardiography. Rapid refinements in this of PH in patients with left-to-right shunts prior to the
modality allowed clear anatomic definition of most forms development of Eisenmenger syndrome; and, it is
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of congenital heart disease (CHD) virtually eliminating the important to identify this subset of patients who would
need for cardiac angiography for anatomic definition. 20 still benefit from the abolition of the left-to-right shunt.
By 1990s, most institutions had stopped performing The quest for a relatively less invasive index to help
diagnostic cardiac catheterization for most forms of CHD. differentiate between reversible and irreversible PH has
For the majority of the world’s children who live in been ongoing since the 1950s with early recognition
LMICs, correction of heart defects in early infancy is not that higher preoperative pulmonary/systemic arterial
realistic. This unfortunate situation exists for most of pressure (Pp/Ps) and resistance [pulmonary vascular
India. This is because of a number of reasons that include resistance and systemic vascular resistance (PVR/SVR)]
a paucity of resources and deficiencies in the health ratios are associated with more advanced stages of PVD
infrastructure that do not allow timely detection of CHD. on lung biopsy and a higher incidence of early and
With improving human development in many parts of the late postoperative PH.21,22 This relationship, however,
world, new centers with congenital heart surgery expertise is neither constant nor predictable and the degree of
are being established. These centers have to deal with a individual variability makes it difficult to apply a single
244
KG-29.indd 244 02-11-2018 13:57:24

cut-off to determine operability in these patients. Studies investigations. Early in the course of disease, when the CHAPTER
comparing hemodynamic data with lung biopsy findings shunt is operable, there is often clear evidence of increased
as a ‘gold standard’ are further limited by the questionable
reliability of lung biopsy in determining operability
pulmonary blood flow. Later, with increasing PVR, there is
evidence of progressive reduction in pulmonary blood
29
Assessment of Congenital Heart Defects with Left-to-Right Shunts...

in these situations. 7,23 Classical teaching that defines flow. As pulmonary blood flow starts to decline, clinical
irreversible PVD as having at least Grade 3 histological correlates become subtle. With further increase in PVR,
changes 9 has been questioned with studies reporting they become equivocal. Eventually, it is clinically obvious
patients deemed operable by histological grading to that PVOD has set in and PVR is severely elevated.
have suffered adverse outcomes with postoperative These patients are often hypoxic from shunt reversal
hypertension. 24,25 Conversely, patients with evidence (Eisenmenger syndrome).
of irreversible PVD on lung biopsy have undergone
a
successful surgery with no correlation between pre- ACCURATE HEMODYNAMIC ASSESSMENT IN
di
and postoperative hemodynamic data and lung biopsy
SHUNT LESIONS: WHO NEEDS IT MOST?
findings. 7 Despite these caveats, a PVR index value of
6–8 Woods units m2 is widely accepted as a cut-off for Accurate hemodynamic assessment is of importance at
In
operability in children with large post-tricuspid left-to- intermediate levels of elevation in PVR and calculations
right shunts. In addition, corollaries have been proposed of flows and resistance through cardiac catheterization
may provide useful additional information. This is in
of
using vasodilators including 100% oxygen, tolazoline, and
NO.26 These arbitrary boundaries are, however, constantly spite of the uncertainties surrounding the predictive
being challenged with the increasing use of postoperative value of preoperative hemodynamics on postoperative
outcomes. Although late presentation of left-to-right
ty
pulmonary vasodilators and the advent of innovative
surgical strategies. 27,28 Although initial reports related shunts is uncommon in the Western world, it still remains
a substantial problem in LMICs. 28,29 Typically, in these
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the pre operative hemodynamic data with postoperative
outcomes recent studies have failed to demonstrate a
significant association between preoperative PVR and
patients, clinical examination, chest X-ray (CXR), ECG
and echocardiogram fail to clearly determine operability
PVR/SVR ratio and outcomes.7,29 status. Cardiac catheterization still remains an important
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tool in the clinician’s diagnostic armamentarium. Cardiac
S
catheterization still does contribute immensely in

CLINICAL AND NONINVASIVE CORRELATES determining the degree of PH and the PVR in patients with
OF HEMODYNAMIC CHANGES IN LEFT-TO- borderline clinical evidence for operability.
al
RIGHT SHUNTS The hemodynamic information from cardiac

There are important clinical, electrocardiogram (ECG), catheterization may also help the clinician to make specific
ic
X-ray, and echocardiographic correlates of changes in recommendations regarding operative and perioperative
the pulmonary vasculature (Figure 1). Elevation in PVR strategies like the use of fenestrated patches, insertion of
og
can, therefore, be easily suspected through these basic pulmonary arterial lines for monitoring, and perioperative
ol
di
ar
C
Figure 1: The clinical and echocardiographic correlates of spectrum of changes in pulmonary vascular resistance
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KG-29.indd 245 02-11-2018 13:57:24

SECTION use of pulmonary vasodilators.27,28,30 Also, decision making clinical and noninvasive evaluation. It is also important
regarding operability becomes critical in some patients to evaluate patients in the ‘borderline situation’ on more
4 as closure of the defect can cause progression of PH
and adversely affect the natural history of a disease that
than one occasion. This is especially true for those with
associated lung and airway issues. Even apparently
would otherwise allow survival into the third or fourth insignificant lung conditions can substantially elevate PVR
decade of life.31 In the context of transcatheter closure, and result in a clinical picture suggesting an inoperable
hemodynamic assessment aids in appropriate device situation.
selection. The fenestrated ASD device which has been The direction of shunting across the defect is a useful
used in patients with PH32 and in the closure of ASDs in tool with predominantly left-to-right shunting favoring
the elderly with decreased left ventricular compliance33 operability. The ventricular septal position in patients
can be used instead of a fenestrated ASD patch in patients without a large VSD, the Doppler flow pattern, and
a
with raised PVR. Similarly, the ASD or VSD device is used gradient across the defect gives further information about
di
in patients with PDA and PH where using an Amplatzer the pulmonary arterial pressure.
PDA plug would carry a high risk of embolization to the In our experience, the presence of clinical cyanosis
In
aorta because of the absence of a retention disc on the or saturations < 90% is a strong predictor of inoperability,
pulmonary arterial end.34-36 whereas the clear detection of a mid-diastolic murmur
on serial assessment strongly favors operability. In our
of
institution, the majority of our patients who present
ROLE OF CLINICAL EXAMINATION, ECG,
beyond infancy with large left-to-right post-tricuspid
CHEST X-RAY, ECHOCARDIOGRAPHY AND
shunts are assessed and operability status determined
ARTERIAL BLOOD GAS
ty
purely on the basis of clinical examination, chest X-ray,
The significance of clinical clues in patients with elevated ECG, and echocardiography. It is only a small minority
18 cie
PVR cannot be overemphasised. Serial assessment by
multiple experienced clinicians improves the reliability of
clinical examination as a tool in determining operability.
that have required cardiac catheterization to obtain
hemodynamic data.
The role of arterial blood gas (ABG) measurement
20 o
Pediatric cardiologists and cardiac surgeons who have has not been adequately investigated in these situations.
been taking care of patients in the developing world place Patients with PDA may show a lower PO2 in the femoral
S
great emphasis on a comprehensive clinical evaluation artery (vs. right radial artery). This may prove to be more
of the patient before a decision is made to operate. sensitive than measurement of oxygen saturation. A
al
Considerable importance is given to history, physical decline in arterial PO2 after exercise may suggest fixed PVR
examination, chest X-ray, arterial blood gas estimation, as the fall in systemic vascular resistance during exercise
ic
ECG and echocardiography (Table 2). These modalities is not balanced by a corresponding fall in PVR allowing
provide independent useful information on the status of for increased right-to-left shunting across the defect and
og
the pulmonary vasculature. There are occasions when increased hypoxia on the blood gas. In addition, blood
inspite of equivocal cardiac catheterization data, the heart gas analysis also allows assessment of respiratory function
defect is successfully corrected based on a comprehensive and the presence of hypercarbia should alert the clinician
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Table 2: Assessment of hemodynamics in left-to-right shunts—basic investigations

Modality Clues suggesting operability Clues suggesting inoperability
ar
History Feeding difficulty, failure to thrive, tachypnea and frequent Absence of symptoms or ‘improvement’ in status as
respiratory infections in infancy suggested by improved feeding, weight gain and resolution
C
of tachypnea
Physical Increased precordial activity, labored respiratory efforts Visible cyanosis, quiet precordium, loud single S2, absence
examination (subcostal and intercostal recession), split second heart sound of flow murmurs, early diastolic murmur of pulmonary
(S2), mid-diastolic ‘flow’ murmurs regurgitation
Oxygen Normal (> 95%) Reduced (< 90–95%)
saturation*
Chest X-ray Cardiac enlargement, increased vascularity suggested by Normal heart size, normal or reduced vascularity, evidence
prominent end-on vessels, visible vascularity in the peripheral of pruning with dilated hilar pulmonary artery and rapid
lung fields decline in vessel size
ECG Prominent left ventricular forces, q waves in lateral precordial Right ventricular dominance, absence of q waves in lateral
leads precordial leads
*Oxygen saturations cut-offs may not be absolute. For example, patients with ventricular septal defects with significant aortic override may have
some resting desaturation at rest. However, saturations below 90% are seldom compatible with operation in simple shunt lesions. For patent
ducts, oxygen saturation should be estimated in the lower limbs.
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KG-29.indd 246 02-11-2018 13:57:24

to look for restrictive or obstructive pulmonary disease as Correct Sequence of Sampling and Pressure CHAPTER
a contributory factor to the PH. Measurement
After obtaining access in the femoral vein and a 4F sheath 29
HEMODYNAMIC ASSESSMENT IN THE or small 22- or 20-gauge intravenous cannula (especially

CATHETERIZATION LABORATORY in young children) in the artery, an arterial blood gas is
Hemodynamic studies need to be done meticulously and obtained (unless a separate arterial access is required for
the study). This will serve as a baseline prior to starting the
efficiently such that all the required samples and pressure
procedure and is particularly useful in determining the
measurements are obtained under more or less identical
carbon dioxide levels (pCO2) which serves as a reflection
physiological conditions. of gas exchange in the lungs. A high pCO2 can cause an
The key factors to successful hemodynamic evaluation increase in PVR and should be excluded before recording
a
in the catheterization laboratory are given below. hemodynamic data.
The usual strategy is to obtain superior vena caval
di
Appropriate Hardware Selection (SVC) saturations and right atrial (RA) pressures on the
way in. In cases where anomalous venous drainage is
In
Wide bore end-hole catheter for accurate pressure
suspected in the SVC, additional samples from the high
measurements.
SVC is needed to get a true mixed venous saturation.
Swan-Ganz balloon tipped catheter to aid entry
Saturations in the IVC tend to be unreliable because of
of
into the pulmonary artery and to obtain pulmonary streaming effect from hepatic (low saturations) and renal
capillary wedge pressures in the absence of an atrial venous returns (high saturations). If there is an atrial septal
communication. opening, the left atrium (LA) is entered and LA pressure is
ty
Thorough evaluation of anatomy by echocardiography recorded. Pulmonary venous entry is then undertaken
with specific attention to: and both pressure and saturation are recorded in one or
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Atrioventricular valve (AVV) abnormalities which
can impact on pressure measurements, e.g. mitral

stenosis can contribute to PH in the presence of a left-
more pulmonary veins. The pulmonary artery (PA) is then
entered and PA pressure and saturation are obtained along
with aortic pressure and saturation measurement from
to-right shunt or preclude repair of the defect, e.g. AVV the arterial route. All hemodynamic data should thus be
20 o
straddle. obtained prior to any angiography as contrast can provoke
S
Presence of an atrial communication which will aid

changes in PVR and alter the baseline hemodynamics.
entry into the pulmonary veins. In the absence of an Sometimes, difficult PA entry may cause an unacceptable
delay in obtaining PA pressure and saturations and data
al
atrial communication, pulmonary venous saturations

may need to be re-obtained from the other chambers on the
are arbitrarily assumed to be 98% and pulmonary
way out. This strategy, however, has the disadvantage of loss
ic
capillary wedge pressures are obtained using a Swan-

of catheter position in case PA angiography is required after
Ganz balloon-tipped catheter in the pulmonary artery. obtaining hemodynamic data.
og
Great artery relationship which will influence the
catheter manipulation strategy. Calculation of Flows and Resistances

Careful attention to obtaining and recording accurate
Detailed discussion of PVR calculation is available in
ol
pressure tracings by ensuring:

Calibration and flushing of pressure lines prior to the
standard textbooks.37 We will briefly discuss an example
of a 13–year-old male with a large VSD who underwent
di
procedure.
Recording and measurement of pressures on paper
cardiac catheterization for hemodynamic assessment of
his VSD (Table 3).
ar
rather than reading measurements off the monitor.

Recording of pressures using appropriate scale and
speed, e.g. atrial pressures can be recorded on a Table 3: Case example from a 13-year-old with ventricular septal
C
defect (VSD)
scale of 20 mm Hg, whereas left ventricular pressures
need to be recorded on a scale of 100 or 200 mm Hg. Chamber Systolic Diastolic Mean Oxygen
pressure pressure pressure saturation
End-diastolic pressure measurement should be done
(mm Hg) (mm Hg) (mm Hg) (%)
on a low scale (20 mm Hg) at fast speed for accurate
SVC 67.5
correlation with the ECG trace.
RA 4 5 2
Accurate measurement of oxygen saturations (SpO2) by:
Availability of a spectrophotometer in the lab
PA 64 48 66 78.6
Taking ample volumes as discard prior to sampling PCWP 10 98*
Removing any air bubbles in the syringe.
Ao 97 53 69 92.5
It is surprising how often these basic measures outlined
*Assumed
above are overlooked resulting in fallacious hemodynamic Abbreviations: SVC, superior vena cava; RA, right atrium; PA, pulmonary
data. artery; PCWP, pulmonary capillary wedge pressure; Ao, aorta
247
KG-29.indd 247 02-11-2018 13:57:25

SECTION We prefer to take a single sample from the SVC as This patient has high PA pressures and an elevated
our mixed venous saturation rather than use formulae PVR (normal < 4 Woods units). It is important in these
4 incorporating SVC and IVC values (e.g. 3 x SVC + 1 x IVC
÷ 4) as the IVC oxygen saturations are very inconsistent
circumstances to rule out other causes of increased PVR
(Table 4).
(sampling near the renal veins gives high saturations and

sampling near the hepatic veins gives low values). Also,
Common Sources of Error with Invasive
the oxygenated IVC blood and deoxygenated coronary
sinus blood more or less cancel each other out in the right Hemodynamic Assessment
atrium. In order to calculate pulmonary (Qp) and systemic A number of errors may substantially interfere with the
(Qs) blood flows and pulmonary (PVR) and systemic accuracy of assessment of flows and resistances in the
vascular resistances (SVR), we use Fick’s principle where: catheterization laboratory (Figure 2).
a
O2 consumption (VO2)
Flow through a circuit = Role of Reversibility Testing for Estimation of
di
Difference in O2 content
between the arterial and Operability
In
venous limbs of the circuit Oxygen and nitric oxide: 100% O2 and NO with O2 have
been conventionally used in preoperative evaluation of
VO2 (L/min) × 100
Qp = patients with an elevated PVR at baseline in order to assess
of
(PV sat – PA sat) × Hb (g/dL) × 1.36 mL/g × 10 the degree of ‘reversibility’. Despite early reports of its
VO2 (L/min) × 100 usefulness, the role of O2 in outcome prediction remains
Qs = questionable.37 In addition, the assumptions regarding O2
[Ao sat – Mixed venous (SVC) sat] ×
ty
Hb (g/dL) × 1.36 mL/g × 10 consumption and O2 content that are routinely employed
in hemodynamic calculations become inaccurate in
Qp/Qs = 18 cie
Ao sat – SVC sat
PV sat – PA sat
patient breathing 100% O2.
Nitric oxide is a well-established short-acting
pulmonary vasodilator and has been used postoperatively
Measurement of VO 2 is laborious and involves
20 o
measuring the O2 concentration in inspired and expired in the management of patients with severe PH following
air using a Douglas bag. Tables are available with values cardiac surgery.27,39 Some authors have even suggested
S
of VO2 that are adjusted for age, sex and heart rate that are a diagnostic role in the postoperative setting to help
used in hemodynamic calculations.38 differentiate between reversible pulmonary vasoreactivity
al
You will notice that we have only considered O 2 and fixed anatomic obstruction giving rise to high right
saturations in calculating oxygen content, ignoring the ventricular pressures. 40 Its role in predicting mid- to
ic
negligible amounts of dissolved O 2 (0.003 O 2/ mm Hg long-term postoperative outcomes in patients with left-
of pO2). This value becomes important only when pO2 to-right shunts and PH is, however, less certain. There
og
exceeds 100 mm Hg following O2 administration. is some data that suggests that response to NO predicts
Therefore, in this patient with a VO2 of 149/m2 and a improved midterm survival in patients with established
body surface area of 1 m2,
PVD.41 Although this may aid in risk stratification and
ol
149 × 100 decision making regarding timing of lung transplantation

Qp = L/min/m2
(98 – 78.6) × 13 × 1.36 × 10 in these patients with advanced PVD, it cannot really be
di
149 × 100 extrapolated to borderline situations where corrective

Qs = L/min/m2 surgery is being considered.
ar
(92 – 67.5) × 13 × 1.36 × 10

92 – 67.5 Table 4: Causes of elevated pulmonary vascular resistance other
Qp/Qs = = 1.29
C
98 – 78.6 than increased pulmonary blood flow
Resistances, expressed in Woods units (Wu) are Mechanism Examples
calculated using the following formula: Reduced oxygen Chronic exposure to high altitude
content in inhaled air
Mean PA pressure – Mean LA pressure Upper airway Enlarged adenoids, sedation (secretions,
PVR =
Qp obstruction upper airway structures, Trisomy 21 and
other similar conditions), tracheomalacia
66 – 10 56
= == 13 Wu Hypoventilation Deep sedation, neuromuscular disorders
4.3 4.3
Restrictive lung Chest wall and spinal deformities,
Mean Ao pressure – Mean RA pressure physiology interstitial lung disease
SVR =
Qs Lower airway Brochiolitis, asthma and similar conditions
obstruction
69 – 2 67
= = = 20 Wu Parenchymal lung Consolidation, collapse, interstitial edema
3.35 3.35 disease (pulmonary venous hypertension)
248
KG-29.indd 248 02-11-2018 13:57:25

valuable technique in the assessment of operability CHAPTER
particularly in adult patients with sizable PDA where
complete occlusion of the duct is feasible.45 Occlusion 29
of septal defects particularly VSDs can, however, be

technically challenging and ensuring complete occlusion
is often difficult. Various criteria have been proposed for
patient selection and these take into account baseline
hemodynamics and post-occlusion fall in PA pressures of
at least 20mm Hg.45 In a recent series of 29 patients with
PDA and PH, successful device closure was achieved in 20
a
patients following trial occlusion. The mean PA pressures
(with range in brackets) before and after occlusion in these
di
patients were 78 mm Hg (50–125mm Hg) and 41 mm Hg
(23–77 mm Hg), respectively. Five out of the remaining
In
9 patients showed increase in PA pressures and 2 had
worsening of symptoms.
We analyzed our own series of 21 patients (median
of
age 6 years) with a large PDA and PH in whom we
performed temporary balloon occlusion prior to deciding
Figure 2: Sources of error in estimation of pulmonary vascular
ty
resistance on suitability for surgical or catheter-based treatment.
Patients with definite clinical evidence of a large left-to-
18 cie
A recent multicenter study of 124 patients with CHD
and PH who underwent hemodynamic testing in room
right shunt or with evidence of irreversible PVD (lower
limb saturations < 80%) were excluded from this series. We
defined ‘responders’ as having a ≥25% fall in PA pressures
air (in 23–30% O2), 100% O2 and NO with O2 concluded
20 o
that the overall reliability of preoperative hemodynamic on balloon occlusion or a ≥50% fall in the ratio between
evaluation was limited despite the use of vasodilators.42 pulmonary and aortic diastolic pressures. By this definition,
S
They suggested that patients with an Rp (PVR): Rs we identified 16 responders and 5 nonresponders. All
(SVR) >0.41 during O2 and NO inhalation are likely to be 16 responders underwent either surgical (5) or catheter-
al
inoperable, whereas patients with an Rp: Rs <0.16 are most based (11) treatment of their PDA. Of the responders,
likely to be operable. However, there is a significant gray there were 5 who remained pulmonary hypertensive at
ic
zone between these values where accurate prediction of 24 hours postprocedure. Of these, 2 patients continued to
have elevated PA pressures/RV systolic pressure on follow-
outcomes is not possible.
og
up. Of the nonresponders, one patient was operated

Studies that examine the role of preoperative testing
elsewhere despite medical advice against surgery and on
with NO are limited by the lack of standardization in the
follow-up had suprasystemic PA pressures. The rest of the
ol
concentration and duration of administration of NO. Also,

nonresponders showed definite symptomatic worsening
most studies have looked at immediate postoperative
over time with further fall in saturations. We noticed that
di
outcomes without any data on long-term survival and

some patients with a high baseline PVR and low Qp/
morbidity. This is an important consideration in a
Qs ratio still responded favorably to balloon occlusion
ar
condition which would normally allow survival into the

and tolerated duct occlusion with normalization of PA
third or fourth decade of life without any intervention.
pressures. Also, there were two instances in our series of
C
Thus, vasodilator testing does not seem to add significantly

patients where despite a favorable response on balloon
to the baseline hemodynamic data and also introduces
occlusion, pulmonary artery pressures remained elevated
scope for errors in calculation.
on follow-up. There needs to be further clarification
Temporary shunt occlusion: Balloon occlusion of the of criteria for response to balloon occlusion in these
pulmonary artery in a patient with a large VSD was circumstances and studies with larger numbers are
originally described as a means of limiting pulmonary warranted.
blood flow and attaining hemodynamic stability prior
to surgery.43 The same effect can be achieved by directly CONCLUSION
occluding the defect to eliminate the left-to-right shunt The issue of determination of operability is important
and has been applied during hemodynamic evaluation in patients with left-to-right shunts who present late.
in order to eliminate flow-related PH. 44 Small case Although a number of unresolved issues exist with the
series have been published on the use of this potentially process of determination of operability using currently
249
KG-29.indd 249 02-11-2018 13:57:25

SECTION available methods, a comprehensive assessment that 14. Holzer R, de Giovanni J, Walsh KP, et al. Transcatheter
incorporates clinical evaluation, noninvasive tests and in closure of perimembranous ventricular septal defects using
4 selected cases, cardiac catheterization with calculation

of flows and resistances allows classification of the vast
the Amplatzer membranous VSD occluder: immediate
and midterm results of an international registry. Catheter
majority of patients. Considerable attention should be Cardiovasc Interv. 2006;68(4):620-8.

paid to accurate collection of hemodynamic data during 15. Kidd L, Driscoll DJ, Gersony WM, et al. Second natural
cardiac catheterization. The role of reversibility studies is history study of congenital heart defects. Results of
treatment of patients with ventricular septal defects.
controversial but may be useful in selected cases. Efforts to
Circulation. 1993;87(Suppl 2):I38-51.
evolve clear guidelines through careful prospective studies
16. Tsuji H, Shapiro M, Magidson O, et al. Surgical treatment
should be undertaken because a number of patients with
of high pressure patent ductus arteriosus. Circulation.
congenital heart defects in LMICs continue to present late
a
1963;27:652-7.
with PH. 17. Bando K, Turrentine MW, Sharp TG, et al. Pulmonary
di
hypertension after operations for congenital heart
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2. Engle MA. Ventricular septal defect in infancy. Pediatrics. dynamics of patients with pulmonary hypertension.
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history of isolated ventricular septal defect - a serial history of pulmonary vascular obstruction associated with
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4. Walker WJ, Garcia-Gonzalez E, Hall R, et al. Interventricular
septal defect: analysis of 415 catheterised cases, ninety with
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20. Sivakumar K, Anil SR, Rao SG, et al. Closure of muscular
ventricular septal defects guided by en face reconstruction
a n d p i c to r ia l re p re s e nt at i o n . A n n Th o ra c Su rg.
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Kammerssheidewand des Herzens. Z Klin Med. 1897; 21. Heath D, Helmholz HJ, Burchell HB, et al. Relationship
32(Suppl 1):1-28.
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between structural changes in the small pulmonary arteries

6. Wood P. The Eisenmenger syndrome or pulmonary and the immediate reversibility of pulmonary hypertension
hypertension with reversed central shunt. Br Med J. following closure of ventricular and atrial septal defects.
al
1958;2(5009):755-62. Circulation. 1958;18(6):1167-74.

7. Sachweh JS, Daebritz SH, Hermanns B, al. Hypertensive 22. Fried R, Falkovsky G, Newburger J, et al. Pulmonary
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pulmonary vascular disease in adults with secundum arterial changes in patients with ventricular septal
or sinus venosus atrial septal defect. Ann Thorac Surg. defects and severe pulmonary hypertension. Pediatr
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2006;81(1):207-13. Cardiol.1986;7(3):147-54.
8. Tynan M, Anderson RH. Ventricular septal defect. Paediatric
23. Frescura C, Thiene G, Giulia Gagliardi M, et al. Is lung
Cardiology, 2nd ed. Edinburgh: Churchill Livingstone.
biopsy useful in surgical decision making in congenital
2002;983-1014.
ol
heart disease? Eur J Cardiothorac Surg.1991;5(3):118-22.

9. Heath D, Edwards. The pathology of hypertensive
24. Haworth SG. Pulmonary vascular disease in ventricular
pulmonary vascular disease: a description of six grades of
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septal defect: structural and functional correlations in lung

structural changes in the pulmonary arteries with special
biopsies from 85 patients, with outcome of intracardiac
reference to congenital cardiac septal defects. Circulation.
ar
repair. J Pathol. 1987;152(3):157-68.

1958;18:533-47.
25. Haworth SG, Radley-Smith R, Yacoub M. Lung biopsy
10. Dinh Xuan AT, Higgenbottam TW, Clelland C, et al.
findings in transposition of the great arteries with
Impairment of pulmonary endothelium-dependent
C
relaxation in patients with Eisenmenger’s syndrome. Br J ventricular septal defect: potentially reversible pulmonary
Pharmacol. 1990;99(1):9-10. vascular disease is not always synonymous with operability.
11. Celermajer DS, Cullen S, Deanfield DE. Impairment of J Am Coll Cardiol. 1987;9(2):327-33.
endothelium- dependent pulmonary artery relaxation 26. Yamaki S, Ogata H, Haneda K, et al. Indications for open
with congenital heart disease and abnormal pulmonary lung biopsy in patients with ventricular septal defect and/
hemodynamics. Circulation. 1993;87(2):440-6. or patent ductus arteriosus and pulmonary hypertension.
12. Lam C, Peterson TE, Croatt AJ, et al. Functional adaptation Heart Vessels. 1990;5(3):166-71.
and remodelling of pulmonary artery in flow-induced 27. Beghetti M, Habre W, Friedli B, et al. Continuous low dose
pulmonary hypertension. Am J Physiol Heart Circ Physiol. inhaled nitric oxide for treatment of severe pulmonary
2005;289(6):H2334-41. hypertension after cardiac surgery in paediatric patients. Br
13. Alt B, Shikes RH. Pulmonary hypertension in congenital Heart J. 1995;73(1):65-8.
heart disease: irreversible vascular changes in young 28. Novick WM, Sandoval N, Lazorhysynets VV, et al. Flap
infants. Pediatr Pathol. 1983;1(4):423-34. valve double patch closure of ventricular septal defects in
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children with increased pulmonary vascular resistance. 37. Keane JF, Lock E. Hemodynamic evaluation of congenital CHAPTER
Ann Thorac Surg. 2005;79(1):21-8. heart disease. In: Lock JE, Keane JF, Perry SB, eds. Diagnostic
29. Kannan BR, Sivasankaran S, Tharakan JA, et al. Longterm
outcome of patients operated for large ventricular septal
and Interventional Catheterisation in Congenital Heart
Disease, 2nd ed. Amsterdam: Kluwer Academic Publishers,
29
defects with increased pulmonary vascular resistance. 2000. pp. 37-72.

Indian Heart J. 2003;55(2):161-6. 38. Lock JE, Einzig S, Bass JL, et al. The pulmonary vascular
30. Faraci PA , Rheinlander HF, Cleveland RJ. Use of response to supplemental oxygen and its influence on
nitroprusside for control of pulmonary hypertension operative results in children with ventricular septal defect.
in repair of ventricular septal defect. Ann Thorac Surg. Pediatr Cardiol. 1982;3(1):41–6.
1980;29(1):70-3. 39. Beghetti M, Morris K, Cox P, et al. Inhaled nitric oxide
31. Somerville J. How to manage Eisenmenger syndrome. Int J differentiates pulmonary vasospasm from vascular
Cardiol. 1998;63(1):1-8. obstruction after surgery for congenital heart disease.
a
32. Fraisse A, Chetaille P, Amin Z, et al. Use of Amplatzer Intensive Care Med. 1999;25(10):1126-30.
di
fenestrated atrial septal defect device in a child with familial 40. Allman KG, Young JD, Carapiet D, et al. Effects of oxygen
pulmonary hypertension. Pediatr Cardiol. 2006;27(6):759- and nitric oxide in oxygen on pulmonary artery pressures
62. of children with congenital cardiac defects. Pediatr Cardiol.
In
33. Holzer R, Cao QL, Hijazi ZM. Closure of a moderately 1996;17(4):246-50.
large atrial septal defect with a self-fabricated fenestrated 41. Post MC, Janssens S, Van de Werf, Budts W. Responsiveness
Amplatzer septal occluder in an 85-year-old patient with to inhaled nitric oxide is a predictor of mid term survival in
of
reduced diastolic elasticity of the left ventricle. Catheter adult patients with congenital heart defects and pulmonary
Cardiovasc Interv. 2005;64(4):513-8. arterial hypertension. Eur Heart J. 2004;25(18):1651-6.
34. Pedra CA, Sanches SA, Fontes VF. Percutaneous occlusion 42. Balzer DT, Kort HW, Day RW, et al. Inhaled nitric oxide as a
ty
of the patent ductus arteriosus with the Amplatzer device preoperative test (INOP Test I): The INOP Test Study Group.
for atrial septal defects. J Invasive Cardiol. 2003;15(7):413-7. Circulation. 2002;106(Suppl 12):I76-81.
35. 18 cie
Spies C, Ujivari F, Schr äder R. Transcatheter closure of a
22 mm patent ductus arteriosus with an Amplatzer atrial
septal occluder. Catheter Cardiovasc Interv. 2005;64(3):
43. Barbero-Marcial M, Verginelli G, Arie S, et al. Intrapulmonary
balloon for temporary relief of pulmonary hypertension. J
Thorac Cardiovasc Surg. 1975;69(6):942-6.
352-5. 44. Ewert P. Challenges encountered during closure of patent
20 o
36. Demkow M, Ruzyllo W, Siudalska H, et al. Transcatheter ductus arteriosus. Pediatr Cardiol. 2005;26(3):224-9.
S
closure of a 16 mm hypertensive patent ductus arteriosus 45. Roy A, Juneja R, Saxena A. Use of Amplatzer ductal occluder
with the Amplatzer muscular VSD occluder. Catheter to close severely hypertensive ducts: utility of transient
Cardiovasc Interv. 2001;52(3):359-62. balloon occlusion. Indian Heart J. 2005;57(4):332-6.
al
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251
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Pregnancy and Congenital
Arima Nigam
a
di
INTRODUCTION Due to enormous anatomic possibilities, every
The most important nonobstetric cause of maternal death female with CHD (whether operated or not) needs an
In
during pregnancy is cardiac disease. 1,2 The cardiologist individualized approach, guidelines are broadly framed
thus is an important member of the multidisciplinary and there is no specific guideline for each congenital
team that takes care of a pregnant female with any cardiac condition.
of
cardiac disease including congenital heart disease There can be myriads of presentations of a pregnant
(CHD). The cardiologist’s opinion is not only essential female with CHD (Figure 1). The patient may present in de
novo state passing through some phase of the unmodified
ty
in prepregnancy counseling, maternal and fetal risk
stratification and genetic counseling but also he is natural history of the disease or the patient may have
undergone some intervention/surgery earlier. The
18 cie
responsible to optimize the maternal hemodynamic
status, discontinue any teratogenic medications, to do a
percutaneous intervention if needed and advise regarding
patient may have undergone total correction or palliative
surgery. The patient may be in a cured state (expected
the mode of delivery. The cardiologist’s care should extend morbidity and mortality same as age and sex-matched
20 o
to puerperium and beyond that. general population) or having residua and sequelae after
S
Though the term ‘congenital heart disease’ includes corrective surgery. The current state of presentation as
a broad spectrum of anatomic abnormalities, yet the outlined in Figure 1 should be clearly ascertained by
spectrum of pathophysiologic states generated by them is history, physical examination and echocardiography.
al
limited (volume overload, pressure overload, ventricular Holter may be needed if arrhythmias are suspected.
dysfunction, cyanosis, pulmonary hypertension (PH), Assessment of functional capacity sometimes plays an
ic
arrhythmia, heart failure, etc.). The same anatomic lesion important role in clinical decision making.
may produce two different pathophysiological states, for
og
example, shunt lesions, such as atrial septal defect (ASD), PHYSIOLOGICAL CHANGES DURING
ventricular septal defect (VSD), and patent ductus (PDA),
PREGNANCY
may present as volume overload state (increased Qp) or
ol
as pressure overload state of right ventricle (RV) due to Pregnancy induces changes in the cardiovascular system
pulmonary vascular obstructive disease (PVOD). Tetrology to meet the increased metabolic demands of the mother
di
of Fallot (TOF) patient may have significant cyanosis or and fetus.

Total blood volume increases by 45% on average.
she may be pink. Even after correction of the anatomy,
ar
Cardiac output increases by 30–50% peaking in the

the physiology of the patient may still be pathological.
For example, TOF patient after palliative shunt surgery second trimester.
C
Heart rate rises progressively, peaking in the third

may become acyanotic but volume overloaded. Even after
total intracardiac repair of TOF, pulmonary regurgitation trimester at 20–25% above baseline.
Hormone-induced vasodilatation causes systemic
(PR) leads to volume load of RV and its dysfunction.
Because of residua and sequelae of the surgery. One blood pressure to fall in early gestation.
Proaggregant effect: These changes can preci-
pathophysiological state may merely get converted to
another without actually causing a total cure. Therefore, pitate critical decompensation in women with CHD
the cardiologist, while assessing a pregnant patient, (Table 1).
should take cognizance of not only the anatomic defect Peak hemodynamic load is reached during the second
but also the pathophysiologic state of the patient (and its trimester so there are two peaks for the development of
likely effect on the fetus). Risk stratification based only heart failure in such women. The first is towards the end of
on an anatomic diagnosis is misleading because multiple second trimester of pregnancy coincident with the plateau
pathophysiologic states (cyanosis, PH) themselves are of the hemodynamic load. The second is in the peri- and
important risk factors. early postpartum period.
KG-30.indd 252 02-11-2018 13:57:10

CHAPTER
30

a
di
In
of
ty
18 cie
20 o S
Figure 1: Algorithm for decision making

al
Depending on the type and complexity of the counseling the patient, it should be kept in mind that while
congenital cardiac defect and the severity of residual all these risk models perform well for predicting maternal
ic
hemodynamic lesions, the normal adaptive responses risk, none of the fetal risk prediction models performs
of the cardiovascular system to the increased demands adequately.
og
of pregnancy, labor, and puerperium get distorted in The adverse maternal cardiovascular events include
numerous ways.3 The occurrence of tachyarrhythmias or arrhythmias, thromboembolic complications [deep
failure to adequately increase heart rate or cardiac output venous thrombosis (DVT), paradoxical embolism, stroke,
ol
(chronotropic incompetence, inadequate adaptation pulmonary embolism], heart failure, mortality, and
of pacemaker programming, valve stenosis, rigid infective endocarditis.
di
conduits, or baffles) during pregnancy and peripartum Three well-established risk prediction models are as
may further impair these adaptive mechanisms and follows:
ar
precipitate decompensation. The occurrence of obstetric 1. CARPREG (CARdiac disease and PREGnancy) risk
complications, such as hypertensive disorders of score: This score developed by Siu et al. 1 is based
pregnancy, pre-eclampsia, or multiple pregnancies,
C
on four risk factors (Systemic ventricular ejection

increase the hemodynamic load of pregnancy and thus fraction (EF) <40%, Poor functional class [New York
increase the risk of maladaptation to hemodynamic needs Heart Association (NYHA) functional class III or IV)
and subsequently increase the risk of cardiovascular or cyanosis, left heart obstruction and cardiac event
complications in vulnerable patients.1,4-6 prior to pregnancy]. Each risk factor is given one point.
Women with risk scores of 0, 1, or >1 had event rates
MATERNAL AND FETAL RISK during pregnancy of 5%, 25%, or 75%, respectively.1
2. ZAHARA (Zwangerschap bij Aangeboren HARt
Maternal Risk Afwijkingen (Dutch; English translation: pregnancy
Assessment of the female for pregnancy counseling is with congenital heart defects) predictors of maternal
done according to well-established risk scoring systems cardiovascular events: It is a weighted risk score that
which take into account both anatomic characteristics as contains eight risk predictors. The weighted scores
well as the pathophysiological state of the patient. When given to each risk predictor varies between 0.75 and
253
KG-30.indd 253 02-11-2018 13:57:14

SECTION Table 1: Physiological change and its effect on pathophysiological state
4
S. no. Physiological change Effect on pathophysiological state
1. Volume overload z If ventricular dysfunction is present, heart failure is precipitated.
z A patient in fixed output state like aortic or pulmonary stenosis or PVOD is likely to
decompensate.
2. Decreased peripheral resistance z The regurgitant lesion is likely to be tolerated better.
z In cyanotic congenital heart disease (CCHD) R→L shunt increases leading to increase in
cyanosis.
3. Increased heart rate z Conditions like AV valve stenosis (MS, TS where the forward flow is dependent upon
diastolic time worsen).
z Arrhythmias due to sequela of atriotomy or ventriculotomy likely to become worse.
z If pacemaker was implanted postsurgery CHB or/congenital CHB needs rate correction to
a
increase heart rate.
di
4. Proaggregant effect z DVT may lead to paradoxical embolism if ASD is present.
z Vulnerability to mechanical valve thrombosis
z Fontan palliation likely to fail
In
5. Uterine enlargement compromising z Fontan palliation likely to fail
venous return from IVC
Abbreviations: PVOD, pulmonary vascular obstructive disease; AV, atrioventricular; MS, mitral stenosis; TS, tricuspid stenosis; CHB, complete heart
of
block; DVT, deep venous thrombosis; ASD, atrial septal defect; IVC, inferior vena cava.
4.25. The minimal weighted risk score is given to Higher perinatal mortality that may be >4-fold higher
ty
valvular regurgitation and maximum 4.25 given to than in the general population (<1%) and is common
mechanical valve prosthesis. Women with risk scores with premature delivery or recurrence of CHD.
18 cie
of 0–0.50, 0.51–1.5, 1.51–2.5, 2.51–3.5, and >3.51 had
event rates of 2.9%, 7.5%, 17.5%, 43.1%, and 70.0%,
Perinatal mortality is the highest in patients with
Eisenmenger syndrome (27.7%).5,10,11
respectively.5,6 Specific maternal risk factors, such as subaortic
20 o
3. Modified World Health Organization (WHO) classi ventricular outflow obstruction, maternal cyanosis, and
fication of maternal cardiovascular risk: In 2006, a
S
reduced cardiac output, have been reported as predictors

British working group created a lesion-specific risk of adverse perinatal events.11,12
classification using a modified WHO classification.
al
This is now widely used. HIGH-RISK PATHOPHYSIOLOGIC STATES

The WHO classification categorizes cardiac lesions as
Pulmonary hypertension: It is defined as a mean
ic

low risk (WHO I), medium risk (WHO II), high risk (WHO
pulmonary artery (PA) pressure of >25 mm Hg at rest
III), and lesions in which pregnancies are contraindicated
og
(WHO IV).7 If pregnancy is confirmed in a woman in WHO and can be because of various anatomical lesions.
class IV, then termination is advised. The European Society Though mild PH can be tolerated well, severe PH
of Cardiology (ESC) guidelines on the management of in pregnancy regardless of the cause carries an
ol
cardiovascular diseases made minor modifications to the extremely poor prognosis with the risk of mortality
WHO classification.8 The modified WHO risk classification up to 20–30% even with optimal management. The
di
appeared to be the most reliable system for risk prediction severity of PH is most commonly determined on
in several studies.9 echo by Doppler evaluation of tricuspid regurgitation
ar
(TR) jet in the absence of right ventricular outflow

Fetal Risk tract (RVOT) obstruction or PA mean/pulmonary
C
Maternal CHD is a major determinant of risk to the fetus artery end-diastolic pressure (PAEDP) by pulmonary
and the neonate, resulting in the following: regurgitation (PR) jet. When PA systolic pressure
Higher frequency of spontaneous abortions, ranging
exceeds 60% of systemic levels, pregnancy is more likely
between 15% and 25%, and intrauterine fetal demise in to be associated with complications. In the presence
selected defects.11,12 of severe PVOD (Eisenmenger syndrome), maternal
Higher frequency of recurrence of CHD, underscoring mortality rate may approach 50%. 13-15 The highest
the need to offer fetal echocardiography to all pregnant incidence of maternal death is during parturition
women with CHD at 18–22 weeks. and puerparium. The volume load of pregnancy is
Higher preterm birth rate (10–12%), especially in those detrimental for the already pressure overlaoaded RV
with complex CHD (22–65%). which is in a state of fixed cardiac output due to PVOD.
Higher frequency of neonatal events; for example, This may precipitate heart failure. Not only maternal
small for gestational age, respiratory distress syndrome, mortality but also perinatal mortality is to the tune of
intracranial hemorrhage, and neonatal death (27.8%). 30%.5,10,11
254
KG-30.indd 254 02-11-2018 13:57:14

Cyanosis: Regardless of the complexity of cyanotic HIGH-RISK ANATOMIC LESIONS CHAPTER
CHD (CCHD), cyanosis poses risk for both mother
30
Obstructive lesions of RV or LV [aortic Stenosis (AS),
and fetus. When the maternal oxygen saturation is pulmonary stenosis (PS), mitral stenosis (MS) or
less than 85%, the fetal outcome is poor with only 12% coarctation of aorta (CoA)]. Any kind of severe

resulting in live born infants. Conversely, when the obstruction is associated with poor maternal and fetal
maternal oxygen saturation is 90% or higher, 92% of the outcome. Associated pathology/ consequence of the
pregnancies result in live birth.16 primary lesion should also be taken into consideration
LV/RV dysfunction and heart failure: Patients with LV while predicting fetomaternal risk ( e.g. LV dysfunction
dysfunction are advised against conception if EF is or aortopathy in case of AS, PH in case of MS).
lower than 40% or they are in NYHA class III or IV. If As a general rule, the pregnancy is well tolerated
EF is between 40 and 50%, exercise testing may help if the obstruction is mild without any associated
a
in clinical decision making. Such patients may not pathology. Moderate stenosis in an asymptomatic
di
tolerate pregnancy well if they have poor functional pregnant patient with normal exercise capacity is also
capacity. well tolerated. However, severe obstruction warrants
In
RV dysfunction after TOF repair may also lead to cardiac intervention [balloon angioplasty (BAP) and
significant morbidity. The patient of uncomplicated aortic or pulmonary balloon valvuloplasty (BAV, BPV),
congenitally corrected transposition of the great adriamycin, bleomycin, vinblastine, and dacarbazine
of
arteries (CCTGA) is expected to have a successful (ABVD), coarctoplasty) or surgery during pregnancy
pregnancy if the EF of the systemic ventricle (RV) itself.
is normal. Since RV is the dominant ventricle after Marfan syndrome with aortic root greater than 40–45
ty
Senning’s repair in D-transposition of the great arteries mm, bicuspid aortic valve with aortic root dilatation >
(D-TGA), its function needs to be carefully assessed 45–50 mm.

18 cie
during evaluation of the pregnant female.
Univentricular heart and Fontan operation: A patient
who has undergone Fontan surgery belongs to WHO
Mechanical prosthetic valves: Older-generation
mechanical prosthetic valves, especially in mitral
position or multiple mechanical valves, are associated
20 o
group III (high-risk group) because of a unique with higher risk of thromboembolic events.18
pathophysiologic state. 7 Successful pregnancy is
S
possible after the Fontan operation 17 but tends to CARDIOVASCULAR DRUGS IN PREGNANCY
be uncomfortable because of increasing systemic
Nearly all drugs cross the placenta and are secreted in
al
venous pressure causing hepatic congestion and

breast milk. There is limited information about the use of
often distressing edema of the lower extremities.
any drug in pregnancy so they are best used only if they are
ic
The development of atrial flutter may jeopardize

absolutely indicated for maternal safety. The United States
the fetus in patients with a right atrial-pulmonary
Food and Drug Administration (USFDA) classification of
og
artery conduit. Thrombosis of Fontan circuit is a

drugs as they relate to fetal safety provides broad guidance
major threat in some patients due to sluggish flow
for drug usage in pregnancy (Table 2).19
and prothrombotic state of pregnancy and continued
ol
anticoagulant treatment becomes essential. Patients

with atrial fenestrations are at risk from paradoxical RECOMMENDATIONS REGARDING
di
embolism and may develop progressive cyanosis ANTICOAGULATION MANAGEMENT8,20

and consequent fetal growth retardation. Moreover, Remember heparin use in any trimester prevents
ar
volume overload of pregnancy may cause the function complications in the fetus, whereas warfarin use with
of the single ventricle to deteriorate. international normalized ratio (INR) in therapeutic range
C
Table 2: The United States Food and Drug Administration (USFDA) pregnancy risk classification of drugs
FDA category
Category A Human and animal studies have not shown fetal risk Diuretics
Category B No adequate human studies. Animal studies have not shown fetal risk Inotropic agents: Digitalis
Metoprolol, Verapamil, Sildenafil
Category C No adequate studies in humans. Teratogenicity shown in animal studies CCB, Atenolol, Flecainide, Sotalol, Diltiazem
Category D Demonstrated fetal risk in human studies
Category X Severe fetal risk in humans shown. Contraindicated in pregnancy Amiodarone, Bosentan, ACE inhibitor, ARB,
Warfarin
Abbreviations: CCB, calcium-channel blocker; ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker.
255
KG-30.indd 255 02-11-2018 13:57:14

SECTION prevents thromboembolic complications in the mother. If low-molecular-weight heparin (LMWH) is used, it
Though it is optional to avoid warfarin use in the first should be administered subcutaneously every 12 hours
4 trimester to decrease the risk of warfarin embryopathy,
yet it is mandatory to switch over to heparin after 36 weeks
and the dose adjusted so that 4 hours postinjection
anti-Xa level is maintained at 1–1.2 units/mL, perhaps
of gestation because the patient may go into labor at any measured weekly.
time and the vaginal delivery, which requires significant LMWH should not be used if the facility to measure
head molding of the fetus, may cause fetal intracranial anti-Xa is not available.
hemorrhage with disastrous consequences. In fact, one of LMWH has to be discontinued at least 36 hours
the few nonobstetric indications for the cesarian section is before delivery. This is especially important if epidural
ongoing warfarin therapy in the mother. analgesia is to be used (risk of spinal hematoma).
All anticoagulant regimens, however carefully managed UFH is a large molecule that does not cross the
a
have the potential for hemorrhagic complications, placenta. This can be started and stopped abruptly so
di
including placental bleeding, miscarriage and fetal death. it is preferable to be used after 36 weeks of gestation.
Though fetal exposure to warfarin in the first trimester is In the first trimester, it can be given subcutaneously
In
associated with fetal embryopathy, the risk may be dose- or intravenously. The activated partial thromboplastin
related. The risk is very low if the warfarin dose is less than 5 time (aPTT) ratio should be maintained at midinterval
mg or less.21 Although there are no randomized controlled postinjection level of at least 2 or anti-factor Xa level of
of
trials (RCTs) comparing the different antithrombotic 0.35–0.70 units/mL.
regimens, the risk of thromboembolic events using
warfarin throughout pregnancy is <4%, compared with THROMBOLYTIC THERAPY IN PREGNANCY
ty
the use of unfractionated heparin (UFH) throughout Valve thrombosis is a life-threatening complication in
pregnancy.20 pregnant women with a mechanical prosthetic heart
18 cie
Against the above background, the recommendations
in various guidelines8,20 can be better understood and can
be summarized as follows (Figure 2):
valve and is more likely to occur in patients with older-
generation mechanical prostheses (Björk–Shiley valve,
Starr–Edwards aortic valve) and with valves in the mitral
20 o
Patient counseling is must and the patient’s desire or tricuspid positions.
should be taken into consideration before embarking Özkan et al. 22 published the largest series of cases
S
on any regimen of anticoagulants because of of prosthetic valve thrombosis (PVT) in pregnancy. All
medicolegal issues. patients were treated with low-dose thrombolytic therapy
al
ESC recommends consideration of continuation of (tissue-type plasminogen activator 25 mg without bolus,

oral anticoagulants in the first trimester if the warfarin given up to 1 hour, if needed; mean dose 48 ± 29 mg),
ic
dose is less than 5 mg. which resulted in complete thrombolysis in all cases with
Oral anticoagulants should be used in the second and very low incidence of fetomaternal complications. So,
og
the third trimesters until the 36th week of pregnancy low-dose thrombolytic therapy seems promising in case of
with strict control of INR values. thromboembolic complications in pregnant females.
ol
di
ar
C
Figure 2: Algorithm for decision making for anticoagulation in pregnancy

Abbreviations: UFH, unfractionated heparin; LMWH, low-molecular-weight heparin
256
KG-30.indd 256 02-11-2018 13:57:15

PERCUTANEOUS INTERVENTION/SURGERY GENETIC COUNSELING CHAPTER
DURING PREGNANCY
The pregnant patient, sometimes, presents in such a
All patients with CHD should be counseled on the risk of
their fetus having CHD. Maternal and paternal evaluation 30
critical state that early intervention is needed as a life- should be performed for clinical features suggestive of a

saving measure. syndromic phenotype. The absence of typical phenotypic
features does not preclude the presence of a genetic or
Percutaneous Intervention chromosomal anomaly; therefore, genetic testing may
It can be done in a pregnant female for severe PS, severe still be offered if the index of suspicion for a genetic
AS (with suitable valve morphology), PDA device closure, pathogenesis is high. Most genetic conditions associated
coarctoplasty, etc. During percutaneous intervention, with CHD are autosomal dominant conditions, which
a
the fetus is exposed to ionizing radiation and to the have a transmission risk of 50%, including the Marfan
di
iodinated contrast agent. Ionizing radiation can cause syndrome, Holt–Oram syndrome, Noonan syndrome,
cell death, teratogenic effect, carcinogenesis, and genetic Alagille syndrome, CHARGE (coloboma, heart defect,
mutation.23 There is a consensus that the risk for the fetus
In
atresia choanae, retarded growth and development,
is very limited when the dose to the mother is less than genital hypoplasia, ear anomalies/deafness) syndrome,
50 mGy.8,23 The radiation dose to the mother during the Williams syndrome, etc.
of
most commonly performed interventions (balloon mitral The 22q11 deletion testing is recommended for all
valvuloplasty and coronary angioplasty) is less than 20 patients with TOF, VSD with aortic arch anomaly, truncus
mGy. Abdominal shielding is recommended although this arteriosus, interrupted aortic arch, and discontinuous
ty
lowers the dose to the fetus by only 2%. The best period branch pulmonary arteries.
to perform invasive procedures is the beginning of the For CHD that arises de novo, the risk of CHD recurrence
18 cie
second trimester when organogenesis is complete and the
uterus is still small. Iodinated contrast agents have been
studied in animals and are not found to be teratogenic;
in offspring is between 3% and 5%.
The risk of recurrence is higher with heterotaxy,
atrioventricular septal defect, and obstructive lesions of
however, the possibility of neonatal hypothyroidism
20 o
the left ventricular outflow tract (LVOT).
cannot be ruled out, so there use should be minimized.23
Two consensus statements from the American Heart
S
Association (AHA) and the Canadian Cardiovascular

Surgery under Cardiopulmonary Bypass Society (CCS) provide excellent guidance for genetic
al
during Pregnancy testing in CHD.27,28

If the cardiac surgery is needed under cardiopulmonary
ic
bypass, the risk to the mother is now similar (3% overall)

MODE OF DELIVERY
to that for a nonpregnant female, but the fetal mortality
og
remains high (14–33%).24-26 Fetal morbidity in the form Cesarean section is indicated for obstetric indications
of late neurological impairment can also occur.25 Cardiac only; however, conditions in which cesarean section is
surgery is ill-advised in the first trimester as the chances of preferred over vaginal delivery are as follows:
ol
fetal malformations are high. Women with an ascending aorta diameter >45 mm.
Postponement of cardiac surgery until after the 13th Preterm labor while on oral anticoagulation.
di
week of gestation is preferred. It is recommended to Women with severe AS experiencing symptoms
monitor uterine contractions and fetal heart rate during during pregnancy (preferably general anesthesia and
ar
surgery. To diminish the risk of fetal bradycardia and endotracheal intubation).

uterine contractions, the ESC guidelines recommend to Severe heart failure.
C
minimize cardiopulmonary bypass time and to maintain

a pump flow >2.5 L/min/m2, a perfusion pressure >70 mm
CARE IN PUERPERIUM
Hg, a maternal hematocrit >28%, and to use pulsatile flow
and normothermic perfusion.8 Close monitoring postpartum is required in women with
During the third trimester, with improvements in the CHD. The hemodynamic changes persist for several weeks
outcome for premature infants with modern neonatal postpartum, and 55% of deaths from heart disease in 2009–
intensive care, delivery of the child immediately before 2014 in the UK occurred in the 6 weeks following delivery.29
commencing cardiopulmonary bypass is a safe option. If The duration of inpatient observation varies, but women
possible the surgery should be delayed until a full course of who required admission antenatally for decompensation
corticosteroids (at least 24 hr) has been administered to the may need a prolonged period of observation until their
mother, since this improves fetal outcome considerably.8 physiology approaches the prepregnant state.
257
KG-30.indd 257 02-11-2018 13:57:15

SECTION REFERENCES
4
1. Siu SC, Sermer M, Colman JM, et al. Prospective multicenter 16. Presbitero P, Somerville J, Stone S, et al. Pregnancy in
study of pregnancy outcomes in women with heart disease. cyanotic congenital heart disease. Outcome of mother and
Circulation. 2001;104(5):515-21. fetus. Circulation. 1994;89(6):2673–6.
2. McFaul PB, Doman JC, Lamki H, et al. Pregnancy 17. Cannobio MM, Mair DD, van der Velde M, et al. Pregnancy
complicated by maternal heart disease. A review of 519 outcomes after the Fontan repair. J Am Coll Cardiol.
women. Br J Obstet Gynecol. 1988;95(9):861-7. 1996;28(3):763-7.
3. Cornette J, Ruys TP, Rossi A, et al. Hemodynamic adaptation 18. Elkayam U, Bitar F. Valvular heart disease and pregnancy: part
to pregnancy in women with structural heart disease. Int J II: prosthetic valves. J Am Coll Cardiol. 2005;46(3):403– 10.
Cardiol. 2013;168(2):825–31. 19. Food and Drug Administration, HHS. Content and format
4. Robson SC, Hunter S, Boys RJ, et al. Hemodynamic of labeling for human prescription drug and biological
a
changes dur ing tw in pregnanc y. A D oppler and products; requirements for pregnancy and lactation
M-mode echocardiographic study. Am J Obstet Gynecol. labeling. Final rule. Fed Regist. 2014;79(233):72063-103.
di
1989;161(5):1273–8. 20. Nishimura RA, Otto CM, Bonow RO, et al. 2014 AHA/
5. Drenthen W, Boersma E, Balci A, et al. Predictors of ACC guideline for the management of patients with
In
pregnancy complications in women with congenital heart valvular heart disease: executive summary: a report of
disease. Eur Heart J. 2010;31(17):2124–32. the American College of Cardiology/American Heart
6. Greutmann M, Von Klemperer K, Brooks R, et al. Pregnancy Association Task Force on Practice Guidelines. Circulation.
of
outcome in women with congenital heart disease and 2014;129(23):2440-92.
residual haemodynamic lesions of the right ventricular 21. Vitale N, DeFeo M, De Santo LS, et al. Dose-dependent
outflow tract. Eur Heart J. 2010;31(14):1764–70. fetal complications of warfarin in pregnant women with
ty
7. Thorne S, Nelson-Piercy C, MacGregor A, et al. Pregnancy mechanical heart valves. J Am Coll Cardiol. 1999;33(6):
and contraception in heart disease and pulmonary 1637–41.
arterial hypertension. J Fam Plann Reprod Health 22. Özkan M, Çakal B, Karakoyun S, et al. Thrombolytic therapy
Care.2006;32(2):75–81. 18 cie
8. European Society of Gynecology (ESG); Association for
for the treatment of prosthetic heart valve thrombosis in
pregnancy with low-dose, slow infusion of tissue-type
European Paediatric Cardiology (AEPC); German Society plasminogen activator. Circulation. 2013;128(5):532–40.
20 o
for Gender Medicine (DGesGM), Regitz Zagrosek V, 23. ACOG Committee on Obstetric Practice. ACOG Committee
Blomstrom Lundqvist C, Borghi C, et al. ESC Guidelines Opinion. Number 299, September 2004 (replaces No. 158,
S
on the management of cardiovascular diseases during September 1995). Guidelines for diagnostic imaging during
pregnancy. Eur Heart J. 2011;32(24):3147–97. pregnancy. Obstet Gynecol. 2004;104(3):647-51.
al
9. Balci A, Sollie-Szarynska KM, van der Bijl AG, et al. 24. John A, Gurley F, Schaff H, et al. Cardiopulmonary bypass
Prospective validation and assessment of cardiovascular during pregnancy. Ann Thorac Surg. 2011;91(4):1191–6.
and offspring risk models for pregnant women with 25. Patel A, Asopa S, Tang AT, et al. Cardiac surgery during
ic
congenital heart disease. Heart. 2014;100(17):1373–81. pregnancy. Tex Heart Inst J. 2008;35(3):307–12.
10. Drenthen W, Pieper PG, Roos-Hesselink JW, et al. Outcome 26. Barth WH Jr. Cardiac surgery in pregnancy. Clin Obstet
og
of pregnancy in women with congenital heart disease: a Gynecol. 2009;52(4):630–46.

literature review. J Am Coll Cardiol. 2007;49(24):2303–11. 27. Jenkins KJ, Correa A, Feinstein JA, et al. Noninherited risk
11. Khairy P, Ouyang DW, Fernandes SM, et al. Pregnancy factors and congenital cardiovascular defects: current
ol
outcomes in women with congenital heart disease. knowledge: a scientific statement from the American Heart
Circulation. 2006:113(4):517–24. Association Council on Cardiovascular Disease in the
di
12. Gelson E, Curr y R, Gatzoulis MA , et al. Effect of Young. Circulation. 2007;115(23):2995–3014.

maternal heart disease on fetal growth. Obstet Gynecol. 28. Silversides CK, Marelli A, Beauchesne L, et al. Canadian
ar
2011;117(4):886–91. cardiovascular society 2009 consensus conference on

13. Avila WS, Grinberg M, Snitcowsky R, et al. Maternal and the management of adults with congenital heart disease:
fetal outcome in pregnant women with Eisenmenger’s executive summary. Can J Cardiol. 2010:26(3):143–50.
C
syndrome. Eur Heart J. 1995;16(4):460–4. 29. Knight M, Nair M, Tuffnell D, et al. Saving Lives, Improving
14. Pieper PG, Lameijer H, Hoendermis ES. Pregnancy and Mothers’ Care – Surveillance of maternal deaths in the
pulmonary hypertension. Best Pract Res Clin Obstet UK 2012–14 and lessons learned to inform maternity
Gynaecol. 2014;28(4):579–91. care from the UK and Ireland Confidential Enquiries into
15. Daliento L, Somerville J, Presbitero P, et al. Eisenmenger Maternal Deaths and Morbidity 2009–14. Oxford: National
syndrome: factors relating to deterioration and death. Eur Perinatal Epidemiology Unit, University of Oxford; 2016;
Heart J. 1998;19(12):1845–55. 69–75.
258
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A Simplified Approach to the
Management of Congenitally Corrected
CHAPTER 31 Transposition of Great Arteries
a
di
INTRODUCTION 1. Systemic afterload: Anatomically, RV is not suitable
Congenitally corrected transposition of great arteries to withstand a high pressure load. The compact
In
(CCTGA) is a congenital heart defect characterized by myocardium (stratum compactum) is much thicker
atrioventricular and ventriculoarterial discordance. This in relation to the spongy myocardium (stratum
spongiosum) in the left ventricular wall compared with
of
double discordance is physiologically corrected, as the
great arteries receive appropriate venous blood. CCTGA the right. Also, the papillary muscle arrangement of RV
constitutes 0.5% of all congenital heart defects. In most predisposes to tricuspid insufficiency when exposed to
pressure load.
ty
cases, CCTGA is accompanied by intracardiac lesions:
ventricular septal defects (VSD) in 60 to 80%, pulmonary 2. Volume overload due to VSD or TR.
3. The systemic RV is supplied by the morphologic right
18 cie
stenosis in approximately 50%, abnormalities of the
conduction system in 15 to 50%, atrial septal defect in 12%
and tricuspid valve abnormalities in 90 to 97%.1
coronary artery in CCTGA. Hence, there is relative
coronary insufficiency in the hypertrophied right
ventricle.
20 o
4. Conduction and rhythm abnormalities.
CLINICAL PRESENTATION AND NATURAL
S
Tricuspid regurgitation is a major contributor to the

HISTORY development of progressive RV dysfunction and failure
The clinical presentation of CCTGA depends on the in adult patients with CCTGA with a systemic RV.4 The
al
associated anomalies. Children with large VSD present survival at 20 years is over 90% in patients without TR, as
with symptoms of heart failure in infancy. They present compared to less than 50% in those with TR. 5 Whether
ic
with cyanosis if the VSD is associated with left ventricular TR is the cause or effect of RV dysfunction is debatable.
outflow tract (subpulmonary) obstruction (LVOTO). Systemic tricuspid valve regurgitation in CCTGA is due to
og
Isolated CCTGA without any associated lesions is usually a combination of the following factors:6
asymptomatic in childhood. A few of them may survive till 1. Anatomical abnormalities of the tricuspid valve (apical
6th and 7th decade. Most of them become symptomatic displacement of septal and mural leaflet)
ol
with effort intolerance in 4th or 5th decade when right 2. Annular dilatation
ventricular (RV) dysfunction starts. Sometimes, symptoms 3. Change in loading conditions
di
become manifest during pregnancy. Bradycardia due to 4. Altered geometry of RV: In CCTGA, RV hypertrophy
heart block may be the presenting manifestation in some. is followed by dilation, and the ventricular shape
ar
A few asymptomatic children may be diagnosed when a becomes more spherical. The tricuspid annulus
LVOTO murmur or tricuspid regurgitation (TR) murmur is dilates, papillary muscles move away from the inflow
C
incidentally found.
tract and tethered chordae do not allow the leaflets to
Graham et al. reported the long-term outcome in 182
occlude the orifice. These mechanisms predispose to
patients with CCTGA. Systemic ventricular dysfunction
the steady increase of TR over time.4
was found to increase with age, being present in 67% of
Those with anatomical abnormalities present with TR
patients with associated lesions by 45 years. TR was strongly
in infancy or early childhood. Others usually develop TR
associated with systemic RV dysfunction. Other factors
beyond first decade.
associated with systemic ventricular dysfunction included
the presence of associated anomalies, history of heart
block, and prior surgical intervention. Overall survival MANAGEMENT
was affected by the age of the patient, RV dysfunction, TR, The foregoing discussion has summarized the key
associated cardiac lesions, and heart block.2 pathophysiologic mechanisms that need to be addressed
There are a number of reasons predisposing the right in CCTGA. Management of CCTGA is challenging due to its
ventricle in CCTGA for dysfunction:3 diverse anatomic and clinical presentation. Management
KG-31.indd 259 02-11-2018 13:56:58

SECTION is determined by the presence and severity of associated supravalvar pulmonary stenosis) and Rastelli surgery
anomalies (Figure 1). (conduit obstruction or regurgitation necessitating
4 conduit replacement).
Though anatomical repair repositions the ventricles
Medical Management
into their natural position and has shown to have good short
Asymptomatic children are advised regular follow up
and midterm survival,12,13 whether it can be aggressively
with electrocardiogram and echocardiogram. Medical
proposed in completely asymptomatic patients is still
management is started when there is evidence of systemic
debatable. Long-term follow-up studies would throw
ventricular dysfunction. Diuretics, angiotensin-converting more light on the superiority of double-switch operation
enzyme inhibitors (ACE inhibitors) and cardiac glycosides over natural history in asymptomatic patients.
are instituted in systemic ventricular dysfunction. There
a
is some data, although non-randomized, to support
the use of beta blockers in systemic right ventricular PA Band in CCTGA
di
dysfunction;7-9 however, they have to be used judiciously PA band is a useful strategy in CCTGA in the following
as there can be conduction abnormalities in CCTGA. ways:
In
1. Preparation of LV for future anatomic repair: PA
band done early (<3 years) in childhood results in
Conventional Repair (Physiological Repair)
LV hyperplasia. LV retraining may be unsuccessful if
of
The concept of physiological repair was introduced in the PA banding is done beyond adolescence.11 PA band
early 1960s. The classical physiological repair of CCTGA done in adolescents and adults results in hypertrophy
involves correction of associated lesions, which include and not hyperplasia. This may result in LV diastolic
ty
VSD closure, LV to pulmonary artery (PA) conduit, tricuspid dysfunction.
valve repair/replacement and palliative PA banding. 2. Palliation in RV dysfunction and TR: PA band increases
18 cie
Atrioventricular and ventriculoarterial discordance is not
addressed, thus leaving the morphologic right ventricle in
the systemic circulation. Hence, the long-term issues of RV
LV pressure and alters the interventricular relative
forces thus reducing the leftward septal shift. This
in turn improves the RV geometry and reduces TR
dysfunction and tricuspid valve regurgitation persist. This
20 o
and helps prevent or improve RV dysfunction. It also
paved the way to the concept of anatomic repairs, which decreases the pulmonary flow and thus the preload to
S
started in 1990s. RV. Hence, the progression of TR is delayed (Figures

2A and B).
Anatomic Repair (Double-switch Operation)
al
Dilatable PA band is an option as open-ended

In 1990, Ilbawi et al. first described the concept of strategy. This may be more acceptable in asymptomatic
ic
anatomic repair.10 In this, atrial switch surgery is combined children, as it is a less invasive procedure. Good
with either arterial switch or Rastelli operation. The pre- intermediate results of this ‘open-ended’ palliation in 15
og
requisite for anatomic repair is preparedness of LV to pediatric patients with CCTGA were reported by Cools and
face the systemic afterload. If LV is at systemic pressure his colleagues.14
(presence of large VSD or PS), then single stage anatomic
ol
correction is possible. If not, PA banding is required prior Univentricular Palliation

to anatomic correction. PA band increases the afterload
di
CTGA with hypoplastic RV or significant straddling of

and induces ventricular hyperplasia/hypertrophy. PA
atrioventricular valve are offered univentricular palliative
band is useful only when done early in life when somatic
ar
growth is possible (usually <15 years age).11 It is ideal to surgeries. There is considerable argument in favor of
do cardiac MRI (for muscle mass and LV function) and univentricular palliation as an alternative to anatomic or
physiologic repair in selected cases of CCTGA with VSD/
C
cardiac catheterization (for ventricular pressure) before

double-switch operation. LVOTO.15
Many investigators have confirmed satisfactory late
results of double-switch procedures. Survival at 10 to Tricuspid Valve Repair/Replacement
20 years after surgery was reported as 75 to 85% in one
large series, and freedom from any reintervention varied The volume overload caused by TR hastens the process
between 49 and 95%, mostly because of the need for of RV dysfunction. Tricuspid valve repair or replacement
conduit change. Functional outcomes of anatomic repair delays the onset and progression of RV dysfunction.
are also reported as good; >86% of survivors are at New However, it may not improve pre-existing RV failure.
York Heart Association functional class I or II.4,12,13 Tricuspic valve repair is technically difficult in mesocardia
Complications and morbidity includes those of atrial and situs inversus situation. In patients referred for
switch (baffle obstruction, baffle leaks, atrial arrhythmias), tricuspid valve replacement, 10-year postoperative
arterial switch (aortic root dilatation, aortic insufficiency, survival was only 19.5% when the preoperative systemic
260
KG-31.indd 260 02-11-2018 13:57:02

KG-31.indd 261
C
ar
di
ol
og
ic
al
20 o S
18 cie
ty
of
Figure 1: Schematic representation of approach to management of CCTGA In
di
a
261
A Simplified Approach to the Management of Congenitally Corrected Transposition of Great Arteries
31
CHAPTER
02-11-2018 13:57:03
SECTION
4
a
di
In
of
A
ty
18 cie
20 o S
al
ic
og
ol
di
B
Figures 2A and B: (A) Echocardiographic image of CCTGA with dilatation of systemic right ventricle and right atrium, non-coapting tricuspid
ar
valve leaflets and severe tricuspid regurgitation; (B) Echocardiographic image following PA banding showing reduction in the size of right
ventricle, improved coaptation of tricuspid valve leaflets and reduction in tricuspid regurgitation
C
ventricular ejection fraction was below 44%, while survival RV dysfunction. Medical management for RV dysfunction
was 100% for patients with an ejection fraction higher than includes diuretics and ACE inhibitors for preload and
44%.16 Hence, tricuspid valve repair or replacement should afterload reduction, cardiac glycosides to improve
be considered in progressive TR before the onset of RV ventricular contractility, and beta blockers. However, beta
dysfunction. blockers have to be used judiciously as it increases the
risk of heart block by increasing the conduction delay. PA
RV Dysfunction Management banding may be considered as an open-ended strategy, as
explained above.
Systemic ventricular failure is the main reason for Cardiac resynchronization therapy (CRT) in CCTGA
morbidity and mortality in CCTGA. Management of RV has been reported to reduce ventricular dys-synchrony
dysfunction in CCTGA is extrapolated from LV failure and improve systemic ventricular function in selected
therapy as there is little evidence on treatment of systemic cases. In a study by Dubin et al., a significant decrease
262
KG-31.indd 262 02-11-2018 13:57:05

in QRS duration, increase in systemic RV ejection progression of ventricular dysfunction. With the advent of CHAPTER
fraction, and clinical improvement was observed in 13 newer treatment strategies like CRT and ventricular assist
out of 17 patients.17 CRT should be considered whenever
there is a significant interventricular conduction delay
devices, it may be possible to favorably alter the natural 31
history of CCTGA.
A Simplified Approach to the Management of Congenitally Corrected Transposition of Great Arteries

(QRSd 120 ms) associated with systemic ventricular
dysfunction. Ventricular assist device (VAD) as a
REFERENCES
bridge to heart transplant may be considered in severe
systemic RV dysfunction, especially those with TR. Heart 1. Dyer K, Graham TP. Congenitally corrected transposition
transplantation is the final option for CCTGA with severe of great arteries: Current treatment options. Curr Treat
RV dysfunction. Options Cardiovasc Med. 2003;5(5):399–407.
2. Graham TP Jr, Bernard YD, Mellen BG, et al. Longterm
a
outcome in congenitally corrected transposition of the
HEART BLOCK IN CCTGA
di
great arteries: a multi-institutional study. J Am Coll Cardiol.
2000;36(1):255–61.
Complete heart block occurs in 10% of CCTGA at birth
In
3. Cowley CG, Rosenthal A . Congenitally corrected
and increases to 30% by adulthood. The risk of developing
transposition of the great arteries: the systemic right
heart block is 2% per year. The risk of surgical AV block
ventricle. Prog Pediatr Cardiol. 1999;10:31–5.
in anatomic repairs varies from 3 to 16%; it is reportedly
of
4. Prieto LR, Hordof AJ, Secic M, et al. Progressive
more frequent in the arterial switch group than in the tricuspid valve disease in patients with congenitally
Rastelli group.18 Pacemaker implantation is indicated in corrected transposition of the great arteries. Circulation.
the presence of one or more of the following: symptoms,
ty
1998;98(10):997–1005.
ventricular dysfunction, heart rate<70/min, long pauses, 5. Scherptong RW, Vliegen HW, Winter MM, et al. Tricuspid
wide QRS complexes, long QT interval, and postoperative valve surgery in adults with a dysfunctional systemic right
18 cie
block persisting for more than 7 days. 19 Primar y
biventricular pacing may be considered in CCTGA with
ventricle: repair or replace? Circulation. 2009;119(11):1467–
72.
heart block, as it delays onset of systemic ventricular 6. Meester PD, Budts W, Meyns B, et al. The systemic tricuspid
20 o
dysfunction.20 valve: The tricuspid valve in congenitally corrected
S
transposition of the great arteries. In: The Tricuspid Valve

in Congenital Heart Disease. Giamberti A, Chessa M (eds).
PREGNANCY IN CCTGA Springer-Verlag, Italia 2014:107–19.
al
7. Bouallal R, Godart F, Francart C, et al. Interest of β-blockers

Pregnancy is a potential source of increased stress for a
in patients with right ventricular systemic dysfunction.
systemic RV. A previously well patient with CCTGA may
ic
Cardiol Young. 2010;20(6):615–9.

develop congestive heart failure during or as a result of
8. Doughan AR, McConnell ME, Book WM. Effect of beta
og
pregnancy. Successful pregnancy can be achieved in many blockers (carvedilol or metoprolol XL) in patients with
women with CCTGA with minimal or no symptoms,21,22 transposition of great arteries and dysfunction of the
but close follow up with experienced physicians is systemic right ventricle.. Am J Cardiol. 2007;99(5):704–6.
ol
recommended because cardiovascular complications can 9. Josephson CB, Howlett JG, Jackson SD, et al. A case series of
occur in up to one-fourth of patients.22 systemic right ventricular dysfunction post atrial switch for
di
simple D-transposition of the great arteries: The impact of

beta-blockade. Can J Cardiol. 2006;22(9):769–72.
CONCLUSION
ar
10. Ilbawi MN, DeLeon SY, Backer CL, et al. An alternative

Management of CCTGA is challenging due to its complex approach to the surgical management of physiologically
anatomic and hemodynamic presentation. Though corrected transposition with ventricular septal defect and
C
the determinants of natural history and prognosis are pulmonary stenosis or atresia. J Thorac Cardiovasc Surg.
multifactorial, right ventricle in the systemic position 1990;100(3):410–5.
seems to be the major reason for long-term complications. 11. Duncan BW, Mee RB. Management of the failing
systemic right ventricle. Semin Thorac Cardiovasc Surg.
Emergence of anatomic repair as a surgical strategy in
2005;17(2):160–9.
pediatric patients has shown promising results on midterm
12. Hiramatsu T, Matsumura G, Konuma T, et al . Longterm
follow up. However, its application as a primary approach
prognosis of double-switch operation for congenitally
in asymptomatic children is yet to be established. Adults corrected transposition of the great arteries. Eur J
with systemic ventricular dysfunction and tricuspid Cardiothorac Surg. 2012;42(6):1004–8.
valve regurgitation pose the greatest challenge in 13. Murtuza B, Barron DJ, Stumper O, et al. Anatomic repair for
CCTGA. Regular assessment of ventricular function by congenitally corrected transposition of the great arteries: a
echocardiography and appropriate management at the single-institution 19-year experience. J Thorac Cardiovasc
earliest sign of RV dysfunction can help in delaying the Surg. 2011;142(2):1348–57.
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SECTION 14. Cools B, Brown SC, Louw J, et al. Pulmonary artery banding 19. Brignole M, Auricchio A, Baron-Esquivias G, et al.
as ‘open end’ palliation of systemic right ventricles: 2013 ESC Guidelines on cardiac pacing and cardiac
4 An interim analysis. Eur J Cardiothorac Surg. 2012; 41(4):913–8.

15. Karl TR. The role of the Fontan operation in the treatment
resynchronization therapy. The Task Force on cardiac
pacing and resynchronization therapy of the European
of congenitally corrected transposition of the great arteries. Society of Cardiology. Developed in collaboration with the
Ann Pediatr Cardiol. 2011;4(2):103-10. European Heart Rhythm Association (EHRA). Eur Heart J.
16. van Son JA, Danielson GK, Huhta JC, et al. Late results of 2013;34:2281–329.
systemic atrioventricular valve replacement in corrected 20. Hofferberth SC, Alexander ME, Mah DY, et al. Impact of
transposition. J Thorac Cardiovasc Surg. 1995;109(4):642–52. pacing on systemic ventricular function in Ltransposition
17. Dubin AM, Janousek J, Rhee E, et al. Resynchronization of the great arteries. J Thorac Cardiovasc Surg. 2016;151(1):
therapy in pediatric and congenital heart disease patients: 131–8.
An international multicenter study. J Am Coll Cardiol. 21. Connelly H, Grogan M, Warnes CA. Pregnancy among
a
2005;46(12):2277–83. women with congenitally corrected transposition of the
di
18. Baruteau AE, Abrams DJ, Ho SY, et al. Cardiac conduction great arteries. J Am Coll Cardiol. 1999;33(6):1692–5.
system in congenitally corrected transposition of the 22. Therrien J, Barnes I, Somerville J. Outcome of pregnancy
great arteries and its clinical relevance. J Am Heart Assoc. in patients with congenitally corrected transposition of the
In
2017;6(12). great arteries. Am J Cardiol. 1999;84(7):820–4.
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In
Congenital Heart
of
Disease—Evaluation
T
of CHD
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I
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ECG in Pediatric Cardiology
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BRJ Kannan
Chest X-ray in Congenital Heart Disease
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O
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Traps and Pitfalls in Echocardiographic Diagnosis of Congenital Heart Disease

K Sivakumar
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Fetal Echocardiography: Current Status and Role

in Management of Congenital Heart Defects
N
Balu Vaidyanathan
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Advances in CT Angiography for Congenital Heart Disease

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Best Use of Cardiac MRI in Congenital Heart Disease
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CHAPTER 32 ECG in Pediatric Cardiology
BRJ Kannan
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INTRODUCTION Box 1: Rule for QRS axis
Electrocardiogram (ECG) is a simple and useful Lead I Lead aVF Interpretation Comment
In
investigation that is often underutilized in children. The Positive Positive Normal axis Abnormal in neonates
and early infancy
ECG plays an important role in arrhythmia detection
Negative Positive Right axis Normal in neonates and
of
and management. Its role is somewhat limited in the deviation in early infancy
diagnosis of structural heart disease. However, it does Positive Negative Left axis Abnormal at any age
provide important clues regarding the changes in cardiac deviation
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chambers and supplements information required for Negative Negative North-west axis Abnormal at any age
diagnosis along with clinical examination and chest
radiography.
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Some of the limitations of pediatric electrocardiography
are as follows:
complex is measured in the lead with an initial Q wave.
The QT interval is often best measured in leads II, V5, and
V6 and the longest value should be used.
Age-dependent changes occur, therefore, single set of
20 o
criteria cannot be applied to children in various age Axis Detection
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groups
Select leads aVF and I. Determine if the net QRS voltage
Absence of specific guidelines for chest lead placement
is positive or negative in these leads. For example, if the
‘Borrowed’ criteria for chamber hypertrophy from
al
R wave height is 10 mm (above the isoelectric line) and

adult experience
S wave height is 3 mm (below the isoelectric line), then
Poor sensitivity, i.e. a child with large ventricular septal
ic
the net QRS voltage is positive (+7). If the R wave is short

defect (VSD) might not have large left ventricular (LV)
and S wave is longer, then the net QRS voltage would be
forces
og
negative.
Complexity of congenital heart diseases (CHDs) with a
The QRS axis can be located using the following simple
very few lesion-specific changes.
rule (Box 1).
ol
Nonetheless, ECG has an important role to play and

this chapter will address its practical utility in the diagnosis
NORMAL VARIATIONS AND RELATED
and management of children with heart diseases.
di
ABNORMALITIES
Many tables of ECG standards for various measurements
ar
BASICS OF RECORDING AND are available. 1,2 However, the practical utility of these
INTERPRETATION tables is limited. The salient age-related changes that one
C
While recording ECG in a small child, limb lead electrodes needs to know are as follows:
should be placed more proximally to reduce motion 1. Normal HR in the neonates vary between 120 and 230
artifacts. The usual ‘12-lead ECG’ is not enough; additional beats/min, it increases further by the first or second
V3R or V4R leads have to be recorded in children with month of life and gradually decreases over the next
suspected CHD. Standard gain (10 mm/mV) is used. If the 6 months. Resting heart rate is about 120 beats/min at
QRS voltages are very large, then the gain might be halved. 1 year, 100 at 5 years, and reaches adult values by 15
In t e r v a l s s h o u l d b e ha n d m e a s u re d , a s t h e years.2
computerized systems are often inaccurate, especially 2. Appearance of secondary r waves (r’ or R’) in right
in the neonates. Intervals in children increase with chest leads is normal in neonates.
increasing age, reaching the adult normal values by 7–8 3. At birth, right axis deviation of mean QRS vector is
years of age. The PR interval is measured from the onset of the rule (Figure 1). The axis becomes normal by
the P wave to the Q wave or R wave if no Q wave is present. 1 year of age. Hence, normal or leftward QRS axis is
It is often best measured in lead II. The duration of QRS abnormal in the neonatal period and early infancy.
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SECTION
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Congenital Heart Disease—Evaluation of CHD
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Figure 1: Normal ECG of a young infant. Note the q waves in inferior leads, right axis deviation of QRS vector and prominent RV forces
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Figure 2: Tricuspid atresia. Left axis deviation of QRS, q waves in leads I and aVL and absence of RV forces in the right-sided leads
ar
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Common conditions with leftward axis of QRS vector When Q waves are absent in inferior leads
are tricuspid atresia and AV canal defects (Figure 2). but are seen in Leads I and aVL, it is due to
4. Dominant R in right precordial leads can persist up to counterclockwise loop of the initial QRS vector.
6 months to 8 years; in the majority, the R/S ratio in This is a feature of tricuspid atresia, AV canal
lead V1 becomes less than 1 by 4 years. defects, and inlet VSD (Figure 2).
5. Q waves are normally seen in leads II, III, aVF, V5, and Deep Q waves in lateral leads might point towards
V6 (Figure 1). underlying anomalous origin of left coronary

If Q waves are seen in other leads, it is abnormal. artery from pulmonary artery (Figure 3).
Presence of Q wave in inferior leads (II, III, and 6. QT interval is highly variable in the first 3 days of life. If
aVF) is due to clockwise loop of initial QRS vector. the corrected QT is more than 0.44 seconds (440 ms), it
This finding is seen in majority of CHDs also. is abnormal.3
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32

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Figure 3: Anomalous left coronary artery from the pulmonary artery. Note the deep Q waves in leads I, aVL, V5, and V6. These leads also
show ST depression and T wave inversion
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Figure 4: QT prolongation in a child with history of syncope

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Hypokalemia, hypocalcemia, hypothermia, and 7. T wave in lead V1 can be upright at birth and it inverts by
cerebral injury are common causes of prolonged 7 days and typically remains inverted until 7 years of age.
QT interval. Upright T waves in right precordial leads (V1–V3)
Drug-induced QT prolongation has to be ruled out between ages 7 days and 7 years usually indicate
and the drugs commonly implicated are macrolide right ventricular hypertrophy even if the voltage
antibiotics, trimethoprim, cisapride, etc. criterion is not fulfilled.
Consider long QT syndrome, if clinically relevant 8. Atrial and ventricular extra systoles are common
(Figure 4). A comprehensive discussion on and are typically abolished with exercise. Also, sinus
congenital long QT syndromes and the management arrhythmia is very common and there could be
flow chart is available in the guidelines given by irregularly irregular rhythm (Figure 5). The heart
European Society of Cardiology (ESC).4 rate slows in expiration and speeds up in inspiration.
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Figure 5: There is significant irregularity of the rhythm. However, all QRS complexes are preceded by P waves with constant PR interval.
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This is due to sinus arrhythmia. Note the ST segment elevation with concavity facing upward due to early depolarization
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Figure 6: Wandering atrial pacemaker. Note the varying morphologies of the P waves and the resulting varying RR intervals
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Some children would present with significant sinus pacemaker from the sinus node to other sites. It is a
bradycardia. Both these conditions are due to excessive nonpathological finding (Figure 6).
vagal tone. Exercise consistently increases the heart 11. Early repolarization: Some children, especially in
rate and the rhythm becomes regular in these children. the adolescent age group, would show ST segment
9. Sinus pauses as long as 800–1000 ms can be seen elevation of 1–4 mm with the concavity facing upwards
especially during feeding, sleep, defecation or other (Figure 4). They can also have terminal T wave
times of increased vagal tone. At times, periods of inversion.
junctional rhythm, i.e. narrow QRS complexes without 12. Premature children, especially those <28 weeks of
preceding P waves can be seen. gestation, may not show RV dominance. Chest leads
10. Wandering pacemaker: Change in P wave axis and may show LV dominance and QRS axis can be normal
morphology in different beats due to the shift of or leftward even at birth.
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ANALYSIS OF P WAVE ANALYSIS OF PR SEGMENT CHAPTER
32
P wave amplitude varies very little with age. Unlike The PR s egment reflects the time taken by the
QRS axis, P wave axis is normal (positive in both lead depolarization impulse to travel across the atrium and
I and aVF) from birth due to sinus nodal origin of the the atrioventricular (AV) node. The AV block results in

atrial impulse (Figure 1). prolongation of the PR interval.
If the P axis is different, it indicates ectopic atrial First-degree block: Prolonged AV interval.
rhythm, i.e. the atrial impulse arises from some other Second-degree block, Mobitz Type I (Wenkebach type):
site. Low atrial origin of the rhythm is common in CHD, With each successive beat, the PR interval lengthens
where the P waves are typically negative in inferior resulting in a ‘dropped’ QRS. This could be a normal
leads (II, III, and aVF). finding and does not usually indicate an adverse
In children with situs inversus, right axis deviation of prognosis.
a

the P wave is seen (Figure 7). Second-degree block, Mobitz Type II: The PR interval
di
is normal or mildly prolonged, but it is constant in
Right Atrial Enlargement successive beats. There is sudden, intermittent loss of
In
conduction resulting in ‘dropped’ QRS. This is always
P wave amplitude is increased to >0.25 mV (2.5 mm)
pathological, carries high risk to progress to complete
with a relatively normal P wave duration (‘tall and
AV block.
of
peaked P waves’). The changes are best visualized in
Third-degree AV block: This is also known as complete
lead II.
heart block (CHB), where no atrial impulse is conducted
Tricuspid atresia, pulmonary atresia with intact
to the ventricles. Atrial rate would be higher than the
ty
ventricular septum, and severe pulmonary stenosis are
ventricular rate with complete AV dissociation. If the
commonly associated with right atrial enlargement.
escape rhythm originates near the bundle of His, the
Left Atrial Enlargement

18 cie resulting QRS would be narrow (Figure 8). If the escape
focus is lower down, the resultant QRS complex would
The changes are best visualized in lead V1 where the be broad. Congenital complete heart block is often not
20 o
terminal negative deflection is increased (>0.1 mV) associated with any underlying CHD. About 2-5% of
and prolonged (>40 ms). Prolonged P wave duration mothers with autoimmune antibodies have children
S
with increased notching can be seen in lead II due to with CHB and this condition carries a high mortality
left atrial enlargement, but it is less specific. risk, especially in the first 3 months.5 The CHB can
al
Mitral atresia and post-tricuspid shunts [VSD, patent be also seen in children with congenitally corrected
ductus arteriosus (PDA), aortopulmonary window) (TGA) and AV canal defects. Acquired CHB can be seen
ic
show left atrial enlargement. in myocarditis, digitoxicity, following cardiac surgery

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Figure 7: There is right axis deviation of P wave consistent with atrial situs inversus. The chest leads show progressive reduction of the QRS
without the normal progression of R wave suggestive of dextrocardia
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Figure 8: Complete heart block. Atrial rate is around 110/min and ventricular rate is 45/min. The PR interval is not constant suggestive of
atrioventricular (AV) dissociation
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Figure 9: Wolff-Parkinson-White syndrome. Short PR interval is seen. The slurring of the initial portion of R wave (delta wave) is seen in all
ar
leads, especially V1
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and rarely, after interventional procedures such as in delta wave and a fusion complex in the ECG. The
catheter closure of the membranous VSD. pre-excitation may be subtle and only detected in the
mid-precordial leads (Figure 9). The prevalence in
Causes of Short PR Interval children has been estimated to be 0.15–0.3%, higher in
those with structural heart disease.6 CHDs with higher
Common causes are Wolff-Parkinson-White syndrome
prevalence of WPW syndrome are: Ebstein’s anomaly of
(WPW syndrome), ectopic atrial pacemaker from the low
tricuspid valve, congenitally corrected TGA, hypertrophic
right atrium, mannosidosis, Fabry’s disease, and Pompe’s
cardiomyopathy, and cardiac rhabdomyoma.
disease.
The WPW syndrome is the most common cause of
paroxysmal supraventricular tachycardia in children.
Wolff-Parkinson-White Syndrome (Pre-excitation) The incidence of sudden death has been estimated to
It is due to premature conduction of atrial impulses be as high as 0.5% and cardiac arrest may be the initial
to ventricles through accessory pathways resulting presentation.7 Hence, it is very important to identify this
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electrical abnormality. Digoxin and verapamil have to be Right Ventricular Hypertrophy CHAPTER
avoided in this condition and beta-blocker therapy is the
32
Many CHDs are associated with right ventricular
ideal choice. hypertrophy. Tall R in V1 (R/S >1), deep S in V6 and
upright T wave in right precordial leads indicate the

ANALYSIS OF QRS COMPLEX presence of right ventricular hypertrophy.
Conditions with pressure overload of right ventricle
Bundle Branch Blocks (RV), e.g. valvar pulmonary stenosis show small q and
Intraventricular conduction abnormalities due to bundle tall R pattern or only tall R could be seen (Figure 10)
branch blocks (BBB) are uncommon in normal children. Conditions with volume overload of RV, e.g. atrial
The BBB result in wide QRS duration of >0.14 sec or more. septal defect show rSR’ pattern (Figure 11).
Right BBB is diagnosed if V1 shows tall wide notched
a
R (rSR’ pattern) and the lateral oriented leads (lead I, Left Ventricular Hypertrophy
di
V5, and V6) show notched wide S wave. In left BBB, the It produces increased voltages in the left-sided leads and
lateral leads show tall notched R wave and V1 shows wide manifests as tall R wave in leads V5, V6, and deep S wave
In
notched QS or rS complex. Right BBB is commonly seen in lead V1 (Figure 12). No definite criteria based on the
following open-heart surgery. voltages are available to diagnose ventricular hypertrophy
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Figure 10: Right ventricular hypertrophy (RVH). There is right axis deviation of QRS. Tall R wave, qR pattern in V1, ST depression, and T
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inversion in inferolateral suggestive of RVH with pressure overload strain

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Figure 11: Features of right ventricle volume overload (rsR’ in V1) seen. Left axis deviation of QRS vectors supports the diagnosis of ostium
primum atrial septal defect
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Figure 12: Biventricular hypertrophy: Tall QRS complexes in the mid-chest leads
with prominent positive waves suggest volume overload hypertrophy
in children. Another important clue for the presence of are commonly taken in the positions corresponding to
20 o
left ventricular hypertrophy is the presence of T wave the left-sided leads that would show ‘normal’ progression
S
abnormalities in leads V5 and V6. of QRS complexes. However, further interpretation of the
Tall T waves would indicate underlying volume right-sided leads regarding chamber enlargement is not
overloading condition (VSD, PDA). possible.
al
The ST depression and T inversion in lateral leads
could result from pressure overloading of left ventricle ANALYSIS OF ST SEGMENT

ic
(LV) (aortic stenosis, coarctation of aorta). The ST segment elevation is commonly due to early
Peculiarly, neonates with coarctation of aorta have
repolarization as mentioned above. The next common
og
ECG features of right ventricular hypertrophy (and cause is pericarditis. Other causes are: hyperkalemia,
not left ventricular hypertrophy) as the RV receives a intracranial hemorrhage, pneumothorax, or
greater proportion of systemic venous return from the
ol
pneumopericardium. Structural anomalies that can

supra vena cava (SVC) and faces the systemic vascular cause ST segment elevation are anomalous origin of left
resistance in the fetal period through the ductus
di
coronary artery from pulmonary artery and Kawasaki

arteriosus. disease-related coronary arteritis. The former more
In children with post-tricuspid shunts, large
ar
commonly presents with deep Q waves in leads I, aVL,

amplitude equiphasic QRS complexes could be seen V5, and V6 with associated T wave inversion. Brugada
in the mid-precordial leads suggestive of biventricular syndrome is a genetic disorder associated with a high
C
hypertrophy (Katz-Wachtel phenomenon). incidence of sudden death due to ventricular fibrillation.

The ECG in this condition shows ST segment elevation
CARDIAC POSITION-RELATED QRS CHANGES with RBBB pattern in the right precordial leads.
In levocardia, the major portion of the ventricles is The ST segment depression is seen secondary to
positioned to the left of the midline with the apex pointing pressure over load strain. In right ventricular strain, ST
to the left. The chest leads show a progressive change from depression is seen in right precordial leads, while it is seen
a dominant S wave in lead V1 to a dominant R wave in in left precordial leads in left ventricular strain.
leads V5 and V6. In children with dextrocardia, where the
major portion of the ventricles is to the right of midline, ANALYSIS OF T WAVE
this normal progression is not seen. Instead, there is In children, T wave is inverted in V1-V3 between 7 days to
progressive reduction in the amplitude of QRS from V2 7 years. At times, T remains inverted in older children and
to V6 (Figure 7). In these children, the right-sided leads adolescents (‘persistent juvenile T’). As mentioned above,
274
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upright T wave in V1 would indicate right ventricular CHDs like D-TGA, total anomalous pulmonary venous CHAPTER
hypertrophy even in the absence of high amplitude R connection, truncus arteriosus, pulmonary atresia, and
wave.
T wave inversion in lateral leads represents relative
hypoplastic left heart syndrome. Other tetralogy of Fallot 32
(TOF)-like situations (double outlet right ventricle,

or absolute ischemia and is a feature of ventricular corrected TGA, single ventricle when associated with PS)
pressure overload strain, anomalous left coronary also show these findings. Hence, the ECG pattern does not
artery from the pulmonary artery (ALCAPA), and help distinguish one condition from the other. However,
Kawasaki disease with coronary involvement. the absence of above-mentioned features points towards
Tall T wave is one of the ECG manifestations of
some other diagnosis.
hyperkalemia. Other manifestations of hyperkalemia The sudden transition of R wave between V1 and V2
are disappearance of P wave, broadening of QRS wave,
a
is one of the findings in TOF (Figure 13). This could be
and ST segment disappearance resulting in sine wave.
due to the fact that the V2 lead is placed right at the level
di
In hypokalemia, there is gradual reduction in the
of the large VSD. However, this finding is neither sensitive
amplitude of T wave with eventual disappearance of T
nor specific to TOF. The degree of the pulmonary blood
In
wave while U wave appears.
flow and hence the severity of the TOF could be indirectly
assessed by the LV forces (R wave) in the lateral chest
SOME DISEASE-SPECIFIC ECG CHANGES
of
leads, especially V5 and V6. Well-preserved R waves are
Situs Identification seen in pink TOF patients, while S wave would dominate
in severe TOF (Figure 14).
Situs solitus: Normal P axis
ty

Situs inversus : Right axis deviation (RAD) of P

wave. Tricuspid Atresia (see Figure 2)
Position of the Major Cardiac Mass

18 cie

Q wave in leads I and aVL
Left axis deviation of QRS
Right atrial enlargement
20 o

Levocardia: Normal progression of QRS in V1-6
Dextrocardia: Non-progression of QRS in V1-V6. Dominant LV forces in the chest leads.
S
Tetralogy of Fallot Common AV Canal Defect (Figure 15)

al
Clockwise loop (q waves in inferior leads), right ventricular Q wave in leads I and aVL
hypertrophy (RVH) and right axis deviation of the QRS Left axis deviation of QRS
ic
vector are seen. However, these are normal findings in the Both right ventricular and left ventricular forces are
newborns and infants. In addition, most other common seen (biventricular hypertrophy pattern)
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Figure 13: Tetralogy of Fallot. Right axis deviation of QRS vector with RV dominance. Note the sudden R wave’s transition from V1 to V2
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Figure 14: Tetralogy of Fallot. Poor left ventricular (LV) forces in the lateral leads suggestive
of significant reduction in the pulmonary blood flow
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Figure 15: Counterclockwise loop (q in I and aVL), left axis deviation of QRS with biventricular hypertrophy pattern suggestive of complete
atrioventricular (AV) septal defect
Corrected Transposition of Great Arteries Ebstein’s Anomaly (Figure 16)

Normally, interventricular septum is depolarized from left Giant P waves, RBBB pattern, low voltage complexes
to right that results in Q waves in lateral leads (leads V5 (especially in limb leads)
and V6). In this condition, as the ventricles are inverted, Look for the presence of delta wave, as WPW syndrome
the septal depolarization is also reversed. Hence, q waves is commonly associated. The accessory pathway is
are absent in V5 and V6, but can be seen in right precordial usually right sided; and hence, V1 will show deep S
leads (V3R, V1). wave.
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32

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Figure 16: Ebstein’s anomaly. Tall P waves due to right atrial enlargement. Broad and bizarre QRS complexes of right bundle branch blocks
(RBBB) morphology typically seen in this condition
of
Double Outlet Right Ventricle Ventricular Septal Defects
When both great arteries arise from the RV, it is called The QRS voltages of the chest leads fairly correlate well
ty
double outlet right ventricle (DORV). It is not a diagnosis with the level of L-R shunt. The RV hypertension is the
by itself. Clinically, it could behave like a simple VSD, TOF, rule in large defects; and hence, there would be features
18 cie
TGA, or single ventricle. The latter is called a complex
DORV. Hence, there is no specific finding for DORV in the
of biventricular hypertrophy. One cannot differentiate
perimembranous, muscular or subpulmonic defects
ECG. For example, if there is large left-to-right (L-R) shunt, based on the ECG. However, if it is an inlet VSD or if there
20 o
ECG findings would be similar to a large VSD. If there is is inlet extension of the VSD, counterclockwise loop is seen
S
TOF-like presentation, there would be RAD and RVH. If (Figure 17). With the development of pulmonary vascular
there is common AV valve, counterclockwise loop and left resistance and fall in pulmonary blood flow, the ventricle
axis deviation are seen. size and hence of QRS voltages would drift towards normal
al
with features of RV strain.

ic
Single Ventricle Pulmonary Stenosis

og
Most of the time, there would be two ventricles, but one There would be features of RVH and RAD. The height
of the ventricles would be hypoplastic. In mitral atresia, of the R in V1 or V3R correlates with the severity of
the large functional ventricle would be RV and in tricuspid PS. Monophasic R in V1 indicates elevation of the RV
ol
atresia, it would be LV. The underlying pathology could pressure to systemic level. The qR pattern in V1 would
be double inlet LV, endocardial cushion defect, corrected mean elevation of RV pressure to suprasystemic levels
di
TGA, etc. Hence, there is no specific ECG finding for single (Figure 10). If the QRS axis is north-west, it could suggest
ventricle in the ECG. Noonan syndrome and dysplastic valve.
ar
Aortic Stenosis and Coarctation of Aorta

Atrial Septal Defects
C
These left ventricular outflow obstructive lesions do not

In ostium secundum defects, P axis is normal, QRS axis show left ventricular hypertrophy (LVH) in the newborn
is normal or rightward, rsr’ pattern is seen in V1. In or in the early infancy period. However, in older children
ostium primum defects, there would be counterclockwise and adults, degree of LVH correlates with the severity of
loop (q in I and aVL) with left axis deviation of QRS axis the lesion.
(Figure 11). In sinus venosus defects, P axis could be
leftward at times. If pulmonary hypertension develops and Pompe’s Disease (Figure 18)
progresses, rsr’ is replaced slowly with monophasic R and This condition produces apparent hypertrophy of the
then to qR pattern. Inferior leads would then show tall R ventricles due to accumulation of glycogen.
waves with ST depression and T inversion suggestive of RV Short PR interval
pressure overload. Very tall QRS complexes in multiple leads.
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SECTION
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Figure 17: Features of biventricular hypertrophy pattern with counterclockwise loop and left axis deviation
of QRS suggestive of inlet ventricular septal defect
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Figure 18: Pompe’s disease. Very tall QRS complexes in all the leads with relatively short PR interval
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CHAPTER
32

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In
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Figure 19: Narrow QRS tachycardia. There is a P before each QRS and this could be wrongly labeled as sinus tachycardia. The Ps are inverted
in the inferior leads suggesting that is a nonsinus rhythm. This long RP tachycardia is called permanent junctional reciprocating tachycardia
20 o S
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ic
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di
ar
C
Figure 20: Pericarditis. ST elevation is seen in almost all the leads with its concavity upward. Note the PR depression
Dilated Cardiomyopathy are ST depression and Q waves in lateral leads

In idiopathic dilated cardiomyopathy, ECG may be (leads V5, V6, I, and aVL) (Figure 3). Persistent high
normal or show broad QRS complexes in sick patients. heart rate should make one to suspect the ongoing
However, in any case of cardiomyopathy, two common tachyarrhythmia (Figure 19). Even when the suspicion is
treatable causes that need to be ruled out are ALCAPA small, it is useful to administer adenosine and record the
and tachycardiomyopathy. The ECG signs of ALCAPA effect on the rhythm.
279
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SECTION Pericarditis 4. Schwartz PJ, Garson A, Paul T, et al. Guidelines for the
interpretation of the neonatal electrocardiogram. A task
5
Pan-ST elevation is seen with its concavity upwards. In
force of the European Society of Cardiology. European
addition, there is PR depression. These changes could Heart J. 2002;23(17):1329-44.
be transient replaced by T inversion. Pericarditis is quite 5. Buyon JP, Hiebert R, Copel J, et al. Autoimmune
common in the postoperative settings (Figure 20). associated congenital heart block: long term outcome of
children and immunogenetic study. J am Coll Cardiol.
REFERENCES 1998;31(7):1658-66.
6. Sorbo MD, Buja GF, Miorelli M, et al. The prevalence of
1. Davignon A, Rautaharju P, Boisselle E, et al. Normal ECG
the Wolff-Parkinson-White syndrome in a population of
standards for infants and children. Pediatr Cardiol. 1979;1:
116542 young males. G Ital Cardiol. 1995;25(6):681-7.
123-52.
7. Munger TM, Packer DL, Hammill SC, et al. A population
a
2. Goodacre S, McLeod K. ABC of clinical electrocardiography:
study of the natural history of Wolf-Parkinson-White
Pediatric electrocardiography. BMJ. 2002;324(7350):1382-5.
di
syndrome in Olomsted County, Minnesota, 1953-1989.
3. Schwartz PJ, Stramba-Badiale M, Segantini A, et al.
Circulation. 1993;87(3):866-73.
Prolongation of the QT interval and the sudden infant
In
death syndrome. N Engl J med. 1998;338(24):1709-14.
of
ty
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Chest X-ray in Congenital
a
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INTRODUCTION SEQUENTIAL APPROACH FOR
Chest radiograph remains an important initial investigation INTERPRETATION
In
in evaluation of patients with congenital heart disease Although chest radiograph provides a static image of
(CHD). Though the findings may be nonspecific in cases heart and the lungs, it provides important physiologic and
with admixture lesions, classic imaging signs can be
of
anatomic information. Moreover, it is operator independent
seen in certain CHDs. Moreover, it provides important in broad sense. It provides valuable information about
information about the pulmonary vasculature in addition the situs, cardiac size, pulmonary vasculature, and the
ty
to specific chamber enlargement, which forms the basis parenchymal or skeletal abnormalities. 1 Pulmonary
for classification of CHDs. A careful interpretation of vasculature forms the basis for classification of CHD. It
18 cie
chest X-ray can provide useful diagnostic information,
including important morphological abnormalities and
their impact on the function of the cardiovascular system.
is important to develop an algorithm for interpretation
so that useful information is sequentially obtained and
stored to arrive at the probable diagnosis. The most
The last two decades have witnessed many advances in commonly followed approach is to evaluate the following
20 o
cardiovascular imaging. Noninvasive diagnosis of CHD in sequential order:
S
is possible with echocardiography and cross-sectional Visceroatrial situs
imaging modalities such as computed tomography (CT) Pulmonary vascularity
and magnetic resonance imaging (MRI). In spite of the Heart size

al
availability of a host of imaging techniques for noninvasive Identification of enlarged chambers
cardiac imaging, chest X-ray remains the most widely Position of great vessels
ic
available, economical initial examination in patients with Size and position of aorta.
suspected heart disease. A proper understanding of the

og
normal anatomy is essential for correct interpretation of Assessment of Cardiac Situs

pathological states. Moreover, the findings of chest X-ray
The evaluation should begin with the assessment of the
should be interpreted in clinical context to avoid any
ol
situs. Normally, in upper abdomen, the liver and inferior

misdiagnosis.
vena cava (IVC) lie on the right side, and fundus of the
di
stomach (identified by stomach bubble) and spleen lie on

TECHNICAL CONSIDERATION the left side. The systemic venous (morphological right)
ar
Optimal acquisition, including the positioning and atrium lies on the right side and opposite to the fundus
technical factors, is essential for suitability of the chest of the stomach. This relationship is referred to as the
C
radiograph for interpretation. Some basic steps will ensure ‘visceroatrial situs’. Atrial situs almost always conforms to
that the acquired X-ray is suitable for interpretation. the situs of the upper abdomen, irrespective of the situs
These include no rotation to any side, optimized film to or position of the remainder of the heart. Ascending aorta
X-ray focus distance to prevent undue magnification. lies on the same side as the systemic venous atrium and
Moreover, exposure factors need to be adequate to show opposite to the fundus of the stomach. Whenever this
the intervertebral disc spaces up to tracheal bifurcation. rule is breached, corrected transposition of great arteries
The X-ray exposure should be made in suspended deep (TGA) is almost always present. The right-sided bronchus
inspiration to push the domes of diaphragm as low is shorter, wider, and more vertically oriented than the left
as possible. These steps generally ensure that there is bronchus. The right lung is trilobed, whereas the left lung
minimum magnification of the cardiac structures which is bilobed. This is referred to as the ‘bronchial situs’. The
will provide for their optimal assessment. position of the heart in the thorax and the orientation of
KG-33.indd 281 02-11-2018 17:01:08

SECTION the cardiac apex are contributive to but not determinative More than 6 vessels in peripheral one-third of the
of the situs; and, accordingly, they must be described lungs.
5 separately. RDPA diameter more than that of the trachea (children)
or RDPA >16 mm in diameter (adults).
Assessment of Pulmonary Vascularity Prominent hilar vessels on lateral view.

Chest X-ray provides comprehensive assessment of
pulmonary vasculature.2 Pulmonary artery (PA) segment Decreased Pulmonary Blood Flow
on the chest X-ray is produced by overlapped segments (Pulmonary Oligemia)
of the main and left PA. Normally, it is slightly concave It is important to ensure that the X-ray film is optimally
or straight. The PA enlargement causes a convexity of exposed before evaluating it, as an underexposed film can
a
the PA segment. Moreover, it should be remembered give a false impression of an increased vascularity and
that the arteries and corresponding bronchial branches an overexposed film can give an erroneous impression
di
are approximately the same diameter at any particular of a decreased vasculature. Some normal persons may
level with a ratio of 1.2:1. Any discrepancy should alert to have small pulmonary vessels. Oligemia can be caused by
In
possible changes in the vasculature or airways. pulmonary outflow tract and/or valvular obstruction and
The right hilum is formed by the confluence of the intracardiac right-to-left (R-L) shunts, besides other causes
shadows of the right upper lobe pulmonary vein and the such as obstructing lesions in the pulmonary vasculature
of
right descending PA (RDPA), which forms a right angle. due to a variety of reasons, congenital, thromboembolic,
Normal RDPA has a straight or mildly concave right lateral and vasculitis among others. The findings on X-ray may
border. A convexity suggests an enlargement and a deep include reduction in the size of pulmonary arteries and
ty
concavity suggests a diminished size. In children, the ratio veins, small central vessels, and difficult to visualize
of RDPA to trachea is <1.0. In adults, the normal transverse peripheral arteries.6
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diameter of RDPA just above the origin of right middle
lobe branch or 1.25 cm distal to the origin of right upper
Various radiological signs of pulmonary oligemia are
as under:
lobe branch is 10–16 mm in males and 9–15 mm in females Concave or absent main PA (MPA).
20 o
in deep inspiration.3 In erect position, blood flow is greater Less than 4 vessels in peripheral one-third of the lungs.
to the lower lobe because of gravity and differential intra-

S
Small hilar, lobar, or segmental vessels.
alveolar pressure. The lower lobe vessels are 2–3 times Decreased size and density of hilar vessels on lateral
larger than the upper lobe vessels. In the erect chest chest radiograph in the presence of cyanosis is
al
X-ray, vessels in the first intercostal space are <3 mm in suggestive of pulmonary oligemia.
diameter and those just above the diaphragm are up to Overall appearance of an overpenetrated film, despite
ic
6 mm in diameter. These facts help in differentiating an optimal exposure.

various changes in pulmonary vasculature as under:
og
Pulmonary Arterial Hypertension

Increased Pulmonary Blood Flow This may be primary or secondary to pulmonary venous
(Pulmonary Plethora)
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hypertension, long-standing left-to-right (L-R) shunts,

This refers to the enlargement of pulmonary vessels due pulmonary thromboembolic disease, respiratory disease,
di
to increased pulmonary flow. The width of the pulmonary high altitude, drugs, and pulmonary arterial occlusion.
vessels depends on flow as long as the vascular reserve It is said to be present if the mean pulmonary artery
ar
is not exceeded. Beyond this, the size depends on flow (PA) pressure is >20 mm Hg. The pulmonary arterial
and pressure or pressure alone. Moreover, there is fair hypertension (PAH) is graded as mild, moderate, and
correlation between vessel enlargement and shunt size. severe with the PA mean pressure ranging from 20–29, 30–
C
Shunts with QP: QS > 2:1 can be reliably detected on 49, and >50 mm Hg, respectively. The central vessels from
radiograph. Very large volume shunts can also cause the main PA to the second-order branching vessels dilate
pulmonary venous hypertension.4,5 and peripheral (lobar) vessels constrict. The transition
Various radiological signs of pulmonary plethora are between centrally dilated and peripherally constricted
as under: vessels is more lateral in L-R shunts. The pruning of the
The presence of shunt vessels, end-on vessels more pulmonary arteries is defined as more than a 50% loss
than two times the diameter of the accompanying of the vessel diameter at any degree branching and is
bronchus. suggestive of PAH. Chronic PAH leads to calcification
En-face vessels below the tenth posterior rib. of the main PA and proximal branches. The presence of
Prominent upper and lower zone vessels. calcification is pathognomonic of PAH. The severity of
Prominent vessels below the crest of the diaphragm. central dilatation has a rough correlation with the severity
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of PAH. In the lower pressure ranges, the ratio of the size of pleura. This usually occurs when systemic venous pressure CHAPTER
the hemithoracic diameter to the size of the MPA shows an is also elevated, as in right heart failure. Several radiologic
approximate correlation with PA pressure.6 findings have been correlated with the level of PCWP in
patients with acute and chronic heart failure.
33

Pulmonary Venous Hypertension
Assessment of Chamber Enlargement
Pulmonary venous pressure (PVH) is said to be present
when the pulmonary capillary wedge pressure (PCWP) Right Atrium
exceeds the normal range of 8–12 mm Hg. Progressive The most reliable sign for right atrium (RA) enlargement in
PVH produces changes reflecting the presence and chest X-ray PA view is the increase in its height (Figure 1).
severity of this disorder. In normal individuals, the distance between the top of
a
Stage 1: Redistribution or cephalization of the blood the aortic arch and the junction of the superior vena cava
and the right atrium is more than the distance between
di
flow:This may precede the clinical signs and symptoms.
The venous pressure ranges from 13–19 mm Hg. The the latter and the right cardiophrenic angle. When the
reverse happens, RA is said to be enlarged.6 The maximum
In
changes are characterized by constriction, blurring
of lower zone vessels, effacement of hilar angle, and convexity of right cardiac border >3 cm beyond right
dilatation of upper lobe vessels. With increase in left atrial lateral vertebral border or >4.5 cm from the anatomic mid-
of
and PCW pressure, there is an increase in the interstitial line may also suggest RA enlargement.
lung water and increased pulmonary lymphatic drainage,
leading to ‘cuffing’ of fluid around small bronchioles. Left Atrium
ty
The increased interstitial water gravitates to dependent The left atrium (LA) does not take part in the formation of
areas, causing increased interstitial pressure and vascular any cardiac border in the PA projection in normal subjects.
18 cie
resistance at lung bases. Thus, blood is diverted to upper
lobes leading to vascular redistribution.
It lies in the mid-line in a posterior location. The earliest
enlargement of LA is usually in the superior direction
Stage 2: Interstitial edema: It is characterized by the and this results in lifting up of the left main bronchus.
20 o
As the LA enlarges further in this direction, the carinal
presence of Kerley lines, peribronchial cuffing, background
angle widens as the carina forms the superior limit of
S
haze, septal and interstitial edema, and pleural effusion.

the normal left atrium. The normal carinal angle ranges
The venous pressure ranges from 20 mm Hg to 24 mm Hg.
between 51° and 71°. With LA enlargement, it becomes
al
Stage 3: Alveolar edema:This occurs when the interstitial right or obtuse angled. The LA may project beyond the left
fluid accumulates at rates faster than it can be removed ventricle, producing localized convexity of the left border
ic
by the lymphatics. The venous pressure generally ranges of cardiac silhouette just below the pulmonary conus.
from 25 mm Hg and above. Milking of edema fluid When enlargement reaches this stage, the chamber is
og
towards the hilum by the expanding lung imparts a ‘bat’s often large enough to produce an oval shaped, localized
wing appearance’. However, a chronic lung disease and density on the right side, and projecting outside the lower
dependent posture may result in atypical patterns of edema. right cardiac border. This can be seen in frontal projection
ol
Pleural effusion occurs when pleural fluid formation by as a double density within the cardiac shadow on the
visceral pleura is faster than its absorption by the parietal right side (Figure 2). In the presence of double density,
di
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Figure 1: Chest radiograph showing right atrial enlargement with Figure 2: Chest radiograph showing left atrial enlargement causing
box-shaped heart in a patient of Ebstein’s anomaly uplifting of left main bronchus with characteristic double density
appearance 283
KG-33.indd 283 02-11-2018 17:01:08

SECTION the margin of LA is differentiated by that of RA by the fact mildly enlarged with LV configuration, aortic knuckle is
that the LA margin never touches the right diaphragm and obliterated or replaced by a bulge, pulmonary conus is
5 turns medially behind the heart shadow before reaching
the diaphragm. The right heart margin that touches the
enlarged, and lung vascularity is increased. In addition,
pulmonary arterial hypertension (PAH) may be present.
diaphragm is produced by the RA. If the ascending aorta is enlarged disproportionate to

the aortic knuckle, the L-R shunt is at the aortic root level.
Left Ventricle The causes include a ruptured aneurysm of the sinus of
Valsalva (RSOV), aortopulmonary window (APW), and
The left ventricle (LV) enlarges mainly to the left and
coronary arteriovenous fistula (AVF).
posteriorly, and only slightly to the right and anteriorly.
Hypertrophy produces rounding of the cardiac apex, Ruptured aneurysm of the sinus of Valsalva: The heart
a
whereas dilatation causes elongation either to the left or size is usually enlarged with a biventricular or LV
to the left and downwards, often combined with rounding configuration. An abnormal shadow of the aneurysm is
di
of the apex. usually present at the level of the aortic root. There may
be curvilinear calcification in it. The aorta is enlarged
In
Right Ventricle with a disproportionate dilatation of the aortic root. The
pulmonary conus is prominent and lung vascularity is
The right ventricle (RV) does not take part in the formation
increased. In addition, in symptomatic patients, some
of
of any heart border in the PA projection in normal
evidence of PVH is also present. Usually, the right coronary
subjects. It lies in the mid-line in an anterior location. It
sinus is involved and ruptures into the RV. Simultaneous
enlarges mainly to the left and anteriorly. The outflow
presence of pulmonary plethora and PVH is characteristic
ty
tract enlarges first and this is best seen in right anterior
of an RSOV.
oblique (RAO) and lateral views. When the enlargement
18 cie
is significant, pulmonary conus becomes prominent in
PA view. In some cases, the left border may be formed by
this ventricle and may cause rotation of LV to the left with
Aortopulmonary window: The heart size is usually enlarged
with an LV configuration, there is disproportionate
enlargement of the aortic root, pulmonary conus is
elevation of the apex. In such situations, the left lower prominent, lung vascularity is increased, and PAH is
20 o
heart border appears lifted up and has a double convexity usually present.
S
produced by the enlarged RV, and displaced and rotated Coronary arteriovenous fistula: The heart size is usually
LV. This rotation tends to swing the aorta to the right, so normal and there may be LV configuration. There
al
that the aortic knuckle becomes less prominent. In lateral is disproportionate enlargement of the aortic root,
view, there is encroachment upon the retrosternal space pulmonary conus is prominent and lung vascularity is
in the upper part.
ic
normal or increased. Chest radiograph may be normal

because the shunt is usually small.
og
Aorta
The ascending aorta does not usually contribute to the Normal Aorta
cardiac borders in PA view. The assessment of the aorta
ol
Normal or apparently small aortic knuckle and

on chest X-ray should include a comment on its looping, inconspicuous ascending aortic shadow in a frontal chest
position of aortic knuckle, enlargement and aortic
di
radiograph in the presence of increased lung vascularity

calcification, which may have a specific localizing value in a pink patient suggest an intracardiac L-R shunt. This
for the diagnosis.
ar
shunt can be at pre- or post-tricuspid level.

Pre-tricuspid shunt: The pre-tricuspid shunt is produced by
CHEST X-RAY AND CHD CLASSIFICATION:
C
an atrial septal defect or a what about TAPVC anomalous

SIMPLIFIED APPROACH (TABLE 1) pulmonary venous drainage.
Atrial septal defect (ASD): The heart size is usually
Left-to-Right (Acyanotic) Shunt
normal (Figure 3). There may be mild cardiomegaly
Chest radiograph is useful in localizing the site of L-R
in approximately 25% of the patients. There is right
shunts in CHD. If the aortic knuckle is enlarged, the shunt
atrial enlargement with right-sided configuration of
is extracardiac; and if the aorta is normal, the shunt is
the heart. Aortic shadow is normal in size with the
intracardiac.7,8
ascending aortic shadow usually conspicuous by its
absence in the upper right cardiac border. This sign
Large Aorta is characteristic of an ASD. The heart appears to be
If the aortic knuckle is enlarged disproportionate to shifted to the left and lung vascularity is increased.
the ascending aorta, the L-R shunt is caused by patent PAH may be present. Associated mitral valve disease
ductus arteriosus (PDA). The heart is usually normal or should be suspected if LA/LA appendage is enlarged,
284
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Table 1: Basic chest radiographic approach towards congenital heart disease CHAPTER
33
Left-to-right shunt Right-to-left shunt
Large aorta Normal aorta Decreased lung Increased lung
(Extracardiac shunt) (Intracardiac shunt) vascularity vascularity

AK>AA AA>AK Pre-tricuspid level Post-tricuspid level Large aorta Normal aorta Small aorta Large aorta
PDA RSOV ASD VSD TOF Ebstein’s D-TGA Truncus
anomaly arteriosus
APW PAPVC VSD with pulmoanry Valvular PS TAPVC
atresia
Coronary AVF TGA with VSD and PS
Tricuspid atresia
a
DORV with PS
di
Abbreviations: AK, aortic knuckle; AA, ascending aorta; PDA, patent ductus arteriosus; RSOV, ruptured sinus of Valsalva; APW, aortopulmonary
window; AVF, arteriovenous fistula; ASD, atrial septal defect; PAPVC, partial anomalous pulmonary venous connection; VSD, ventricular septal
In
defect; TOF, tetralogy of Fallot; TGA, transposition of great arteries; PS, pulmonary stenosis; DORV, double outlet right ventricle; D-TGA, dextro-
transposition of great arteries; TAPVC, total anomalous pulmonary venous drainage
of
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Figure 3: Chest radiograph showing near normal sized heart with Figure 4: Chest radiograph shows cardiomegaly with left atrial
convex pulmonary artery segment in a patient with atrial septal enlargement and pulmonary plethora in a patient with ventricular
og
defect septal defect
PVH (especially if Kerley’s lines) is present, or if present. In addition, there may be evidence of differential
ol
the mitral valve is calcified. The association of ASD increase in lung vascularity in the right upper zone. In
with mitral stenosis of rheumatic etiology is called 3–5% of the patients, an associated right-sided aortic arch
di
‘Lutembacher’s syndrome’. may be present.

Partial anomalous pulmonary venous drainage: This
ar
should be suspected if, in the presence of radiographic Right-to-Left (Cyanotic) Shunt

features of ASD, there is an abnormally enlarged
Although chest radiographic features of most of the
shadow of SVC or rarely an abnormally directed
C
following conditions can be characteristic, it is important

pulmonary vein is seen.
to remember that typical features are not usually seen in
most patients. As with L-R shunts, the size of the aortic
Post-tricuspid L-R Shunt
shadow is important in the localization of R-L shunts.
Ventricular septal defect: This is the most common form
of acyanotic CHD. The findings on chest radiograph in
Large Aorta with Decreased Lung Vascularity
ventricular septal defect (VSD) depend on the shunt size
and the direction of predominant flow. In small (<2:1) Large aortic knuckle in the presence of cyanotic CHD
shunts, the chest radiograph may be normal. In the and decreased vascularity is produced by tetralogy of
presence of a large (>2:1) shunt, the heart size is usually Fallot (TOF), pulmonary atresia with VSD, tricuspid
enlarged with a left or a biventricular configuration, and atresia, transposition of great arteries (TGA) with VSD and
there is evidence of LA enlargement, a normal aorta, and pulmonary stenosis (PS), and double outlet right ventricle
increased lung vascularity (Figure 4). The PAH may be (DORV) with PS.
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SECTION
5
a
di
In
Figure 5: Tetralogy of Fallot with characteristic coer-en sabot heart Figure 6: Chest radiograph shows cardiomegaly with enlarged
with wide vascular pedicle bilateral central pulmonary arteries and peripheral oligemia in a
patient of tetralogy of Fallot with absent pulmonary valve
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20 o S
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Figure 7: Chest radiograph shows severe cardiomegaly (in Figure 8: Chest radiograph shows straight right heart border and
comparison to tetralogy of Fallot with normal sized heart) with pulmonary oligemia in a patient of tricuspid atresia with pulmonary
og
uplifted cardiac apex a patient of ventricular septal defect- stenosis

pulmonary atresia
ol
Tetralogy of Fallot : This is the most common form right. When this happens, parenchymal lung abnormalities
of cyanotic CHD in children. It classically includes are frequently associated.9
di
malaligned VSD, infundibular PS, overriding of the VSD with pulmonary atresia: There is mild cardiomegaly
aorta and RV hypertrophy. Additional valvular PS and of RV configuration, a large aortic knuckle that frequently
ar
hypoplasia of the main PA are also frequently present. crosses the sternoclavicular joint into the neck, pulmonary
The chest radiograph shows a characteristic picture bay, and peripheral oligemia (Figure 7). Aortic arch
C
produced by a normal heart size, RV configuration with

is right-sided in 30–40% patients. Bronchial collateral
an uplifted apex (coer-en sabot appearance), a large aortic
circulation is frequently present. Rib notching may be
knuckle, presence of pulmonary bay, and pulmonary
seen.
oligemia (Figure 5). A right-sided aortic arch is present
in approximately 25% of the cases. Rarely, TOF may be Tricuspid atresia: The chest radiographic picture depends
associated with an absent pulmonary valve. This produces on the relationship of great vessels, presence of PS, and
a pathognomonic appearance consisting of an enlarged the degree of RV hypoplasia. A typical picture is seen in
heart, large central pulmonary arteries with peripheral only 15–20% of the cases and consists of a normal-sized or
oligemia in the setting of TOF (Figure 6). In addition, mildly enlarged heart, LV configuration, straight right heart
a host of lung abnormalities largely due to a defective border (Figure 8), some evidence of LA enlargement,
bronchial cartilage and resultant tracheobronchomalacia enlarged aorta, pulmonary bay, and decreased vascularity,
may be associated. Occasionally, TOF may be associated provided that there is PS and the great vessels are normally
with congenital absence of a PA, left more commonly than related. The aortic arch is right-sided in one-third of
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CHAPTER
33

a
di
In
Figure 9: Chest radiograph shows typical ‘egg-on-side’ appearance Figure 10: Chest radiograph shows typical snowman or ‘Figure
with narrow vascular pedicle in a patient of dextro-transposition of of 8’ appearance in a patient of supracardiac nonobstructive total
great arteries anomalous pulmonary venous drainage
of
the cases. If the pulmonary arteries are not located in more often seen on the left side. The aortic arch is right
their normal position, an abnormal relationship of great sided in about 50% of the cases.
ty
vessels should be suspected. In the absence of PS, there is
Total anomalous pulmonary venous drainage: This may
evidence of increased lung vascularity.10
be divided into four main groups according to the site or
18 cie
Dextro-transposition of great arteries (D-TGA), VSD and
PS: A chest radiograph may superficially resemble TOF.
The heart size is usually normal or may be mildly enlarged.
sites of connection; supracardiac, cardiac, infracardiac,
and mixed. The chest radiographic picture depends on
the type of TAPVC. In supracardiac type, which is also
20 o
The aortic knuckle is normal or the pedicle may appear the most common, the heart is enlarged, the pedicle
narrow. The PA segment is not present in the normal is wide with a classical “figure of 8 or Snowman’s”
S
position and is located in a high and medial position. The appearance, produced by the dilated left vertical and left
lung fields are oligemic. innominate veins and the right SVC (Figure 10). The left
al
atrium is small and there is increased flow, as evidenced

Small Aorta with Increased Vascularity by pulmonary plethora. In cardiac or mixed types, the
ic
D-TGA: This is the second most common cause of cyanotic picture may be nonspecific and consists of cardiomegaly,
heart disease in infancy. It is caused by a ventriculoarterial normal or enlarged aorta, and increased lung vascularity.
og
discordance in which the aorta originates from RV Shadow of an enlarged abnormal pulmonary vein may be
and PA from LV. The chest radiographic findings are seen. The scimitar sign is seen in the infradiaphragmatic
characteristic, consisting of an enlarged heart, narrow type of TAPVC and is caused by the drainage of the right
ol
pedicle, abnormally located pulmonary arteries, and pulmonary vein into the IVC, hepatic or portal vein.
increased lung vascularity. The shape of the heart is This syndrome is often associated with hypoplasia or
di
typical and resembles an ‘egg-on-side’” (Figure 9). There sequestration of the right lung.
may be a differential increase in right lung vascularity,
ar
especially in the upper zone. This pathognomonic picture Normal Aorta with Decreased Lung Vascularity
is seen in patients in whom there is no evidence of PS. The This combination can be seen in patients with Ebstein’s
C
typical chest radiograph findings are seen in about half the anomaly, and valvular PS in failure.
patients.
Ebstein’s anomaly: This produces a characteristic
radiographic picture. There is cardiomegaly, evidence
Large Pedicle with Increased Vascularity
of RA enlargement, sharp, well-delineated cardiac
This combination is seen in truncus arteriosus, total margins, as if drawn by a pencil, normal aorta, and
anomalous pulmonary venous drainage (TAPVC), and pulmonary oligemia (see Figure 1). It can superficially
tricuspid atresia without PS.
resemble pericardial effusion, valvular PS in failure,
Truncus arteriosus: The heart is usually enlarged, there tricuspid regurgitation caused by chronic rheumatic
is LV configuration, the aorta is enlarged, PA is not in its heart disease (RHD), dilated cardiomyopathy (DCM), and
usual position, and lung vascularity is increased. The Uhl’s anomaly. The pulmonary vascularity is important in
abnormal location of the PA may produce a characteristic differentiating these conditions. In pericardial effusion,
picture described as ‘comma or water-fall’ sign. This is the lung vasculature is normal and no specific chamber
287
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SECTION enlargement is present. In RHD, there is PVH and tell-tale notching. If the coarctation is proximal to an aberrant right
signs of the underlying valvular disease are always present. subclavian artery, unilateral notching of the left ribs occurs.
5 In DCM, there is evidence of PVH. The LA and LV may be
enlarged.
Abnormal appearance of the aorta is seen in most patients.
The ascending aorta is slightly dilated. The ‘Figure of 3’
appearance of the descending aorta is characteristic but

Valvular PS: A chest radiograph may be normal except for
not commonly seen. The upper convexity is formed by the
prominent pulmonary conus till there is severe PS with
dilated subclavian artery and the lower convexity by the
congestive failure. In such cases, there is cardiomegaly,
poststenotic dilatation of the descending aorta. Usually,
RA enlargement, a normal aorta, prominent pulmonary
a prominent or a flat knuckle is seen. If there is associated
conus produced by poststenotic dilatation of main and left
left ventricular decompensation, PVH may be present.11,12
PA, and peripheral pulmonary oligemia.
a
CONCLUSION
Other Conditions
di
Detailed sequential interpretation of chest radiograph
Coarctation of Aorta provides important clues to the underlying heart disease
In
This refers to a narrowing of the distal aortic arch and/or and the functional impairment produced by it. Moreover,
proximal descending aorta due to a discrete membrane chest radiograph also serves as a useful method for follow-
or narrowing of the aortic isthmus. Findings on chest up after treatment in most cardiac conditions. Distinctive
of
radiograph depend on the age of the patient, location of the radiographic abnormalities in CHDs allow them to be
coarctation, ventricular function, competence of the aortic differentiated from each other before resorting to other
valve, and associated abnormalities. In an uncomplicated forms of cross-sectional imaging.
ty
isolated coarctation, the heart size is usually normal.
There may be left ventricular configuration. The classical REFERENCES
18 cie
feature of bilateral notching of the posterior and inferior
margins of the 4th-8th ribs is usually not seen in the first
1. Radiology of the heart. Braunwald E (Ed). Heart Disease:
A Textbook of Cardiovascular Medicine. Philadelphia: WB
decade of life. The coarcted segment is usually located in Saunders; 1992. pp. 204-324.
20 o
the juxtaductal region. Occasionally, it can be postductal 2. Coussement AM, Gooding CA. Objective radiographic
and rarely preductal. Postductal or juxtaductal coarctation
S
assessment of pulmonary vascularity in children.

produces typical radiographic features in the cardiac Radiology. 1973;109(3):649-54.
configuration, ribs, and aorta. Rib notching is caused by 3. Chang CH. The normal Roentgenographic measurement of
al
the hypertrophied intercostal arteries that run along the the right descending pulmonary artery in 1085 cases. Am J
posterior and inferior margins of the ribs (Figure 11). Roentgenol Ther Nucl Med. 1962;87:929-35.
ic
In juxtaductal coarctation, the fourth to eight ribs are 4. Roberts WC. Radiologic differentiation of common
anomalies. Adult Congenital Heart Disease. 1988. pp. 191-
usually involved. Coarctation proximal to the origin of the
og
219.
left subclavian artery results in unilateral right-sided rib
5. Moes CA. Analysis of the chest in the neonate with
congenital heart disease, Radiol Clin North Am.
ol
1975;13(2):251-76.
6. Jefferson K, Rees R (Eds). Clinical Cardiac Radiology.
Butterworth: London; 1980.
di
7. Roberts WC. Radiologic differentiation of common

anomalies. In: Carol A Warnes. Adult Congenital Heart
ar
Disease. 1988. pp.191-219.

8. Bessolo RJ, Vincent WR. Diagnosis of congenital heart disease
C
in first two weeks of life. Calif Med. 1969;110(3):200-6.

9. Gyepes MT, Vincent WR. Severe congenital heart disease
in the neonatal period. Am J Roentgenol Ther Nucl Med.
1972;116(3):490-500.
10. Elliot LP, Van Mierop LH, Gleason DC. Roentgenology of
tricuspid atresia. Semin Roentgenol. 1968;3:399-409.
11. Sharma S. Proceedings of symposium and workshops in
Cardiovascular and Interventional Radiology.1997.
Figure 11: Chest radiograph shows characteristic bilateral inferior 12. Lapierre C, Dery J, Guerin R, et al. S egmental Approach
rib notching with normal sized heart in a patient of coarctation of to Imaging of Congenital Heart Disease. RadioGraphics.
aorta 2010;30(2):397–411.
288
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Traps and Pitfalls in
Echocardiographic Diagnosis of
CHAPTER 34
Congenital Heart Disease
K Sivakumar
a
di
INTRODUCTION Table 1: Common errors in CHD echocardiography
In the pre-echocardiographic era before 1980s, diagnosis I: Anatomical errors
In
of congenital heart disease (CHD) traditionally was 1 Coarctation of aorta
considered to be resting on three pillars namely clinical 2 Aortic arch interruption
3 Peripheral pulmonary artery stenosis
of
examination, chest X-ray, and electrocardiography.
4 Supravalvar aortic stenosis
Once echocardiography came into clinical practice, it 5 Aortopulmonary window
has completely transformed the way diagnosis is made 6 Anomalous pulmonary venous drainage
7 Pulmonary vein stenosis/atresia
ty
in pediatric cardiology and in evaluation of grown-up
8 Venacaval anomalies with or without cyanosis
congenital heart (GUCH) diseases. Echocardiography has 9 Sinus venosus or coronary sinus defects
18 cie
become the key investigation of choice in the diagnosis
and in many instances the only final investigation to be
done before a final corrective intervention is performed,
10 Muscular ventricular septal defects
II: Functional errors
1 Assessment of right ventricle
either surgically or in the catheterization laboratory. The 2 Assessment of single ventricle
20 o
increasing comfort of the correct diagnosis provided by this 3 Diastolic function in congenital heart disease
S
4 Quantify valvar regurgitation in hypoplastic/dysplastic valves

diagnostic tool has made many institutions to avoid more
5 Quantify valve area in stenotic valves
invasive additional imaging even in complex CHD, where 6 Ventricular mass in right/single ventricle
the accuracy of the data matters the most. One spectacular
al
example is the complete reliance of echocardiography in

diagnosing the coronary artery patterns before arterial follow-up studies will be necessary to better define their
ic
switch operation in d-transposition of great arteries real impact in the clinical setting.2
In this context, it is mandatory for the operators to
og
(dTGA), where the success of the surgery depends on the

harvest of the coronary buttons and their anastomosis to clearly understand the traps and pitfalls in this modality
the neo-aortic root.1 of imaging for recognizing its limitations. This knowledge
ol
Echocardiography defines the morphological and is crucial for ordering additional three-dimensional
functional findings in CHD, as completely as possible imaging investigations such as computed tomography
di
in almost all the cases. It requires a different approach (CT) or magnetic resonance (MR). It also may clarify the
compared to other forms of heart diseases by providing precise role of diagnostic cardiac catheterization and
angiography which lost its favor in routine practice due
ar
information on the heart position in the thorax, the

viscera-atrial situs, the venoatrial and the atrioventricular to its invasiveness and ionizing radiations.3 The errors in
connections, the relationship between the ventricles, the the assessment of patients with CHDs can be broadly be
C
ventriculoarterial connection and the relationship of the grouped as shown in Table 1.

great arteries which is described as systematic segmental
analysis. It also assesses the ventricular function for ANATOMICAL ERRORS
optimal pre- and postoperative management in patients
with CHD using ‘pump indices’ (i.e. ejection fraction or Coarctation of Aorta
fractional shortening), which unfortunately depend on Coarctation of aorta accounts for 6-8% of all forms of
loading conditions and heart rate. As a consequence, CHD and is commonly missed in clinical practice due
indices to reflect intrinsic myocardial contractility like fiber to nonreliance of simple clinical examination of femoral
shortening or rate-corrected velocity of circumferential pulses. Poor suprasternal windows in extreme premature
fiber shortening—end-systolic stress relationship, Doppler neonates, obese infants or grown-up adolescents may
myocardial imaging, strain/strain rate, and backscatter pose challenges in the diagnosis.4 When good aortic arch
are increasingly adopted to get regional, functional, and views are not obtained, the following clues might indicate
textural findings of the myocardium. However, long-term a possibility of an underlying coarctation:
KG-34.indd 289 02-11-2018 17:00:58

SECTION
5
a
A B
di
In
of
ty
C
18 cie D
20 o
Figures 1A to D: Pitfalls in diagnosis of coarctation. Clues to diagnose include: (A) Low velocity abdominal aortic spectral Doppler signals;
(B) Mild increase in mitral inflow gradients; (C) Unexplained left ventricular hypertrophy; (D) Unexplained pulmonary artery hypertension
S
Low velocity abdominal aortic spectral pulse Doppler

al
Mild unexplained dilatation of left ventricle (LV) in an

infant or a child in apical views or mild LV hypoplasia
in a neonatal echocardiography
ic
Mildly increased mitral inflow Doppler gradients in the

og
absence of mitral stenosis

Identification of a bicuspid aortic valve
Unexplained pulmonary arterial hypertension (PAH)

ol
Unexplained increased LV hypertrophy (Figures 1A
to D)
di
A suspicion based on these clues should alert the

clinician to resort to additional imaging like CT.
ar
Aortic Arch Interruption Figure 2: Aortic arch interruption Type A. In view of large duct
C
Arch interruption is classified into three types depending perfusing the descending aorta at systemic pressures, there will not
on the level of interruption, whether it is beyond or before be any turbulence on color Doppler and the arch may appear to be
anatomically continuous to the descending thoracic aorta
the left subclavian or it is between the right innominate and Abbreviations: PDA, patent ductus arteriosus; AA, ascending aorta;
left carotid artery. It is likely to be missed especially when DA, descending aorta
it coexists with other anomalies like truncus arteriosus or
other conotruncal malformations.5 Once again, simpler
vascular resistance is a valuable clue that points to
clinical tools, such as four-limb pulse oximetry, may show
the presence of aortic arch interruption, which can be
light about the possibility of this association. Identification
confirmed by CT.
of a third vessel arising from the main pulmonary artery
which represents the ductus arteriosus (Figure 2) and
detection of diastolic flow reversal in the ductus with Peripheral Pulmonary Artery Stenosis
color Doppler flows back into the pulmonary artery from Significant stenosis of pulmonary arteries especially in the
descending aorta due to relatively lower pulmonary post-hilar regions or isolation of the pulmonary arteries
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CHAPTER
34

a
di
In
A B
Figures 3A and B: Peripheral pulmonary artery stenosis. The only clues in the absence of detectable abnormality in the pulmonary arteries
will be (A) Unexplained right ventricular hypertrophy and dilatation; and (B) High tricuspid regurgitation Doppler velocities indicating
of
elevated right ventricular systolic pressure
ty
are again notorious for misses in the clinical practice.
Indirect clues in patients with bilateral pulmonary
18 cie
artery stenosis are evidence of high right ventricular
(RV) systolic pressures through tricuspid regurgitation
Doppler interrogation and hypertrophied RV with or
20 o
without chamber dilatation, corroborated with evidence
of peripheral long systolic lung field murmurs (Figures 3A
S
and B). In unilateral severe pulmonary artery stenosis, the

pulmonary blood flows are redirected to the contralateral
al
nonstenotic side and so the indirect clue will be reduction

in the pulmonary venous return from the ipsilateral side.
ic
This can be recognized by low velocity of spectral Doppler

on the pulmonary veins or less bright color signals on
og
color Doppler study compared to contralateral pulmonary

Figure 4: Severe intrahilar left pulmonary artery stenosis. The
veins (Figure 4). only clue for this diagnosis in a neonate who presents with
severe unexplained pulmonary artery hypertension diagnosed as
ol
persistent pulmonary hypertension of newborn was identification

Supravalvar Aortic Stenosis of bright color signals in right pulmonary vein indicative of
di
The part of aorta above the sinotubular junction may redistribution of blood flow to the right lung
sometimes be not clearly delineated by echocardiography
ar
from parasternal views. This will lead to misdiagnosis of

Aortopulmonary Window
supravalvar aortic stenosis. If there is color flow turbulence
Lack of awareness of this relatively uncommon CHD
C
in aortic root associated with high velocity continuous

is one of the major reasons for missing this lesion on
Doppler signal, it is often interpreted as valvar aortic
echocardiography. 7 As most of the aortopulmonary
stenosis and these patients may get scheduled for balloon
window (APW) are nonrestrictive and large, there is often
aortic valvotomy.6 The real diagnosis will be shown once
no gradient between the aorta and pulmonary arteries,
an aortic root angiogram is performed. In rare instances,
which makes it difficult to identify with color Doppler
where there is very poor visualization of the entire echocardiography. Indirect clues are dilatation of left
supravalvar aorta, the diagnosis is missed altogether. atrium and ventricle on apical views, unexplained PAH and
One of the way of circumventing this problem is clinical dilatation of the aortic root. Delays in identification of this
examination which demonstrates an outflow ejection large shunt lesion leads to undetected progression of the
murmur on right sternal border with Coanda effect, where hemodynamics to irreversible pulmonary vascular disease
the right arm pulses are bounding and have high pulse within the first decade of life. If the lesion is suspected,
pressures than left arm counterparts. Additional imaging but not convincingly diagnosed on echocardiography, it is
with CT might confirm the diagnosis. better dealt with diagnostic aortic root angiography. 291
KG-34.indd 291 02-11-2018 17:01:01

SECTION
5
a
di
A B
In
of
C D
ty
Figures 5A to D: Right pulmonary vein atresia. The color Doppler pattern (A and B) in the pulmonary artery (PA) bifurcation shows brisk color
flows into the left PA and poor flows in right PA. Spectral Doppler in RPA; (C) Shows sharp early systolic signal with very short pulmonary
18 cie
acceleration indicative of high vascular resistance in right lung, trace in LPA; (D) Shows normal flow pattern, which indicates that lung
perfusion is selectively redistributed to the left lung
20 o
Pulmonary Vein Stenosis TAPVC. The hallmark of diagnosis of TAPVC in a neonate
presenting with respiratory distress is identification of
S
Unilateral pulmonary vein stenosis or atresia may present

with respiratory distress in neonates or infants as it right-to-left shunt across the ASD and nonvisualization
leads to severe PAH. If there is a complete occlusion of of connections between any pulmonary vein and the
al
the pulmonary veins, there will not be any turbulence left atrium. While the former is easy to recognize, an
in the flow in the left atrium and this will not alert the untrained echocardiographer may miss the latter. As all
ic
echocardiographer of this possibility.9 Often, pulmonary symptomatic neonates with TAPVC have significant PAH,
vein stenosis, atresia or veno-occlusive disease gets they often get misdiagnosed as persistent PAH of newborn
og
misdiagnosed as persistent PAH of newborn and medically (Figures 6A to D).

managed with pulmonary vasodilators, which worsens
the clinical situation by causing pulmonary edema. Venous Anomalies Leading to Cyanosis
ol
This clinical entity is another difficult diagnosis on Cyanosis in the absence of clinically detectable murmurs
echocardiography. Identification of reduced velocities
di
and findings on precordial examination baffles the

in the blood flows in ipsilateral pulmonary artery either examiner. A group of conditions ranging from pulmonary
spectral Doppler or reduced color signals on color Doppler
ar
arteriovenous fistula, anomalous systemic venous

will serve as a clue since blood is redistributed to the lung drainage to left atrium, and pulmonary artery to left
without pulmonary vein stenosis (Figures 5A to D). atrial window may lead to this cyanosis. None of these
C
clinical conditions cause cardiomegaly, forcible precordial

Anomalous Pulmonary Venous Drainage pulsations, alterations in heart sounds, and do not lead
Pa r t i a l o r t o t a l a n o m a l o u s p u l m o n a r y v e n o u s to any clinically detectable murmurs. An apical view of
connections (TAPVC) are often misdiagnosed on routine echocardiogram shows a normal study, which might
echocardiography.8 Failure to identify the latter is often prompt the echocardiographer to write the report as a
serious, as 90% of infants born with the disease do not ‘normal echo study’. Adopting agitated saline contrast
survive beyond the first birthday. TAPVC often gets echocardiography will show immediate filling of the left
diagnosed as secundum atrial septal defect (ASD), but atrium after injection in a systemic vein, that will alert
careful identification of flows from right atrium to left to the possibility of these diseases. Filling of left atrium
atrium in the former will prevent misdiagnosis. Familiarity direct from the systemic veins excludes pulmonary
with subxiphoid and suprasternal views will help in arteriovenous fistula and pulmonary artery to left atrium
preventing misses of infra- and supracardiac types of connections (Figures 7A to F).
292
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CHAPTER
34

A B C D
a
Figures 6A to D: Total anomalous pulmonary venous return: right atrial and right ventricular dilatation on apical view (A) and high tricuspid
regurgitation Doppler signal indicative of pulmonary artery hypertension (B) should alert the clinician about possibility of abnormal
di
pulmonary venous return. Suprasternal view demonstrates supracardiac total anomalous pulmonary venous connections (TAPVC) through
left vertical vein (C) and subxiphoid view shows infracardiac through a vertical vein (D) in another patient
In
of
ty
18 cie
20 o
A B C
S
al
ic
og
ol
D E F
Figures 7A to F: Systemic venous anomalies may present with normal apical view (A), but subxiphoid view (B) with color Doppler (C) indicates
di
anomalous drainage of right superior vena cava to left atrium causing cyanosis. Agitated saline injection from right arm vein demonstrates
immediate filling of the left atrium (D) confirming the diagnosis. Anomalous left superior vena cava draining through a completely unroofed
ar
coronary sinus into the roof of the left atrium (E) also causes cyanosis as shown in the color Doppler study (F)
Abbreviations: RA, right atrium; LA, left atrium; RV, right ventricle; LV, left ventricle; IVC, inferior vena cava; Ao, aorta; PA, pulmonary artery;
LSVC, left superior vena cava; SVC, superior vena cava
C
Venous Anomalies without Clinical Findings closures (Figures 8A to D). Unroofed coronary sinus is
yet another example, where left atrial blood enters the
Some venous anomalies may not result in any cyanosis,
unroofed coronary sinus to drain to the right atrium and
if the systemic venous blood ultimately reaches the
contribute to an interatrial shunt.
right atrium.10 One such example is interruption of the
suprarenal part of inferior vena cava (IVC) with azygos
continuation, leading to drainage of the IVC to the lower Sinus Venosus Defects and
part of superior vena cava (SVC). This relatively benign Coronary Sinus ASD
anomaly of no major clinical significance may cause The ASD represents one of the common forms of CHD; two
significant difficulty in cardiac catheterization laboratory rare forms of interatrial septal communications namely
to perform a right heart cardiac catheterization and more sinus venosus ASD and coronary sinus ASD are more likely
troubles to perform interventions in the heart like device to be missed on echocardiography. Sinus venosus ASD is
293
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SECTION
5
a
A B C D
di
Figures 8A to D: Systemic venous anomalies always do not lead to cyanosis, as shown in interrupted inferior vena cava with azygos
continuation to right superior vena cava (A), confirmed on color Doppler signal (B). This patient also had a secundum atrial septal defect (C)
In
which was closed with a device (D) through the right jugular vein as femoral venous access fails to get a stable sheath position into the heart
Abbreviations: RA, right atrium; LA, left atrium; RV, right ventricle; LV, left ventricle; SVC, superior vena cava
of
ty
18 cie
20 o
A B C D
S
Figures 9A to D: Anterior marginal and posterior marginal muscular ventricular septal defect seen in parasternal short axis (A) and
subxiphoid short axis (B) are easy to miss on echocardiography unless carefully looked for. When there is a large ventral septal defect,
al
additional defects also may be missed as seen in this example with a large perimembranous defect, mid-muscular defect and apical defect
shown by three color jets (C) from left ventricle to right ventricle. Swiss cheese defects (D) also may need careful evaluation
Abbreviations: RA, right atrium; LA, left atrium; RV, right ventricle; LV, left ventricle; Ao, aorta
ic
og
difficult to image from apical views or parasternal views be excluded, conventional left ventriculography in
and tends to be underdiagnosed often. Unless subxiphoid catheterization laboratory is justified before surgical
views are routinely utilized, SVC type of sinus venosus correction.
ol
defects is likely to be underdiagnosed. Some of the clues

that point to the presence of these defects are unexplained FUNCTIONAL ERRORS
di
right-sided chamber enlargement. Transesophageal

echocardiogram in yet another useful investigation to Ventricular Function Assessment
ar
avoid these misses. Raghib’s defect refers to unroofed Conventional assessment of ventricular systolic
coronary sinus with persistent left SVC, where interatrial function relies on LV volume assessments by Simpson
C
communication leads to right chamber enlargement.11 method, ventricular shortening fraction on M mode
echocardiography. The load dependence of these indices
Muscular Ventricular Septal Defects forced the clinician to depend on parameters like velocity
While perimembranous, inlet and outlet VSD are of circumferential shortening; however, the normative
diagnosed with ease in echocardiography, muscular values in various forms of operated and unoperated CHDs
defects especially in the marginal areas and Swiss cheese are largely unknown.14 The complexity increases when
muscular defects may get missed out on echocardiography there is single ventricle or systemic RV which needs the
(Figures 9A to D). This is often the case when these detailed analysis. New echocardiographic techniques
muscular defects coexist with large membranous or outlet namely tissue Doppler imaging, speckle tracking with
defects.12 Muscular defects between the apex of the right strain and strain rate, vector velocity imaging (VVI),
ventricular infundibulum and apex of the left ventricle myocardial performance index, myocardial acceleration
is more notorious to be missed on echocardiography.13 during isovolumic acceleration (IVA), the ratio of systolic
If the possibility of additional muscular defects cannot to diastolic duration (S/D ratio), and two-dimensional
294
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CHAPTER
34

A B C D
Figures 10A to D: Assessment of valvar regurgitations. In common atrioventricular valve with multiple leaflets (A), quantification of multiple
a
jets of regurgitation (B) is challenging. Similarly in a truncus arteriosus (C), quantification of regurgitation across the truncal valve (D) is also
not clearly defined
di
measurements of systolic right ventricular (RV) function 5. Kaulitz R, Jonas RA, van der Velde MR. Echocardiographic
In
(e.g., tricuspid annular plane systolic excursion, TAPSE) assessment of interrupted aortic arch. Cardiol Young.
along with three-dimensional assessment with volumes 1999;9(6):562-71.
6. Cuenza LR, Adiong AA. Isolated supravalvar aortic
and speckle tracking. These may become valuable
of
stenosis without William’s syndrome. J Cardiovasc Echogr.
indicators of ventricular performance, compliance, and
2015;25(3):93-5.
disease progression; however, data on normative values 7. Kiran VS, Singh MK, Shah S, et al. Lessons learned from a
ty
are not available.15 series of patients with missed aortopulmonary windows.
Cardiol Young. 2008;18(5):480-540.
Valvar Quantifications 18 cie
Conventional parameters used in decision making in
8. Chin AJ, Sanders SP, Sherman F, et al. Accuracy of subcostal
two-dimensional echocardiography in prospective
diagnosis of total anomalous pulmonar y venous
interventions for regurgitant valvar lesions include connection. Am Heart J. 1987;113(5):1153-9.
20 o
assessment of regurgitant volume, regurgitant fraction, 9. Pazos-López P, García-Rodríguez C, Guitián-González
S
and orifice area. Similar parameters used in stenotic valves A, et al. Pulmonary vein stenosis: etiology, diagnosis and
include valve area by planimetry or other measures. 16 management. World J Cardiol. 2016;8(1):81-8.
In complex CHDs with hypoplastic or dysplastic valves, 10. Arunakumar P, Ayyappan A, Sasikumar D, et al. Anomalous
al
which have a combination of stenosis and regurgitation, systemic and pulmonary veins – an unusual coexistence.
Echocardiography. 2018;35(5):733-4.
clear guidelines do not exist. Normative data for children
ic
11. Johri AM, Rojas CA, El-Sherief A, et al. Imaging of atrial

of various ages and weight also do not exist. The errors get
septal defects: e chocardio graphy and CT correlation.
og
compounded in the setting of common atrioventricular Heart. 2011;97(17):1441-53.

valve or common truncal valve (Figures 10A to D). 12. Ludomirsky A, Huhta JC, Vick GW 3rd, Murphy DJ Jr,
Danford DA, Morrow WR. Color Doppler detection of
ol
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1. Pasquini L, Sanders SP, Parness IA, et al. Diagnosis of coronar
di
13. Kumar K, Lock JE, Geva T. Apical muscular ventricular

y arter y anatomy by two-dimensional echocardiography in
septal defects between the left ventricle and right
patients with transposition of the great arteries. Circulation.
ar
ventricular infundibulum. Diagnostic and interventional

1987;75(3):557-64. considerations. Circulation. 1997;95(5):1207–13.
2. Pacileo G, Di Salvo G, Limongelli G, et al. Echocardiography 14. Cotts T, Khairy P, Opotowsky AR, et al. Clinical research
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in congenital heart disease: usefulness, limits and new priorities in adult congenital heart disease. Int J Cardiol.
techniques. J Cardiovasc Med (Hagerstown). 2007;8(1):17-22. 2014;171(3):351–60.
3. Lange RA, Hillis LD. Cardiology patient pages. Diagnostic 15. Koestenberger M. Transthoracic echocardiography in
cardiac catheterization. Circulation. 2003;107(17):e111-3. children and young adults with congenital heart disease.
4. Sun Z, Cheng TO, Li L, Zhang L, Wang X, Dong N, et al. ISRN Pediatr. 2012;2012:753481.
Diagnostic value of transthoracic echocardiography in 16. Unger P, Clavel MA, Lindman BR, et al. Pathophysiology
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295
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Fetal Echocardiography: Current
CHAPTER 35
Status and Role in Management
of Congenital Heart Defects
Balu Vaidyanathan
a
di
INTRODUCTION established for the practice of fetal echocardiography by
Prenatal diagnosis of congenital heart disease (CHD) various clinical societies.5 The protocol typically includes
In
is accurately possible in the current era by fetal evaluation of the fetal lie and cardioabdominal situs,
echocardiography, even in the early stages of gestation.1 four-chamber view, the left and right ventricular outflow
tracts (crossing), the three vessel and the three vessel
of
This has provided a major impetus to the field of pediatric
cardiology since counseling and management of the heart tracheal view. Additional views include the sagittal views
lesion can start even before the baby is born. Prenatal for systemic veins (bicaval view), the ductal and the aortic
arches. Color Doppler evaluation and an evaluation of
ty
diagnosis offers a dual advantage to the management of
CHD that is particularly relevant for low- and middle- the fetal heart rate and rhythm complete a typical cardiac
evaluation protocol. Figures 1A to F summarize the
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income countries (LMIC). Early prenatal diagnosis
can reduce the burden of very complex forms of CHD
and those associated with multisystem anomalies.
common views in the conduct of a mid-trimester fetal
cardiac evaluation.
Prenatal diagnosis and planned peripartum care improves Table 1 summarizes the recommended indications for
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postnatal outcomes with infants with critical CHD. This fetal echocardiography.
S
review focuses on the recent developments in the field

of fetal echocardiography and discusses its role in the 3D/4D STIC FETAL ECHOCARDIOGRAPHY
modern-day management of children with CHD.
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One of the promising developments in the field of prenatal

diagnosis is the development of 3D/4D technology
CONCEPT OF UNIVERSAL SCREENING OF
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with spatiotemporal image correlation (STIC).6 In this

FETAL HEART technology, using specialized transducers including the
og
Since most forms of CHD occurs in low-risk pregnancies, it recently introduced matrix probes, a volume dataset
is important to perform a basic screening of the fetal heart of the fetal heart is obtained. It is possible to display a
in all pregnancies. A combination of the four-chamber multiplanar model of the fetal heart from this volume
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view and outflow tract view enables accurate screening of dataset and then use postprocessing tools to render and
the fetal heart and most anomalies can be suspected using display the information in multiple ways. This also permits
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these 2 views.2,3 In high-risk pregnancies (Table 1), a direct functional studies of the fetal heart including volumetric
referral for a fetal echocardiography may be considered.4 assessments of the ventricular function and cardiac
ar
The optimal timing for fetal echo is between 16 and output. Recent studies have shown the incremental
20 weeks of gestation. Detailed guidelines have been benefit of this technology in the evaluation of extracardiac
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Table 1: Indications for fetal echocardiography

Fetal Maternal Familial
1. Abnormal 4C view 1. Maternal CHD 1. Previous child with CHD
2. Extracardiac anomalies—GIT, spina bifida 2. Teratogen exposure 2. Paternal CHD
3. Chromosomal anomalies—VACTERL, Trisomies, Digeorge 3. Metabolic disorders—diabetes 3. Mendelian syndromes—TS, Noonan’s,
4. Increased first trimester NT scan mellitus DiGeorge
5. Non-immune hydrops 4. Maternal autoimmune disease
6. Irregular heart beat—tachy/bradyarrhythmias 5. Intrauterine infections
7. Abnormal cardiac axis
8. IVF/ICSI ?
Abbreviations: GIT, gastrointestinal tract; VACTERL, vertebral defects, anal atresia, cardiac defects, tracheoesophageal fistula, renal anomalies, and
limb abnormalities; NT, nuchal translucency; IVF, in vitro fertilization, ICSI, intracytoplasmic sperm injection; CHD, congenital heart disease; TS,
Turner syndrome
KG-35.indd 296 02-11-2018 17:00:49

CHAPTER
35
Fetal Echocardiography: Current Status and Role in Management of Congenital Heart Defects
A B C
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D E F
Figures 1A to F: Common views used in the conduct of fetal cardiac evaluation. (A) Abdominal situs showing the aorta (A) and stomach (St)
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on left side and liver (L) and IVC (v) on the right side; (B) Four-chamber view; (C) The left ventricular outflow tract; (D) The right ventricular
outflow tract and branch pulmonary arteries (color); (E) The three vessel view—PA (P) anterior and left, aorta (A) in middle and SVC (S)
posterior and right; (F) The 3-vessel tracheal view showing equal sized ductal (PA) and aortic arches (Ao) with color flow in same direction. Sp
denotes spine position. MB denotes moderator band (B)
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vascular structures like aortic arch, branch pulmonary CHD (typically the single ventricle heart) and if the cardiac
arteries, and anomalies of systemic and pulmonary lesion is associated with major extracardiac or genetic
veins.7,8 It permits postprocessing of the volume dataset, abnormalities. 11 The challenges on quality of life and
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thereby reducing initial evaluation time besides offering long-term complications in adult survivors of complex
the possibility of re-interpretation of the cardiac anatomy CHDs are enormous.12 According to the American College
ic
in very complex CHDs like isomeric hearts. Development of Cardiology (ACC) Bethesda conference task force in
of automatic fetal heart evaluation algorithms like fetal 2001, it was estimated that 787,800 adult patients with
og
intelligent navigation echocardiography (FINE) may CHD lived in the USA in 2000 (of which 117,000 were
simplify fetal heart evaluation further in future and make severe lesions), corresponding to a prevalence of 3.51
cases of all CHD and 0.52 of severe CHD per 1000 adults,
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wide spread screening in large population more feasible

and cost effective.9 respectively.13 It is quite possible that these challenges
may prove overwhelming for LMIC countries in future
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Figures 2A to E show the utilization of 3D/4D STIC

fetal echocardiography in generating rendered images of with an ever-increasing number of patients surviving
tertiary cardiac care into adult life. Many states in India
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the normal fetal heart.

have started developing government-aided schemes and
projects for supporting care of children with CHD (e.g.
IMPACT OF FETAL ECHOCARDIOGRAPHY
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Hridyam scheme in Kerala).14 Early prenatal diagnosis by

AND PRENATAL DIAGNOSIS OF CHD implementing a mandatory screening policy may be a very
The principal role of a pediatric/fetal cardiologist comes cost-effective strategy for care of children with CHD by
after the diagnosis of CHD has been made in utero. The reducing the burden of complex CHDs, permitting more
counseling plan has to be individualized and will depend efficient utilization of resources towards the care of more
upon several factors like the gestational age at diagnosis, correctable CHDs.
complexity of the CHD, socioeconomic, cultural and
religious factors and access to tertiary pediatric cardiac Changing the Natural History of Complex CHDs
care. Several centers in India are now undertaking
complex surgical procedures in very small hearts with Impact of Early Prenatal Screening of the
excellent short-term and intermediate outcomes. 10 Fetal Heart
However, it is generally agreed that the prognosis even These include CHDs with an anatomic or functional
after palliation is suboptimal for very complex forms of form of univentricular heart as well as CHDs that are
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KG-35.indd 297 02-11-2018 17:00:50

SECTION
5
A B C
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In
of
D E
Figures 2A to E: The 4-dimensional spatiotemporal image correlation (4D STIC) rendering of the normal heart. (A) Four-chamber view;
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(B) Crossing of outflow tracts; (C) Aortic arch; (D) Ductal arch; (E) Pulmonary veins draining into the left atrium
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associated with multisystem anomalies or genetic
syndromes. Typical examples include hypoplastic left
lower prevalence of complex CHDs of the univentricular
type during the second trimester as well as postnatal
heart syndrome, isomeric hearts with single ventricle, period.21 In India, the legal limit for medical termination of
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pulmonary atresia with intact ventricular septum and pregnancy is up to 20 weeks of gestation and termination
S
other forms of anatomic and functional single ventricle. may be considered if ‘there is a substantial risk of the child
Most of these conditions can only be palliated at best and born to suffer from such physical or mental abnormalities
the adult survival with palliation even in the developed as to be seriously handicapped’. 29 This is particularly
al
societies is not optimal. 15–18 Recently, selected centers important for LMICs like India since it can have a very
in developing countries have started doing very complex significant impact on healthcare policies for CHDs.
ic
neonatal palliative procedures like the Stage 1 Norwood

Operation with reasonable results.19 However, it remains Concept of Planned Peripartum Care for Critical CHD
og
extremely contentious whether embarking on a program This scenario applies to those cardiac conditions that
for palliation of extremely complex CHD is a priority of are potentially lethal in the neonatal period without
LMICs, considering its overall burden on health economic
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intervention and where corrective surgery offers excellent

and long-term quality of life.20 long-term outcomes. In most of these conditions, the
Several studies have reported higher prevalence of
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survival of the infant depends on the continued patency

termination of pregnancy when the prenatal diagnosis of the arterial duct after birth to maintain pulmonary or
of CHD is made in early gestation.21-27 Bull et al. reported
ar
systemic blood flow. This is accomplished by starting

a termination of pregnancy rates of 70% and 61% when an infusion of prostaglandin E1 when indicated. Once
diagnosis of CHD was made before 19 and 23 weeks, the duct starts to close, these babies can present with
C
respectively.23 A study from Boston Children’s Hospital severe cyanosis or shock. It may be extremely hazardous
reported a higher rate of termination for fetuses with to transport such sick babies to a tertiary care pediatric
univentricular hearts when the diagnosis was made before cardiac facility after they have started showing symptoms
24 weeks.24 In a population-based study from Paris, of the of decompensation. Typical examples of these CHDs
703 fetuses diagnosed with CHD, 46% were terminated, include transposition of great arteries, critical forms
with 3.2 times higher odds of termination in those of obstruction to the outflow tracts resulting in duct-
diagnosed before 22 weeks.27 dependent circulatory states (pulmonary atresia, left heart
Hence, screening the fetal heart in all mid-trimester obstruction) and obstructed form of total anomalous
anomaly scans becomes particularly important in pulmonary venous drainage. The counseling in these
the current era, especially in the LMICs. Most of the patients should include detailed information about the
complex forms of CHD of the univentricular type can be cardiac diagnosis, expected timing of interventions after
detected using the four-chamber view with high degree birth, nature of the postnatal interventions including the
of sensitivity. 28 First trimester screening resulted in a costs and the expected outcomes in a given institution.
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KG-35.indd 298 02-11-2018 17:00:51

CHAPTER
35
A B C
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D E F
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Figures 3A to F: Common CHDs diagnosed by fetal echocardiography. (A) Hypoplastic left heart; (B) Ebstein’s anomaly; (C) Right isomerism
with single ventricle; (D) Tetralogy of Fallot with over-riding aorta; (E) Transposition of the great arteries; (F) Coarctation of aorta
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Studies have shown that the major determinant the tachycardia and continue pregnancy till term. Most
of outcomes after corrective intervention in such infants require continued medications after birth. Recent
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patients is the preoperative status of the baby. 30 An reports from LMICs also highlight the role of prompt
excellent coordination between all concerned specialties diagnosis and aggressive transplacental and direct fetal
S
(cardiology, obstetrics, cardiac surgery, neonatology, therapy in achieving optimal outcomes in fetuses with
anesthesia, nursing, and counselor) is required to ensure tachyarrhythmias.37
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that there is a smooth transition of care for these critically

Bradyarrhythmias: The most significant bradyarrhythmia
ill infants. Hence, in such conditions, the best possible
that requires treatment in utero is congenital complete
ic
option after prenatal diagnosis would be to plan delivery

heart block. Many cases are associated with maternal auto-
in a center with pediatric cardiac facility so that immediate
immune disease (Ro/La antibodies). Since transplacental
og
care can be delivered to the baby after birth. Studies have

transfer of these antibodies occurs principally after 18
shown that such a strategy may improve outcomes in
weeks, most of these cases manifest by around 20–24 weeks.
babies with critical forms of CHD.31-34 Recent studies from
ol
The overall prognosis of fetuses with complete heart block

developing countries have shown the benefit of a planned
in the absence of associated structural heart disease and
peripartum care on outcomes of neonatal cardiac surgery
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high-risk features is very good and the majority survives

in infants with critical forms of CHD.35
till term without need for any intervention.38 Studies have
Figures 3A to F summarize some of the common
identified high-risk features associated with fetal demise;
ar
CHDs that can be diagnosed by fetal echocardiography.

and in such fetuses, targeted transplacental therapy with
maternal steroids (dexamethasone) in conjunction with
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In Utero Therapy for Rhythm Disorders beta-agonists may improve outcomes.39

This includes fetuses diagnosed with various types of
tachy- and bradyarrhythmias. Fetal Interventions for Structural Heart Defects
Tachyarrhythmi as : The most common for ms of At present, the scope of fetal interventions is limited to very
tachyarrhythmias in the fetus include supraventricular few conditions especially severe obstruction to the outflow
tachycardia and atrial flutter. Most of these arrhythmias tracts.40 The most common fetal intervention reported
are diagnosed between 20 and 30 weeks of gestation. Many is fetal balloon aortic valvuloplasty for critical aortic
of these tachyarrhythmias can be effectively managed stenosis with left ventricular dysfunction. Preliminary data
using transplacental therapy.36 The various drugs given to suggest that this intervention may prevent progression
the mother include digoxin, flecanaide, amiodarone, etc. of aortic stenosis into a more ominous form of heart
Frequent monitoring of both the mother and the fetus is disease, hypoplastic left heart syndrome.41 Fetal balloon
required. In most cases, it is possible to effectively control pulmonary valvuloplasty also has been successfully
299
KG-35.indd 299 02-11-2018 17:00:51

SECTION performed for fetuses with critical pulmonary stenosis.42 9. Yeo L, Romero R. Fetal Intelligent Navigation Echocardio-
The third fetal cardiac intervention reported is balloon graphy (FINE): a novel method for rapid, simple and
5 atrial septostomy (enlargement of the restrictive atrial

septal communication) in fetuses with hypoplastic left
automatic examination of the fetal heart. Ultrasound
Obstet Gynecol. 2013;42(3):268-84.
10. Bakshi KD, Vaidyanathan B, Sundaram KR, et al.
heart syndrome and restrictive patent foramen ovale in

Determinants of early outcome after neonatal cardiac
order to decompress the left atrium.43 Needless to say,
surgery in a developing country. J Thorac Cardiovasc Surg.
these interventions are extremely resource intense and 2007;134(3):765-71.
require a multidisciplinary team approach. At present, 11. M a r i n o B S , L i p k i n P H , N e w b u r g e r J W , e t a l .
the scope of fetal cardiac interventions in developing Neurodevelopmental outcomes in children w ith
countries is very limited. congenital heart disease: evaluation and management. A
scientific statement from the American Heart Association.
a
CONCLUSION Circulation. 2012;126(9):1143-72.
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12. Lantin-Hermoso MR, Berger S, Bhatt AB, et al. The Care of
Fetal cardiology has evolved into a separate discipline Children with Congenital Heart Disease in Their Primary
within the field of pediatric cardiology with widespread
In
Medical Home. Pediatrics. 2017;140(5):1-12.
implications on the diagnosis and management of CHD 13. van der Bom T, Zomer AC, Zwinderman AH, et al. The
in the current era. 44 For LMICs, it offers the unique changing epidemiology of congenital heart disease. Nat
opportunity to stratify and prioritize the limited healthcare Rev Cardiol. 2011;8(1):50-60.
of
resources for the management of children with CHD by 14. National Health Mission - Hridyam for little hearts.
the twin strategy of reducing burden of complex CHD and Available at: http://hridyam.in/chd.php. Accessed June 14,
2018.
ty
planned peripartum care for critical CHDs. Hence, the
15. Moons P, Bovijn L, Budts W, et al. Temporal trends in
necessity of educating obstetricians and radiologists on
survival to adulthood among patients born with congenital
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early prenatal screening of the fetal heart should become a
major priority for policy makers in LMICs.45 A coordinated
multidisciplinary system for diagnosis, early referral,
heart disease from 1970 to 1992 in Belgium. Circulation.
2010;122(22):2264-72.
16. Nieminen HP, Jokinen EV, Sairanen HI. Late results of
counseling and peripartum care needs to be established
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pediatric cardiac surgery in Finland; a population-based
for optimal care of the pregnancy once the diagnosis of study with 96% follow-up. Circulation. 2001;104(5):570-5.
S
CHD is made.46 17. Fixler DE, Nembhard WN, Salemi JL, et al. Mortality in the
first 5 years in infants with functional single ventricle born
in Texas, 1996 to 2003. Circulation. 2010;121(5):644-50.
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36. Perles Z, Gavri S, Rein AJJT. Tachyarrythmias in the fetus: sonographers. Heart. 2000; 84(3):294-8.
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Advances in CT Angiography
CHAPTER 36 for Congenital Heart Disease
a
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INTRODUCTION high heart rates encountered in a pediatric population.
Computed tomography (CT) imaging of congenital heart Latest high-pitch scan and volumetric scanners provide
In
disease (CHD) requires an in-depth understanding full coverage of pediatric thorax in less than a second or
of the core teaching elements of both cardiology and a single heartbeat, nearly freezing respiratory motion.5,6
It virtually eliminates the need for beta-blockers and
of
radiology, with a focused step-wise approach to image
interpretation in the clinical context. Echocardiography sedation, or anesthesia in these patients. Moreover,
remains the initial investigation of choice for patients with retrospective-gated scans may provide quantification of
ventricular function with adequate accuracy. Technical
ty
CHD. Beyond echocardiography, the choice of further
imaging needs to be individualized, based upon the advancements in CT equipment have also been successful
in reducing radiation exposure by influencing many
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clinical question, patient’s condition, imaging expertise,
and availability. While magnetic resonance imaging
(MRI) is currently preferred for CHD evaluation due to
factors including tube current and voltage, slice thickness,
over-lap, scan range, pitch, and ECG-gating. 7,8 Besides,
its multiparametric approach and lack of exposure to prospective gating with iterative reconstruction in selected
20 o
ionizing radiation or potentially nephrotoxic contrast, patients allows for even greater reduction in radiation
S
CT offers unique benefits for this patient group due to its doses while maintaining diagnostic image quality.
speed, need for minimal sedation, and ability to provide
information on structures not well evaluated with MRI.
CHOOSING THE OPTIMAL IMAGING
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MODALITY IN CHD
CHALLENGES TO CARDIAC IMAGING
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Noninvasive imaging evaluation of the heart is technically Echocardiography

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challenging as it is complicated by the off-axis rotation of Echocardiography remains the initial investigation of
the heart, and motion artifacts due to cardiac, respiratory, choice for majority of CHD patients. It optimally visualizes
and diaphragmatic movements. In addition, heart most of the intracardiac anatomy and provides functional
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hemodynamics change rapidly during different phases information. Mitral valve flow patterns help in detecting
of cardiac and respiratory cycle, adding to the difficulty abnormalities in left ventricular filling in many diseases.
di
for optimal imaging evaluation. These challenges are ECHO is, however, limited in accurately quantifying single
compounded by the presence of wide variation in the or right ventricular size and systolic function. Besides, it
ar
densities of surrounding tissues, resulting in an adverse

is often difficult to adequately assess complex systemic or
impact on the tissue contrast.
pulmonary venous anatomy, distal pulmonary arteries,
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and cavopulmonary anastomoses in patients with single

TECHNICAL IMPROVEMENTS IN CARDIAC CT ventricle physiology. Moreover, older or operated patients
Initial CT scanners were limited for cardiac evaluation due may have suboptimal windows for ECHO assessment.
to poor temporal and spatial resolution, and long scan
times. Many technical improvements in CT technology
Catheter Angiography
have come up in recent years, allowing sub-millimeter
isotropic spatial resolution, improved temporal resolution Catheter angiography remains the gold standard
(up to 66 msec) and rapid coverage of large anatomic investigation for assessing pressure difference across a
volumes.1-4 With latest multislice (256 and 320 slice) and vessel or cardiac chamber. Moreover, it is the only method
dual source CT scanners, it is possible to have a spatial to determine pulmonary artery pressure and pulmonary
resolution of less than 0.4 mm and gantry rotation time vascular resistance accurately, which play an important
of 82 msec or less. This is particularly important in role in decision making for surgery. However, it is invasive
evaluation of small cardiovascular structures, even at the and provides only luminal details with 2-dimensional
KG-36.indd 302 02-11-2018 17:00:40

assessment. With the advent of recent improvements in CLINICAL APPLICATIONS OF CT IN CHD CHAPTER
cross-sectional imaging, catheter angiography is no longer
required for the diagnosis and management of most forms
of CHD and is generally reserved for patients requiring
There are several generally accepted clinical indications
of CT in these patients, for which the benefits of imaging 36
outweigh the risks. These are discussed in brief below.

invasive hemodynamic evaluation or endovascular
treatment.
Situs Evaluation
Cardiovascular MRI The CT allows accurate assessment of situs with detailed
information on bronchial branching pattern, atrial
In recent years, MRI has become an essential component sidedness, and relationship of abdominal viscera.
of CHD evaluation complimentary to ECHO.9,10 It serves as Sequential segmental approach allows accurate
a
a problem-solving tool in the evaluation of preoperative identification of situs abnormalities and intracardiac
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and postoperative cardiovascular anatomy and for certain lesions, in addition to depiction of associated extracardiac
postoperative complications. It characterizes cardiac lesions (Figures 1A to D).
In
structures very well (improved tissue differentiation
with higher signal and contrast to noise ratio) and
provides functional assessment with additional advantage Great Vessel Anatomy
of
of perfusion and viability imaging. However, higher The pulmonary arteries, pulmonary veins, and aortic arch
cost, limited availability, long acquisition time, and may be inadequately characterized at echocardiography,
operator dependency have limited the widespread use necessitating further assessment with CT. Marked
ty
of MRI. Moreover, MRI may be limited due to poorer morphologic variability in the source and arborization
spatial resolution, presence of image degrading artifacts pattern of the pulmonary blood supply is seen in CHDs.
18 cie
from implanted metal, such as intravascular stents and
embolization coils, pacemakers and greater need for
general anesthesia in younger children.
Confluent, good sized pulmonary arteries are associated
with successful surgical outcome, whereas small arteries
would need augmentation procedures to improve
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pulmonary blood flow (Figure 1A). Isolated stenosis or
Cardiovascular CT absence of pulmonary artery, presence of pulmonary
S
artery sling and anomalous arterial supply such as seen

Due to newer generation multislice CT scanners, it has now in scimitar syndrome with sequestration are all well seen
become possible to image the heart with more accuracy in
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on CT.11-16
shorter time.2,3 Shorter acquisition times (4–5 seconds
vis-à-vis an hour in MRI) and higher spatial resolution
ic
have made CT the investigation of choice for assessment

Coronary Arteries
og
of children with arrhythmia or in situations where purely Coronary anomalies are common in patients with CHD,
anatomic information is required beyond an ECHO. It and precise delineation prior to surgical intervention is
also scores over MRI in imaging evaluation of critically often indicated, as it may alter the surgical course. Any
ol
ill and uncooperative pediatric patients. Simultaneous interventions on right ventricular outflow tract should
assessment of the airway, lungs, and skeletal anatomy be preceded by unambiguous definition of coronary
di
also helps in mapping optimal treatment strategy. artery anatomy for uneventful surgical management.
Cardiovascular CT is now recommended as an adjunct to Coronary artery origin and course (Figures 1D and 2),
ar
echocardiography when cardiac MRI is contraindicated ostial narrowing, dominance, angulations from the aortic
or considered high risk and is unlikely to provide optimal root, coronary artery fistula, and presence and length of
quality images to answer a specific clinical question. intramural course can be well seen on CT.17-20
C
A B C D
Figures 1A to D: CT angiography images in a patient with tetralogy of Fallot shows confluent small pulmonary arteries (broken arrows in A),
subaortic ventricular septal defect (* in C), multiple significant aortopulmonary collaterals (arrowheads in B) with normal coronaries (arrows in D) 303
KG-36.indd 303 02-11-2018 17:00:41

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Figure 2: CT angiography image shows high take off of right coronary artery (arrow)
from ascending aorta in a patient with congenital heart disease
20 o S
Aortopulmonary Collaterals sinus and coronary venous anatomy on CT can help

The aortopulmonary collaterals (APCs) are usually seen in determine the procedural approach for electrophysiology
(EP) device lead placement in these patients.23
al
association with cyanotic congenital heart diseases such as

tetralogy of Fallot (TOF) or pulmonary atresia (Figure 1B).
Aortic Arch Anomalies and Airway
ic
They may serve as an additive or the only source of blood

supply in these cases, depending upon the status of native Compression
og
pulmonary arterial supply. These are fragile vessels and Aortic arch anomalies may be seen associated with
may rupture easily. Moreover, they flood the surgical field CHDs. Right aortic arch with mirror image branching is
and may become major source of gaseous microemboli. strongly associated with CHDs in more than 98% of cases,
ol
Postoperatively, they represent a common cause of including TOF, truncus arteriosus, tricuspid atresia, and
persistent pleural effusions. The CT provides detailed transposition of great arteries. Detailed evaluation of
di
information about the site of origin, number, size (exact aortic arch anatomy is important for planning surgical
diameter, areas of stenosis, or aneurysm), course, and the or endovascular treatment option, as the presence and
ar
areas of the lungs they supply, which may offer an efficient pattern of arch variants and anomalies may influence the
road map for safe and successful selective embolization. surgical incision, cardiopulmonary bypass cannulation,
C
and/or interventional approach. The CT has been shown

Systemic and Pulmonary Veins to accurately visualize congenital aortic anomalies such
as double aortic arch, aortic coarctation (Figures 4A
It accurately delineates systemic venous anomalies, which
and B), interrupted aortic arch, and circumflex aorta.24
may be important for patients undergoing univentricular
Dominance of aortic arch, length of atretic segment,
repair. These may include persistent left superior vena
origins of aortic arch vessels, and associated airway
cava (SVC), retro-aortic innominate vein, interruption of
compression are well seen on CT.
the inferior vena cava, or double SVC (Figure 3A). The
exact type of anomalous pulmonary venous return, site of
drainage, and presence of anatomic obstruction (Figure 3B) Evaluation of Ventricular Size and Function
are well seen on CT.21,22 Another potential indication includes Though cardiac MRI remains the gold standard technique
pacemaker-dependent patients, who are referred for cardiac for cardiac function assessment, cardiac CT with
resynchronization therapy (CRT). Evaluation of coronary retrospective ECG-gating can be utilized to obtain
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Figures 3A and B: CT angiography image shows double superior vena cava (* in A) in patient with tetralogy of Fallot. CT angiography image
from different patient shows obstructed (arrow in B) total anomalous pulmonary venous drainage with common channel (arrowhead in B)
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draining into dilated portal vein (* in B)
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C
A B
Figures 4A and B: CT angiography images show postductal coarctation (arrow in A)
with multiple collaterals (arrowheads in B) from descending thoracic aorta
accurate ventricular assessments comparable to cine Postoperative Evaluation

magnetic resonance (CMR). 25,26 Ventricular dilatation, The CT can be used in the assessment of patients operated
myocardial thinning and hypodensity, presence or for CHD (Figures 5A and B) who may have a variety of
absence of intracardiac thrombus, and regional wall treatment-related complications. It can evaluate systemic
motion abnormalities can all be seen on CT. and pulmonary venous baffle obstruction and may help
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A B
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Figures 5A and B: CT angiography image shows patent modified left Blalock-Taussig shunt (arrow in A).
Occluded modified right Blalock-Taussig shunt (arrow in B) is seen in a different patient with congenital heart disease
18 cie
in evaluating right ventricle (RV) size and function. 27 sternotomy should be carefully seen and reported for
20 o
Baffle leaks are, however, difficult to optimally visualize consideration of peripheral bypass at the time of sternal
on CT, unless there is differential opacification showing entry.31,32
S
a negative or positive contrast jet between the atria.

Complications of CHD surgery, such as coronary ostial LIMITATIONS
al
stenosis, neopulmonary artery and branch pulmonary

The CT imaging has some inherent limitations such
artery stenosis, and neoaortic root stenosis, and dilatation
as poor myocardial tissue characterization, inability to
ic
or insufficiency can also be well seen on CT. Shunt quantify valve regurgitation (with multiple regurgitant
obstruction (Figure 5B), thrombus in Fonton circuit, and lesions or shunt), need for iodinated contrast, and
og
kinks in reimplanted coronary arteries can also be well exposure to ionizing radiation. Moreover, breath holding
seen on CT.28-30 It is particularly useful for evaluation of is still needed for images acquired over several heart beats
the aortic arch after endovascular intervention to clearly
ol
such as for functional imaging and detailed coronary

demonstrate pseudoaneurysm, aortic wall injury, or artery imaging at high heart rates.
recurrent arch obstruction, which may be seen in these
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patients.
CONCLUSION
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Newer CT technologies are constantly evolving, thus

Associated Findings (Pre-and Postoperative)
widening the scope of cardiac CT from traditional
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The CT is able to provide rapid comprehensive assessment coronary artery assessment to complete depiction
of lungs, airways, and skeletal anatomy (Figures 6A and B). of intracardiac morphology, function, perfusion,
The CT quickly displays evidence of a variety of CHD- postoperative complications, and follow-up in addition
related complications (both pre- and postoperative) and to the depiction of extracardiac details. Judicious use
numerous other medical conditions such as pulmonary of CT is recommended in selected patients with CHD
embolism, pneumonia, pleural and pericardial effusion, such as those where anatomic information mandates the
and pneumothorax. The CT can be useful before a choice and type of surgery. Knowledge of cardiovascular
reoperation to assess altered anatomic features related to anatomy, physiology, and various surgical techniques
previous surgery. Proximity of the coronary arteries and is important with a step-wise, segmental approach for
cardiac structures to the posterior sternum prior to repeat optimal interpretation of imaging appearances.
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36

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In
A B
Figures 6A and B: CT angiography images in lung window shows presence of multiple nodular lesions with areas of cavitation (arrow in A)
of
suggestive of septic emboli in a patient of tetralogy of Fallot. Left lung hypoplasia (arrowheads in B) with small left bronchus (arrow in B) is
seen in another patient with congenital heart disease
ty
REFERENCES 11. Balci TA, Koc ZP, Kirkil G, et al. Isolated left pulmonary
18 cie
1. Dillman JR, Hernandez RJ. Role of CT in the evaluation of
congenital cardiovascular disease in children. AJR Am J
Roentgenol. 2009;192(5):1219-31.
artery agenesis: a case report. Mol Imaging Radionucl Ther.
2012;21(2):80-3.
12. Hernanz-Schulman M. Vascular rings: a practical approach
to imaging diagnosis. Pediatr Radiol. 2005;35(10):961-79.
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2. Goo HW, Park IS, Ko JK, et al. Computed tomography for
13. Haest RJ, van den Berg CJ, Goei R, et al. Scimitar syndrome;
the diagnosis of congenital heart disease in pediatric and
S
an unusual congenital abnormality occasionally seen in

adult patients. Int J Cardiovasc Imaging. 2005;21(2):347-65.
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3. Danad I, Fayad ZA, Willemink MJ, et al. Recent Advances
14. Yu H, Li HM, Liu SY, et al. Diagnosis of arterial sequestration
al
in Cardiac Computed Tomography: Dual Energy, Spectral

using multidetector CT angiography. Eur J Radiol.
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2015;8(6):710–23.
ic
15. Maeda E, Akahane M, Kato N, et al.Assessment of major

4. Siegel MJ. Cardiac CTA: congenital heart disease. Pediatr aortopulmonary collateral arteries with multidetector-row
Radiol. 2008;38(Suppl 2):S200-4.
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computed tomography. Radiat Med. 2006;24(5):378-83.

5. Han BK, Lindberg J, Grant K, et al. Accuracy and safety 16. Greil GF, Schoebinger M, Kuettner A, et al. Imaging of
of high pitch computed tomography imaging in young aortopulmonary collateral arteries withhigh-resolution
children with complex congenital heart disease. Am J
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multidetector CT. Pediatr Radiol. 2006;36(6):502-9.

Cardiol. 2011;107(10):1541-6. 17. Yu FF, Lu B, Gao Y, et al. Congenital anomalies of coronary
6. Flohr TG, Leng S, Yu L, et al. Dual-source spiral CT with
di
arteries in complex congenital heart disease: diagnosis

pitch up to 3.2 and 75 ms temporal resolution: image and analysis with dual-source CT. J Cardiovasc Comput
reconstruction and assessment of image quality. Med Phys. Tomogr. 2013;7(6):383-90.
ar
2009;36(12):5641-53. 18. Machida H, Tanaka I, Fukui R, et al. Current and novel

7. Siegel MJ, Schmidt B, Bradley D, et al. Radiation dose and imaging techniques in coronary CT. Radiographics. 2015;
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image quality in pediatric CT: effect of technical factors and 35(4):991-1010.

phantom size and shape. Radiology. 2004;233(2):515-22. 19. Stein PD, Beemath A, Kayali F, et al. Multidetector
8. Huang MP, Liang CH, Zhao ZJ, et al. Evaluation of image computed tomography for the diagnosis of coronary artery
quality and radiation dose at prospective ECG-triggered disease: a systematic review. Am J Med. 2006;119(3):203-16.
axial 256-slice multi-detector CT in infants with congenital 20. Deibler AR, Kuzo RS, Vohringer M, et al. Imaging of
heart disease. Pediatr Radiol. 2011;41(7):858-66. congenital coronary anomalies with multislice computed
9. Crean A. Cardiovascular MR and CT in congenital heart tomography. Mayo Clin Proc. 2004;79(8):1017-23.
disease. Heart. 2007;93(12):1637-47. 21. Bonelli-Sica JM, de la Mora-Cervantes R, Diaz-Zamudio M,
10. Chan FP. MR and CT imaging of the pediatric patient with et al. Dual-source 256-MDCT for diagnosis of anomalous
structural heart disease. Semin Thorac Cardiovasc Surg. pulmonary venous drainage in pediatric population. AJR
2008;20(4):393-9. Am J Roentgenol. 2013;200(2):W163-9.
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of total anomalous pulmonary venous connections: multidetector row computed tomography to quantify right
5 comparison with echocardiography. Pediatr Radiol.

2009;39(9):950-4.
ventricular size and function in adults with either tetralogy
of Fallot or transposition of the great arteries. Am J Cardiol.
23. N i a z i I , D h a l a A , C h o u d h u r i I , e t a l . C a r d i a c 2005;95(5):683-6.
Resynchronization Therapy in Patients with Challenging 28. Piggott KD, Nykanen DG, Smith S. Computed tomography
Anatomy Due to Venous Anomalies or Adult Congenital angiography successfully used to diagnose postoperative
Heart Disease. Pacing Clin Electrophysiol. 2014;37(9): systemic-pulmonary artery shunt narrowing. Case Rep
1181-8. Cardiol. 2011;2011:802643.
24. Brown ML, Burkhart HM, Connolly HM, et al. Coarctation 29. Grewal J, Al Hussein M, Feldstein J, et al.Evaluation of silent
of the aorta: lifelong surveillance is mandatory following thrombus after the Fontan operation. Congenit Heart Dis.
surgical repair. J Am Coll Cardiol. 2013;62(11):1020-5. 2013;8:40-7.
a
25. Brodoefel H, Kramer U, Reimann A, et al. Dual-source 30. Lee SY, Baek JS, Kim GB, et al. Clinical significance of
di
CT with improved temporal resolution in assessment thrombosis in an intracardiac blind pouch after a Fontan
of leftventricular function: a pilot study. AJR Am J operation. Pediatr Cardiol. 2012;33:42-8.
Roentgenol.2007;189(5):1064-70. 31. Russell JL, LeBlanc JG, Sett SS,et al. Risks of repeat
In
26. Guo YK , Gao HL , Zhang XC , et al. Accurac y and sternotomy in pediatric cardiac operations. Ann Thorac
reproducibility of assessing right ventricular function Surg. 1998;66(5):1575-8.
with 64-section multi-detector row CT: comparison with 32. Adibi A, Mohajer K, Plotnik A, et al. Role of CT and MRI
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Best Use of Cardiac MRI in
CHAPTER 37 Congenital Heart Disease
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INTRODUCTION and shunt quantification, and also an opportunity for
Congenital heart diseases (CHD) are the most common intervention. But angiographic imaging is limited to
In
specific planes, and catheter-derived shunt/resistance
structural birth defects among humans, and the reported
calculations rely on mathematical assumptions.
incidence of moderate to severe CHD is between 4–7 per
Advanced radiological imaging tools—multi-detector
1000 live births. The incidence is much higher (50–75 per
of
cardiac computed tomography (MDCT) and cardiac
1000 live births) if one includes minor lesions like bicuspid
magnetic resonance imaging (CMRI) have recently
aortic valves, atrial septal aneurysms, tiny muscular
found increasing role in evaluation of CHD. CT provides
ventricular septal defects (VSD), etc.1,2
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volumetric imaging datasets with high spatial resolution,
The range and complexity of lesions in the spectrum
allowing multi-planar visualization, reconstructions and
of CHD can be extremely varied, from minor defects
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to heterotaxy syndromes with complex intracardiac
abnormalities. What makes CHD assessment and
precise 3-dimensional understanding of cardiovascular
structures—including extracardiac structures. However,
it involves exposure to ionizing radiation, and has limited
management particularly challenging is the fact that these
ability to provide hemodynamic information.
20 o
structural malformations go hand-in-hand with a wide
range of physiological and hemodynamic consequences.
S
CARDIAC MRI
Management principles, timing of treatment, and
outcomes depend on precise understanding of both Cardiac magnetic resonance imaging (CMRI) is
al
anatomical and physiological aspects. While some CHD rapidly gaining importance as a powerful, versatile
present early and may require repair/palliation in newborn and multidimensional imaging tool for comprehensive
ic
period or infancy, others may require intervention later in assessment of CHD. Based on the phenomenon of nuclear
life; some may go undetected/unrepaired and present magnetic resonance (NMR)—this technique uses the NMR
og
much later with complications. Many forms of CHD signal emitted by molecules of body tissues (hyodrogen
require multiple staged procedures (e.g. single ventricular atoms) upon application of an external radiofrequency
physiology, surgeries requiring prosthetic conduits or (RF) energy while within a high magnetic field—to
ol
generate images. The contrast between different tissues

valves, etc.); most require long-term follow-up for various
is determined by the rate at which excited atoms return
events occurring in their natural history. Cardiovascular
to the equilibrium state. By changing the parameters on
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imaging is crucial to understanding CHD, planning its

the scanner this effect is used to create contrast between
management, and for long-term follow-up. Challenges
different types of body tissue.
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and requirements from the imaging are different at

Unlike CT, CMRI is not a single homogenous modality,
different stages.
rather it comprises of multiple NMR-based techniques
The fundamental, most commonly used modalities
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or “pulse sequences”, which provide different forms of

for cardiovascular imaging include echocardiography and
morphological and physiological information. Pulse
angiocardiography.
sequences are different software programs that encode
Ech o ca rd i o g rap hy i s n o n - i nva si ve, sa f e a n d
magnitude and timing of RF pulses emitted by the MR
inexpensive, and provides substantial anatomic and
scanner, switching of the magnetic field gradient, and data
hemodynamic information. Echocardiogram has
acquisition, each one tailored for a specific purpose. Each
good spatial and temporal resolution, but is limited by CMR study, typically, is comprised of a set of different
acoustic windows, poor signal/noise ratio, geometric sequences that are chosen to answer the specific study
assumptions and limited ability to assess extracardiac questions of the particular case.
structures.
Cardiac catheterization and angiocardiography
is invasive, and involves exposure to ionizing Basic CMRI Sequences

radiation—but offers ability to obtain excellent CMRI sequences are broadly classified into ‘bright-blood’
hemodynamic information pertaining to pressures and ‘dark blood’ sequences.3
KG-37.indd 309 02-11-2018 17:00:26

SECTION Bright-blood sequences: Also called gradient recalled characteristics and pathologic changes are generally
sequences (GRE), shows fast flowing blood as bright or more pronounced on black blood images. Signal intensity
5 high intensity, and the surrounding tissue appears dark.
Cine GRE sequences can be used to produce moving
on GRE images largely reflects differences in proton
density; these images inherently show lower tissue
images (much like 2D echocardiographic images that contrast. A newer pulse sequence known as steady state
cardiologists are used to seeing) by stitching together free precession (SSFP) has been applied to cardiac cine
different phases of the cardiac cycle. These sequences studies, leading to greater contrast between myocardium
allow excellent anatomical delineation of intracardiac and blood pool (Figure 1).
and vascular anatomy. The cine sequence allows Imaging data can be acquired in any plane, allowing
excellent dynamic visualization, as well as computation
infinite options. Imaging planes are decided according
of cardiac functions—due to excellent temporal resolution
to the needs of the case, and optimized against the time
a
(Figure 1).
required for the acquisitions.
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Dark-blood or black blood sequences: Fast flowing blood
appears dark or low intensity. Static black blood images Other Pulse Sequences
In
allow excellent anatomic delineation of cardiac chambers
and vascular structures. The technique is particularly Phase contrast MRI (PC-MRI): A pulse sequence with
useful to differentiate between the vessel wall and inner velocity encoding of the signal intensities—gradient pulses
of
lumen, and intracardiac masses from normal structures. induce shifts in moving protons, directly proportional to
Tissue contrast in MRI is related to signal intensity their velocity along direction of gradient. PC-MRI allows
differences, which are mainly determined by the proton accurate estimation of flow velocity profiles across any
ty
density, T1 and T2 relaxation time differences, flow and valvular or vascular structure. This is among the most
motion effects, and magnetic susceptibility, as they are valuable hemodynamic assessment tools in CMRI,
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related to the pulse sequence applied. In general, tissue allowing accurate flow quantifications (Figure 2).4,5
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Figure 1: Shows a frozen frame from cine SSFP ventricular short axis stack. This is a “bright blood” pulse sequence. The short axis stack is
used for calculating end-diastolic and end-systolic ventricular volumes and determining the ejection fraction. The sequence gives excellent
dynamic assessment of anatomy and function
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Figure 2: Shows phase contrast MRI (PC-MRI) image prescribed Figure 3: Shows a frozen frame from SSFP sequence in a patient
in axial plane. PC-MRI sequence is used for assessing flows across with double outlet right ventricle (DORV). The sequence has been
vascular/valvular structures prescribed in a plane that clearly shows the left ventricle (LV) to
Aorta (AO) pathway, the ventricular septal defect (vsd), and the
of
MR angiography (MRA): Mainly for assessment of the relationship between the right ventricle (RV) and pulmonary artery
(PA). Conal septum (cs) can be seen intruding in the LV-AO pathway
blood vessels. Contrast-enhanced MRA is a standard
ty
3-dimensional spoiled gradient echo sequence with Myocardial scarring and fibrosis (MDE)
intravenous injection of gadolinium contrast, enhancing Myocardial wall motion, myocardial strain.
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anatomic visualization. Non-contrast 3-dimensional
segmented SSFP sequence (‘whole heart’) can be used for
evaluating intracardiac anatomy and the coronaries. MRA
Goals of imaging need to be clearly defined prior to the
scan, and sequences need to be planned and optimized
on case-to-case basis. Specialized reporting software
thus provides volumetric imaging data (like CT) which can
20 o
platforms are used to store and post-process the imaging
be post-processed through multiplanar visualization and
data—to calculate ventricular volumes and functions,
S
3-dimensional volume reconstructions (Figure 3).

calculate blood flows, generate graphic representations of
Myocardial perfusion imaging: Magnetization-prepared the data (e.g. blood-flow versus time) and for multi-planar
al
gradient echo sequences which allow differentiation viewing and reconstruction.

between non-ischemic and ischemic myocardial
ic
segments. Ischemic segments appear dark (perfusion Specific Advantages of CMR in CHD
defects) as compared to normal segments, soon after Evaluation
og
injection of contrast agent (first pass). Stress perfusion

Noninvasive and devoid of radiation exposure (as
studies (using adenosine infusion) allow assessment of
compared to CT and angiocardiography)—therefore
reversible ischemia.
suitable for multiple, serial evaluations.
ol
Myocardial delayed enhancement (MDE) sequence: Powerful tool that is independent of imaging windows
Inversion recovery gradient echo sequence taken 10–15 (acoustic windows limit the imaging abilities of
di
minutes after injecting contrast–allows myocardial scars echocardiography). This becomes particularly
and infarcts to be identified by their bright appearance important as acoustic windows become increasingly
ar
as compared to normal myocardium, due to retention of difficult with age and growth. Adolescents and adults
contrast in the scarred/fibrotic regions. with CHD, particularly those with complex lesions, are
C
Other sequences that can be applied where needed, prime examples (Figure 4).
include myocardial tissue tagging for myocardial wall Allows a combination of morphological and
motion calculations and strain analysis, T2* for myocardial physiological assessment in a single comprehensive
iron assessment. study.
Thus, CMRI is a bouquet of multiple techniques Functional assessment tools provide unique and
that can be used in versatile ways and in case-specific powerful ways to assess physiology.
combinations, to answer a host of study questions relevant Contouring of endocardial borders and derivation of
to CHD: end-diastolic and end-diastolic volumes irrespective
Morphology (cine SSFP, black blood, MRA) of the cardiac-chamber geometry allows accurate and
Ventricular functions (cine SSFP) reproducible assessment of volumes and function.
Blood flow (PC-MRI) Short axis or axial stacks (SSFP) are typically used
Myocardial ischemia (perfusion sequence) for assessing ventricular volumes and systolic
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SECTION as well as that of all ancillary equipment has to be
ensured.
5 Difficult in patients with claustrophobia or poor
cooperation—necessitating general anesthesia.
Monitor ing dur ing scans, and access dur ing

emergencies is challenging. Therefore, may not be
ideal for critically ill or unstable patients.
Potential risk of gadolinium-induced nephrogenic
systemic fibrosis in patients with end-stage renal
failure.6
a
Specific Applications in Congenital Heart
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Disease
Postoperative assessment of tetralogy of Fallot: CMRI
In
Figure 4: Shows 3-dimensional rendering on the cardiac and
is the modality of choice for serial assessment in this
extracardiac anatomy in a case of complex heart disease following
Glenn (superior vena cava to right pulmonary artery) shunt. Multiple subset of patients. Following TOF repair, CMRI can
veno venous collaterals can be seen be used to obtain comprehensive information on
of
the following: (1) biventricular volumes and mass;
functions (Figure 1). While echocardiogram is well (2) biventricular function (stroke volume, ejection
validated for calculating left ventricular volumes fraction, regional wall motion abnormalities); (3)
ty
and functions, it is highly inadequate when it comes accurate quantification of flows – residual shunts,
to assessing the right ventricle (RV) or complex valve regurgitation, differential pulmonary artery flows
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ventricle anatomies. CMRI is the modality of choice
for assessment of the RV as well as all types of complex
(Figure 5); (4) description of anatomy of the RVOT,
branch pulmonary arteries, aortic root, ascending
ventricular morphologies (including single-ventricles) aorta, aortopulmonary collaterals; (5) assessment
20 o
irrespective of geometry or spatial orientation. of myocardial viability and scar tissue; (6) coronary
S
PC-MRI is the gold standard for assessment of arteries.

blood flow. Determining flow data across structures CMRI is indicated for routine surveillance, beginning
representing pulmonary and systemic blood flow the second decade and the frequency of evaluation is
al
gives accurate estimate of Qp:Qs, independent of dictated by the baseline condition. Data has emerged
the mathematical assumptions used in cardiac that shows that CMR-derived ventricular volumes and
ic
catheterization. PC-MRI is the gold standard for functions help in risk-stratification by predicting risk
calculating regurgitation fractions across valves. It also for heart failure, sustained ventricular tachycardia
og
allows assessment of very specific flow information, and SCD.7-10 Current guidelines on pulmonary valve
e.g. differential blood flows in branch pulmonary implantation are based on CMR-derived data.
arteries, flows through aortopulmonary collaterals, Comprehensive assessment of complex CHD, especially
ol

pulmonary venous flows, etc. Used in combination, in older patients:

— Heterotaxy syndromes – wide range of viscero-
these tools for CMRI functional assessment can
di
provide unique and deep insight into physiology cardiac abnormalities.

— Multiple extracardiac abnormalities.
accurately and non-invasively.
ar
— Complex venoatrial, atrioventricular, inter-
ventricular and ventriculo-arterial relationships,

Disadvantages of CMRI
C
e.g. double-outlet right ventricle (DORV ),

CMR facilities are not widely available in resource- congenitally corrected transposition of great
limited environments: arteries (CCTGA), anatomically corrected
— Expensive hardware and software malposition of great arteries (ACMGA), superio-
— Expertise and training required for performing inferior ventricular relationships, criss-cross
and interpreting CHD-CMR. atrioventricular connections.
Relatively expensive, particularly in comparison to Decision-making for single-ventricle versus biventricular
echocardiography. repair in complex lesions.11
Does not provide pressure data (as opposed to cardiac — Adequacy of ventricular volumes for biventricular
catheterization). repair: Accurate estimation of ventricular volumes

Technically challenging with long scan times. (SSFP) irrespective of the shape, size or lie of the
MRI-compatibility and MRI-safety of patient’s cardiac chambers aids decision-making regarding
prothetics, artificial valves, stents and pacemakers, suitability for 2-ventricle (2V) repair. Calculated
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Figure 5: Representative images from CMRI assessment of post-tetralogy of Fallot (TOF) repair—SSFP image of the right ventricular
outflow tract, and PC-MRI-derived flow-time graphs for calculating regurgitation fractions across the pulmonary arteries
20 o S
volumes can be compared against normative CMRI can be used to calculate the total effective
values. Chambers can be contoured according to pulmonary blood flow in these situations by
the anticipated lie of the VSD patches or tunnels to calculating the pulmonary venous return from
al
estimate post-surgical volumes. each lung segment.12

— Routability of ventricular septal defects for — CMRI allows internal cross validation of
ic
intraventricular tunneling in DORVs: SSFP images hemodynamic data by comparing different means
provide dynamic assessment of the pathways, of deriving a desired physiological value, e.g.
og
allowing anticipation of surgical challenges pulmonary blood flow can be calculated using
(Figure 4). PC-MRI on the main pulmonary artery (MPA), or
— Need for conduits: 3D anatomical understanding of as a sum of the flows in both branch PAs, and/or
ol
intracardiac anatomy allows accurate prediction factoring-in the flows through surgical shunts and
of the need for right-ventricle-to-pulmonary artery collaterals, or as a sum of the flow-return through
di
conduits in complex repairs. each pulmonary vein. Similarly, systemic venous

— Coronary anatomy (especially the origins and return may be calculated using PC-MRI derived
ar
proximal course) can be well understood on 3D flows in ascending aorta, or by the sum total of
SSFP (whole heart) sequences and MRA. flows in inferior vena cava (IVC) and superior vena
Physiological and blood-flow assessment for decision- cava (SVC). SSFP ventricular contouring derived
C

making in complex lesions : CMRI can provide ventricular outputs can also be compared against
vital hemodynamic information using PC-MRI the flows entering each great vessel. Thus, CMR
sequences—Qp:Qs, valve regurgitation fractions and provides a unique way to acquire and validate
differential flows in vessels. vital information on blood flows, aiding decision-
— Qp:Qs is traditionally calculated using oxymetry making.
data obtained during cardiac catheterization. This — Combining invasive pressure data (e.g. internal
technique is prone to errors due to assumption jugular vein cannulation in post-Glenn patient)
of oxygen consumption and technical issues with CMRI-derived anatomic and physiological
with sampling. Estimations are also likely to be information greatly augments the overall
erroneous when there are multiple sources of understanding and aids clinical decisions. Need
pulmonary blood flow, e.g. antegrade pulmonary for routine pre-Fontan cardiac catheterization
flows + flow through aortopulmonary collaterals can be eliminated in most patients using this
+ flows via Blalock Taussig or Glenn shunts. PC- technique.
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SECTION
5
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Figure 6: 3-D printed models of complex cardiac lesions, created using CMRI-derived volumetric data
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CMR is likely to become the modality of choice in greater safety and lesser scan times—CMR is likely to
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the long-term follow-up and serial evaluation for the be increasingly adopted for CHD-care even in resource-
large majority of complex surgical repairs including limited environments.
post arterial switch operation, DORV-repair, repair
al
of anomalous left coronary artery from pulmonary REFERENCES

artery (ALCAPA), Senning’s operation, double-switch 1. Hoffman JIE, Kaplan S. The incidence of congenital heart
ic
operation and single-ventricle palliations. disease. J Am Coll Cardiol. 2002;39(12):1890-900.

Volumetric imaging datasets (3D MRA, 3D SSFP) are 2. Fyler DC, Buckley LP, Hellenbrand WE, et al. Report of the
og

used for 3D rendering, giving excellent 3-dimensional New England Regional Infant Cardiac Program. Pediatrics.
spatial understanding. Latest technological advance- 1980;65(Suppl.):377-460.
3. Biglands JD, Radjenovicand A, Ridgway JP. Cardiovascular
ments now allow creation of 3D printed prototypes
ol
magnetic resonance physics for clinicians: Part II. J

of complex cardiac anatomies for surgical planning
Cardiovasc Magn Reson. 2012;14:14-66.
(Figure 6).13
di
4. Meier D, Meier S, Bosiger P. Quantitative flow measurements

on phantom and on blood vessels with MR. Magn Reson
CONCLUSION
ar
Med. 1988;8:25-34.
5. Rebergen SA, Niezen RA, Helbing WA, et al. Cine gradient-
Different modalities of cardiac imaging have their own
echo MR imaging and MR velocity mapping in the
C
strengths and weaknesses. Choice of modality depends evaluation of congenital heart disease. Radiographics.
upon the specific clinical questions that need to be 1996;16(3):467-81.
answered, weighed-in against multiple other factors that 6. Perazella MA, Reilly RF. Nephrogenic systemic fibrosis:
include cost, accessibility, safety and accuracy. In most recommendations for gadolinium-based contrast use in
cases, multiple modalities need to be used in an efficient patients with kidney disease. Semin Dial. 2008;21(2):171–3.
manner, complimenting each other. 7. G e v a T. R e p a i re d Te t ra l o g y o f Fa l l o t : t h e ro l e s
T h e ro l e o f C M R I i n C H D - i ma g i n g i s l i k e l y of cardiovascular magnetic resonance in evaluating
pathophysiology and for pulmonary valve replacement
to exponentially grow in the future, complimenting,
decision support. J Cardiovasc Magn Reson. 2011;20:13:9.
and at times even replacing some other modalities in
doi: 10.1186/1532-429X-13-9.
specific circumstances. With advances in computational 8. Geva T, Sandweiss BM, Gauvreau K, et al. Factors associated
technology, the already versatile range of CMR sequences with impaired clinical status in long-term survivors of
is likely to expand further in application, accuracy tetralogy of Fallot repair evaluated by magnetic resonance
and efficiency. With increasing access, reducing costs, imaging. J Am Coll Cardiol. 2004;43(6):1068-74.
314
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9. Knauth AL, Gauvreau K, Powell AJ, et al. Ventricular size towards single-ventricle repair. Interact Cardiovasc Thorac CHAPTER
and function assessed by cardiac MRI predict major Surg. 2014;18(3):266-71.
adverse clinical outcomes late after tetralogy of Fallot
repair. Heart. 2008;94(2):211-6.
12. Kappanayil M, Kannan R, Kumar RK. Understanding the
physiology of complex congenital heart disease using 37
cardiac magnetic resonance imaging. Annals of Pediatric

10. Valente AM, Gauvreau K , Babu-Narayan SV, et al.
Cardiology. 2011;4:177-82.
Ventricular size and function measured by cardiac MRI
13. Kappanayil M, Koneti NR, Kannan R, et al. Three-
improve prediction of major adverse clinical outcomes
dimensional-printed cardiac prototypes aid surgical
independent of prolonged QRS duration in patients with decision-making and preoperative planning in selected
repaired tetralogy of Fallot (abstr). Circulation. 2011. cases of complex congenital heart diseases : Early
11. Kottayil BP, Sunil GS, Kappanayil M, et al. Two-ventricle experience and proof of concept in a resource-limited
repair for complex congenital heart defects palliated environment. Ann Pediatr Cardiol. 2017;10(2):117-25.
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Acyanotic Congenital
of
Heart Disease
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I
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Natural History of Ventricular Septal Defect
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Ventricular Septal Defect with Aortic Regurgitation
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Imaging of Atrial Septal Defect
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Lutembacher’s Syndrome
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N
Which Device for which Patent Ductus Arteriosus?
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IB Vijayalakshmi
Aneurysms of the Sinuses of Valsalva
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Kewal C Goswami, Sivasubramanian Ramakrishnan, Siddharthan Deepti

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Coarctation of Aorta in Adults: Diagnosis and Current Management Strategies

PV Suresh
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Natural History of Ventricular
CHAPTER 38 Septal Defect
a
di
NATURAL HISTORY OF VENTRICULAR VSDs are further classified into anterior, posterior, mid,
SEPTAL DEFECT apical, or outlet muscular depending on their location in
In
the trabecular septum (Figures 1A and B).
Appreciation of the natural history of ventricular septal
The VSDs can be classified as small, moderate, and
defect (VSD) is a prerequisite for appropriate management
large depending upon their size in comparison to diameter
of
of children born with this defect. The VSD is the most
of aortic valve.5 The defects which are less than one-third
common congenital heart defect (CHD) and isolated VSD
the size of aortic valve are small VSDs; those more than
constitutes about 30% of the total congenital heart defects two-thirds of aortic valve diameter are large defects;
ty
(CHD).1 In general, CHD occurs in about 0.8–1% of live while those between one-third and two-thirds of aortic
births throughout the world uniformly with marginal valve diameter are moderate defects. Depending upon
18 cie
differences such as higher incidence of subarterial VSDs
in the oriental regions.2,3 This article deals with the natural
the pressure gradient across the defect, they are labeled
as nonrestrictive if gradient is ≤20 mm Hg; moderately
history of isolated VSDs and does not include VSD in other restrictive defects have 20–40 mm Hg pressure gradient
20 o
congenital defects such as tetralogy of Fallot, etc. where a across them; and restrictive defects have >40 mm Hg
malaligned VSD is seen which is in fact a space and not a
S
gradient. Perimembranous defects account for 80% of all

defect in the septum; thus such malaligned VSDs never VSDs, followed by muscular defects with 5%. Subarterial
close spontaneously. VSDs form 5–10% of all defects, and inlet VSDs account
al
It is important to follow a common nomenclature for <5% of all VSDs.3 There is slight variation in Asians
in order to maintain uniformity in communication; with respect to frequency of types of defects. Subarterial
ic
thus nowadays, VSDs are classified as: subarterial; defects may account for almost 25% of all the VSDs in the
perimembranous; inlet; and muscular VSDs.4 Muscular Orientals.
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A B
Figures 1A and B: Diagram showing location of four types of VSD in en-face view of IVS from RV side. (A) I denotes inlet septum, T: trabecular
septum, O outlet septum. (B) a: subarterial VSD; b: tricuspid valve; c: perimembranous VSD; d: anterior muscular VSD, e: mid-muscular VSD; f:
inlet muscular VSD, g: apical muscular VSD
Source: Adapted from Moss and Adams’ Textbook of Heart Disease in Infants, Children and Adolescents, 9th edition, 2016
KG-38 (Sec-6).indd 319 02-11-2018 16:57:11

SECTION Much information on the natural history of VSDs was the PVR in them falls relatively earlier. It is also pertinent
obtained in the era prior to the time when curative cardiac to note that factors influencing PVR will alter the course
6 surgery became available and from the natural history
studies (NHS-1 and 2) done subsequently. More recently,
of CHF and a small minority of neonates who persist with
high PVR since birth (persistent fetal circulation) might
Acyanotic Congenital Heart Disease
echocardiography in newborns and also in the fetus has never develop CHF.9 With CHF, recurrent LRTI is the rule
improved our ability to study the natural history of VSD and mortality in early infancy remains high. In India,
significantly. where estimated 5–10% infants with heart disease might
be undergoing corrective heart surgeries, the highest
Antenatal Natural History of VSD attrition occurs during the early infancy in children born
with VSD.10 There is failure to thrive in these infants with
With the advent of fetal echocardiography, VSDs in the
CHF and failure to gain in weight is more than compromise
a
fetal life can be diagnosed frequently and it is apparent
in height. The ventricular contractile functions are normal
that a number of small VSDs close during the fetal or early
di
and therefore medical therapy other than diuretics have
neonatal life. Such small VSDs have no clinical significance
a limited role in changing the natural history. The CHF
but can increase the prevalence of VSDs in population
In
improves with time in the naturally selected survivors due
studied by echocardiography. Since the left and right
to either: (a) reduction in the size of defect by mechanisms
ventricular pressures are equal in the fetus, VSD in the
described below, or (b) the rise in PVR with time, or (c)
fetus has no significant hemodynamic impact, although
of
development of pulmonary stenosis.
the small shunt is still left to right as the resistance to
The occurrence or worsening of CHF in children
left ventricular outflow is higher than that to the right
with VSD beyond 1 year is unusual and might result
ventricle. In some reports of fetal echo, the incidence of
ty
from development of additional lesions such as infective
extracardiac defects, chromosomal anomalies and large
endocarditis or aortic regurgitation or some other illness.
VSDs were higher than what is seen postnatally due to
18 cie
selection bias of the referred population for fetal echo.6-8
Children with small-to-moderate VSD generally tolerate
the shunt well and do not develop CHF, although might
have more LRTI than their peers. The presence of other
Postnatal Natural History of VSD associated defects, lung disease, recurrent aspirations,
20 o
The natural history of VSD vary with the size of defect, type genetic syndromes, nutritional status, ciliary functions,
S
of VSDs, associated defects, other patient-related factors, immune status, and other factors would obviously
and unknown variables. It can take any of the following influence the clinical condition of these children.
paths:
al
a. Premature death due to congestive heart failure (CHF) Spontaneous Reduction in Size or Closure
or recurrent lower respiratory tract infections (LRTI)
ic
of the Defect
b. Spontaneous reduction in size or closure of the
Spontaneous closure of VSD or some reduction in
og
defectc)
the size of VSD is an expected event in the majority of
c. Right ventricular outflow tract obstruction
perimembranous defects and in most muscular defects.
d. Aortic regurgitation
Documentation of occurrence of such an event in various
ol
e. Pulmonary vascular obstructive disease

series has been quite variable due to differences in study
f. Infective endocarditis
population characteristics with respect to age, type
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g. Small VSD with chronic volume overload

of VSD, methods employed (clinical, catheterization,
h. Survival like general population.
or echocardiography) and duration of follow-up. The
ar
closure rates varied from 34% spontaneous closure at

Premature Death due to Congestive Heart Failure or 1 year and 67% at 5 years of age to 75% by 10 years of age.
Recurrent Respiratory Tract Infections
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Smaller VSDs <3-4 mm have a higher chance of closure

Almost all the patients with a large VSD will suffer from compared to larger defects.11-17The rate of closure follows
CHF and LRTI and might succumb to it in the absence an exponential decay curve with the increasing age of
of treatment. It is important to remember that CHF in a the patient. The closure is infrequent but does occur in
neonate with VSD does not occur in the first week or two of the adults also. There are hardly any reports of small
life, and such an event should force the clinician to identify VSDs in the large number of unselected autopsies in
other associated factors such as coarctation of aorta, etc. the literature, thus suggesting that small VSDs must be
With decrease in the pulmonary vascular resistance (PVR) getting closed. Even large VSDs might close, albeit less
with age, the left-to-right shunt through the VSD increases. likely. However, inlet VSDs and subarterial VSDs almost
In normal newborns, the decline is rapid and almost never close. Various mechanisms leading to spontaneous
complete by 1 week, but the decline in PVR is delayed in closure have been described; muscular defects close by
the patients with VSD, and it might take 6–8 weeks for CHF direct apposition of margins due to muscular growth or
to occur. The CHF may be earlier in premature infants as the hypertrophy of muscle bundle in right ventricle (RV)
320
KG-38 (Sec-6).indd 320 02-11-2018 16:57:12

closing the defect from RV side. Perimembranous defects prolapse, which progresses on to diastolic prolapse as well CHAPTER
close by septal tricuspid leaflet adhering to the margins due to the leaflet wall thickening.
or by aortic cusp prolapse. Septal aneurysm or rarely
an infective endocarditis vegetation causing closure of
Prolapse occurs in perimembranous, subarterial and
outlet muscular defects as they are in direct contact with
38

VSD has been reported. Tomita et al. have described up the aortic valve.23 Incidence of prolapse varies from 9–12%
to 4% closure rate of subarterial VSDs by adolescence, and incidence of AR varies from 2–7%. The AR is rare at
mechanism being aortic cusp prolapse with minimal or no birth, it starts developing by 2 years of age. If AR has not
AR.18,19The closure of perimembranous VSD by aneurysmal developed by 10 years of age, it is unlikely to develop
pouch of tissue from the tricuspid leaflet is the most later. Grade of AR increases and becomes severe by the
common mechanism of closure of the perimembranous end of 2nd decade. It is most common in Asians and with
VSD and such an event is often accompanied with a mild subarterial defects, where its incidence is 50% at 8 years of
a
tricuspid regurgitation leading to a physiologically small age and >80% by 20 years of age.24 Prolapse may fully close
di
left ventricle to right atrial shunt (a VSD, TR combination the VSD, abolishing the shunt and completely replacing it
actually). This should be differentiated from a true left by aortic regurgitation. A dilated sinus of Valsalva might
In
ventricle to right atrial shunt (a true Gerbode defect). For also close the VSD without causing AR. Some of these
some unknown reasons, the patients with a closing VSD patients might later present with a ruptured sinus of
and TR also develop small tissue tags in the subaortic area Valsalva. The proportion of patients where this may occur
of
such as a subaortic membrane. is not known.
Development of Right Ventricular Outflow Pulmonary Vascular Obstructive Disease
ty
Tract Obstruction The occurrence of increase in PVR and eventual reversal
of shunt (Eisenmenger syndrome) remains the most
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Infrequently, the improvement in symptoms in a
patient with large VSD might be due to development of
infundibular pulmonary stenosis. Such right ventricular
mysterious aspect of the VSD natural history.25 The precise
mechanisms of this event are gradually being understood,
outflow tract (RVOTO) can occur due to hypertrophy but it is certain that closure of the defect after the changes
20 o
of muscle bundle in RV outflow tract; hypertrophy and in PVR has established in the lungs is detrimental. There
is a high degree of misunderstanding regarding PVR and
S
progressive obstruction of malaligned infundibular

septum; or prolapse of aortic cusp through the defect. operability of the defect even amongst the physicians.
Phenomenon of reduction in left-to-right shunt in VSD due Whatever be the mechanism(s) of increase in PVR
al
to development of RVOTO was first reported by Gasuland in the lungs, an increase in the PVR results in decrease
is famously known as Gasulization. 20 Its incidence is in the left-to-right shunt and an improvement in the
ic
reported between 3 and 7%. It is thought to result from high symptoms of the patients. Unfortunately, once the trigger
velocity jet of VSD hitting the RV wall, causing hypertrophy that is responsible for increase in PVR is initiated, it leads
og
of muscle in RV outflow, at the site of jet impact. Another to slow and inexorable rise in the PVR accompanied
proposed reason is that they are fundamentally different with structural changes in the lungs. There seems to be a
time window during which the closure of the defect can
ol
anatomic subset with an abnormal angle between the IVS

and outflow that gradually lead to hypertrophy of the right abort the process of progressive alterations in the lungs;
and it must be appreciated that this time window is only
di
ventricle outflow and eventually significant infundibular

during early infancy in patients with large defects. The
obstruction.21,22 Such patients physiologically resemble
patients with large defects and raised PVR are not much
ar
tetralogy of Fallot and will require corrective surgery. The

symptomatic during early childhood, they might adjust to
infundibular obstruction is progressive and majority are
somewhat decrease in exercise capacity (or might not have
asymptomatic in the early childhood.
C
limitations) but their lung vasculature is undergoing the

alterations that progressively leads to further rise in PVR
Aortic Regurgitation and eventually symptoms occur with right-to-left shunt
The AR occurs due to aortic cusp prolapse in the VSD (Figures 2A and B).
causing deformation and noncoaptation of cusps. A large VSD exposes the pulmonary circulation to
Generally, right coronary cusp (RCC) gets prolapsed, both high flow and high pressure which causes vascular
rarely noncoronary cusp (NCC) can prolapse, but left remodeling consisting of endothelial cell activation,
coronary cusp (LCC) almost never prolapses. More than increased muscle elastase activity, endogenous growth
one cusp might prolapse. Mechanism of cusp prolapse factor release, and smooth muscle proliferation, which
is lack of support to the aortic cusp due to the absence extends the muscle more peripherally into the arterioles.
of septum beneath it in subarterial defects. Another Due to hyperplasia and hypertrophy of smooth muscle
mechanism is Venturi effect resulting from high velocity cells, there occurs reduction in number and size of
jet of blood through the VSD initially causes systolic intraacinar arteries and total capacity of pulmonary
321
KG-38 (Sec-6).indd 321 02-11-2018 16:57:12

SECTION Wood series. Other uncommon (<5%) causes of death
in different series were pregnancy, noncardiac surgery,
6 cerebral abscess, cerebral thrombosis, and infective
endocarditis. 32,33In Paul Wood series, 40% of patients
with Eisenmenger syndrome develop exertional dyspnea

class II-III. But in other two series, almost all patients had
dyspnea on exertion (85–95%). Incidence of hemoptysis
A B was 17–33%. Hemoptysis almost never occurs before the
Figures 2A and B: Serial X-rays in a patient with VSD. (A) Increased age of 24 years, gradually increased in frequency and is
pulmonary vasculature in VSD in infancy; (B) Same patient at 18 almost always present by age of 40 years as was observed
years of age. (Picture courtesy: Dr S Shrivastava). Note the findings by Wood also.25 It might result from pulmonary infarction
a
of Eisenmenger syndrome, no cardiomegaly, peripheral pruning,
from pulmonary artery thrombosis, or due to rupture of
dilated right descending PA, and prominent main PA
di
weak pulmonary arterioles immediately distal to the thick
wall artery. Syncope occurred in 7–14% patients; angina
arteriolar circulation progressively reduces. 26,27These
In
occurred in 4–14% patients, and congestive cardiac failure
changes are reversible till 6 months age, but progressive (CCF) occurred in 8–13% patients. History of syncope,
intimal thickening with medial hypertrophy combined elevated right-sided filling pressure and systemic arterial
of
with intravascular thrombosis, leads to vascular occlusion. oxygen saturation less than 85% indicated a poorer
Angiogenesis in areas of vascular obstruction forms outcome in an Indian series.34
complex plexiform lesions. This evolving process of
ty
pulmonary vascular occlusive disease (PVOD), initially Unresolved Issues about VSD and Raised PVR
reduces the left-to-right shunt but later reverses it with Although the progress in cardiac surgery has almost
18 cie
appearance of cyanosis called Eisenmenger syndrome.
Thus, the patient with Eisenmenger syndrome might
present to the physicians with symptoms during the
completely prevented Eisenmenger syndrome in the
Western world, there are large numbers of such patients
in many parts of the world including India. The issue
20 o
second decade (as in the Paul Wood series), the changes in of operability in a borderline case has not been well
his/her lungs had already began during early infancy and characterized and remains an inexact science. The age
S
could have been aborted ONLY if the defect was operated of the patient and PVR remains the most important
by 1–2 years of age or earlier. This time window could be variables, but much remains to be learnt. There are some
al
somewhat more for moderate VSDs, and such changes do rare patients with large VSD and still operable at older
not occur in patients with small VSDs. It has never been ages, and a study of these outliers might throw some light
ic
established with certainty as to how many patients with on the issue of operability. Further, there are factors that
large VSD might develop Eisenmenger syndrome, but accelerate occurrence of Eisenmenger syndrome like
og
textbooks have written an estimated number as 50% of Down syndrome, but it is still unclear why a patient with
large VSDs. large shunt and mitral stenosis remains operable despite
Once the patient have developed Eisenmenger similar pressures.35-37 A protective effect on structural
ol
syndrome, there is small decline in functional capacity changes with high altitude is also reported even though
with time but many productive years of life are possible PVR is raised at high altitude.
di
with some limitations. The natural history of Eisenmenger

patients is better than that of idiopathic pulmonary arterial Infective Endocarditis
ar
hypertension (PAH) and the worst natural history is that of Infective endocarditis (IE) remains a dreaded complication
a patient who has surgical closure of shunt with a high PVR and this threat is often cited as a reason to close a small
C
(such that it should not have been operated).28-31 Several VSD. However, currently, the data do not support such an
large series of patients with Eisenmenger have shown the approach. A study of 125 patients with isolated VSD aged
average age at death to range from 33 to 40 years. It was 10 years and above who were followed up for a mean of
28 years for patients with Down syndrome. The cause 15 years showed no statistical difference in the incidence
of death was sudden in 30% patients, which was mostly of bacterial endocarditis between the untreated patients
due to hemoptysis. Dehydration and acute subarachnoid (4.3%) and those that were surgically closed (2.7%)
hemorrhage due to anticoagulant use were other causes of although the sample size of the study was small.38 Risk of IE
sudden death. Chronic right-sided CHF as cause of death is more with small defects and is higher during adolescent
was found in 17–25% cases. Arrhythmias, i.e. ventricular and adulthood. Risk increases with age and a past history
fibrillation (VF) causing sudden death, have been reported of IE. Gersony et al. have reported 7 per 10,000 person year
in 14% patients in one series.25 Surgical closure of defect incidence of IE in patients treated surgically and 14.5 per
causing mortality accounted for 26% mortality in Paul 10,000 person years in those followed medically, which is
322
KG-38 (Sec-6).indd 322 02-11-2018 16:57:12

CHAPTER
Table 1: Large and small ventricular septal defects
Large VSD Small VSD

38
Mortality <1 year 30% Nil

CHF Almost all develop Rare unless IE/AR
Spontaneous closure 10–15% Up to 75% by 10 years age
Eisenmenger syndrome 50% (?) None
Infective endocarditis 1.4% 11%
Aortic regurgitation 2% 20%
a
Abbreviations: CHF, congestive heart failure; IE, infective endocarditis; AR, aortic regurgitation
di
almost twice of the surgically treated group. Considering natural history of VSD. For example, whether to close
In
life expectancy as 60 years, lifetime incidence should be small VSDs is not completely settled especially with the
8.7% in a non-surgically treated patient, compared to 4.2% availability of nonsurgical closure of the VSD. Whether to
of
in a surgically closed VSD.39,40 The incidence of IE might be close all subarterial VSDs, or the impact of VSD closure
drastically altered by proper attention to dental hygiene. in patients with mild AR and its progression remains in
completely clarified.
ty
Further, when to operate the VSD in a patient with
Small VSD with LVVO
raised PVR remains a problematic issue as alluded earlier.
Patients with small VSD defined as VSD with a <1.5:1 Whether the changes of Èisenmengerization` might
18 cie
shunt, no cardiomegaly and normal pulmonary artery
pressures usually have good outcomes. A proportion of
somehow be reversed remains to be studied. The group
of patients with persistent fetal circulation that show up
these patients (5–13%) have evidence of large heart, some as Eisenmenger adults remains a challenge; and whether
20 o
systolic dysfunction and ventricular arrhythmias and operating them in infancy reverse the PVR is unclear. Also,
symptoms on long-term follow-up. How to distinguish
S
does there exist patients who have raised PVR due to VSD
them from other patients with small VSD is not known; it and subsequently the VSD has become small in size is not
might be that these patients had a relatively larger shunts. defined.
al
Such patients suggest lowering the threshold for closure of Finally, a snapshot at some of the events in the natural
small VSDs.41-43 history of VSDs as discussed above is tabulated here in the
ic
small and large VSD empirically (Table 1).

Survival Like General Population
og
Most small VSD patients survive like general population. REFERENCES

In the NHS 2 study, a 25-year survival was 87%, slightly 1. Fyler DC, Buckley LP, Hellenbrand WE, et al. Report of
inferior to the general population. 44 The patients who the New England Regional Infant Cardiac Programme.
ol
expired, two-thirds deaths were due to cardiac etiology. Pediatrics. 1980;65(Suppl):376–461.

Predictors of survival are size of defect, pulmonary 2. Ferencz C, Rubin JD, McCarter RJ, et al. Congenital
di
vascular resistance, and presence of CHF at admission to heart disease: prevalence at live birth. The Baltimore–
Washington Infant Study. Am J Epidemiol. 1985;121(1):31–
study.
ar
6.
3. Kirklin JK. Kirklin/Barratt-Boyes Cardiac Surgery, 4th edn.
Unnatural History of VSD Elsevier: Canada. 2013;35:1274-323.
C
Most neonates born with large VSD undergo operations in 4. Jacobs JP, Burke RP, Quintessenza JA, et al. Congenital
the Western world; and in the absence of residual defects, Heart Surgery Nomenclature and Database Project :
there natural history should be quite similar to general ventricular septal defect. Ann Thorac Surg. 2000;69(Suppl
population. The operative mortality of VSD is quite low 4):S25–35.
in the contemporary cardiac surgical practice, 0.6% 5. Allen HD, Shaddy RE, Penny DJ, et al. Moss and Adams’
(0–0.9%). 45 However, rare instance of ventricular Heart Disease in Infants, Children and Adolescents
arrhythmias, sudden death, and infective endocarditis (on Including the Fetus and Young Adult. 9th edn. Lippincott
Williams & Wilkins: Philadelphia. 2016;30;783-802.
a residual defect) can occur as seen in the NHS 2 study.44
6. Paladini D, Palmieri S, Lamberti A, et al. Characterization
and natural history of ventricular septal defects in the fetus.
Unresolved Issues Ultrasound Obstet Gynecol. 2000;16(2):118–22.
Several issues in the management of a patient with VSD 7. Allan L. Abnormalities of the ventricular septum. In:
remain unclear due to incomplete understanding of the Allan L, Hornberger L, Sharland G, eds. Textbook of Fetal
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SECTION Cardiology. London: Greenwich Medical Media. 2000. pp. Anatomical, angiographic, and surgical considerations.
195–208. Circulation. 1973;48(5):1028–37.
6 8. Allan LD, Sharland GK, Milburn A, et al. Prospective

diagnosis of 1,006 consecutive cases of congenital heart
25. Wood P. The Eisenmenger syndrome or pulmonary
hypertension with reversed central shunt. Br Med J.
disease in the fetus. J Am Coll Cardiol. 1994;23(6):1452-8. 1958;2(5099):755-62.

9. Rudolph A. Congenital Diseases of the Heart: Clinical- 26. Rabinovitch M, Haworth SG, Vance Z, et al. Early pulmonary
Physiological Considerations. 3rd ed. Wiley Blackwell: UK, vascular changes in congenital heart disease studied in
2009; pp. 148-178. biopsy tissue. Hum Pathol. 1980;11(Suppl 5):499–509.
10. Adatia I, Kothari SS, Feinstein JA. Pulmonary hypertension 27. Heath D, Edwards JE. The pathology of hypertensive
associated with congenital heart disease pulmonary pulmonary vascular disease: a description of six grades of
vascular disease: the global perspective. Chest. 2010; structural changes in the pulmonary arteries with special
a
137(Suppl 6):52S-61S. reference to congenital cardiac defects. Circulation.
11. Corone P, Doyon F, Gaudeau S, et al. Natural history of 1958;18(14:1):533–47.
di
ventricular septal defect. A study involving 790 cases. 28. Manes A, Palazzini M, Leci E, et al. Current era survival of
Circulation. 1977;55(6):908-15. patients with pulmonary arterial hypertension associated
In
12. Alpert BS, Cook DH, Varghese PJ, et al. Spontaneous closure with congenital heart disease: a comparison between
of small ventricular septal defects: ten-year followup. clinical subgroups. Eur Heart J. 2014;35(11):716–24.
Pediatrics. 1979;63(2):204–6. 29. Benza RL, Miller DP, Gomberg-Maitland M, et al. Predicting
of
13. Alpert BS, Mellits ED, Rowe RD. Spontaneous closure of survival in pulmonary arterial hypertension. Insights from
small ventricular septal defects: probability rates in the first the registry to evaluate early and long-term pulmonary
five years of life. Am J Dis Child. 1973;125(2):194–6. arterial hypertension disease management (REVEAL).
ty
14. Krovetz LJ. Spontaneous closure of ventricular septal Circulation. 2010;122(2):164–72.
30. Barst RJ, McGoon MD, Elliott CG, et al. Survival in
defect. Am J Cardiol. 1998;81(1):100–1.
15. 18 cie
Mehta AV, Goenka S, Chidambaram B, et al. Natural history
of isolated ventricular septal defect in the first five years of
childhood pulmonary arterial hypertension: insights from
the registry to evaluate early and long-term pulmonary
arterial hypertension disease management. Circulation.
life. Tenn Med. 2000;93(4):136–8.
2012;125(1):113–22.
20 o
16. Mehta AV, Chidambaram B. Ventricular septal defect in the
31. Dimopoulos K, Wort SJ, Gatzoulis MA . Pulmonary
first year of life. Am J Cardiol. 1992;70(3):364–6.
S
hypertension related to congenital heart disease: a call for

17. Saxena A, Tandon R, Shrivastava S. Clinical course of
action. Eur Heart J. 2014;35(11):691–700.
isolated ventricular septal defect: an Indian experience.
32. Campbell M. Natural history of ventricular septal defect. Br
al
Indian J Pediatr. 1993;60(6):777-82.

Heart J. 1971;33(2):246-57.
18. Tomita H, ArakakiY, Yagihara T, et al. Incidence of
33. Daliento L, Somerville J, Presbitero P, et al. Eisenmenger
ic
spontaneous closure of outlet ventricular septal defect. Jpn

syndrome. Factors relating to deterioration and death. Eur
Circ J. 2001 65(5):364–6.
Heart J. 1998;19(12):1845-55.
og
19. Zhang J, Ko JM, Guileyardo JM, et al. A review of spontaneous

34. Saha A, Balakrishnan KG, Jaiswal PK, et al. Prognosis for
closure of ventricular septal defect. Proc (Bayl Univ Med
patients with Eisenmenger syndrome of various aetiology.
Cent). 2015;28(4):516-20. Int J Cardiol. 1994;45(3):199–207.
ol
20. Gasul BM, Dillon RF, Vrla V, et al. Ventricular septal defects; 35. Gupta A, Kothari SS. Operable patent ductus even with
their natural transformation into those with infundibular differential cyanosis: a case of patent ductus with mitral
di
stenosis or into the cyanotic or noncyanotic types of stenosis. Cardiol Young. 2017;27(9):1845-8.
tetralogy of Fallot. J Am Med Assoc. 1957;164(8):847–53. 36. Kalantre A, Sunil GS, Kumar RK. Pulmonary venous
ar
21. Jain V, Subramanian S, Lambert EC. Concomitant hypertension may allow delayed palliation of single
development of infundibular pulmonary stenosis and ventricle physiology with pulmonary hypertension. Ann
spontaneous closure of ventricular septal defect. An
C
Pediatr Cardiol.2016;9(2):147-52.
unusual variant in the natural history of ventricular septal 37. Leopold JA. Pulmonary venous remodeling in pulmonary
defect. Am J Cardiol. 1969;24(2):247–54. hypertension. The veins take center stage. Circulation.
22. Shepherd RL, Glancy DL, Jaffe RB, et al. Acquired 2018;137(17):1811–3.
subvalvular right ventricular outflow obstruction in patients 38. Otterstad JE, Frøysaker T, Erikssen J, et al. Long-term
with ventricular septal defect. Am J Med. 1972;53(4): results in isolated ventricular septal defect surgically
446–55. repaired after age 10. Comparison with the natural course
23. Van Praagh R, McNamara JJ. Anatomic types of ventricular in similarly-aged patients. Scand J Thorac Cardiovasc Surg.
septal defect with aortic insufficiency. Diagnostic and 1985;19(3):221–9.
surgical considerations. Am Heart J. 1968;75(5):604–19. 39. Viswanathan S, Kumar RK. Should we close small ventricular
24. Tatsuno K , Konno S, Ando M, et al. Pathogenetic septal defects? Ann Pediatr Cardiol. 2017;10(1):1-4.
mechanisms of prolapsing aortic valve and aortic 40. Gersony WM, Hayes CJ, Driscoll DJ, et al. Bacterial
regurgitation associated with ventricular septal defect. endocarditis in patients with aortic stenosis, pulmonary
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stenosis, or ventricular septal defect. Circulation. 1993; ventricular dysfunction justifies lifelong care. Int J Cardiol. CHAPTER
87(Suppl 2):121–6. 2016;208:102–6.
41. Neumayer U, Stone S, Somerville J. Small ventricular septal
defects in adults. Eur Heart J. 1998;19(10):1573–82.
44. Kidd L, Driscoll DJ, Gersony WM, Hayes CJ, Keane JF,
O’Fallon WM, et al. Second natural history study of
38

42. Gabriel H, Heger M, Innerhofer P, et al. Long-term outcome congenital heart defects. Results of treatment of patients
of patients with ventricular septal defect considered not with ventricular septal defects. Circulation. 1993;87(Suppl
to require surgical closure during childhood. J Am Coll 2):I38-51.
Cardiol. 2002;39(6):1066-71. 45. Jacobs JP, Mayer JE Jr, Pasquali SK, et al. The Society of
43. Karonis T, Scognamiglio G, Babu-Narayan SV, et al. Clinical Thoracic Surgeons Congenital Heart Surgery Database:
course and potential complications of small ventricular 2018 Update on Outcomes and Quality. Ann Thorac Surg.
septal defects in adulthood: Late development of left 2018;105(3):680-9.
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Ventricular Septal Defect with
CHAPTER 39 Aortic Regurgitation
a
di
HISTORY There are two principal pathogenic factors that lead
to AR: anatomical defect leading to lack of support to the
In
The first description of a ventricular septal defect (VSD)
valve tissue and hemodynamic effects. In uncomplicated
with aortic regurgitation (AR) dates back to 1921 when
VSDs and in normal subjects, the aortic annulus and the
Laubry and Perzzi published the first postmortem report.1
sinuses of Valsalva are supported by a thick muscular
of
A decade later, Laubry and colleagues described a couple
conal tissue from the right ventricular side. In patients
of patients with VSD with a loud aortic diastolic murmur
with subpulmonary VSD, there is a fibrous continuity
and prolapsed aortic valves at autopsy.2 The syndrome of
between the aortic and pulmonary valves because of the
ty
VSD and AR includes the heart in which AR is of congenital
deficient infundibular septum and the septal portion of the
origin, although rarely present at birth, caused by cusp
subpulmonary infundibulum. Since the aortic valve lacks
18 cie
prolapse, bicuspid aortic valve, or subaortic membrane.
support, the right coronary cusp and/or noncoronary cusp
prolapse in the right ventricular outflow tract (RVOT),
EPIDEMIOLOGY leading to AR and very frequently, a subpulmonary
20 o
Ventricular septal defect is the most common congenital gradient. In patients with infracristal defects, AR is usually
S
cardiac malformation, occurring in approximately 50% due to two anatomical defects: underdeveloped right or
of all patients with congenital cardiac defects. 3 The noncoronary commissure and abnormal development of
development of new onset AR is an uncommon but a the sinuses of Valsalva.7
al
serious manifestation of VSD. The prevalence of AR with There are two principal hemodynamic factors that
VSD depends on the relative prevalence of perimembranous affect the prolapse of aortic cusp through the VSD. The
ic
versus doubly committed subarterial or subpulmonary early systolic shunting of blood through the VSD forces
VSDs. AR occurs in 5–8% of the Caucasian population, the aortic valve to prolapse due to the Venturi effect. The
og
who have a higher prevalence of perimembranous VSDs.4,5 prolapsed aortic valve leads to the narrowing of VSD
Conversely, AR has an incidence rate approaching 30% in opening and increased shunt velocity, thus drawing the
aortic cusp into the right ventricular cavity. The ejection
ol
some Eastern populations (China and Japan), who have a

much higher prevalence of subarterial/doubly committed of blood through the aortic valve in midsystole expands
the aortic root and the sinus of Valsalva. This leads to
di
defects.6 There is a striking male preponderance in the

prevalence of VSD with AR. further shifting of the unsupported aortic cusp into the
right ventricular side. During diastole, the three cusps
ar
close and become competent. As the unsupported cusp

PATHOGENESIS
shifts towards right ventricle side, it elongates, separates
C
The three principal causes of AR in patients with VSD from two cusps and ultimately leads to AR, which begets
are aortic valve prolapse, bicuspid aortic valve and AR.7 The role of hemodynamic factors is highlighted by
subaortic membrane. Several reports have documented the fact that AR occurs years after birth and does not
that in all cases of aortic valve prolapse and AR, the occur in patients with Eisenmenger syndrome who do not
VSD is close to the aortic annulus.7 The development of have a restrictive defect.9 For the Venturi effect to be the
AR in patients with VSD is most frequently due to the mechanism for AR, the VSD has to be restrictive, which is
prolapse of the aortic cusp into the VSD. In 1968, Van found in most of the cases. Additionally, since right and
Praagh described two types of VSDs which are associated left ventricular pressures are equal in utero, AR has to be
with AR: infracristal or perimembranous (type I) and acquired and is rarely found at birth.
subpulmonary or subarterial doubly committed (type II). Subaortic membrane is another cause of AR that
Infracristal defects were further classified into two types: is occasionally encountered during the follow-up of
type Ia (without subpulmonary stenosis) and type Ib (with patients with VSD. The high-velocity jet of blood due to
subpulmonary stenosis).8 the subaortic obstruction leads to aortic valve thickening
KG-39.indd 326 02-11-2018 16:56:59

and asymmetric poststenotic dilation of the aorta. NATURAL HISTORY CHAPTER
Nearly 65% of patients with subaortic membrane have
39
It has been established unequivocally, that in no case
AR, which may be progressive even after the excision of of VSD is AR present at birth. AR develops much more
subaortic membrane. AR, although usually trivial to mild, frequently in patients with subpulmonary defects as

is generally progressive due to injury to the aortic valve by compared to perimembranous defects. Aortic prolapse
the high-velocity jet of blood. Studies have shown that a occurs with large infracristal defects and after a long
high peak Doppler gradient (>50 mm Hg) is a predictor or evolution. The natural history of AR is that of insidious
at least moderate AR.10 onset, gradually progressive valve deterioration and
increasing degrees of insufficiency. Sometimes, the
MORPHOLOGY aortic valve prolapse produces occlusion of the VSD and
produces finding of isolated severe AR with VSD diagnosed
a
Approximately two-thirds of all cases of AR are due
to the prolapse of right coronary cusp. The remaining only during the surgery.12,13 The rate of progression of AR
di
one-third is due to the prolapse of noncoronary cusp or is the same irrespective of the type of VSD. AR generally
combined prolapse of the right and noncoronary cusp. becomes severe by the end of second decade of life.14
In
Infrequently, there is no cusp prolapse, but the aortic valve The increasing grades of AR generally lead to significant
is bicuspid. Variable degree of RVOT obstruction is noted. patient symptoms and ultimately warrant intervention of
Several factors can lead to RVOT obstruction—anterior the VSD with or without repair or replacement of the aortic
of
and leftward deviation of the outlet septum as in TOF, valve.
moderator band hypertrophy, right ventricular trabecular
hypertrophy and low lying infundibular stenosis (double- CLINICAL PRESENTATION
ty
chambered right ventricle).8 In one large series, significant
In contrast to the equal gender distribution of isolated
RVOT gradient was found in a quarter of all patients.
18 cie
The aortic cusps exhibit a variety of anomalies, the most
severe being prolapse through the VSD. Some patients
VSDs, AR with VSD has a striking male preponderance
with a male to female ratio of 2:1. Aortic cusp prolapse can
be detected before the onset of AR by echocardiography.
may develop changes due to infective endocarditis, which
AR typically occurs between 2 and 10 years of age
20 o
leads to acute AR with rapid worsening. The sinuses of
and peaks between 5 and 9 years of age. 15 The typical
Valsalva often enlarge considerably. This is associated
S
presentation is that of a male child, with a previously

with the dilation of aortic annulus. The wall of the
known systolic murmur of VSD who develops an additional
enlarged sinus may protrude into the right ventricle above
diastolic murmur at 5-9 years of age. AR due to subaortic
al
the prolapsed cusp, mimicking ruptured congenital sinus

membrane is also unusual in infants. The usual symptoms
of Valsalva aneurysm.
include nocturnal palpitations particularly in the left
ic
The subaortic membrane, which occasionally occurs

lateral position, chest pain, neck pulsations, increased
during the follow-up of patients with VSD, may also be
og
precordial activity, and diaphoresis. Infective endocarditis

seen following surgical repair of VSDs. The most common
is fairly common, particularly in bicuspid aortic valves and
morphologies include discrete subaortic membrane
accelerates the development of AR.16
and fibromuscular ridge. The other types include diffuse
ol
Examination reveals the classical bounding Corrigan

fibromuscular tunnel and accessory mitral valve tissue.
water hammer pulse with a wide pulse pressure, brisk
Anatomic factors that predispose to the development of
di
arterial rise, pulsus bisferiens, pistol shot sound over

subaortic membrane are long and narrow left ventricular
the femoral arteries and prominent nailbed capillary
outflow tract (LVOT), steep aortoventricular septal angle,
ar
pulsations when aortic regurgitation has become severe.

aortic override and increased aortomitral separation.11
In acute severe AR, the left ventricle cannot adapt
rapidly to the increased preload. Hence, the contractility
C
PHYSIOLOGICAL EFFECTS is depressed and ejection velocity and stroke volume

The left ventricle bears the brunt of the combined declines. Hence, the pulse pressure is not increased and
effects of VSD and AR, which greatly increase the left rate of rise is not brisk.4,5
ventricular volume overload owing to the regurgitant Cardiovascular examination reveals a very active
(leaking) blood from the aorta and the shunt volume precordium. The murmur of VSD and AR is not continuous,
from the VSD. Perimembranous defects tend to reduce but to and fro (holosystolic and early diastolic). The
in size with increasing severity of AR. Hence, the severity corresponding systolic and diastolic murmurs represent
of the AR rather than the shunt volume becomes the the classical murmurs of VSD and AR. These murmurs do
major contributor to left ventricular volume overload. In not peak around the second heart sound and hence can
contrast, subpulmonary defects do not tend to reduce in be differentiated from the continuous murmur of patent
size and the degree of shunting increases with increasing ductus arteriosus (PDA). In contrast to the murmur of PDA
degree of AR.4 which is best audible in the left second intercostal space,
327
KG-39.indd 327 02-11-2018 16:57:00

SECTION the systolic murmur of VSD is best heard in the left third arising from the membranous septum. Continuous wave
or the fourth intercostal space and the diastolic murmur Doppler can detect the peak and mean gradient across the
6 in the mid-to-lower left sternal border.17 In contrast, the
murmur of AR due to subaortic membrane is classically
membrane.
VSD, in the presence of AR, is usually restrictive with
best heard at the right sternal border; and, unlike a case of Qp/Qs of less than 2:1. With the progression of AR, there
bicuspid aortic valve, patients with subaortic stenosis do may be a reduction in the left-to-right shunt. Hence,
not have ejection systolic click. pulmonary artery hypertension is uncommon as both new
onset AR and subaortic membrane are generally seen or
ECG and Chest X-ray noted in small-to-moderate VSD.
The ECG in these patients resembles that of AR rather
Cardiac Catheterization
a
than a restrictive VSD. Deep Q waves, tall R waves, coved
ST segments and deeply inverted T waves are seen in the Echocardiography has supplanted the role of cardiac
di
left precordial leads and deep S waves are seen in the catheterization in the diagnosis and management of VSD
right precordial leads, typical of left ventricular volume with AR. The Qp/Qs is generally less than 2:1. Most of
In
overload. Chest X-ray also resembles AR rather than a VSD these patients have a Qp/Qs greater than 1.5:1, suggesting
and shows marked left ventricular enlargement. that there is a minimum shunt required to produce aortic
cusp distortion. Right ventriculography accurately depicts
of
Echocardiogram subpulmonary stenosis. Left ventriculography can assess
the size of the VSD and aortogram can depict the severity
Echocardiography is the primary diagnostic modality
of AR and morphology of the aortic root. The absence of
ty
for the detection of AR and VSD. Transthoracic and
aortic valve prolapse and normal aortic root dimensions
transesophageal echocardiogram can identify the VSD
may suggest bicuspid aortic valve as the etiology which
18 cie
as perimembranous or subpulmonary. It also detects
the prolapse of right or noncoronary cusp (Figures 1A
and B) and color flow imaging can quantify the degree
can be confirmed on transesophageal echocardiography
if required.
of AR and detect shunt across the VSD. Subpulmonary
20 o
doubly committed VSDs can be diagnosed by their close TREATMENT
S
proximity to the aortic valve and systolic jet directed The first operative reports of VSD with AR were published
into the pulmonary trunk (Figures 2A and B). Doppler by Garamella and Starr in 1960.18 Subsequent analysis of
interrogation can also detect the RVOT obstruction due results from the Mayo Clinic showed a 33% rate of residual
al
to aortic valve prolapse. Serial echocardiograms can AR after aortic valve repair.19 Apart from results from the
be used to follow-up the severity of AR, the degree of Mayo Clinic, several other reports forced the operators
ic
subpulmonary obstruction and size of VSD. AR is mild to to adopt an approach of aortic valve replacement with a
og
moderate in half and severe in another half of the patients prosthetic valve due to unsatisfactory results with valve
at the time of repair. Echocardiogram can also detect repair. However, the publication of Spencer and Trusler
other causes of AR such as subaortic membrane and renewed the interest in valve reconstruction surgery.20,21
ol
bicuspid aortic valve. It is useful to assess LV dimensions Although the results of VSD closure have improved
and function. The subaortic membrane is generally seen considerably over time, the additional valve surgery adds
di
ar
C
A B
Figures 1A and B: A parasternal long-axis 2D echocardiogram of a 2-year-old male child with a subpulmonary ventricular septal defect
(VSD) shows right coronary cusp (RCC) prolapse through the VSD (red arrows in A and B)
328
KG-39.indd 328 02-11-2018 16:57:00

CHAPTER
39

a
di
In
of
A B
ty
Figures 2A and B: Parasternal short-axis 2D echocardiogram image of the same patient as in Figure 1 showing a large (9 mm) subpulmonary
ventricular septal defect (VSD) (red arrow in Figure A) shunting into the pulmonary artery (yellow arrow). Figure B shows the large left-to-
right shunt across the VSD. The asterisk in panel A is the aorta
18 cie
to the morbidity and mortality during the perioperative Surgery is usually done on cardiopulmonary bypass
period. The prevention of AR is better than its treatment. and under transesophageal echocardiography (TEE)
20 o
If valve repair fails to treat aortic valve prolapse and AR, guidance. The aortic valve is assessed for the feasibility of
repair. Retracted and thickened valve cusps make repair
S
aortic valve replacement remains the only option, which

in children is associated with its hazards of long-term difficult in some cases. The various surgical modalities
anticoagulation and in young children this may lead to that are practised include Trusler’s method, Carpentier’s
al
Ross surgery. technique, Yacoub’s technique. 26.27 No comparison

Heart failure, large shunt, poor growth, and high between the different methods is currently available.
ic
pulmonary artery pressures are traditional indications Aortic valve repair is preferred over valve replacement
in children due to the attendant long-term risks of
og
of surgery for VSD. However, AR usually occurs in the

absence of other symptoms of heart failure that can be anticoagulation and small size of the aortic annulus in
children. Several series have shown an excellent long-term
attributed to VSD. Closure of VSD and aortic valve repair
survival of patients after surgery, with a mortality rate of
ol
or replacement is indicated for both subarterial and

around 1%. Heart block rarely occurs after surgery, and
perimembranous VSDs when more than trivial AR is
none were reported in the Yacoub series.28
di
detected.22 Aortic valve replacement is reserved for adults

When AR is mild, VSD closure alone can prevent the
with moderate-to-severe AR. For patients with moderate-
progression of AR. However, the chances of a good result
ar
to-large subpulmonary VSD and aortic valve prolapse

are decreased in patients with severe AR preoperatively.
with no AR, VSD closure is indicated to prevent the
Perimembranous VSD is considered to be a risk factor for
C
development of AR. Since the spontaneous closure rate of

residual AR.29 Bicuspid aortic valves are less satisfactorily
subpulmonary VSDs is low, some authors have suggested repaired and frequently need to be replaced. Studies
closure of all such defects more than 5 mm in size with have cited 89% freedom from aortic valve replacement at
presumption that subpulmonic defect of more than 8 years and 81% at 15 years follow-up after VSD closure
5 mm has very high incidence of AR in the tune of 70%.23,24 and aortic valve repair.22
The natural history of hemodynamically insignificant The management of subaortic membrane and timing
infracristal VSD with aortic valve prolapse without AR is of surgery is controversial and highly debated. In patients
unclear. AR progression is variable and spontaneous VSD with low-moderate left ventricular outflow tract (LVOT)
closure is possible. Hence, surgical closure is not indicated gradient (<50 mm Hg) and trivial AR, surgery is deferred.
for defects with aortic valve prolapse in the absence of AR Surgery is generally advocated when peak LVOT gradient
and serial echocardiography can be used for the follow-up is ≥50 mm Hg and mean gradient is ≥30 mm Hg. Infants
of these patients (Table 1).25 with LVOT gradient <30 mm Hg should be followed
329
KG-39.indd 329 02-11-2018 16:57:01

SECTION
Table 1: Management of VSD with AR32
6 Condition
Small (<3 mm) subpulmonary VSD without aortic valve prolapse
Management, timing and type of surgery
Yearly follow-up to look for valve prolapse
Small subpulmonary VSD with aortic valve prolapse without AR Elective surgical closure at 2–3 years of age
Subpulmonary outlet VSD with any degree of AR Prompt surgery while AR is still mild
Small perimembranous VSD with valve prolapse and no or mild AR Yearly follow-up for assessment of AR severity
Small perimembranous VSD with aortic valve prolapse and more Surgery when AR is detected
than trivial-mild AR
VSD with bicuspid aortic valve and AR Generally needs valve replacement. Surgery can be delayed till
a
symptoms develop or left ventricular enlargement mandates valve
replacement
di
Subaortic membrane with LVOT gradient >50 mm Hg Surgical excision with VSD closure
In
Adult patients with VSD and moderate-severe AR Usually need valve replacement
Abbreviations: VSD, ventricular septal defect; AR, aortic regurgitation; LVOT, left ventricular outflow tract
of
biannually and older children annually. Patients with regurgitation associated with ventricular septal defect.
mild or more AR generally need surgical correction to Anatomical, angiographic, and surgical considerations.
Circulation. 1973;48(5):1028–37.
ty
prevent the progression. The definitive treatment consists
of surgical excision of the membrane or myectomy for 8. Van Praagh R, McNamara JJ. Anatomic types of ventricular
tunnel-like obstruction.30,31 septal defect with aortic insufficiency. Diagnostic and
CONCLUSION
18 cie 9.
surgical considerations. Am Heart J.1968;75(5):604–19.
Halloran KH, Talner NS, Browne MJ. A study of ventricular
septal defect associated with aortic insufficiency. Am Heart
VSD with AR is a more sinister entity compared to VSD
20 o
J. 1965;69:320-6.
alone. It has a classical clinical presentation beyond 10. McMahon CJ, Gauvreau K, Edwards JC, et al. Risk factors for
S
infancy and has an insidious onset and gradually aortic valve dysfunction in children with discrete subvalvar
progressive course. There are varied etiologies of AR in aortic stenosis. Am J Cardiol. 2004;94(4):459–64.
al
patients with VSD, the most common of which is aortic 11. Edwards JE. Pathology of left ventricular outflow tract
cusp prolapse. Patients with subpulmonary doubly obstruction. Circulation.1965;31(4):586–99.
ic
committed VSDs need to be managed more aggressively 12. Azcárate MJM, Azcárate MJM. Ventricular septal defect
than infracristal VSDs, with some centers suggesting with aortic regurgitation. an unsolved problem. Rev Esp
og
closure of all subpulmonary defects. The detection of cusp Cardiol. 2002;55(9):897–9.

prolapse, subaortic membrane and even trivial grades of 13. Hernández Morales G, Vázquez Antona CA, Muñoz
AR warrants close follow-up of these patients with surgical Castellanos L, et al. Aortic valve complications associated
ol
correction once mild AR develops. w ith subar ter ial infundibular ventr icular septal
defect. Echocardiograpic followup. Rev Esp Cardiol.
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3. Minette MS, Sahn DJ. Ventricular septal defects. Circulation.
2006;114(20):2190–7. morphological criteria with echocardiographic and
4. Nadas AS, Thilenius OG, Lafarge CG, et al. Ventricular angiocardiographic correlation. Br Heart J. 1988;59(4):
septal defect with aortic regurgitation: medical and 474–9.
pathologic aspects. Circulation. 1964;29:862–73. 16. Hor KN, Border WL, Cripe LH, et al. The presence of
5. Rhodes LA, Keane JF, Keane JP, et al. Long follow-up (to bicuspid aortic valve does not predict ventricular septal
43 years) of ventricular septal defect with audible aortic defect type. Am J Med Genet A. 2008;146A(24):3202–5.
regurgitation. Am J Cardiol.1990;66(3):340–5. 17. Perloff JK. Physical Examination of the Heart and
6. Lue HC, Sung TC, Hou SH, et al. Ventricular septal defect in Circulation. 4th edition. Shelton Connecticut: People’s
Chinese with aortic valve prolapse and aortic regurgitation. Medical Publishing House; 2009.
Heart Vessels. 1986;2(2):111–6. 18. Starr A, Menashe V, Dotter C. Surgical correction of aortic
7. Tatsuno K , Konno S, Ando M, et al. Pathogenetic insufficiency associated with ventricular septal defect. Surg
mechanisms of prolapsing aortic valve and aortic Gynecol Obstet. 1960;111:71–6.
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19. Keck EW, Ongley PA, Kincaid OW, et al. Ventricular 26. Trusler GA, Moes CA, Kidd BS. Repair of ventricular septal CHAPTER
septal defect with aortic insufficiency. A clinical and defect with aortic insufficiency. J Thorac Cardiovasc Surg.
hemodynamic study of 18 proved cases. Circulation.
1963;27:203–18.
1973;66(3):394–403.
27. Carpentier A . Cardiac valve surgery--the “French
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20. Spencer FC, Doyle EF, Danilowicz DA, et al. Long-term correction.” J Thorac Cardiovasc Surg. 1983;86(3):323–37.

evaluation of aortic valvuloplasty for aortic insufficiency 28. Yacoub MH, Khan H, Stavri G, et al. Anatomic correction
and ventricular septal defect. J Thorac Cardiovasc Surg. of the syndrome of prolapsing right coronary aortic cusp,
1973;65(1):15–23. dilatation of the sinus of Valsalva, and ventricular septal
21. Frater RW. The prolapsing aortic cusp. Experimental and defect. J Thorac Cardiovasc Surg. 1997;113(2):253–60;
clinical observations. Ann Thorac Surg. 1967;3(1):63–7. discussion 261.
22. Elgamal MA, Hakimi M, Lyons JM, et al. Risk factors for 29. Okita Y, Miki S, Kusuhara K, et al. Long-term results of
failure of aortic valvuloplasty in aortic insufficiency with aortic valvuloplasty for aortic regurgitation associated
a
ventricular septal defect. Ann Thorac Surg. 1999;68(4): with ventricular septal defect. J Thorac Cardiovasc Surg.
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1350–5. 1988;96(5):769–74.
23. Tomita H, Arakaki Y, Yagihara T, Echigo S, et al. Incidence of 30. Brauner R, Laks H, Drinkwater DC Jr, et al. Benefits of early
spontaneous closure of outlet ventricular septal defect. Jpn surgical repair in fixed subaortic stenosis. J Am Coll Cardiol.
In
Circ J. 2001;65(5):364–6. 1997;30(7):1835–42.
24. Lun K, Li H, Leung MP, et al. Analysis of indications 31. Karamlou T, Gurofsky R, Bojcevski A, et al. Prevalence and
for surgical closure of subarterial ventricular septal associated risk factors for intervention in 313 children with
of
defect without associated aortic cusp prolapse and aortic subaortic stenosis. Ann Thorac Surg. 2007;84(3):900–6;
regurgitation. Am J Cardiol. 2001;87(11):1266–70. discussion 906.
25. Gabriels C, De Backer J, Pasquet A, et al. long-term outcome 32. Saxena A, Ramakrishnan S, Tandon R, et al. Consensus
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of patients with perimembranous ventricular septal defect: on timing of intervention for common congenital heart
results from the Belgian registry on adult congenital heart disease; Working Group on Management of Congenital
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disease. Cardiology. 2017;136(3):147–55. Heart Diseases in India. Indian Pediatr. 2008;45(2):117–26.
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CHAPTER 40 Imaging of Atrial Septal Defect
a
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INTRODUCTION ANATOMY OF OSTIUM SECUNDUM
Imaging of interatrial septum has gained paramount ATRIAL SEPTAL DEFECT
In
importance since the advent of device closure of atrial To close the ASD using the transcatheter techniques,
septal defects. Successful outcome of the procedure, it is important for the interventional cardiologists to
of
to a very large extent, depends on appropriate patient have a sound knowledge of the atrial septal rims and
selection, which in turn is dependent on pre- and the structures that surround the secundum ASD. In the
intraprocedural imaging. The purpose of this chapter is to past, the rims of the atrial septum were named according
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discuss the anatomic features and their echocardiographic to their physical location (anterior, inferior, superior,
equivalents that identify patients who are the suitable posterior, and so on) in reference to the patient. For
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candidates for transcatheter closure of an atrial septal
defect (ASD). Although CT, MRI and conventional
angiography are used for imaging the interatrial septum,
example, the atrial septal rim that is close to the anterior
chest wall was called anterior or one that was closer to the
spine was called posterior. However, when the orientation
various types of echocardiographic imaging remain the of the patient changed ( e.g. from upright to lying down
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mainstay for defining the anatomy of the ASD along with its position) the description of the rims got confusing. To
S
suitability for the device closure; therefore, the discussion avoid this confusion, a nomenclature was proposed by
in this chapter is limited solely to echocardiographic Srivastava et al.1 based on naming the rims based on the
imaging. surrounding structure in its close vicinity. Thus, the rims
al
are now named as follows (Figure 1): The atrioventricular

EMBRYOLOGY OF INTERATRIAL SEPTUM (AV) valve rim is the one close to mitral and tricuspid
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valves; the rim opposite to this is the posterosuperior

The formation of the interatrial septum (IAS) occurs
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rim. The aortic rim is the rim that is adjacent to the

in several stages. The first stage is the development of
aortic valve; while the rim opposite the aortic rim is the
the septum primum, a crescent-shaped piece of tissue
posteroinferior rim. The inferior vena caval (IVC) rim is
forming the initial divider between the right and left
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the rim adjacent to the inferior vena cava, also referred to

atria. As the septum primum grows, the ostium primum
as inferoposterior (IP); while the one close to the superior
progressively narrows. Before the ostium primum is
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vena cava is called the superior vena caval (SVC) rim, also
completely occluded, a second opening called the ostium
referred to as superoposterior (SP) rim. These are the
secundum begins to form in the septum primum. To the
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6 important rims which decide whether or not a patient

right of the septum primum, the septum secundum begins
is suitable for transcatheter closure of ASD. The other two
to form. This thick, muscular structure initially takes
rims often described are the right superior pulmonary
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on the same crescent shape as the septum primum,

venous (RSPV) rim and the coronary sinus rim. The RSPV
except that it originates anteriorly, whereas the septum
rim which lies adjacent to the right superior pulmonary
primum originates posteriorly. As the septum secundum
vein and is located between the aortic rim anteriorly and
grows, it leaves a small opening called the foramen
the SVC rim posteriorly. The coronary sinus rim is the
ovale. The foramen ovale is continuous with the ostium
one adjacent to the os of the coronary sinus and located
secundum, providing for continued shunting of blood.
between the IVC and the AV valve rims.
The ostium secundum progressively enlarges and the size
of the septum primum diminishes. Eventually, the septum
primum is nothing more than a small flap that covers the TYPES OF ATRIAL SEPTAL DEFECT (FIGURE 2)
foramen ovale on its left side. This flap of tissue is called Ostium secundum atrial septal defect (60–70%)
the valve of the foramen ovale. Ostium primum atrial septal defect (15%)
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CHAPTER
40

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Figure 1: Rims of ostium secundum atrial septal defect Figure 2: Types of atrial septal defect
Abbreviations: IVC, Inferior vena cava; SVC, Superior vena cava;
of
CS, Coronary sinus; TV, Tricuspid valve; Ao, Aorta; AV valve, Atrio-
implantation and in many during the process of patient
ventricular valve. (Image courtesy: Zahid Amin)
selection.
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The intracardiac echocardiography (ICE) has also
Sinus venosus defect (10%):
been used extensively to guide percutaneous ASD closure
— Superior vena cava type
Inferior vena cava type. 18 cie

Coronary sinus atrial septal defect (rare).
procedures and provides comparable imaging to TEE.
TTE is easily available, simple to perform with a short
learning curve, does not require any anesthesia and has no
Of all the atrial septal defects, only ostium secundum associated morbidity, but its use is limited by suboptimal
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defects are amenable to device closure. However, within imaging in adults, difficulty in imaging the adequate
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this subset, it is imperative to select the patients judiciously capturing of the rims once the device is deployed and the
for good outcomes because all the secundum ASDs cannot inability to do real-time echo during device deployment
be closed using a device. due to the logistics of the operator’s hand being irradiated
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during fluoroscopic imaging.

ECHOCARDIOGRAPHIC IMAGING OF THE TEE produces very high resolution images and is less
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ATRIAL SEPTAL DEFECT expensive with a smaller learning curve as compared

to ICE. However, it needs general anesthesia and has
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Transthoracic Echocardiography a potential to cause esophageal injury. It produces

significant throat discomfort lasting for 24 to 48 hours after
The transthoracic echocardiography (TTE) remains the
the procedure.
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most widely used ultrasound modality to evaluate patients

The ICE has comparative images to TEE, can be
with ASD and remains the most important screening
done by a single operator without the need of general
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tool. TTE is especially useful in small children in whom

anesthesia. Although, this can save cost, the ICE probe is
the ultrasound image quality will typically permit a full much more expensive. It also has a steep learning curve
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diagnostic study. Therefore, in some centers, it is used and limited availability. Also, it can cause cardiac as well
not only for patient selection but also for intraprocedural as vascular injury.
C
monitoring in children where pediatric transesophageal The atrial septum can be evaluated fully using TTE.
echocardiography (TEE) is not available or is thought to be Multiple views from subcostal, apical and parasternal
not necessary.2 windows are used to evaluate the number, size, shape, and
TTE is also used for the initial evaluation of ASD in location of the atrial communication and the relationship
adults. However, TEE is required in the majority of the of the defect to its surrounding structures. It also allows the
patients to further characterize the atrial septal defect and length estimate of various rims.
the surrounding rims in order to decide its suitability for
the device closure. This is because the TTE image quality, Subxiphoid Frontal (4-chamber) View (Figure 3A)
most often, does not permit a comprehensive evaluation The subxiphoid frontal (4-chamber) view allows imaging
of the IAS in this group of patients. The 2D and 3D TEE of the atrial septum along its long axis extending from
offer significant incremental anatomic information as the RSPV to the AV valves. This is the preferred view for
compared to TTE. Therefore, it has been our practice to imaging the atrial septum, because the atrial septum runs
perform it in all adult patients at the time of the device near perpendicularly to the ultrasound beam, providing 333
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Figures 3A to E: Transthoracic echocardiography views. (A)

Subxiphoid 4-chamber view; (B) Sub-xiphoid sagittal view; (C) Apical
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four-chamber view; (D) Modified 4-chamber view; (E) Parasternal

short axis view
Abbreviations: AR, aortic rim; AVR, atrioventricular valve rim; IR,
ar
inferior rim; LA, left atrium; LV, left ventricle; PIR, posteroinferior rim;
PSR, posterosuperior rim; RA, right atrium; RSPVR, right superior
E pulmonary venous rim; RV, right ventricle; SR, superior rim
C
the highest axial resolution and permitting measurement chamber view. Sweeping the transducer from right to
of the defect diameter along its long axis. Placing the left in this axis allows determination of the orthogonal
septum perpendicular to the ultrasound beam helps dimension of the ASD. Hence, we can determine if the
distinguish a true defect from a false dropout resulting defect is circular or oval. This view is ideal for assessing
from an artifact, which is commonly seen in the apical the SVC and the IVC rims apart from estimating the ASD
4-chamber view. diameter in the superoinferior plane.
Subxiphoid Sagittal TTE View (Figure 3B)

Apical 4-chamber and Modified Apical 4-chamber
The subxiphoid sagittal TTE view is acquired by turning the
TTE View (Figures 3C and D)
transducer 90° clockwise from the frontal view. This view is
ideal for imaging the atrial septum along its superoinferior Apical 4-chamber view has to be avoided as the ultrasound
334 axis in a plane orthogonal to the subxiphoid frontal four- beam is parallel to the septum and there may be false
KG-40.indd 334 02-11-2018 16:56:52

dropouts. The modified apical 4-chamber TTE view is Mid-esophageal 4-chamber View (Figure 4A) CHAPTER
obtained by sliding the transducer medially from the apical
40
The mid-esophageal 4-chamber view is obtained from
4-chamber view towards the sternal border. This view the mid-esophagus beginning with a multi-plane angles
highlights the atrial septum at a more optimum angle of of 0° and stepwise increases of the multi-plane angle to

incidence of the ultrasound beam (30–45°). In the patients 15–30°. This view is used to evaluate the AV valve rim and
in whom the subcostal views are difficult to obtain, the the posterosuperior rim. This view is extremely useful in
modified apical 4-chamber view is an alternative method studying the relationship of the left and the right discs of
for imaging the atrial septum in the direction of the axial the device with the anterior mitral leaflet and the septal
resolution. This view gives a good estimate of AV valve rim leaflet of the tricuspid valve, respectively. This assessment
and the posterosuperior rim. is mandatory prior to releasing the device. In case of any
encroachment by the device on the AV valves, one needs
a
Parasternal Short-axis TTE View (Figure 3E) to consider downsizing the device to avoid long-term
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Parasternal short-axis (SAX) view demonstrates the complications of AV valve regurgitation.
anterior (retroaortic) rim and the posteroinferior rim.
In
This view also gives an estimate of the defect size in the Mid-esophageal Aortic Valve Short-axis View
anteroposterior plane. (Figure 4B)
of
The mid-esophageal aortic valve SAX view is obtained
Transesophageal Echocardiography from the mid-esophagus 4-chamber view by turning the
The transesophageal echocardiography (TEE) provides probe anticlockwise and pulling the probe till the level
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far more high resolution images as compared to TTE. of aortic valve. It is then swept sequentially from 30–45°
As with TTE, multiple and sequential TEE views should and 60°. This progression of transducer angles allows
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be used to completely and systematically evaluate the
IAS, the number, size, shape, and location of any atrial
communication present, and the relationship of the defect
transitional interrogation of the IAS from the aortic valve
SAX view to the bicaval view. This view facilitates imaging
of the aortic rim and the posteroinferior rim. Also, it gives
to its surrounding structures. the dimension of the defect in the anteroposterior plane.
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A B
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Figures 4A to C: Transesophageal echocardiography. (A) Mid-

esophageal 4-chamber view; (B) Mid-esophageal aortic valve short-
axis view; (C) Mid-esophageal bicaval view
Abbreviations: AR, aortic rim; AVR, atrioventricular valve rim; IR,
inferior rim; PIR, posteroinferior rim; PSR, posterosuperior rim; SR,
C superior rim
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SECTION The absence of aortic rim along the entire scan from 30 to size remains an approximation no matter what strategy of
70° is considered as an incremental risk factor for cardiac sizing you adopt.
6 erosion following device closure.
Why is the appropriate sizing of the defect so crucial?
This probably is the single most important parameter
Mid-esophageal Bicaval View (Figure 4C) which decides the short- and long-term outcomes of
The mid-esophageal bicaval view is obtained from the the procedure. ‘Undersizing’ the defect can lead to
mid-esophagus with multi-plane angles of 90–105° to 120°. device embolization resulting into emergency surgery
It is used to image the atrial septum in the superoinferior while ‘oversizing’ may result in an injury to the mitral or
plane and the surrounding structures such as the IVC, tricuspid valves, can cause AV blocks or atrial arrhythmias,
SVC and right pulmonary veins. This view estimates the can obstruct flows in the systemic and pulmonary veins
a
defect size in superoinferior plane and helps in imaging and most importantly can cause cardiac erosion, which
the IVC and the SVC rims. At times, it is difficult to assess may have life-threatening consequences.
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IVC rim with the standard imaging plane; in such cases,
the probe needs to be pushed in deeper and retroflexed.
THREE-DIMENSIONAL TRANSESOPHAGEAL
In
This maneuver is successful in viewing the IVC rim in the
majority of the patients. Three-dimensional transesophageal images of the ASD
are acquired from multiple views and multiple 3D imaging
of
Role of TEE measurements in determining the device size: modes. A comprehensive 3D examination usually begins
Lately, many centers have given up on balloon sizing of the with a real-time or narrow-angled acquisition from the
defect to decide the device size. They go by measurements standard imaging views. To obtain images with higher
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on TEE in 4-chamber, short axis of aorta and bicaval views. temporal and spatial resolution, electrocardiographically
Although there is no universal formula to decide on the gated, 3D wide-angled acquisitions are performed. Hani
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size of the device to be used, most go by the maximum
diameter in these views and then add 4 mm or 6 mm or
some others will increase the measured diameter by 10%
Mahmoud et al.3 have described RATLe 90 maneuver in
3D-TEE for anatomically oriented visualization of the
interatrial septum.
20 o
to arrive at the size of the device to be used. Still, some
The ASD shape can be defined as round (Figure
others, average the 3 diameters measured in these views
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6A), oval (Figure 6B), or triangular, or at times, shaped

and then add 10 to 15%. In short, choice of the device has
somewhat like an egg or a pear or slightly irregular. The
remained an approximation rather than a precise science.
ASD orientation is defined according to the long-axis
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It is our practice to add 10% to the maximum diameter

(LAX) orientation of the defect as vertical, horizontal,
recorded on TEE in the above-mentioned views to decide
oblique with an anterior tilt, or oblique with a posterior
ic
the size of the device to be used.

tilt. One of the most important applications of 3D TEE is in
Balloon sizing of the defect: The alternative method of the assessment of multi-fenestrated ASD. Apart from the
og
selecting the device size is by estimating the balloon number of defects, it helps in knowing their precise size,
stretched diameter (BSD). Amplatzer sizing balloon is relationship to each other and the exact length of tissue
used for the purpose. It is placed across the defect and
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separating these defects. This certainly helps in planning

gradually inflated till the time flow stops. Thereafter, one the number, size and type of devices to be used. In this
needs to start deflating till the point the flow just restarts.
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subset of patients, 3D-TEE also helps in guiding the entire

This diameter is referred to as the BSD and this technique procedure of device deployment right from the passage
of estimating the BSD is called the ‘stop flow’ technique.
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of the guide wire to the release of the device. 2D-TEE is

Any of the views can be selected to estimate the BSD severely limited in these cases.
provided one is able to visualize the entire balloon waist
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across the defect. The SAX view of aorta usually gives a

good visualization of the balloon diameter for estimating
Intracardiac Echocardiography
the BSD (Figures 5A and B). The BSD can also be A systematic assessment of the atrial septum, including
estimated using a fluoroscopy by looking at the waist on the presence, size, site and number of septal defects
the sizing balloon (Figures 5C and D). However, if one and surrounding tissue rims, can be performed with
were to go only by fluoroscopy, and inflate the balloon till intracardiac echocardiography (ICE). The major advantage
such time the waist appears, there is a danger of oversizing of ICE over TEE is avoiding of general anesthesia and
the defect in patients having thin and redundant rims. better visualization of IVC rim. The major limiting factor is
It is advisable to use the device of the same size as the cost as the probe is ideally a single use and disposable one.
BSD or may be an mm more. Some operators add 2 mm The ICE system has a catheter that can be held in a
to the BSD in case of very large (>30 mm BSD) defect or flexed position in up to four directions (anterior, posterior,
even 4 mm, if such a large defect has a floppy IVC rim. left, and right). Pushing forward and pulling back of the
As we stated earlier, sizing the defect to decide the device ICE probe will result in imaging more superiorly and
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CHAPTER
40

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Figures 5A to D: (A and B) The short-axis view of aorta; (C and D) Balloon-stretched diameter estimation
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Figures 6A and B: Three-dimensional transesophageal echocardiography. (A) Round-shaped atrial septal defect; (B) Oval-shaped atrial septal defect
Abbreviations: Sup, superior; inf, Inferior; Ant, anterior; Post, posterior
inferiorly. Axial rotation allows for sweeping of the image cephalad will produce a bicaval view from which the
through multiple planes (Figure 7). superior and inferior rims of the ASD can be measured
The ICE probe is initially positioned in the mid-RA in a (Figure 8B). Rotation of the entire catheter handle
neutral catheter position to visualize the tricuspid valve in clockwise until the intracardiac transducer is near the
the LAX. This is referred to as the ‘home view’ (Figure 8A). tricuspid valve; followed by slight leftward rotation of the
There is no 4-chamber view in ICE. Advancing the catheter right–left knob until the aortic valve appears creates a
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SECTION septal SAX view similar to the TEE-SAX plane Figure 8C). Difficult substrate for device closure: Most of the secundum
However, in contrast to TEE, the near field is RA. From the ASDs can be closed by transcatheter route. Defects with
6 ‘home view’ position, posterior deflection of the posterior– deficient IVC, posterior and AV valve rim should not be
anterior knob and applying slight rightward rotation of the attempted. Defects with absent or deficient aortic rim,
right–left knob helps in obtaining the septal LAX view. over a long range of the scan, are at higher risk of aortic
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Figure 7: Orientation Of Intracardiac Echocardiography Probe In The Right Atrium

(Image Courtesy: Dr Zahid Amin)
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A B
Figures 8A to C: Intracardiac echocardiography images. (A) ICE

home view; (B) ICE bicaval view; (C) ICE short-axis view
Abbreviations: AV, aortic valve; ICE, intracardiac echocardiography;
LA, left atrium; RA, right atrium; RV, right ventricle; SVC, superior
vena cava
C (Image courtesy: Dr Zahid Amin)
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CHAPTER
Table 1: Protocol of imaging the interatrial septum in patients with atrial septal defect
Patient population
Pediatric patient <25 kg
Establishing diagnosis of ASD
TTE
Imaging for transcatheter procedure
TEE + TTE
Postprocedure follow-up
TTE
40

Pediatric patient >25 kg TTE +/- TEE TEE +/– 3D TEE TTE
Adult patient TTE +/- TEE TEE +/– 3D TEE TTE
Abbreviations: ASD, atrial septal defect; TTE, transthoracic echocardiography; TEE, transesophageal echocardiography
erosion. Multi-fenestrated ASDs and malaligned ASDs CONCLUSION

are a difficult substrate and may require 3D-TEE or ICE to
a
Ideal imaging strategy is based on patient characteristics
assess suitability for the procedure. and intended application. TEE provides superior image
di
Table 1 summarizes the imaging strategy for atrial quality as compared to TTE but is not mandatory. 3D
septal defect. imaging provides unique views of the IAS and allows
In
Role of echo during device closure: Apart from patient for en face viewing of the defect and the surrounding
selection and device selection, echocardiography (TEE or structures for accurate determination of ASD size and
shape, to delineate the rims of surrounding tissue,
of
ICE) plays a very important role in monitoring the device
deployment and release. In our experience, it is essential and to determine the relationship of the ASD to the
to confirm that the surrounding rims are adequately surrounding cardiac structures. Echocardiography in
ty
captured in multiple views. We prefer the same basic views patients undergoing transcatheter closure is critically
viz., zero, 45 and 90° views to look at the margins being important for appropriate patient selection, real-time
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captured. When the device is still hanging by the cable,
it is not always easy to see the rims being captured by the
device on TEE. For this purpose, the TEE probe needs to
procedure guidance, assessment of device efficacy
and complications in the short and long terms.
Therefore, it remains a very integral part of the device
be moved up and down and anteflexed and retroflexed closure of ASD.
20 o
and rotated clockwise and anticlockwise to see the rims
S
precisely. Unless, one is completely convinced about the ACKNOWLEDGMENT

rims being adequately held by the discs of the device, it is
We would like to thank Dr Zahid Amin for his contribution
not a good idea to release the device.
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towards ICE images.

Prior to release, protocol must include looking at the
relationship of the discs to the AV valves, systemic and REFERENCES
ic
pulmonary veins. One needs to confirm that the discs are

1. Amin Z. Transcatheter closure of secundum atrial septal
not impinging on the mitral or tricuspid valve leaflets or
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defects. Catheter Cardiovasc Interv. 2006;68(5):778–87.

encroaching on the lumen of the systemic or pulmonary
2. Silvestry FE, Cohen MS, Armsby LB, Burkule NJ, Fleishman
veins causing partial obstruction. In such an event, the CE, Hijazi ZM, et al. Guidelines for the Echocardiographic
device needs to be downsized.
ol
Assessment of Atrial Septal Defect and Patent Foramen

After the release, it is important to look at the Ovale: From the American Society of Echocardiography
pericardium for the presence of any pericardial effusion. and Society for Cardiac Angiography and Interventions.
di
This is crucial because it may be the sign of cardiac injury J Am Soc Echocardiogr. 2015;28(8):910-58.
during device deployment or may be the early sign of 3. Mahmoud HM, Al-Ghamdi MA, Ghabashi AE, Anwar AM. A
ar
cardiac erosion. If there is a presence of neopericardial proposed maneuver to guide transseptal puncture using real-
effusion, such a patient will need a very close monitoring time three-dimensional transesophageal echocardiography:
C
for 48 hours or even longer. pilot study. Cardiol Res Pract. 2015;2015:174051.
339
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CHAPTER 41 Lutembacher’s Syndrome
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INTRODUCTION less due to left-to-right shunt; hence, these patients do not
Lutembacher’s syndrome (LS) was first described by develop orthopnea and paroxysmal nocturnal dyspnea
In
anatomist Johann Friedrich Meckel in 1750. Corvisart due to pulmonary venous hypertension (PVH). There
described the association of atrial septal defect (ASD) may be transient right-to-left shunting through the defect
when pulmonary pressures increase either transiently due
of
and mitral stenosis (MS) in 1811. However, the first
comprehensive account of these two defects was to lung condition or persistently due to development of
reported by a French physician, Rene Lutembacher, in Eisenmenger syndrome.
Moreover, the augmented pulmonary flow leads to
ty
1916 in a 61-year-old woman and attributed the mitral
valvular lesion to congenital MS. The definition of LS has development of right ventricular volume overload and
hyperkinetic pulmonary hypertension (PH) earlier than
18 cie
undergone several changes and adaptations including any
combination of ASD (congenital or iatrogenic) and mitral
valve disease (congenital or acquired) with the more
in patients with an isolated atrial defect. The pulmonary
arterial hypertension (PAH) is due to increased pulmonary
generally accepted definition of a congenital ASD with blood flow and not due to increased pulmonary vascular
20 o
acquired MS (commonly rheumatic).1 resistance as in isolated MS.
S
Another form described in the literature is the ‘reverse

LS’; which is a mirror image of LS in terms of a right-to- CLINICAL FEATURES
left shunt through an ASD in the presence of significant
al
In up to 40% of cases from developing countries, there

tricuspid stenosis.2
is a past history of rheumatic fever in early childhood.5
‘Iatrogenic LS’ is defined as the presence of ASD with
ic
Symptoms are explained easily by the hemodynamics of

MS, where ASD is the result from atrial septal puncture
the disease process.
done during balloon mitral valvuloplasty (BMV).
og
Decreased cardiac output due to MS, and right-to-

left shunting leads to symptoms of easy fatigability and
EPIDEMIOLOGY exercise intolerance. The left-to-right shunt also causes
ol
In a case series by Bashi et al. in 1987, a history of acute atrial dilatation leading to atrial arrhythmias and these
rheumatic fever was found in nearly 40% of patients with patients complain of palpitations as the presenting
di
LS in areas with high endemicity for rheumatic fever. 1 symptoms. Due to chronic volume overloading of the
In patients with ASD living in areas with high incidence right ventricle (RV), patients develop symptoms late in the
ar
of rheumatic fever, 4% patients had associated MS.2-4 course of the disease unless there is development of PAH
The LS is common among young adults and a female or RV failure due to development of atrial arrhythmias.
C
preponderance has also been noted. Patients may present with syncope and peripheral edema
due to advanced right heart failure. Right-to-left shunting
Hemodynamics of Lutembacher’s Syndrome through the defect may present as paradoxical embolism
The LS is characterized by the presence of ASD along and may cause stroke or peripheral artery embolization.5
with MS. Both ASD and MS affect the hemodynamic and Unlike isolated MS, paroxysmal nocturnal dyspnea (PND)
clinical features of each other and the clinical features and orthopnea are usually not seen in these patients.
result from a balance of ASD and MS. Generally, nonrestrictive ASD in LS later cause
In LS, the presence of MS increases the resistance progressive PH and development of Eisenmenger
to blood flow from left atrium (LA) to left ventricle (LV); syndrome.
hence, blood preferentially gets shunted via ASD leading However, in cases of predominant MS and restrictive
to decreased flow to the LV and decreased cardiac output. ASD, patients present much earlier with symptoms of PVH
As LA gets decompressed via ASD, this will lead to of important MS, such as orthopnea, PND, hemoptysis,
decreased transmitral gradients. The LA pressure will be and pulmonary edema, much earlier.4
KG-41.indd 340 02-11-2018 16:56:35

Physical Examination Assessment of Mitral Stenosis CHAPTER
41
Arterial pulses: These are generally of small volume with Both anatomy of MV apparatus and severity can be
regular rhythm in the earlier stage of the disease. Later assessed by echocardiography. The 2D echocardiography
with atrial disease and development of atrial arrhythmias, assesses MV morphology, leaflet thickening, calcification,
the pulse becomes irregular.6 and subvalvular apparatus. Severity of MS is assessed by
Jugular venous pulse (JVP): In nonrestrictive ASD, both using planimetry, diastolic pressure gradient, pressure
atria function as a single chamber; hence, height and half-time (PHT), and continuity equation. Because the
contour of LA pressure is transmitted to RA. Thus, patients flow across MV is decreased, estimation of gradients as
may have prominent ‘a’ wave in the JVP.3 well as mitral valve area (MVA) by PHT is not accurate.
Planimetry is the best method to estimate MVA in LS
Precordium: Increased RV volume overload leads to a
a
(Figure 1).
left parasternal lift due to transmitted RV and pulmonary The MVA is measured by carefully tracing the opening
di
impulses. The LV impulse may be diminutive due to of mitral orifice at leaflet tips in mid-diastole in parasternal
reduced LV filling and due to the same reason, diastolic short axis view. Planimetry has advantage of directly
In
thrill is not palpable.7
measuring MVA being independent of flow, compliance
Auscultation (heart sounds): The first heart sound may of cardiac chambers, and associated valvular lesion. It
be loud due to MS, and the second heart sound is has limitation of need of experienced echocardiographer,
of
accentuated in the presence of PAH. The second heart measurement has to be on leaflet tip; otherwise, it will
sound is often widely split due to early closure of the aortic overestimate MVA and is difficult in cases of poor acoustic
ty
valve (diminished cardiac output) and late closure of the window. Transeosophageal echocardiography (TEE) is
pulmonary valve (increased RV outflow). Increased flow at useful in case of poor acoustic window on transthoracic
the RV outflow leads to a flow murmur at the pulmonary
18 cie
valve and mid-diastolic murmur at the tricuspid valve.
Mid-diastolic rumble of MS is heard only if there is a
echocardiography (TTE), for detection of associated
lesions like left atrial thrombosis.10-14
In a study conducted by Savitri et al. Doppler
significant gradient at the mitral valve (MV) usually in echocardiographic estimation of MVA was compared
20 o
the presence of a restrictive ASD. Severe PAH can lead with cardiac catheterization-derived MVA using Gorlin
S
to auscultation of holosystolic murmur of tricuspid formula in LS patients.15 It found good correlation between
regurgitation (TR). Severe MS with a restrictive ASD may catheterization-derived MVA with MVA derived from
cause a continuous murmur.4 planimetry and by continuity equation. However, PHT
al
consistently overestimated MVA.15

INVESTIGATIONS
ic
Chest radiography is often very helpful in determining the Assessment of Atrial Septal Defect
og
relative significance of the two conditions. The presence of

PVH and dilated LA suggests hemodynamically significant The 2D echocardiography is the preferred diagnostic tool
MS or restrictive ASD; while the presence of dilated to assess ASD. The ASD is directly visualized as drop out
ol
pulmonary arteries in the absence of PVH would suggest in interatrial septum and color flow across it. It is best
a large ASD. seen from subcostal coronal and sagittal view on TTE and
di
ECG abnormalities in patients with LS range from TEE in case of poor acoustic views. The direction of flow is
rhythm to P-wave and QRS morphology changes and
ar
finally axial abnormalities. For P-wave morphology, a

tall, broad and/or bifid wave form may be seen in lead II
C
and a deep negative force in lead V1 suggesting bi-atrial

enlargement. Isolated left atrial enlargement (LAE) is
suggested in significant MS patients. In PAH, features of RV
hypertrophy may be seen.5-8
Echocardiography is the gold standard technique to
diagnose LS. It has advantage of being noninvasive, easily
available, accurate in diagnosing structural lesion (ASD
and MS), and hemodynamics. The 2D echocardiography
helps to assess interatrial septum, MV, chamber
enlargement, and pulmonary artery enlargement. Color
flow and Doppler imaging helps diagnosing severity of
ASD, MV stenosis and regurgitation as well as TR and
pulmonary pressure changes. Figure 1: Mitral valve area by planimetry
341
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SECTION Box 1: Typical Hemodynamics of Lutembacher syndrome
6 Chamber
Superior Vena Cava

O2 Saturation
52
Pressure
—
Right atrium 90 a13 v11 (12)
Right ventricle 91 85/10
Pulmonary artery 91.7 85/25 (50)
Left atrium 99 a12 v14 (12)
Left ventricle 99 125/8
a
Femoral artery 98 125/80 (95)
di
In
Note the significant step up in saturation in RA level. The pressures are same in RA and LA, suggesting an unrestricted ASD. There is severe PAH.
of
The gradient between LVEDP and ‘a’ wave of LA trace (as can be seen from the trace above) is not as high as usually seen in isolated severe MS.
This is due to the fact that the blood is diverted through the ASD into RA.
ty
left to right due to increased LA pressure in the presence Cardiac Catheterization
18 cie
of MS. There will be no gradient across ASD in case of
unrestrictive defect. The presence of gradient in case
of restrictive ASD helps to assess LA pressure in LS. It is
Being invasive and associated risk in case of low cardiac
output situation in LS, cardiac catheterization is not
routinely recommended. But it may prove useful in cases
20 o
important to carefully assess the size of defect, PH, and the of nonconclusive echocardiographic examination as well
presence of rims of ASD to plan for percutaneous/surgical as in patients with severe PH.9 It is also useful to diagnose
S
intervention. associated coronary artery disease in high-risk cases. The

typical hemodynamic findings of Lutembacher syndrome
al
Assessment of Pulmonary are summarized in Box 1.

Artery Hypertension
ic
In the presence of associated TR, modified Bernoulli CT Angiography and Cardiac MRI
equation is used to get TR velocity; to this, RA pressure
og
The CT angiography and cardiac MRI can also be done

is added to predict RV systolic pressure and indirectly in case of LS and have advantage of being noninvasive;
systolic PA pressure (in case of no pulmonary flow however, they have limitation of being costly, need for
obstruction). Similarly, mean PA pressure can be predicted
ol
technical expertise, and not widely available.

by measuring peak PR gradient and PA diastolic pressure
is predicted by the sum of PR end-diastolic gradient and
di
Management of Lutembacher’s Syndrome

RV end-diastolic pressure.
Management of LS depends upon:
ar
Qp/Qs >1.5
Role of Echocardiography to Assess Suitability Severity of MS
for Percutaneous Intervention vs. Surgical
C
Severity and reversibility of PH.
Management Medical therapy consists of treatment of right heart

Echocardiography plays an important role in deciding failure with diuretics such as furosemide, sub acute
management of LS. The MV should be assessed for bacterial endocarditis prophylaxis, and treatment of
suitability for BMV and ASD for suitability for device arrhythmia. Atrial fibrillation is the most common rhythm
closure. In case of MV for BMV, there should be no disorder and is treated with beta blockers, calcium-
commisural calcification, no significant MR, and no LA channel blockers and cardiac glycoside for rate control
appendage clot. For device closure, ASD should be ostium and amiodarone for maintaining sinus rhythm.
secundum type with adequate rims. The ASD >38 mm is Early diagnosis and treatment is the key for better
usually not suitable for device closure. If LS is not suitable outcome. Surgical correction should be considered early
for percutaneous intervention, surgical management because chances of heart failure and arrhythmia increase
should be considered. with age. Surgical correction before development of PH
342
KG-41.indd 342 02-11-2018 16:56:36

and heart failure prolongs survival. Patients diagnosed 7. Arora R, Patted S, Halkati P, et al. Definitive treatment of CHAPTER
after development of PH and heart failure have bad lutembacher syndrome. J Sci Soc. 2014;41(3):215-9.
prognosis.16
At present, percutaneous intervention for LS consisting
8. Ledesma M, Martinez P, Cázares MA, et al. Transcatheter
treatment of Lutembacher syndrome: combined balloon 41
mitral valvuloplasty and percutaneous atrial septal defect
of BMV followed by ASD closure using atrial septal closure. J Invasive Cardiol. 2004;16(11):678-9.
occluder is the norm in patients with morphology 9. Vahanian A, Baumgartner H, Bax J, et al. Guidelines on the
suitable for both procedures. Surgical correction should management of valvular heart disease: The Task Force on
be considered for cases not suitable for percutaneous the Management of Valvular Heart Disease of the European
Society of Cardiology. Eur Heart J. 2007;28(2):230-68.
correction. It consists of MV replacement along with ASD
10. Baumgartner H, Hung J, Bermejo J, et al. Echocardiographic
closure. It should also be considered in patients with
assessment of valve stenosis: EAE/ASE recommendations
financial limitations. Moreover, in patients with persistent
a
for clinical practice. J Am Soc Echocardiogr. 2009;22:1-23;
AF, concomiant Cox-maze procedure may help ameliorate quiz 101-2.
di
symptoms.17 11. Nishimura RA , Rihal CS, Tajik AJ, et al. Accurate
measurement of the transmitral gradient in patient with
In
mitral stenosis: a simultaneous catheterization and
REFERENCES
Doppler echocardiographic study. J Am Coll Cardiol.
1. Bashi VV, Ravikumar E, Jairaj PS, et al. Coexistent mitral 1994;24:152-8.
of
valve disease with left-to-right shunt at the atrial level: 12. Rahimtoola SH, Durairaj A, Mehra A, et al. Current
clinical profile, hemodynamics, and surgical considerations evaluation and management of patients with mitral
in 67 consecutive patients. Am Heart J. 1987;114(6):1406- stenosis. Circulation. 2002;106(10):1183-8.
ty
14. 13. Thomas JD, Weyman AE. Doppler mitral pressure halftime:
2. Patil CV, Vijaykumar M, Pande AV, et al. Familial a clinical tool in search of theoretical justification. J Am Coll
Heart J. 1997;49(4):415-7. 18 cie

Lutembacher’s syndrome in mother and daughter. Indian
3. Perloff JK, Marelli AJ, editors. The Clinical recognition of

Cardiol. 1987;10(4):923-9.
14. Messika-Zeitoun D, Meizels A , Cachier A , et al.
Echocardiographic evaluation of the mitral valve area
Congenital Heart Disease. 6th edition. Philadelphia: WB before and after percutaneous mitral commissurotomy: the
20 o
Saunders; 1994. pp. 323-8. pressure half-time method revisited. J Am Soc Echocardiogr.
4. Ross J Jr, Braunwald E, Mason DT, et al. Interatrial 2005;18(12):1409-14.
S
communication and left atrial hypertension: a cause of 15. Vasan RS, Shrivastava S, Kumar MV. Value and limitation
continuous murmur. Circulation. 1963;28:853-60. of Doppler echocardiographic determination of mitral
al
5. Garcia JA, Krajcer Z, Pechacek LW, et al. Echocardiography valve area in Lutembacher syndrome. J Am Coll Cardiol.
in the diagnosis of Lutembacher syndrome. Cathet 1992;20(6):1362-70.
ic
Cardiovasc Diagn. 1978;4(3):283-8. 16. Levin AR, Spach MS, Boineau JP, et al. Atrial pressure-
6. Aminde LN, Dzudie AT, Takah NF, et al. Occurrence of flow dynamics and atrial septal defects (secundum
og
Lutembacher syndrome in a rural regional hospital: case type). Circulation. 1968;37(4):476-88.

report from Buea, Cameroon. Cardiovasc Diagn Ther. 17. Sandoval N, Velasco VM, Orjuela H, et al. Am J Cardiol.
2014;4(3):263-6. 1996;77(8):591-6.
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Which Device for which Patent
CHAPTER 42 Ductus Arteriosus?
IB Vijayalakshmi
a
di
INTRODUCTION
Patent ductus arteriosus (PDA) is seen in approximately
In
1 in 2000 of term live births accounting for 10! 15% of
congenital heart diseases.1 Percutaneous device closure is
of
widely considered as the treatment of choice for patients
with PDA.2,3 The evolution of transcatheter PDA closure
from just 40 years ago, with 18 F sheaths to device delivery
ty
via a 4 F sheath is a remarkable journey. The nonsurgical
transcatheter device closure has revolutionized the
18 cie
management of PDA and has become a safe, effective, and
very attractive alternative to surgery in most of the centers
with almost 100% success rate in most of the patients.
A number of types of devices with different delivery
20 o
techniques have been used. It is anticipated that further
S
improvements will result in better safety and efficacy of Figure 1: Diagrammatic and angiographic pictures of various types
transcatheter device closure techniques of PDA. Despite of patent ductus arteriosus and the likely devices to be chosen
tremendous progress, to this date, no consensus opinion
al
exists with regard to what type of device is most efficacious B, when PDA is short and window type Type C, when it is
and ideal in which cases. This dilemma is due to the varied long and tubular, Type D is with multiple narrow segments
ic
morphology of the PDA, perhaps there is no single device is complex, and in Type E the ampulla of PDA is elongated.
of choice is there for closure. Hence, the question most The diagrammatic and angiographic pictures of all the
og
often asked is ! Which device for which PDA?’ five types of PDA with choice of device are shown in
Figure 1. The operator should understand the anatomy,
ol
SELECTION OF VARIOUS DEVICES morphology, type of PDA by both detailed echocardiogram

in ductal view and descending aortogram in left lateral and
The selection of either Amplatzer duct occluder I (ADO I),
di
right anterior oblique (RAO) projections. Measure the

or Amplatzer duct occluder II (ADO II) or Amplatzer duct
narrow end of the duct and ampulla accurately. If duct
occluder II additional size (ADO II AS), or Amplatzer
ar
vascular plugs (AVP) or Amplatzer ventricular septal is not visualized well in left lateral projection repeat the
occluder (AVSD O) or Amplatzer atrial septal occluder angiogram in RAO projection. If still not visualized, then
one should do the balloon sizing to assess the accurate
C
(AASDO) will depend on multiple factors. In some

situations, one or more devices could be suitable. One has size of PDA.
to choose a device which the operator is familiar with and
is available in cath lab at that time.
WHEN IS EACH DEVICE USED?
Arterial or Venous Delivery The Amplatzer duct occluder family, (ADO I and ADO
II), are the only devices currently available in the USA
The ADO II, ADO II AS, and AVP can be delivered from
that have undergone specific testing and have an ! on-
either arterial or venous access, but ADO I has to be
label! indication for PDA closure. However, in India, the
delivered from venous end only.
interventionalists have been using an array of devices
and vascular plugs under the umbrella of ! off-label!
MORPHOLOGIC CLASSIFICATION OF PDA use due to heterogeneous PDA morphology and small
According to Krichenko! s classification, 4 there are five sized, symptomatic babies in whom approved devices
types of PDA simply known as Type A when conical, Type cannot be used safely. Patients less than 5 kg and those
KG-42.indd 344 02-11-2018 16:56:26

with unfavorable PDA morphology still pose significant pulmonary artery pressure. The ADO II with retention disc CHAPTER
challenges in PDA closure.4-7 on either side is best suited for both arterial and venous
The selection of either ADO, ADO II or ADO II AS,
AVP will depend on multiple factors like: (1) type of the
delivery (Figures 3A and B). The ADO II and ADO II AS
and AVP can be delivered from either arterial or venous
42

duct, (2) size of the duct, (3) size of the ampulla, (4) shape access, but ADO is delivered from venous end only. The
of the duct, (5) length the of the duct, (6) distendability, advantage of the ADO II is that it has a very low profile, and
(7) pulmonary artery hypertension (PAH), (8) size of the can be easily delivered through 4 or 5 F sheath in infants.7
aorta, (9) abnormal origin of duct (e g. vertical duct), and
last but not least (10) infants with low weight. Anatomic Length of PDA
Assessment of anatomic length of PDA is crucial in
Amplatzer Duct Occluder I
a
choosing the device. The length of the duct includes the
The amplatzer duct occluder I (ADO I) was the first device ampulla. ADO-II ! elongates! upon separating the two
di
that was specifically designed for transcatheter closure of discs further apart. Duct ampulla closing length becomes
PDA and also the first device that was approved by Food ! shorter! if the aortic disc is pulled into the ampulla. The
In
and Drug Administration (FDA). The ADO I device is a superelasticity of the device tends to shorten the length
wire mesh made up of nickel and titanium alloy (nitinol) of PDA, more so on the pulmonary side due to the greater
that is filled with three layers of polyester fabric to enhance pliability of the pulmonary artery (PA) (Figures 4A and B).
of
thrombogenicity (Figure 2).
The ADO device comes with a delivery sheath with Device Closure in Infants <6 kg
controlled release mechanism, used for closure with
ty
The ADO II is ideal for long tubular PDA in infants with
PDA diameter of 2! 14 mm as available sizes are 6/4 to
PAH as it has retention skirt on either side. Successful
16/14 mm. Contraindications for use of ADO devices are
18 cie
patients less than 6 kg and younger than six months of age.
However, this weight bar has been crossed safely in many
device placement was achieved in 60/61 infants (98.4%).
Mild aortic obstruction occurred in 2 cases (3.3%), as the
ADO device got displaced towards the aorta after release.
centers.7
The device embolized in 2 cases (3.3%).7 Device closure of
20 o
large PDA in infants weighing ≤6 kg with left ventricular
Amplatzer Duct Occluder II
S
failure is challenging but possible, safe and effective, as

The amplatzer duct occluder II (ADO II) is the first device for example can be seen in a 9-day-old neonate (Figures
especially designed for long ducts in infants. It is a self- 5A to C). The ADO II is not an answer for all PDAs in
al
expanding device, composed of finer nitinol wire mesh infants, especially when ampulla is shallow and aorta is
with no polyester fabric inside, but with two retention very small, the aortic disc may bulge in aorta.
ic
skirts (at both aortic and pulmonary ends) that articulate

og
with a central plug, which is sized to the diameter of the Amplatzer Duct Occluder II Additional Size
midpoint of the PDA. The ADO II is ideal for long tubular
The amplatzer duct occluder II additional size (ADO II AS)
PDA in infants with PAH as it has retention skirt on either
is a self-expanding nitinol mesh occlusion device with a
ol
side. One should be very careful while closing the tubular

central plug and retention discs at each end. To minimize
duct with narrow or no ampulla with near systemic
interference with contiguous structures, the discs are only
di
1 mm larger in diameter than the plug and articulate up

to about 30°. The device is fully recapturable and passes
ar
easily through a 4 F delivery catheter and can be delivered

either by the aortic or venous route. New ADO II AS comes
C
pre-attached to a delivery cable. The delivery cable! s distal

tip is extremely flexible and has angiographically visible
properties, which help precise placement of the proximal
disc during device placement and unscrewing procedure.
The ADO II AS may represent a more suitable choice
than ADO II in the smaller infants, where the procedure
carries a non-negligible risk of device protrusion in either
aorta or left pulmonary artery (LPA) (Figures 6A to D).
However, care is required in sizing the device to ensure
it is adequately secured in place within the ductus to
prevent embolization which is reported more often with
ADO II AS. Devices with 3, 4, and 5 mm plug diameters
Figure 2: Amplatzer duct occluder with three layers of polyester
sewn inside
and 2, 4, and 6 mm plug lengths are available. Careful
345
KG-42.indd 345 02-11-2018 16:56:27

SECTION
6
a
A B
di
Figures 3A and B: (A) Picture of Amplatzer duct occluder (ADO II) with retention discs on either side and central lobe attached to
introducing cable; (B) Diagrammatic representation of ADO II deployed from pulmonary (antegrade) end and from aortic end (retrograde)
In
of
ty
18 cie
20 o S
A B
al
Figures 4A and B: (A) Diagrammatic picture of Type B long tubular patent ductus arteriosus (PDA); (B) Schematic representation of length
of PDA and Amplatzer duct occluder (ADO II) device in situ shortening the length of PDA
ic
og
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di
ar
C
A B C
Figures 5A to C: (A) Hand injection of diluted dye injected in descending aorta in right anterior oblique projection shows Type A patent
ductus arteriosus (PDA) with roomy ampulla in a 9-day-old neonate with left ventricular failure; (B) After crossing PDA with Terumo guide
wire, Cobra catheter is pushed into main pulmonary artery (MPA) hand injection of dye is given to confirm the catheter is in MPA after
recording the PA pressure and checking the blood sample for SO2; (C) Hand injection of diluted dye in aorta shows 3 × 4 Amplatzer duct
occluder II (ADO II) device in situ and no obstruction of aorta in a 9-day-old neonate
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CHAPTER
42

A B C D
Figures 6A to D: (A) Descending aortic angiogram done in right anterior oblique projection illustrates long tubular patent ductus arteriosus
(PDA) with hardly any ampulla in 4 months old infant; (B) PDA is crossed with J tipped Terumo guide wire over which 4F catheter is introduced;
a
(C) Amplatzer duct occluder II additional size (ADO II AS) device is deployed and check angiogram done with hand injection from the side
port of Y connector; (D) Fluoroscopy in left lateral projection shows the ADO II AS device in situ in 4 months old infant weighing 3.5 kg
di
In
ductal diameter sizing and obtaining good images have (e.g. ADO and ADO II, VSD devices), the interventionists
paramount importance in small infants with relative large have been using AVPs I, II and IV,8-11 microvascular plugs12
ducts. for closing PDA.
of
The diagrammatic representation of AVP III is shown
AMPLATZER VASCULAR PLUGS in Figure 9A. The AVP IV has a multilayered, double-lobed
Delaney et al. case series, documented the first limited design which provides rapid embolization (Figure 9B).
ty
use of the Amplatzer vascular plug II (AVP II) for PDA.8 The AVP II was highly effective for closing PDAs in smaller
Individual case reports show that AVP II device is a babies with varying morphologies and is safe when
18 cie
valuable addition to the transcatheter armamentarium
for closing tubular PDAs and those in very small, often
premature infants.
used in small-sized patients with relatively low risk of
complications. 5 The absence of disc makes the AVP II
attractive for small-sized patients with short PDAs when
The AVPs are made up of finely braided nitinol wire
20 o
there is a higher risk of device protrusion in the LPA or the
mesh which provides a high radial force to secure the aorta (Figures 10A to C).13
S
device within the vessel (Figures 7A and B). There is

no Dacron mesh sewn in the AVP, which decreases the
WHICH DEVICE IN PDA WITH PAH?
al
sheath size required for delivery. The AVP II is uniform in

diameter, with three lobes (Figures 8A to C). In order to In cases of large PDA with severe pulmonary artery
ic
reduce the risks of device embolization (as in cases of ADO hypertension (PAH) device closure with very large duct
II AS), left pulmonary artery (LPA) stenosis and coarctation occluder (custom-made Lifetech occluder up to 28 × 26) or
og
of the aorta (CoA) seen with the use of approved devices muscular ventricular septal defect occluder (mVSDO) (up
ol
di
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C
A B
Figures 7A and B: (A) Amplatzer vascular plug (AVP); (B) Diagramatic picture of AVP
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KG-42.indd 347 02-11-2018 16:56:29

SECTION
6
A B C
a
Figures 8A to C: (A) Type D-complex patent ductus arteriosus (PDA); (B) Amplatzer vascular plug II (AVP II);
di
(C) Diagramatic picture of AVP II
In
of
ty
A
18 cie B
20 o
Figures 9A and B: Amplatzer vascular plug III (AVP III) and AVP IV
S
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ic
og
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di
A B C
ar
Figures 10A to C: (A) Descending aortic angiogram in left lateral projection shows long tubular narrow patent ductus arteriosus (PDA)
with no ampulla; (B) Amplatzer vascular plug (AVP) deployed in PDA; (C) Check angio shows AVP II in situ13
C
to 24 mm) is feasible and safe in most older children and sides can also be unsuitable. For example, in a 7-year-old
young adults (Figures 11A and B). At times, retrieval of male with large PDA on angiogram was closed with 16 mm
embolized large device is very difficult and rarely surgical mVSDO developed obstruction of LPA (Figure 13).
retrieval is needed (Figures 12A and B). In neonates and Whenever VSD septal occluder is used, we must do the
infants with PDA with PAH, the low profile ADO II is a pulmonary artery angiogram to check LPA stenosis and
better device.14 take the pullback gradients in LPA. Avoid using VSD device
in small children as LPA stenosis can cause hypoperfusion
in left lung.
FEASIBILITY TEST FOR DEVICE CLOSURE
Device closure for large PDA with severe PAH (>45
In large PDA with PAH, we have to be very cautious, mm Hg) is challenging and utmost care has to be taken
sometimes VSD occluders with retention disc on both the as incidence of device embolization is high and using
348
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CHAPTER
42

a
A B
di
Figures 11A and B: (A) Diagrammatic and angiographic illustration of large window type patent ductus arteriosus; (B) Fluoroscopy shows
22 mm muscular ventricular septal defect occluder in situ
In
of
ty
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20 o S
al
A B
Figures 12A and B: (A) Large patent ductus arteriosus (PDA) closed with 22 mm muscular ventricular septal defect occluder as pulmonary
ic
artery pressure (PAP) dropped from 88/61-70 to 68/30-43 mm Hg; (B) Device embolized to PA after one hour. And retrieval was difficult, as
snare could not catch the huge device. Hence, surgical extraction of device and PDA closure (Bhatis technique) was done
og
very large devices, cause either aortic or left pulmonary

ol
artery obstruction. Both selection of patient, type, and

size of the device is extremely important and crucial.
di
Otherwise, PDA with PAH will be converted into what

appears like postpartum hemorrhage (PPH) after device
ar
closure, which is worse. But older children, adolescents,

and adults are likely to have irreversible PAH. Hence,
hemodynamic changes are slow, reduction in diastolic
C
and mean pressure occurs. The systolic pressure takes

longer time to come down. Table 1 shows various devices
used to occlude PDA.15
CONCLUSION
A large number of devices have been designed and tested;
Figure 13: Angiogram in main pulmonary artery shows obstruction however, only a few devices like Amplatzer duct occluder
of left pulmonary artery after 16 mm muscular ventricular septal
defect occluder was deployed in a 7-year-old boy
are approved by FDA for general clinical use. Several other
devices are undergoing clinical trials and are available
349
KG-42.indd 349 02-11-2018 16:56:30

SECTION Table 1: Various devices used to occlude PDA15
6
Year of first report Name of the device
1998 Amplatzer duct occluder
1999 Folding plug buttoned device
2001 Wireless PDA devices

2001 Reinforced duct-occlude pfm
2001 Angulated nitinol plug—Amplatzer
2002 Swivel disc and plug occluders—Amplatzer
2005 Amplatzer vascular plug
2005 Nit-occlud coils
a
2005 Inoue single-branched stent graft
di
2008 Amplatzer duct occluder II (ADO II)
2008 Non-ferromagnetic Inconel MReye embolization coils
In
2008 Amplatzer vascular plug with prefilled embolization coils
2009 Self-expanding platinum-coated nitinol device
of
2009 Chinese self-expandable occluder, similar to the Amplatzer occluder
2009 Amplatzer vascular plug II
2009 Valved stent
ty
2010 Cardio-o-fix occluder
2011 Nit-occlud PDA-R (reverse) device
2011 18 cie
Amplatzer duct occluder II additional sizes (ADO II AS)
only at institutions that participate in clinical trials. At 7. Vijayalakshmi IB, Chitra N, Praveen J, et al. Challenges in
20 o
the present time ADO appears to be the most commonly device closure of a large patent ductus arteriosus in infants
S
used device worldwide in the closure of moderate-to-large weighing less than 6 kg. J Interv Cardiol. 2013;26(1):69-76.
PDAs. The PDAs with high pulmonary artery pressure may 8. Delaney JW, Fletcher SE. Patent ductus arteriosus closure
using the Amplatzer vascular plug II for all anatomic
al
require special devices such as muscular VSD occluder,

variants. Catheter Cardiovasc Interv. 2013;81(5):820-4.
in older patients and ADO II in infants. The other modified
9. Baruteau, AE, Lambert, V, Riou, JY, et al. Closure of tubular
ic
devices are effectively and safely used in anatomically rare

patent ductus arteriosus with the Amplatzer Vascular Plug
and difficult cases.
IV: feasibility and safety. World J Pediatr Congenit Heart
og
Surg. 2015;6(1):39-45.
REFERENCES 10. Garay, FJ, Aguirre, D, Cardenas, L, et al. Use of the
1. Schneider DJ, Moore JW. Patent ductus arteriosus. Amplatzer vascular plug II device to occlude different types
ol
Circulation. 2006;114:1873-82. of patent ductus arteriosus in pediatric patients. J Interv

2. Feltes TF, Bacha E, Beekman RH 3rd, et al. Indications Cardiol. 2015;28(2):198-204.
di
for cardiac catheterization and intervention in pediatric 11. Hoyer, MH. Novel use of the Amplatzer plug for closure
cardiac disease: A scientific statement from the American of a patent ductus arteriosus. Catheter Cardiovasc Interv
ar
Heart Association. Circulation. 2011;123:2607-52. 2005;65(4):577-80.

3. Bilkis AA, Alwi M, Hasri S, et al. The Amplatzer duct 12. Sathanandam, S, Justino, H, Waller, et al. Initial clinical
occluder: Experience in 209 patients. J Am Coll Cardiol. experience with the Medtronic Micro Vascular Plug
C
2001;37:258-61. TM in transcatheter occlusion of PDAs in extremely

4. Krichenko A, Benson LN, Burrows P, et a. Angiographic premature infants. Catheter Cardiovasc Interv. 2017;89(6):
classification of the isolated, persistently patent ductus 1051-8.
arteriosus and implications for percutaneous catheter 13. Choi EY, Jang SI, Kim SJ. Use of an Amplatzer Vascular
occlusion. Am J Cardiol. 1989;63(12):877-80. Plug to occlude a tubular type of patent ductus arteriosus.
5. Backes CH, Cheatham SL, Deyo GM, et al. Percutaneous Korean J Pediatr. 2009;52:1035-7.
patent ductus arteriosus closure in very preterm infants: 14. Vijayalakshmi IB, Setty N, Narasimhan C, et al. Percutaneous
Feasibility and complications. J Am Heart Assoc. 2016;5(2). device closure of patent ductus arteriosus with pulmonary
pii: e002923. artery hypertension: long-term results. J Interv Cardiol.
6. Narin N, Pamukcu O, Baykan A, et al. Percutaneous PDA 2014;27(6):563-9.
closure in extremely low birth weight babies. J Interv 15. Yarrabolu TR, Rao PS. Transcatheter closure of patent
Cardiol. 2016;29(6):654! 60. ductus arteriosus. Pediat Therapeut. 2012:S5:005.
350
KG-42.indd 350 02-11-2018 16:56:30

Aneurysms of the Sinuses
CHAPTER 43 of Valsalva
Kewal C Goswami, Sivasubramanian Ramakrishnan, Siddharthan Deepti
a
di
INTRODUCTION Overall, congenital ASOVs account for about 3.5% of
Aneurysms of the sinuses of Valsalva (ASOVs) are surgical cases of congenital heart disease.3 The reported
In
uncommon cardiac anomalies characterized by thin prevalence is higher is Asian population.4
walled saccular or tubular outpouchings from aortic
sinuses, usually involving a single sinus. The congenital PATHOLOGICAL ANATOMY AND ETIOLOGY
of
form results from failure of fusion of the elastic layer of the The three sinuses of Valsalva are specialized segments of
aortic media with the annulus fibrosus of the aortic valve. aorta, each of which is a focal expansion bound medially by
Acquired ASOVs may result from infectious, traumatic, its respective aortic valve leaflet and laterally by the origin
ty
autoimmune or atherosclerotic causes. ASOVs are often of aorta (the sinotubular ridge). The sinuses are named
silent and remain undetected for decades. Most of the as left, right and posterior according to the valve cusps to
18 cie
ASOVs come to light because of rupture. A spectrum of
clinical manifestations may result from rupture ranging
which they are related (Figure 1). Alternatively, the same
are called left, right and non-coronary cusps respectively
from an acute large rupture with catastrophic consequences according to the origins of left and right coronary arteries
20 o
including sudden death to minimal symptoms due to the above them. The sinuses provide space behind the valve
gradual progression of a small perforation. The following
S
leaflets, prevent the occlusion of the coronary ostia during

chapter will discuss the epidemiology, pathoanatomy,
ventricular systole and reduce damage to the valve leaflets
etiology, clinical presentation and management of ASOVs.
as a result of striking the aortic root wall.
al
EPIDEMIOLOGY Types of ASOV based on Etiology

ic
The prevalence is difficult to compute accurately as the The congenital form of ASOV results from failure of
og
disease is often latent and may lead to sudden death insertion of the elastic layer of the aortic media into the
after rupture. Before the advent of echocardiography, the annulus fibrosus of the aortic valve.5
prevalence was estimated to be about 0.09% in the general This is believed to result from incomplete fusion
ol
population in large autopsy study of 8,138 postmortem of the distal bulbar septum in early fetal life with a
examinations.1 In patients undergoing open heart surgical resultant deficiency of elastic lamellae in the wall of
di
procedures, the incidence is between 0.14% and 0.96%.2 the affected sinus. To begin with, there is no aneurysm
ar
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Figure 1: Normal anatomy of the sinuses of Valsalva
KG-43.indd 351 02-11-2018 16:56:16

SECTION at or soon after birth; however, there is an assumed result from rupture ranging from an acute large rupture
weakness at the junction of the media of the aortic sinus with catastrophic consequences including sudden death
6 and the annulus fibrosis. This structural deficiency
serves as a prelude for avulsion and secondary
to minimal symptoms due to the gradual progression of a
small perforation.
aneurysm formation with passage of time.

Acquired ASOVs are less common. The most common
Unruptured ASOVs
etiological causes are infectious processes including
Uncommonly large unruptured ASOVs may encroach
infective endocarditis, syphilis and tuberculosis. Other
upon nearby structures and lead to symptoms of ventricle
causes include:6
— Trauma (including cardiac surgery and percuta-
outflow tract obstruction, myocardial ischemia by
compression of the coronary arteries and arrhythmias. A
neous interventions)
a
— Autoimmune diseases (Behcet’s disease, Takayasu
large ASOV may also serve as a cul-de-sac for thrombosis
leading to systemic embolization. Sudden death
di
arteritis, etc.)
— Atherosclerosis
may happen due to complete heart block secondary
to dissection of a large, unruptured ASOV into the
In
There is diffuse dilatation of all the sinuses rather than
focal aneurysm formation in patients with conditions interventricular septum.
causing annuloaortic ectasia such as Marfan and Ehler
DIAGNOSIS
of
Danlos syndromes. These are more appropriately classified
as aortic root aneurysm since the clinical presentation and
management usually differ from that of ASOV. History
ty
Rupture of aneurysms is most frequently observed in the
Sinuses involved in Order of Frequency third and fourth decades. As discussed earlier, there is
18 cie
In the majority of cases, the aneurysm tends to involve a
single aortic sinus. In an echocardiographic series from
only a weakness or diverticulum in early life; therefore,
presentation in infancy or early childhood is rare. There
is a male preponderance with the male to female ratio
India (n = 131 cases), the proportion of aneurysms arising
ranging from 4:1.
20 o
from the right, non-coronary and left aortic sinuses were
A large, acute rupture is typically described to be
81.6%, 16.7%, and 1.5% respectively.7 This is in accordance
S
heralded by the sudden onset of severe retrosternal chest

with the surgical series reported from the West 2 and
pain or upper abdominal pain, often but not always
from Southeast Asia,8 wherein ruptured aneurysms were
following exertion. The pain is associated with acute onset
al
observed to originate most commonly from the right

dyspnea. There is gradual subsidence of pain with time,
coronary sinus (69–77%) followed by the non-coronary
though there is simultaneous worsening of congestive
ic
sinus (21–23%) with rare involvement of the left coronary

heart failure. Death usually ensues within a year of onset
sinus (1–2%). The more frequent involvement of the right
og
of symptoms unless definitive surgical or percutaneous

coronary sinus likely stems from the fact that the aortic jet
treatment is provided. Though this is the typical clinical
is directed in a rightward and posterior direction. The rare
presentation, in several cases, a history of onset with chest
involvement of the left sinus is likely due to the fact that the
ol
pain or following exertion is lacking.

left sinus does not originate from the bulbar septum.
Small, insiduous ruptures may remain undetected
Only exceptionally, there is simultaneous involvement
di
initially and come to attention subsequently because

of multiple aortic sinuses. Simultaneous involvement of
of slowly, progressive heart failure or the presence of a
two or more sinuses is often associated with a secondary
ar
murmur.
cause like syphilis, bicuspid aortic valve, Noonan syndrome
and Behcet’s disease. This is to be differentiated from the
Physical Examination
C
diffuse dilatation of all the sinuses seen in patients with

Marfan and Ehler Danlos syndromes. The arterial pulse shows all grades of an aortic runoff. The
pulse pressure depends on the acuity of rupture, becoming
CLINICAL PRESENTATION wider with a bounding pulse (a rapid rise followed by a
rapid fall with or without a bisferiens configuration) if
Ruptured ASOVs survival is permitted, as the left ventricle adapts to the
ASOVs are often latent and remain undetected for increase in volume and the left ventricular end diastolic
decades. The symptoms are most commonly heralded pressure falls.
by rupture and most of the ASOVs are diagnosed after The jugular venous pressure (JVP) is elevated in large
rupture. The outcomes and course of rupture of ASOV ruptures of ASOV. The size and acuteness of the rupture
depend on the rapidity of the process, the receiving and the degree of right heart failure determine the height
chamber, the size of the intracardiac shunt and associated and the waveform of JVP. The JVP is elevated with large a
abnormalities. A spectrum of clinical manifestations may and v waves in sudden large ruptures into right atrium or
352
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CHAPTER
43

a
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A
In
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B
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20 o S
C
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Figures 2A to C: Jugular venous pressure waveforms in ruptured ASOV according to site of rupture
ic
og
right ventricle (Figure 2A). There is selective elevation of over the lower sternum. The continuous murmur has been
the ‘v’ when the rupture into right atrium causes tricuspid described as loud, superficial, harsh with a sawing quality
regurgitation (Figure 2B). On the other hand, there is (Refer to Chapter 5 for further details). There is no peaking
ol
selective elevation of the ‘a’ wave with rupture into the around the second heart sound, unlike the continuous
right ventricular outflow tract (Figure 2C). murmur of a patent ductus arteriosus.
di
On auscultation, the first heart sound is normal and the A continuous murmur is absent in the rare case where
second heart sound splits normally with a loud pulmonary the left ventricle is the receiving chamber. Instead, an
component. A right and/or left third heart sound is heard
ar
early diastolic murmur of aortic regurgitation and a short

because of biventricular failure. midsystolic murmur from augmented aortic flow are
The hallmark of ruptured ASOV is the sudden
C
observed. The variations in the murmur according to the

appearance of a continuous murmur in a previously
site of rupture has been shown in Figure 4. The diastolic
healthy individual. The characteristics of the murmur vary
component can be made louder by increasing aortic
according to the site of rupture and the receiving chamber
systolic pressure during isometric handgrip or valsalva
(Figure 3). The continuous murmur is best heard along the
mid to lower left sternal border if the ASOV ruptures into the release.
body of the right ventricle and along the upper left sternal Occasionally, unruptured aneurysm may come to
border if the rupture is into the right ventricular outflow attention on physical examination due to presence of a
tract. Diastolic accentuation of the murmur may be present murmur generated by encroachment on nearby structures
when the right ventricle receives the rupture. This has been or due to associated anomalies. A ventricular septal defect
attributed to the compression of the ruptured ASOV by (VSD) is often associated with right sinus aneurysm and
right ventricular contraction, thereby decreasing the flow results in a holosystolic murmur. Obstruction of the right
during systole. Murmurs arising from rupture into the right ventricular out flow tract may cause a long mid-systolic
atrium are heard along the right or left sternal border, or murmur. Projection into the right atrium may lead the
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SECTION
6
a
di
In
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20 o S
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ic
og
ol
di
ar
C
Figure 3: The characteristics of the murmur according to the site of ASOV rupture and the receiving chamber
pansystolic murmur of tricuspid regurgitation. Interference Electrocardiogram

with aortic cusp coaptation may result in an isolated The rhythm is usually sinus though there might be
diastolic murmur of aortic regurgitation. Lastly, a to-and-fro prolongation of the PR interval. The presence of bundle
murmur may be heard in an unruptured ASOV secondary branch block, bifascicular block or frank complete
to flow of blood in and out of the aneurysmal pouch. heart block should alert the physician to the possible
354
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CHAPTER
43

a
di
In
Figure 4: Chest radiograph in a patient with large ruptured ASOV Figure 5: Parasternal short-axis view at level of aortic sinuses
showing cardiomegaly and pulmonary venous hypertension showing aneurysm (A) of right coronary sinus (R) of Valsalva
rupturing into right ventricular (RV) outflow tract (upper arrow)
Abbreviations: RA, right atrium; LA, left atrium; N, noncoronary sinus;
of
involvement of the atrioventricular node by extension of L, left coronary sinus
the aneurysm into the interventricular septum. Even in Source: American Heart Journal
cases with biventricular enlargement secondary to rupture
ty
on the right side of the heart, the electrocardiogram
usually shows left ventricular enlargement with secondary
ST-T changes. 18 cie
Chest Radiograph
20 o
In large acute ruptures, the chest radiograph shows
S
increased cardiothoracic ratio with a left ventricular apex

and varying degrees of pulmonary venous hypertension
al
(Figure 4). If the receiving chamber is on the right side, the

pulmonary blood flow is increased with enlargement of
ic
the pulmonary trunk. Rarely, calcification in the aneurysm

may be seen.
og
Echocardiography
Figure 6: Parasternal short-axis view at level of aortic sinuses
Echocardiography with color flow imaging and Doppler
ol
showing aneurysm of noncoronary sinus (N) of Valsalva protruding

evaluation establishes the diagnosis of ASOV with or and rupturing into right atrium (RA) like a windsock
without rupture. Abbreviations: LA, left atrium; RV, right ventricle; R, right coronary
di
A true ASOV can be differentiated from a prolapse sinus; L, left coronary sinus
Source: American Heart Journal
of an aortic cusp by its location above the aortic valve
ar
annulus, while the latter projects below the level of the

annulus. Large ruptures appear as ‘‘wind-sock’’extensions abnormalities that are either intrinsic features of the ASOV
C
of the sinus that expand and contract through the cardiac or that are in addition to the aneurysm. These include the
cycle. The parasternal short-axis view at the level of the presence of a VSD (most prevalent), aortic regurgitation
aortic sinuses is the most useful view to delineate the (AR), abnormalities of aortic valve including bicuspid
anatomy of the aneurysm. This view clearly shows the aortic valve, right ventricular outflow tract obstruction,
aortic sinuses, the site of origin of the aneurysm and the aortic coarctation, anomalous coronary arteries and atrial
receiving chamber (Figures 5 and 6). The parasternal
septal defect.
long-axis view is useful in cases where the rupture is into
the left ventricle. It is also a good view to demonstrate the
Site of Rupture
extension into the interventricular septum (Figure 7).
D oppler inter rogation at the site of r upture In a large echocardiographic series, the most common site
demonstrates continuous signal (or diastolic signal in of rupture was the right ventricular outflow tract (58.2%)
case of rupture into the left ventricle). Additionally, followed by the right ventricular cavity (25.5%), the right
echocardiography shows the presence of associated atrium (9.0%), both right atrium and ventricle (1.8%) and
355
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SECTION Interventricular Septal Dissection and
Conduction Abnormalities
6 Another notable association is the presence of dissection
of r ight AS OV into the inter ventr icular septum
with conduction abnormalities. Dissection of the

interventricular septum has been described in about
7.5–11% of patients in echocardiographic7 and surgical
series. 11 The aneurysm almost always originates from
the right coronary sinus and is unruptured in more
than two-thirds of the cases. The intraseptal extension
a
is actually believed to represent intramural rupture
of the aneurysm with formation of a hematoma and
di
subsequently a pseudoaneurysm.10 The pseudoaneurysm
may increase in size gradually, ultimately rupturing into
In
Figure 7: Parasternal long-axis view showing ASOV dissecting into
interventricular septum and rupturing into left ventricular (LV’) apex
one of the cardiac chambers. The clinical presentation
(double arrow) in such cases is dominated by conduction abnormalities
Abbreviations: LA, left atrium; Ao, aorta and AR.12 It appears on echocardiogram as a cystic mass
of
Source: American Heart Journal burrowing into the membranous or the upper muscular
IVS communicating with the right sinus with a to-and-fro
ty
uncommonly the left ventricle (5.5%).9 Noncoronary sinus Doppler signal at the mouth of the aneurysm.
aneurysms rupture mainly into the right atrium (68.2%)
18 cie
or the right ventricle (27.2%).7 These observations are in
agreement with the surgical series from the Westii and
from Southeast Asia,8 wherein >90% of ruptured ASOVs
Limitations of Echocardiography
Echocardiography is highly accurate in localizing the sinus
of origin, the site of rupture, associated defects, and other
20 o
communicated with the right ventricle followed by the anatomic features and patterns of abnormal blood flow.9
right atrium. Rupture into the left ventricle was again The drawback is that small VSDs and right outflow tract
S
uncommon occurring in less than 7% of the cases and obstruction may be missed in some cases. The Doppler
occured mainly from aneurysms of the left sinus. Other signal of a small VSD may be missed in the presence of
al
rare sites of rupture include the left atrium, the pulmonary the continuous signal in the right ventricular outflow
artery and the pericardium (Figures 8A to D). tract, especially if the defect is not clearly visible on two-
ic
dimensional echocardiography due to the overlapping

Associated Ventricular Septal Defect sinus. Conversely, an unruptured ASOV with a closely
og
adjacent VSD may be misdiagnosed as a ruptured aneurysm.

The most prevalent associated structural cardiac anomaly
Mechanical compression of the right ventricular
is VSD which is often associated with an aneurysm of the
outflow tract by a bulging, ruptured ASOV makes Doppler
ol
right coronary sinus. The right coronary sinus has a direct

identification of the separate outflow tract stenotic signal
relation to the interventricular septum. Separation of the of small gradient difficult in the presence of the loud
di
ASOV from the septum results in a peri-membranous continuous signal at the same point caused by the rupture
Associated Ventricular Septal Defect (VSD). In the of the aneurysm. Transesophageal echocardiography may
ar
aforementioned echocardiographic series from India,7 help in cases with suboptimal acoustic windows and to
VSD was present in about one-third of cases, all of which differentiate isolated aneurysm rupture from perforation
C
were associated with right sinus aneurysm and had with a co-existing VSD.
ruptured into the right ventricle.
Computed Tomography
Aortic Regurgitation Contrast-enhanced computed tomography (CT) is being
AR is seen in 30–50% of cases either due to prolapse of increasingly used to complement echocardiography in
aortic cusp into the associated VSD or due to distortion delineating the anatomy of the ASOV and associated
of the aortic leaflets by the aneurysm in patients without cardiac abnormalities.11 It is useful in differentiation of
VSD. 10Morphologic abnormalities of the aortic valve ruptured ASOV from aortic dissection and aortocameral
may be present and include thickening of the cusps or fistulas. However, CT is unable to provide flow information
vegetations in cases with infective endocarditis. Aortic which limits its reliability in diagnosing small ruptures, AR
valve replacement is required in 50–80% of these cases. and VSD.
356
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CHAPTER
43

a
di
A B
In
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20 o S
C D
Figures 8A to D: RSOV of right coronary cusp draining into right atrium. Note the clear wind sock pattern (A) and turbulence (B).
al
The characteristic T sign is shown in Figure C. The relationship of displaced tricuspid valve leaflets are marked in Figure D
ic
Cardiac Catheterization and Angiography consensus. In small aneurysms, expectant management

og
Cardiac catheterization reliably identifies the receiving may be followed with a decision to intervene guided by
chamber, presence of VSD and associated AR. The biggest development of symptoms or interval increase in size on
disadvantage is obviously its invasive nature. VSD may serial noninvasive imaging. Surgical repair remains the
ol
mainstay of treatment for both ruptured and indicated

still be missed on angiography and colour Doppler
unruptured ASOVs. Percutaneous transcatheter closure
echocardiography still fares better in detecting VSD.
di
is a feasible alternative in selected patients with ruptured

Therefore, this modality is usually reserved for performing
aneurysm of the right sinus in the absence of VSD or AR.
percutaneous device closure in suitable cases.
ar
The defect should be at a site where encroachments on the

coronary ostia or aortic valve dysfunction are unlikely after
MANAGEMENT
C
device closure.
Urgent intervention, surgical or percutaneous, is Device closure of RSOV is generally done under general
imperative in ruptured aneurysms that cause hemo- anaesthesia with transesophageal echocardiographic
dynamic compromise. Small ruptures should also be (TEE) guidance. Femoral venous and artery access are
repaired in a timely fashion to prevent progression of obtained. The patient is adequately heparinised. A right
heart failure. In cases with unruptured ASOVs, the clear- heart catheterisation with oxymetry run is done. There is
cut indications for surgery include infective endocarditis, usually pulmonary venous hypertension with increased
intractable arrhythmias, coronary artery compression and pulmonary blood flow. There will be a step up in the
outflow tract obstruction. chamber of mixing and all the saturations will be higher
The optimal management strategy for unruptured beyond the chamber of mixing. Angiograms are done to
asymptomatic ASOVs however remains unclear as the profile the defect and to exclude associated VSD and/or
natural history is not well defined. Repair should be AR. RSOV draining into right atrium and right ventricle
considered in large aneurysms according to expert inflow are better profiled in left anterior oblique (LAO)
357
KG-43.indd 357 02-11-2018 16:56:21

SECTION
6
a
di
A B
In
Figures 9A and B: RSOV draining into right atrium and RV inflow gets well profiled in LAO cranial view (A) and RSOV draining into RV
outflow tract gets profiled in RAO view (B)
of
ty
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A B
ic
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di
ar
C
C D
Figures 10A to D: Device closure of an RSOV involving right coronary cusp draining into right atrium under transesophageal
echocardiographic (TEE) guidance. Note the classic windsock appearance with turbulence (A). The defect is crossed with a delivery sheath
(B). The Device is deployed under TEE guidance (C). Final deployed position of the device (D)
cranial view and RSOV draining into right ventricle outflow 2–4 mm larger than the diameter of RSOV. The defect
tract are better profiled in right anterior oblique (RAO) view is crossed from aorta and the wire is snared from the
(Figures 9A and B). Note should be made of the coronary venous side. Thus, an arterio-venous rail road is created.
artery origins and the distance from RSOV. The size of the A suitable delivery sheath is advanced from the venous
RSOV is measured angiographically and on TEE. side. The device is deployed under TEE and fluoroscopic
Various devices have been used to close RSOV, but guidance (Figures 10A to D). TEE and angiograms are
most commonly a duct occluder is preferable because of done to document residual flow, AR and impingement on
suitable shape. The size of the device is usually chosen right sided structures etc. Then the device is released.
358
KG-43.indd 358 02-11-2018 16:56:22

A few series of device closure of RSOV are reported 3. Taguchi K, Sasaki N, Matsuura Y, et al. Surgical correction CHAPTER
with good technical success and excellent mid-term of aneurysm of the sinus of Valsalva. A report of forty-five
outcomes.13 Periprocedural AR is the single most important consecutive patients including eight with total replacement
of the aortic valve. Am J Cardiol. 1969;23(2):180-91.
43
determinant of long-term outcomes. Trivial procedure-
4. Wang ZJ, Zou CW, Li DC, et al. Surgical repair of sinus of

related AR is found in 4 out of 18 patients in one series13 Valsalva aneurysm in Asian patients. Ann Thorac Surg.
and often due to slight deformity of the cusps related to the 2007;84(1):156-60.
device and sudden increase in afterload. However, almost 5. Edwards JE, Burchell HB. The pathological anatomy
half of peri-procedural AR disappears on follow up. of deficiencies between the aortic root and the heart,
including aortic sinus aneurysms. Thorax. 1957;12(2):125-
39.
CONCLUSION 6. Goldberg N, Krasnow N. Sinus of Valsalva aneurysms. Clin
a
ASOVs are uncommon cardiac anomalies. Most of the Cardiol. 1990;13(12):831-6.
di
cases are congenital in origin resulting from incomplete 7. Goswami KC, Arora P, Anandraja S, et al. Sinus of Valsalva
fusion of the aortic media to the aortic valve annulus. Aneurysm : Our experience. Indian Heart Journal.
2003;55;503-11.
In
Less frequently, ASOVs may be acquired, most often
8. Au WK, Chiu SW, Mok CK, et al. Repair of ruptured sinus
secondary to infective endocarditis. The spectrum of of Valsalva aneurysm: determinants of long-term survival.
clinical presentation ranges from the detection of a Ann Thorac Surg. 1998;66(5):1604-10.
of
silent, unruptured aneurysm on imaging for an unrelated 9. Dev V, Goswami KC, Shrivastava S, et al. Echocardiographic
condition to the catastrophic consequences of a large, diagnosis of aneurysm of the sinus of Valsalva. Am Heart J.
acute rupture. Early diagnosis is prudent in the latter 1993;126(4):930-6.
ty
10. Harkness JR, Fitton TP, Barreiro CJ, et al. A 32-year
case and is often made accurately with examination and
experience with surgical repair of sinus of Valsalva
transthoracic echocardiography. Surgical repair remains
device closure in selected cases.

18 cie
the mainstay of management with an emerging role for
aneurysms. J Card Surg. 2005;20(2):198-204.
11. Choudhary SK, Bhan A, Reddy SC, et al. Aneurysm of sinus
of Valsalva dissecting into interventricular septum. Ann
Thorac Surg. 1998;65(3):735-40.
20 o
12. Hoey ET, Gulati GS, Singh S, et al. The role of multi-modality
REFERENCES
S
imaging for sinus of Valsalva aneurysms. Int J Cardiovasc

1. Smith WA. Aneurysm of the sinus of Valsalva, with report of Imaging. 2012;28(7):1725-38.
two cases. JAMA. 1914;62(24):1878-80. 13. Kerkar PG, Lanjewar CP, Mishra N, Nyayadhish P, Mammen
al
2. Takach TJ, Reul GJ, Duncan MJ, et al. Sinus of Valsalva I. Transcatheter closure of ruptured sinus of Valsalva
aneurysm or fistula: management and outcome. Ann aneurysm using the Amplatzer duct occluder: immediate
ic
Thorac Surg. 1999;68(5):1573-7. results and mid-term follow-up. Eur Heart J 2010;31:2881-87.
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Coarctation of Aorta in Adults:
Diagnosis and Current Management
CHAPTER 44 Strategies
PV Suresh
a
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INTRODUCTION surgery is about 10% irrespective of the type of surgical
Coarctation of aorta (CoA) is a relatively common repair.8 It is also encountered, to a lesser extent, following
In
congenital heart defect and is present in approximately balloon angioplasty. 9 Primarily, it is seen in children
1 in 2900 live births. 1-5 While majority of cases are and adolescents due to inadequate aortic wall growth at
the site of repair, as balloon angioplasty or surgery was
of
diagnosed in childhood, it is not uncommon for a patient
performed before the aorta has reached the adult size.
with coarctation of aorta to present for the first time in
adulthood. This is partly because of hypertension being
CLINICAL PRESENTATION
ty
the sole manifestation in majority although the problem
of inadequate clinical examination is also to be blamed. The clinical presentation of CoA differs in different age
18 cie
Approximately 25% of cases are diagnosed beyond 10 years
of age. 6 CoA in adulthood is a heterogeneous group,
comprising of recoarctation following prior catheter or
groups. Children may have variable range of symptoms
ranging from being completely asymptomatic to duct
dependant systemic circulation with cardiogenic
surgical treatment as well as missed untreated cases. shock. Adolescents and adults commonly present with
20 o
The patients who are not untreated are at risk of systemic systemic hypertension. Patients presenting with severe
S
hypertension, accelerated coronary artery disease, stroke, hypertension may have angina, headache, epistaxis,
aortic dissection and heart failure.5 As a result, without blurring of vision and heart failure. Rarely, adults may
correction, the mean life expectancy is reduced and have claudication in lower extremities due to lower limb
al
90% die before reaching the age of 50 years. 7 Therefore, ischemia.

all patients with CoA with hemodynamically significant On physical examination, femoral arterial pulses
ic
obstruction should be treated. There are different methods are diminished and radiofemoral delay is almost always
available for the treatment of CoA in adults, including
og
appreciated. Though not universal, a continuous

surgical or percutaneous balloon angioplasty with or murmur is audible in interscapular area in the back. This
without stent placement. Medical therapy remains the murmur arise from the collaterals developed as a result
ol
cornerstone for management of systemic hypertension of long standing untreated CoA.10 These collaterals are
before and after the relief of aortic obstruction. hypertrophied intercostal arteries and therefore, can be
di
palpable on the undersurface of the ribs. Discrepancy

CLASSIFICATION in the upper limb and lower limb blood pressure is the
ar
most important diagnostic clue towards the diagnosis of

Native coarctation of aorta: In its classic form, there
CoA. Normally, blood pressure is higher in lower limb
is discrete narrowing at aortic isthmus consequent to
compared to the upper limb. Higher blood pressure in
C
ridge-like thickening of the media of the aortic wall

the upper limb indicates the presence of CoA or aortic
leading to formation of a posterior shelf. The origin of
obstruction. As has been highlighted, the left subclavian
the left subclavian artery is sometimes involved within
artery may be involved within the CoA segment and
the narrowed segment. Uncommonly, the narrowing in
therefore, blood pressure in the left upper limb may not
aorta is not discrete. Instead there is tubular hypoplasia
be reflective of true blood pressure in aorta proximal to
involving isthmus and part of the transverse arch.
the coarctation. It is for this reason, blood pressure should
Recurrent coarctation of the aorta: Recoarctation of the always be checked in right upper limb although it is the
aorta refers to restenosis following an initially successful best to record blood pressure in all the four limbs. The
surgical or catheter-based repair. It is thought to result importance of using appropriate sized cuff for measuring
either from residual obstruction or development of blood pressure particularly in the lower limbs cannot be
restenosis. The incidence of recoarctation following overemphasized.10
KG-44.indd 360 02-11-2018 16:56:04

Sometimes, CoA is associated with Turner syndrome. (figure of 3 appearance). Rib notching can be observed as CHAPTER
A careful physical examination provides necessary clues irregularities and scalloping on the undersurface of the
to the diagnosis. posterior ribs. 44
Echocardiography: Two-dimensional echocardiography

DIAGNOSTIC EVALUATION and Doppler studies are the investigation of choice for
Electrocardiogram : The electrocardiogram can be initial assessment. Unfortunately, a complete assessment
completely normal in patients with CoA. In others, left solely on the basis of echocardiogram is not possible in
ventricular hypertrophy consequent to chronic pressure a significant minority among adolescents and adults.
overload is evident (Figure 1). From the suprasternal long-axis view, typical thoracic
coarctation appears as a localized stenosis just beyond the
Radiography: Radiographic findings vary with the clinical
a
origin of the left subclavian artery (Figures 2A and B).
presentation of the patient. The chest radiograph typically The narrowing in aorta appears as a shelf protruding
di
shows a prominent aortic knuckle, and the stenotic from the posterior aspect of the aorta oriented toward
region may be observed as an indentation of the proximal the ductus arteriosus (the “posterior shelf”). Associated
In
thoracic descending aorta in the shape of a number 3 findings such as hypoplasia of aortic isthmus and
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Figure 1: ECG with LVH in a 24-year-old patient with coarctation of aorta

di
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A B
Figures 2A and B: Showing narrowing at juxtaductal segment of aorta with flow turbulence across the coarctation segment
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KG-44.indd 361 02-11-2018 16:56:04

SECTION MRI provides exceptional visualization of aortic arch
and detection of postrepair complications like ‘Kinking’
6 and pseudoaneurysm. 16 Thoracic magnetic resonance
angiography allows assessment of post stenotic dilatation
or aneurysmal formation at the site of previous repair. Lack

of ionizing radiations provides an advantage of cardiac
MRI over computed tomography (CT). Recognizing the
benefits of MRI/CT scan, the 2008 American College of
Cardiology/American Heart Association (ACC/AHA)
guidelines for the management of adults with congenital
heart diseases recommend that patients with CoA should
a
have CT or MRI at least every 5 years.
di
Computed tomography (CT): Multidetector CT angiography
also provides excellent anatomic information in patients
In
Figure 3: Continuous wave Doppler tracing with significant systolic with coarctation and aortic arch anomalies (Figure 5). CT
gradient across coarctation segment with diastolic spillage angiographic data are acquired very rapidly and therefore,
is the preferred choice of imaging in sick patients. CT scan
of
transverse arch, poststenotic dilation of descending is also preferred in those with transcatheter stents who
thoracic aorta, and diminished systolic pulsations in may have artefacts during cardiac MRI (Figure 6). During
abdominal aorta serve to confirm the presence of a MRI, metallic stent can interfere with the visualisation.17
ty
significant coarctation. 10 Doppler echocardiography Patients with pacemakers or implantable cardioverter
provides an estimate of the hemodynamic severity defibrillators that are also not suitable for cardiac MRI and
18 cie
of CoA. A continuous wave Doppler study from the
suprasternal window allows detection of high-flow velocity
CT angiography is preferred. Unlike MRI examinations,
however, CT angiography exposes the patient to ionizing
across the stenosis. The Doppler-flow display across the radiation and iodinated contrast.
20 o
coarctation often demonstrates a pattern of diastolic Small studies of patients with postcoarctation
runoff, particularly in patients with a severe stenosis repair have shown good correlation of Aortic diameter
S
or with a robust collateral circulation (Figure 3). The measurements between helical CT and cardiac MRI.
continuous wave Doppler flow profile across a coarctation Nonetheless, it is recommended that same imaging
al
is composed of two superimposed signals representing should be used in the serial follow up assessments to avoid
low-velocity flow in the proximal descending aorta intertest variability.
ic
(proximal to the coarctation) and higher-velocity flow Cardiac catheterization and angiography: Cardiac
across the coarctation itself. catheterization can serve both diagnostic and therapeutic
og
Two-dimensional and Doppler echocardiography is purposes in patients with CoA. In modern era of non-
particularly important in evaluating intracardiac lesions invasive imaging, diagnostic cardiac catheterization
that are often associated with CoA such as ventricular is seldom necessary for anatomic delineation. The
ol
septal defects (VSDs) (30%), 11,12 bicuspid aortic valve hemodynamic significance of CoA, however, is best
(90%), Shone’s complex (40%).13 assessed by cardiac catheterization. A systolic peak to
di
Magnetic resonance imaging: Magnetic resonance imaging peak gradient of >20 mm Hg across coarctation segment
suggests hemodynamically significant obstruction
ar
(MRI) can provide very high-quality images of coarctation.

MRI images in the sagittal and parasagittal projections and necessitates intervention. The pressure gradient
can demonstrate the location and severity of coarctation, may be diminished in the setting of left ventricular
C
and the anatomy of the aortic arch (Figures 4A dysfunction and low cardiac output. The gradient is also
and B). Information about the presence of a patent ductus underestimated in the presence of associated patent
arteriosus and the collateral arterial circulation may also ductus arteriosus, other left-sided obstructive lesions
be obtained. Three-dimensional surface rendering can such as mitral stenosis or aortic stenosis. The pressure
provide anatomic detail in these patients14, and three- gradient may be completely absent in the presence of
dimensional printed models from the same MRI datasets significant collaterals decompressing aorta proximal to the
provide an opportunity to plan surgical and transcatheter coarctation. Thus, measured coarctation gradient must be
interventions. MRI studies are particularly suited to assessed in the context of the patient’s overall anatomy
patients who require high-resolution serial imaging, and physiology.
such as before and after surgical repair, angioplasty,
or stenting.15 MRI studies also provide an assessment INDICATIONS OF INTERVENTION
of aortic flow, and can estimate pressure gradients. The most widely accepted indication for intervention
Compared with conventional echocardiography, cardiac in adolescents and adults is the presence of systemic
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CHAPTER
44

a
di
A B
In
Figures 4A and B: (A) MRI images of a 16-year-old male with focal coarctation of aorta with poststenotic dilatation of aorta; (B) MRI image
of the same patient with stent in situ across the coarctoplasty segment
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Figure 5: CT scan 3 D reconstruction showing coarctation of aorta, Figure 6: Sagittal multiplanar reconstruction (MPR) image post
focal segment of coarctation seen distal to left subclavian artery coarctation stenting with some beam hardening artifacts
og
arterial hypertension, with an upper and lower extremity abnormal exercise blood pressure response, or
systolic blood pressure difference >20 mg.18 In 2008, ACC/ significant left ventricular hypertrophy.
ol
AHA guidelines for adults19 with congenital heart disease ii. Class IIa recommendation indicates intervention
recommended intervention for CoA in the following should be considered in hypertensive patients
di
settings: with more than 50% aortic narrowing relative to the

a. Peak-to-peak coarctation gradient >20 mg; which is the aortic diameter at the level of the diaphragm (as
ar
difference in peak pressure proximal and beyond the seen on MRI, CT scan, or invasive angiography),
narrowed segment. (Level of evidence: C). regardless of the pressure gradient.
C
b. Peak-to-peak coarctation gradient <20 mg with imaging iii. Class IIb recommendation indicates intervention
evidence of significant CoA and radiologic evidence of may be considered in patients with more than 50%
significant collateral flow. The resting gradient alone aortic narrowing relative to the aortic diameter
may be an unreliable indicator of severity when there is at the level of the diaphragm (as seen on MRI,
CT scan, or invasive angiography), regardless of
significant collateral circulation. (Level of evidence: C)
the pressure gradient and the presence of hyper-
The European Society of Cardiology (ASC) guidelines
tension.
largely agree with the ACC/AHA recommendations (all
level of evidence: C).20
i. Class I recommendation is for intervention in all Recommendations for Interventional and
patients with a noninvasive pressure difference Surgical Treatment of Coarctation of the
above 20 mm Hg between the upper and lower Aorta in Adults19
limbs, regardless of symptoms but with upper 1. Choice of percutaneous catheter intervention versus
limb hypertension (>140/90 mm Hg in adults), surgical repair of native discrete coarctation should 363
KG-44.indd 363 02-11-2018 16:56:06

SECTION be determined by consultation with a team of Adult (Figures 7A to F). Stenting works by stretching
Congenital Heart Disease (ACHD) cardiologists, and scaffolding rather than tearing the aorta as in
6 interventionalists, and surgeons at an ACHD center
(Level of Evidence: C)
the case of balloon coarctoplasty. As a result, there
are lesser complications with aneurysm formation
2. Percutaneous catheter intervention is indicated for and restenosis.27 In 1991, O’Laughlin et al reported
recurrent, discrete coarctation and a peak-to-peak the first use of Palmaz iliac artery stent 28 to reduce
gradient of at least 20 mm Hg. (Level of Evidence: B) pressure gradient in coarctation segment in thoracic
3. Surgeons with training and expertise in CHD should aorta of a 12-year-old boy previously treated with
perform operations for previously repaired coarctation balloon angioplasty. Subsequently, larger scale studies
and the following indications:) showed optimal results with significant reduction
a. Long recoarctation segment. (Level of Evidence: B) in pressure gradient in stent group compared to
a
b. Concomitant hypoplasia of the aortic arch. (Level balloon coarctoplasty. A recent report of intermediate
di
of Evidence: B). outcomes from Coarctation of Aorta Stent Trial
(COAST)29 demonstrated that after the placement of
In
Class IIb Cheatham–Platinum bare metal stents in patients
older than 8 years of age, at 2 years follow-up, 13%
Stent placement for long-segment CoA may be considered,
required repeat catheterization for stent dilatation, but
but the usefulness is not well established, and the long-term
of
none needed surgical management. Stent fractures
efficacy and safety are unknown. (Level of Evidence: C).
were seen in 22% of patients, however, none had
adverse outcomes. Overall the results are promising.
Endovascular Strategies in Management of
ty
At present, transcatheter stenting of CoA is indicated in
Coarctation of Aorta adults with native or recurrent coarctation of aorta, or
18 cie
1. Balloon coarctoplasty for recurrent coarctation of
Aorta: In a recent study of patients who underwent
surgical correction for CoA at mean age of 10 years, the
in those with diffuse lesions where balloon dilatation
results in higher risk aneurysmal dilatation, or in older
adults with long segment coarctation with modestly
cumulative 40 years survival was 79%.21 Recoarctation compromised aortic wall elasticity as an alternative to
20 o
was seen in 16% of survivors. Balloon dilatation insertion of interposition graft or patch.
S
of coarctation segment can be performed using

antegrade or retrograde approaches depending Surgical Treatment Strategies
al
on clinician preferences. Balloon coarctoplasty for

Surgical repair of coarctation of the aorta was first
the treatment of recurrent CoA has been accepted
reported in 1945 by Crafoord and Nylin,30 who described
ic
as treatment of choice, based on assumption that

the technique of resection and end-to-end anastomosis.
the scar tissue is resistant to rupture or aneurysm
In most centers, this procedure remains the surgical
og
formation.22 Histological reports have revealed that the

treatment of choice for patients with a discrete coarctation.
acute increase in lumen size and reduction in systolic
An extended end-to-end anastomosis using a broader
pressure gradients due to balloon coarctoplasty are
longitudinal incision across the proximal aorta improves
ol
due to tears in the lumen of aorta. These are generally

the effectiveness of this operation in infants with
confined to intimal and medial layer, rarely can be
hypoplasia of the isthmus or transverse arch. Prosthetic
di
transmedial. The transmedial tears are associated

patch aortoplasty was the second surgical technique
with aneurysm formation and occasionally aortic
described for coarctation repair, by Vosschulte31 in 1961.
ar
dissection. 23 Mortality rates among adult patient

Compared with coarctation resection, patch aortoplasty
undergoing balloon coarctoplasty being 1%.24
has the advantages of requiring less extensive aortic
2. Balloon coarctoplasty for native coarctation of aorta:
C
mobilization, preserving intercostal arteries, and avoiding

This may be a preferred option in children. However,
a circumferential suture line. Patch aortoplasty also
in adults due to tough aortic wall balloon dilatation
can be used for long-segment coarctation. Jump graft
is not recommended. Recoarctation develops in
or a prosthetic graft may be used in patients with long
6–19% in adults with balloon coarctoplasty for native
segment CoA with compromised aortic wall elasticity.
CoA.25 McCrindle et al.26 reported the recurrence rate
The disadvantages of this technique include the use of
of approximately 7%, with a further 7% of patients
prosthetic material and a relatively high incidence of late
having a suboptimal primary outcome. Thus, for
aortic aneurysm formation.
localized discrete narrowing, balloon angioplasty is an
acceptable alternative to surgical repair as a primary
intervention but is less suitable for long-segment or Outcomes and Late Complications
tortuous forms of CoA. Patients without a significant residual systolic gradient
3. Stent implantation: The stents are being increa- (<10 mm Hg at rest), with normal upper-extremity
singly used for the treatment of CoA in adults blood pressure at rest and with exercise, and without an
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CHAPTER
44

a
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In
A F
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ty
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20 o
B C D E
S
Figures 7A to F: Stenting across coarctation segment. (A) Absent flow across coarctation segment; (B) Predilatation of coarctation segment
with balloon; (C) Following pre-dilatation increased collateral flow; (D) Placement of stent and simultaneous angiography to define stent
position; (E) Stent deployment with premounted balloon; (F) Deployed stent with angiogram showing good flow across coarctation segment.
al
aortic aneurysm or significant associated intracardiac more follow-up data are necessary to precisely define
ic
lesions, normal lifestyle is generally recommended. 32 this risk. Aortic dissection may occur with or without the
Nevertheless, irrespective of the results of interventional or presence of an aortic aneurysm at the coarctation repair
og
surgical therapy, patients with CoA require lifelong expert site. Dissection is a feared complication of pregnancy in
care as they require careful surveillance and often require woman with a repaired coarctation.46 Factors predisposing
therapy. 33 The long-term prognosis following repair
ol
to dissection include cystic medial necrosis of the aortic

of coarctation may be adversely affected by persistent wall, atherosclerosis, persistent arterial hypertension,
systemic hypertension and an increase in premature
di
and dilation of the ascending aorta, which is particularly

atherosclerotic cardiovascular events.34,35 Even in the common in patients with Turner syndrome. Intracranial
absence of a residual coarctation gradient, patients may
ar
hemorrhage may occur late following coarctation repair,

exhibit late systolic and diastolic hypertension; particularly with or without associated hypertension, and may be
if they are treated beyond childhood.36 An aortic aneurysm related to the presence of berry aneurysms in the circle of
C
may develop at the site of coarctation repair, regardless Willis. The patients with CoA are also at risk of infective
of whether the repair was surgical or percutaneous. The endocarditis. Endocarditis may occur on a bicuspid aortic
incidence of postoperative aortic aneurysm is highest valve or other associated intracardiac lesions. Endarteritis
following prosthetic patch aortoplasty, 37-40 although typically occurs at or just distal to the site of coarctation
aneurysms have been reported following other surgical repair.
procedures as well. Once present, such aneurysms may
progress rapidly and may be responsible for aortic rupture
and sudden death.41 The risk of aortic aneurysm following
Medical Management of Systolic Arterial
coarctation angioplasty varies widely in published Hypertension
reports, with the larger follow-up studies estimating its Numerous studies have demonstrated that hyper tension
incidence to be in the range of 5–16%.42-45 Late aneurysms is prevalent in patients with CoA. Two studies by Wells
may occur less commonly after coarctation stenting, and coworkers47and Bhat et al.48 looked at the effect of
particularly if a covered stent is employed primarily, but coarctation repair on systolic blood pressure. In these
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SECTION studies all the patients had systolic hypertension of or heavy weight lifting, and sudden stop-start sports. It
>140 mm Hg. Following coarctation repair, there was an would be prudent to have a cardiology consultation, stress
6 improvement in systolic blood pressure in all patients with
decrease in the requirement of antihypertensive agents.
testing, and an echocardiogram before permitting low- to
moderate-level dynamic sports or light-weight lifting.
The prevalence of systemic hypertension postcoarctation

Reproduction : 19 Pregnanc y in coarctation of the
repair ranges from 25–65%, 49 the mechanism of
aorta continues to be a source of concern, but major
hypertension being unclear, probably related to abnormal
cardiovascular complications are infrequent. An
vascular compliance or increased baroreceptor sensitivity.
assessment of the hemodynamic status, severity of
There are limited data on the efficacy of different classes
coarctation, and associated lesions, particularly BAV, AS,
of antihypertensive medications in hypertensive patients
or a significantly dilated root, should be undertaken before
following CoA repair. A study of 128 young adults with
a
pregnancy for proper planning and advice. The potential
hypertension after CoA repair reported better control of
for aortic dissection remains, although it is quite small
di
hypertension with Candesartan over Metoprolol with
unless the aorta is dilated significantly.
fewer side effects.50 The 2008 ACC/AHA guidelines for
In
management of CoA in adults recommended use of beta Endocarditis prophylaxis:19 Patients with uncomplicated
blocker, angiotensin–converting enzyme inhibitor or native coarctation or uncomplicated, recurrent coarctation
angiotensin II receptor blocker as first-line therapy, with that is successfully repaired do not require endocarditis
of
a preference of one agent over another dependant on prophylaxis unless there is a prior history of endocarditis or
presence of aortic root dilatation or aortic regurgitation.19 a conduit has been inserted or if surgical repair or stenting
has been performed less than 6 months previously.
ty
Recommendations for Key Issues to Evaluate
and Follow-up19 REFERENCES
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18 cie 1. Samanek M, Slavik Z, Zborilova B, et al. Prevalence
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MR angiography, correlation with echocardiography and guidelines for the management of adults with congenital
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surgery. Int J Cardiovasc imaging. 2006;22(3-4):457-75. heart disease. J Am Coll Cardiol. 2008;52(23):143-263.
17. Rosenthal E, Bell A. Optimal imaging after Coarctation 34. Maron BJ, Humphries JO, Rowe RD, et al. Prognosis of
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Stenting. Heart. 2010;96(15):1169-71.
18. Marshall AC, Perry SB, Keane JF, et al. Early results and
medium-term follow-up of stent implantation for mild 35.
surgically corrected coarctation of the aorta: a 20-year post-
operative appraisal. Circulation. 1973;47(1):119-26.
Toro-Salazar OH, Steinberger J, Thomas W, et al. Long-term
residual or recurrent aortic coarctation. Am Heart J. follow-up of patients after coarctation of the aorta repair.
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2000;139(6):1054-60. Am J Cardiol. 2002;89(5):541-7.
19. Warnes CA, Williams RG, et al. ACC/AHA 2008 Guidelines 36. Brown ML, Burkhart HM, Connolly HM, et al. Coarctation
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for the Management of Adults with Congenital Heart of the aorta: lifelong surveillance is mandatory following
Disease: Executive Summary: a report of the American surgical repair. J Am Coll Cardiol. 2013;62(11):1020-5.
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College of Cardiology/American Heart Association Task 37. Bromberg BI, Beekman RH, Rocchini AP, et al. Aortic
Force on Practice Guidelines (writing committee to develop aneurysm after patch aortoplasty repair of coarctation:
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heart disease). Circulation. 2008;118(23):2395-451. risks. J Am Coll Cardiol. 1989;14:734-41.
og
20. Erbel R, Aboyans V, Boileau C, et al. 2014 ESC Guidelines on 38. del Nido P, Williams WG, Wilson GJ, et al. Synthetic patch
the diagnosis and treatment of aortic diseases: Document angioplasty for repair of coarctation of the aorta: experience
covering acute and chronic aortic diseases of the thoracic and with aneurysm formation. Circulation. 1986;74(3 Pt 2):32-6.
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abdominal aorta of the adult. The Task Force for the Diagnosis 39. Clarkson PM, Brandt PW, Barratt-Boyes BG, et al. Prosthetic
and Treatment of Aortic Diseases of the European Society of repair of coarctation of the aorta with particular reference
Cardiology (ESC). EUR Heart J. 2014;35(41):2873-926. to dacron onlay patch grafts and late aneurysm formation.
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21. Toro–Salazar OH, Steinberg J, Thomas W, et al. Long term Am J Cardiol. 1985;56:342-6.
follow-up of patients after coarctation of aorta repair. Am J 40. Cramer JW, Ginde S, Bartz PJ, et al. Aortic aneurysms
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1982;143(3):689-91. progression of aortic aneurysms after patch aortoplasty
24. Hellenbrand WE, Allen HD, Golinko RJ, et al. Balloon repair of coarctation of the aorta. J Am Coll Cardiol.
angiplasty for Aortic recoartation: results of valvuloplasty 1992;20:381-5.
and angioplasty of congenital anomalies registry. Am J 42. Mendelshon AM, Lloyd TR, Crowley DC, et al. Late
Cardiology. 1990;65(11):793-7. follow-up of balloon angioplasty in children with a native
25. Tyagi S, Arora R, Kaul UA, et al. Balloon coartoplasty of coarctation of the aorta. Am J Cardiol. 1994;74:696-700.
native coarctation of aorta in adolescents and young. Am 43. Fletcher SE, Nihill MR, Grifka RG, et al. Balloon angioplasty
Heart J. 1992;123(3):674-80. of native coarctation of the aorta: mid-term follow-up and
26. McCrindle BW, et al. Acute results of balloon angioplasty prognostic factors. J Am Coll Cardiol. 1995;25(3):730-4.
of native coarctation vs recurrent aortic obstruction and 44. Fawzy ME, Fathala A, Osman A, et al. Twenty-two years of
equivalent. Valvuloplasty and Angioplasty of Congenital follow-up results of balloon angioplasty for discreet native
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Heart J. 2008;156(5):910–7. Coarctation of Aorta in Adults: the fate of systolic hyper-
6 45. Harris KC, Du W, Cowley CG, et al. Congenital Cardiac

Intervention Study Consortium (CCISC). A prospective
tension. Ann Thoracic Surg. 1996;61(4):1168-71.
48. Bhat MA, Neelakandhan KS, Unnikrishnan M, et al. Fate of
observational multicenter study of balloon angioplasty for Hypertension after repair repair of coarctation of aorta in
the treatment of native and recurrent coarctation of the adults. Br J Surg. 2001;88(4):536-8.
aorta. Catheter Cardiovasc Interv. 2014;83(7):1116-23. 49. Canniffe C, Ou P, Walsh K, et al. Hypertension after repair
46. Silversides CK, Kiess M, Beauchesne L, et al. Canadian of coarctation; systematic review. Int J Cardiol. 2013;167(6):
Cardiovascular Society 2009 Consensus Conference on 2456-61.
the management of adults with congenital heart disease: 50. Giordano U, Cifra B, Giannico S, et al. Midterm results
outflow tract obstruction, coarctation of the aorta, tetralogy and therapeutic management, for patients suffering
of Fallot, Ebstein anomaly and Marfan’s syndrome. Can J hypertension after surgical repair of aortic coarctation.
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Cardiol. 2010;26(3):80-97. Cardiol Young. 2009;19(5):451-5.
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Approach to Cyanosis in Newborn
Anita Saxena
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Cyanosis in Adults
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Eisenmenger Syndrome: An Update

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Adults with Repaired Tetralogy of Fallot
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Snehal Kulkarni
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Single Ventricle Pathway: Simplified

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Fontan Circulation: Simplified

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Ebstein’s Anomaly: What’s New?

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Total Anomalous Pulmonary Venous Connection: An Overview

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Pulmonary Arteriovenous Malformations
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Systemic Effects of Cyanosis
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Approach to Cyanosis
CHAPTER 45 in Newborn
Anita Saxena
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INTRODUCTION
Cyanosis in the newborn is a frequently encountered
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problem. The term cyanosis is derived from the Greek
word kuaneos meaning dark blue, referring to the bluish
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discoloration of the skin, nailbeds, or mucous membranes.
Cyanosis is classified into central and peripheral cyanosis.
If cyanosis is limited to the extremities, it is referred to
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as peripheral cyanosis or acrocyanosis. This is relatively
common in young infants, and is generally a physiologic
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finding due to the large arteriovenous oxygen difference
that results during slow flow through peripheral capillary
beds. In contrast to acrocyanosis, central cyanosis is
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present throughout the body, and is evident in the mucous
membranes and tongue. Central cyanosis indicates
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the presence of potentially serious and life-threatening Figure 1: Effect of fetal vs. adult hemoglobin on oxygen dissociation
curve. A saturation of 80% indicates a PaO2 of 45 mm Hg in an adult,
disease, and requires immediate evaluation. The clinician
but much lower value for a neonate (PaO2 <30 mm Hg)
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will need to rapidly consider respiratory and central

nervous systems, and hematologic, cardiac, and metabolic
NORMAL CARDIOPULMONARY ADAPTATION
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causes.1
AT BIRTH
Cyanosis is dependent on the absolute concentration
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of the reduced hemoglobin and not on the ratio of reduced At birth, profound changes in the cardiovascular and
hemoglobin to oxyhemoglobin. With careful observation, respiratory systems occur to allow the infant to adapt to air
breathing. An understanding of these normal transitional
cyanosis may become apparent when the deoxygenated
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changes is important in evaluating a cyanotic infant, as

hemoglobin content is as little as 3 g/dL. Therefore, infants
their disruption is likely to lead to cyanosis. During fetal
with polycythemia may exhibit cyanosis at relatively high
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life, the placenta, and not the lungs, serves as the organ
arterial saturations, while it is more difficult to discern
of gas exchange. Less than 10% of the cardiac output is
cyanosis in a severely anemic infant unless the oxygen
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circulated through the pulmonary vascular bed, and the

saturation is extremely low. In general, the relatively high
placenta, as the organ of gas exchange, receives nearly half
hemoglobin of the normal infant tends to facilitate the
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of the cardiac output. Pulmonary blood flow (PBF) remains

recognition of cyanosis. low due to elevated pulmonary vascular resistance;
The ratio of fetal to adult hemoglobin varies from infant pulmonary pressure is equivalent to systemic pressure due
to infant, and the proportions of each hemoglobin affect to active vasoconstriction. Fetal circulation shunts blood
the oxygen saturation resulting at any given PaO2. Thus, from the right-to-left atrium across the foramen ovale and
if a child has mostly adult hemoglobin, central cyanosis from the pulmonary artery to descending aorta through
(arterial saturation 75–85%) will be observed when the the ductus arteriosus providing direct blood flow to the
PaO2 falls below 45 mm Hg. In contrast, if the baby has placenta.
mostly fetal hemoglobin, central cyanosis may not be The fetal lungs produce fluid that fills the alveoli,
observed until the PaO2 drops well below 30 mm Hg. Thus, bronchi, and trachea. As the catecholamines and other
infants with a high proportion of fetal hemoglobin may hormones increase during labor, a rapid switch occurs
have a serious reduction in oxygenation before cyanosis is from net secretion to net absorption of liquid in alveolar
clinically apparent (Figure 1). spaces. As the lungs fill with air, lung fluid is removed via
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SECTION the trachea and absorption by the pulmonary capillaries Cardiac Diseases
and lymphatics. With this, the pulmonary pressures
7 and pulmonary vascular resistance drops dramatically
allowing a 10-fold rise in PBF. Simultaneously, the low
A number of congenital heart diseases (CHDs) result in
cyanosis. They produce cyanosis, either due to reduced
PBF or due to poor mixing. Another important cause
Cyanotic Congenital Heart Disease
vascular resistance bed of the placenta is removed and

systemic vascular resistance increases. As pulmonary of cyanosis in newborn period is persistent pulmonary
pressure falls to less than systemic pressure, PBF increases hypertension of the newborn where heart is structurally
and blood flow through the patent ductus arteriosus normal.
(PDA) reverses direction. Functional closure of the
ductus occurs over the first several hours of life; largely INITIAL EVALUATION OF THE NEWBORN
in response to the increased oxygen tension. Left atrial
WITH CYANOSIS
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pressure also increases leading to closure of the foramen
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ovale. These events eliminate the fetal right-to-left shunts, The evaluation should systematically assess the infant for
and establish the normal postnatal circulatory pattern of airway, pulmonary, and circulatory causes as described
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pulmonary and systemic circulations. Within 24 hours above. Because the majority of the causes for tachypnea
after birth, pulmonary artery pressure typically decreases and cyanosis are due to cardiopulmonary problems, it is
to approximately 50% of mean systemic arterial pressure, important to differentiate the etiology between cardiac
of
and continues to drop over the next 2–6 weeks until adult and pulmonary causes for tachypnea and cyanosis. The
values are attained. importance of history of antenatal exposures to teratogens,
radiations, viral illness, especially with rashes, cannot
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be overemphasized. Maternal diabetes is associated
CAUSES OF CENTRAL CYANOSIS IN with higher prevalence of congenital heart disease
THE NEWBORN
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Cyanotic neonates are usually encountered in emergency
department, neonatal nursery/intensive care unit and
and there is higher incidence of transient tachypnea,
hyaline membrane disease, and hypoglycemia in large-
for-gestational-age infants born to diabetic mothers.
Prolonged rupture of membranes may suggest bacterial
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outpatient department of pediatrics. Cyanosis can result
from cardiac and noncardiac causes. It is important to infection and sepsis in newborns. A difficult vaginal
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distinguish the two as the management will be done breech delivery can give rise to intracranial hemorrhage,
accordingly. Common causes of central cyanosis are listed Erb’s palsy which may be associated with phrenic nerve
paralysis, giving rise to respiratory distress.
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below.
The time of onset of the respiratory distress and
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cyanosis may give some clues towards the diagnosis.

Airway Diseases Newborns symptomatic at birth may have transient
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The airway diseases include choanal atresia, micrognathia, tachypnea of the newborn, meconium aspiration
Pierre Robin sequence, laryngomalacia, vocal cord syndrome, respiratory distress syndrome, pneumothorax,
paralysis, tracheal stenosis, hemangioma, and other neck or congenital diaphragmatic hernia. Cyanosis associated
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masses. From a cardiac perspective, vascular rings and with feeding may point to vocal cord palsy or laryngeal
slings caused by abnormal development of mediastinal cleft. Babies with cyanotic heart disease usually develop
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vessels can compress or deviate the trachea causing cyanosis and respiratory distress several hours or 1–2 days
airway obstruction and episodic cyanosis. An anomalous after birth.
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distal origin of the innominate artery from the aortic arch The physical examination should be performed
is the most common cause, but other anomalies include after making the newborn warm and quiet. The growth
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double aortic arch or an aberrant right subclavian artery. characteristics are noted, but the main focus should be
on determining the degree of respiratory distress and
cyanosis. This is important from management point of
Lung Diseases
view also. Respiratory distress due to pulmonary disease
A number of congenital and acquired lung diseases is typically characterized by tachypnea accompanied by
cause cyanosis. Examples include neonatal pneumonia, retractions and nasal flaring. Hypoventilation, which may
congenital diaphragmatic hernia, hypoventilation, occur due to neurological cause, is often associated with
phrenic nerve palsy, pulmonary sequestration, pulmonary slow or irregular respirations. Babies should be evaluated
hypoplasia, congenital lobal emphysema, etc. In most for muscle tone, activity and any apneic spells. One should
cases of lung diseases, the newborn is in respiratory look for evidence of any birth trauma, Erb’s palsy or stridor.
distress. Sometimes, preterm or even term neonates may The cardiac examination should be performed in detail,
present with apneic episodes as a cause of cyanosis. especially if no other cause of cyanosis is obvious.
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HYPEROXIA TEST generally comfortable at rest without respiratory distress. CHAPTER
The hemodynamic classification of various CHDs is given
45
In cases where it is difficult to differentiate a cardiac cause
from a pulmonary cause of cyanosis, the hyperoxia test in Table 1.
has been advocated. This test is based on the principle Examination should include the respiratory rate,

that in the absence of fixed cardiac shunts, 100% oxygen any sign of distress and perfusion (assessed by capillary
will increase alveolar PO 2, leading to an increase in filling time). As given in Table 2, the cardiac examination
pulmonary venous and systemic arterial PaO2. Little or no should include assessment of heart rate, peripheral pulses,
increase is expected in cyanotic CHD even when breathing any evidence of heart failure in the form of tachycardia,
tachypnea, and hepatomegaly. It is very important
100% O2. However, in babies with significant pulmonary
to palpate for lower limb pulses, else coarctation of
hypertension, PaO2 may not increase due to right-to-left
aorta may be missed. Similarly, one should record four
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shunting occurring at ductus arteriosus or foramen ovale
limb blood pressure. Since many complex CHDs occur
level. With wide availability of echocardiography, the
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with situs abnormalities and malposition of heart, one
hyperoxia test is rarely required.
should look for any evidence of dextrocardia, situs
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inversus. Auscultation of heart is important, but one
APPROACH TO A NEWBORN WITH CYANOTIC must remember that some of the most serious cyanotic
CONGENITAL HEART DISEASE heart defects do not produce any murmurs. The second
of
Once it has been decided that the cyanosis in the newborn heart sound is often single in most cyanotic CHD. Loud
is due to CHD, all attempts should be made to diagnose the murmurs may indicate relatively benign lesions. Certain
underlying defect. It is often not possible to reach lesion- specific findings on examination may point to certain
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specific diagnosis by bedside examination; one should type of cyanotic lesions. A left ventricular impulse
try to decide whether underlying heart disease involves will indicate tricuspid atresia or single ventricle of left
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increased or decreased PBF. Features of heart failure,
such as rapid breathing, difficulty in feeding, sweating
while feeding, and poor weight gain, are symptoms of
ventricular morphology as the underlying cardiac defect.
Dextrocardia or mesocardia with situs solitus is most
often associated with congenitally corrected trasposition
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heart failure and point to cardiac lesions with increased of great arteries (CCTGA). A sea-saw (systolodiastolic)
PBF. Neonates with reduced PBF are cyanosed, but are murmur at upper sternal border is quite typical of tetralogy
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Table 1: Hemodynamic classification of cyanotic congenital heart diseases

S. No. Hemodynamic classification Cyanotic CHD
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1. Reduced PBF/PA pressure Critical PS/pulmonary atresia with IVS

Tetralogy of Fallot (VSD + PS) physiology
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z Tetralogy of Fallot (VSD/PS)
z DORV/VSD/PS
z AVSD/PS
z TGA/VSD/PS
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z Single ventricle/PS
z Tricuspid atresia with restrictive VSD and/or PS

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2. Increased PBF/PA pressure Transposition physiology:

z Complete TGA
z DORV/subpulmonic VSD
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(Taussig-Bing)
Admixture physiology without PS:
z At systemic or right atrial level:
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— TAPVC
— Mitral/aortic atresia with IVS
z At left atrial level:

— Tricuspid atresia
z At ventricle/great artery level:
— Single ventricle
— Complete AVSD with straddling AV valve
— DORV/subaortic or inlet VSD
— Persistent truncus arteriosus
3. Pulmonary venous hypertension Obstructed TAPVC

HLHS/mitral atresia with restrictive ASD
4. Normal PBF/PA pressure LSVC to left atrium, single atrium, Ebstein anomaly
Abbreviations: ASD, atrial septal defect; AVSD, atrioventricular septal defect; DORV, double outlet right ventricle; HLHS, hypoplastic left heart
syndrome; IVS, intact ventricular septum; LSVC, left superior vena cava; PS, pulmonary stenosis; TAPVC, total anomalous pulmonary venous
connection; TGA, transposition of great arteries; VSD, ventricular septal defect.
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SECTION Table 2: Cardiovascular examination in neonates with suspected cyanotic congenital heart disease
7
1. Evaluate airway, breathing and circulation (ABC)
2. Dysmorphism, associated anomalies
3. Signs of respiratory distress and pattern
4. Heart rate: rate, rhythm

5. Peripheral pulses and perfusion: preductal and postductal pulses, capillary refill
6. Precordial impulse: cardiac sidedness
7. Murmur/thrill: timing, site, intensity and radiation
8. Heart sounds, mainly S2: single or split, loud or soft
9. Evidence of heart failure: poor weight gain, hepatomegaly, tachycardia, tachypnea
10. Abdomen: liver sidedness (situs), hepatomegaly
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of Fallot (TOF) with absent pulmonary valve. In TOF, reveal lung abnormalities such as pneumonia, cystic
the intensity of cyanosis is inversely proportional to the malformations, congenital diaphragmatic hernia, and
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intensity of ejection systolic murmur. If the cyanosis is phrenic nerve palsy. Pulmonary vascular markings are very
deep and the murmur is also loud, conditions such as useful to decide if the neonate has reduced or increased
double outlet right ventricle (DORV), associated with PBF. Decreased vascular markings (pulmonary oligemia)
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pulmonary stenosis (PS), should be suspected. A slow, are characteristic of TOF, pulmonary atresia and other
regular pulse rate of 70 beats per minute or lower indicates lesions associated with pulmonary stenosis. Increased
complete heart block, associated CHD include CCTGA pulmonary vascularity (pulmonary plethora) suggests
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and heterotaxy syndromes. Such findings are helpful, but lesions such as transposition of great arteries (TGA), and
often absent in neonates. total anomalous pulmonary venous connection (TAPVC).
ROLE OF PULSE OXIMETRY

18 cie Characteristic ground glass appearance of lungs is very
typical of obstructive total anomalous venous connection
with obstruction (Figures 2A to D). However, similar
Pulse oximeters provide continuous assessment of oxygen
appearance of lungs is also seen in hyaline membrane
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saturation noninvasively and are an important tool not
disease. The cardiac shape may yield some clues to
only for diagnosis but also in management of neonates
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the underlying heart defect, but one must remember

with cyanosis. 2,3 These are currently the standard of
that typical shapes are seen only in a minority of cases
care for all infants who have respiratory distress and
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(<10%). The commonly described cardiac silhouette in

cyanosis. Pulse oximeters are very reliable and the newer
CHD include: egg-on-side appearance (cardiomegaly
generations have improved performance when the
with typically narrow pedicle) of transposition of the
ic
baby is moving and in low perfusion states. It is useful

great vessels, snowman (figure of 8) sign of TAPVC, and
to obtain simultaneous measurements from the right
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boot-shaped heart of TOF (Figures 2A to D). Severe

hand and a foot to determine flow patterns through the
cardiomegaly is seen in Ebstein’s anomaly and in those
ductus arteriosus. As the left subclavian artery may have
with congestive cardiac failure.
a preductal or postductal origin from the aorta, it is best
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not to utilize the left hand for pulse oximetry monitoring.

Postductal origin of umblical artery also should be kept in ELECTROCARDIOGRAPHY
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mind, especially in neonatal intensive care setup where Normal newborns have fast heart rate and a predominance
umbilical artery catheterization is commonly practiced. of right-sided forces, and moderate right ventricular
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Pulse oximetry does not provide PaO2 for which arterial hypertrophy. Heart rates of over 180–200 may indicate
blood gas analysis is required. Measurement of arterial an abnormal rhythm, most often supraventricular
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blood gas oxygen tension requires an arterial sample tachycardia. Most cyanotic CHD cause right ventricular
and may compromise artery and produce agitation in hypertrophy, which could be difficult to differentiate
the baby. Alternatively, a venous blood gas may be useful from normal right ventricular dominance. Therefore, the
for evaluating the newborn, as it provides assessment of ECG is seldom helpful in the evaluation of the infant with
pH, PaCO2 and lactate, and the presence of a significant CHD, and is often completely normal even in infants with
metabolic acidosis may indicate cardiac failure, sepsis, serious disease such as transposition. A notable exception
asphyxia, or metabolic disorders. would be the infant with left axis deviation due to left
ventricular hypertrophy, which would strongly suggest
CHEST RADIOGRAPH tricuspid atresia.
A chest radiograph is an integral part of the initial
assessment of the newborn who has respiratory distress/ ECHOCARDIOGRAPHY
cyanosis. The X-ray also helps to localize the position Based on clinical suspicion, urgent echocardiography
374 of liver, heart and stomach to assess the situs. It can should be performed to ascertain the etiology of cyanosis.
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CHAPTER
45

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Figures 2A to D: Chest radiograph in various cyanotic CHD. (A) Tetralogy of Fallot showing no cardiomegaly and oligemic lung fields; (B)
Transposition of great arteries: cardiomegaly, narrow pedicle with pulmonary plethora, i.e. egg-on-side appearance; (C) Supracardiac TAPVC:
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typical snowman or ‘figure of 8’; (D) Infracardiac obstructed TAPVC: no cardiomegaly with severe pulmonary venous hypertension
Abbreviations: CHD, congenital heart disease; TAPVC, total anomalous pulmonary venous connection
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It helps in confirming the diagnosis and planning Role of Prostaglandin E1

definitive treatment. The advent and advancements
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Neonates presenting within 1–3 weeks of life are likely to

in echocardiographic imaging has limited the need of
have a lesion which is dependent on patency of ductus
cardiac catheterization to therapeutic balloon atrial
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arteriosus. These neonates should be immediately started

septostomy, pulmonary valvulotomy, and ductal stenting
in neonatal period. on intravenous prostaglandin E1 (PGE1) infusion, even if
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the diagnosis is not confirmed by echocardiography. This

strategy works for majority of cyanotic CHD, although
INITIAL MANAGEMENT
cases with obstructed total anomalous pulmonary venous
If the cyanosis is severe or the neonate has presented
return (TAPVR) may worsen. PGE1 is given as a continuous
with shock, supportive therapy must be started while
infusion, started at 0.05 ug/kg/min, can be increased up to
establishing the diagnosis. The baby should be kept in a
a maximum dose of 0.4 ug/kg/min. The dose should be
warmer to prevent hypothermia. Similarly, hypovolemia,
hypoglycemia, acidosis, and other metabolic abnormalities reduced once the patient has improved. The response is
should be corrected. Assisted ventilation is to be considered typically seen as improvement in saturation and acidosis
for those in respiratory distress. If the infant is <10 days old and should guide titration of infusion dose. About 10–12%
and the umbilical stump is still attached, umbilical venous neonates have side effects, most importantly apnea, which
and arterial lines can frequently be placed for rapid central occurs usually within first 6 hours of administration. The
access. incidence is lower at lower dosage of infusion.
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SECTION
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Figure 3: Flow diagram showing the timing and type of surgery for various cyanotic congenital heart disease
Abbreviations: AP, aortopulmonary; DORV, double outlet right ventricle; PA, pulmonary artery; PAH, pulmonary artery hypertension; PBF, pulmonary blood flow; PS, pulmonary stenosis;
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TAPVC, total anomalous pulmonary venous connection; TGA, transposition of great arteries; TOF, tetralogy of Fallot; Tr, tricuspid; Vent, ventricle; TV, tricuspid valve
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02-11-2018 16:55:56
Role of Supplemental Oxygen However, a neonate presenting to the emergency CHAPTER
department with cyanosis requires urgent assessment,
45
In cyanotic CHD, there is no definite number to define
diagnosis, and initiation of therapy. An understanding
adequate saturation. Oxygen should be provided, but
of the normal transitional physiology is essential when
there are concerns about the potential risks with oxygen

dealing with a cyanotic newborn. A precise anatomic
therapy.4,5 Exposures to extreme hyperoxia can increase
diagnosis of the type of cyanotic CHD at the bedside is
oxidative stress damaging lung parenchymal and vascular
not always possible. It is important, however, to assess
functions and may close the ductus arteriosus. Further,
whether the baby has a life-threatening condition, as is
oxygen is a potent pulmonary vasodilator and will further
likely in a deeply blue child, in a child with respiratory
increase PBF in neonates with increased PBF situations,
distress, or in a newborn with a ductus-dependent heart
and thus worsen respiratory distress. Therefore, oxygen
disease. Emergency management is based on the clinical
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supplement, if started, should be at 40–60% FiO 2. One
diagnosis and attention to hemodynamic stability, PGE1
should try and keep the arterial saturation between 80 and
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infusion, judicious oxygen administration, and referral
85%.
to the appropriate inpatient hospital setting. In a stable
The management should aim at stabilizing the
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neonate, further investigations, such as echocardiography,
neonate and avoidance of tissue hypoxia and acidosis.
should be performed before treatment is initiated. The
The urgency of evaluation by pediatric cardiologist
prognosis for most cyanotic CHD is good after a timely
depends upon likelihood of underlying CHD. Critical
of
intervention.
lesions like PDA-dependent pulmonary or systemic
circulation, TGA with intact ventricular septum, critical
pulmonary stenosis and obstructed TAPVR needs urgent REFERENCES
ty
confirmation of diagnosis and definitive interventional 1. Sasidharan P. An approach to diagnosis and management
and/or surgical management. All neonates with cyanosis of cyanosis and tachypnea in term infants. Pediatr Clin
18 cie
need an intervention; the time of intervention varies
depending on the diagnosis and the condition of the baby.
North Am. 2004;51(4):999–1021.
2. Levesque BM, Pollack P, Griffin BE, et al. Pulse oximetry:
what’s normal in the newborn nursery? Pediatr Pulmonol.
In most cases, a detailed echocardiography is enough to
20 o
2000;30(5):406-12.
provide details for further intervention. Various lesions 3. Jennis MS, Peabody JL. Pulse oximetry: an alternative
S
have different timing of surgery, surgical approach, and method for the assessment of oxygenation in newborn
outcomes. This understanding is essential to understand infants. Pediatrics. 1987;79(4):524-8.
long-term follow-up and prognosis of underlying cardiac 4. Saugstad OD, Ramji S, Vento M. Oxygen for newborn
al
lesion (Figure 3). resuscitation: how much is enough? Pediatrics. 2006;118(2):

789-92.
ic
5. Lakshminrusimha S, Russell JA, Steinhorn RH, et al.

CONCLUSION Pulmonary arterial contractility in neonatal lambs
og
Cyanosis is commonly encountered in neonates. One increases with 100% oxygen resuscitation. Pediatr Res.
should focus on identifying the underlying etiology. 2006;59(1):137-41.
ol
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CHAPTER 46 Cyanosis in Adults
a
di
INTRODUCTION
Cyanosis (Greek: kyanos blue; osis condition) is defined
In
as bluish discoloration of skin and mucous membrane,
resulting from increase in the reduced hemoglobin to
of
more than 5% in capillary blood, or 7% in arterial blood
(normal 2–3%), or 15% in venous blood (normal 5–12%).
Rarely, cyanosis may also result from abnormal pigments
ty
(e.g. methemoglobin).
Cyanosis was first described in 1761 by Morgagni, who
18 cie
attributed it to pulmonic stenosis. This bluish discoloration
is produced by the color of the blood within the capillaries
of the dermal papillae, mucous membranes, and in the
subpapillary venous plexus of the dermis. Cyanosis is best
20 o
appreciated in areas with minimal melanotic pigment,
S
where the overlying epidermis is thin and subepidermal

vessels are abundant, such as the lips, nose, cheeks, Figure 1: Central cyanosis and pan digital clubbing in a child
al
ears, hands, feet, conjunctiva, and mucous membrane of with cyanotic heart disease
the oral cavity. Tongue is considered the most sensitive
ic
area. Several factors, such as skin pigmentation, room

lighting, and hemoglobin status, have an effect on clinical
Pulmonary Disease
og
manifestation of cyanosis. As appearance of cyanosis A decrease in the partial pressure of oxygen within
depends on the absolute amount of reduced hemoglobin, the alveoli may result in desaturation of pulmonary
patients with polycythemia appear cyanotic with even venous blood. Sudden onset of cyanosis may result
ol
mild hypoxemia (e.g. SpO2 88%, pO2 56 mm Hg), while from pneumonia, pulmonar y edema, atelectasis,
anemic patients do not manifest cyanosis till hypoxemia is pneumothorax, and pulmonary emboli. Insidious onset of
di
severe (e.g. SpO2 70%, pO2 36 mm Hg). cyanosis is noted in chronic conditions like:
a. Obstructive airway disorders: Emphysema, chronic
ar
PATHOPHYSIOLOGY bronchitis, obstruction at larynx or anywhere along the

respiratory tree.
Central Cyanosis b. Alveolar hypoventilation: Chest deformity, central
C
Central cyanosis is caused by arterial desaturation or nervous system (CNS) disease, neuromuscular
abnormal hemoglobin derivative. Central cyanosis is disorders, extreme obesity, primar y alveolar
found in the following conditions. hypoventilation.
c. High altitude.
Cyanotic Heart Disease d. Abnormal diffusing capacity of alveolar-capillary
membrane: Scleroderma, sarcoidosis, berryliosis,
Cardiac conditions causing mixing of deoxygenated
asbestosis.
blood with oxygenated blood result in central cyanosis.
The clues to a cardiac etiology of cyanosis are early age
of appearance, presence of exertional breathlessness Pulmonary Arteriovenous Malformations (PAVMs)
and worsening of cyanosis on exertion. Secondary In this condition, cyanosis and clubbing occur in the
erythrocytosis and clubbing are most marked in this group absence of significant cardiorespiratory symptoms. The
(Figure 1). severity of cyanosis depends on the size and number
KG-46.indd 378 02-11-2018 16:55:45

of PAVMs. Hereditary hemorrhagic telangiectasia is a In type II, the enzyme deficiency is more generalized, CHAPTER
common association. Diffuse PAVMs may occur in the especially affecting the CNS. This is a debilitating disorder
presence of congenital (Abernethy malformation) or
acquired (liver disorders) portosystemic shunts.
with progressive neurological deterioration and usually
proves fatal in the first decade. In the autosomal dominant
46
Cyanosis in Adults
variant, there is abnormal hemoglobin (hemoglobin
Peripheral Cyanosis M) which oxidizes readily to methemoglobin. They are
usually asymptomatic and do not respond to methylene
Peripheral cyanosis is characterized by increased amount
blue.
of reduced hemoglobin in the peripheral capillary bed.
Arterial saturation is normal on blood gas analysis as the
Acquired Methemoglobinemia
amount of reduced hemoglobin within the central arterial
Acquired methemoglobinemia can occur due to certain
a
system is normal. Thus, the secondary effects, such as
erythrocytosis and clubbing, are characteristically absent. drugs such as acetanilide, aniline, nitrobenzene, dapsone,
di
It may be generalized in all peripheries, in conditions sulfonamides, chlorate, benzocaine, lidocaine, prilocaine,
like low cardiac output and hypothermia. It may be sodium nitroprusside, nitroglycerine, chloroquine,
In
localized to a particular region, when there is arterial primaquine, phenytoin, nitrates, and nitrites.
thrombus or embolus, venous obstruction, and in severe
vasoconstriction like Raynaud phenomenon. In all these Sulfhemoglobinemia
of
conditions, the peripheral circulation is slow, resulting This rare disorder is caused by sulfur binding to
in increased oxygen extraction by the tissues, leading to hemoglobin. This can occur following exposure to drugs
elevation of reduced hemoglobin in the capillary bed. such as aniline compounds and phenacetin. Unlike
ty
They have an ashen appearance with cold extremities. methemoglobin, it is not affected by methylene blue. It
remains in the red blood cell till its destruction.
METHEMOGLOBINEMIA 18 cie
Cyanosis may rarely occur due to the presence of abnormal
Methemalbuminemia
forms of hemoglobin-methemoglobin, sulfhemoglobin or Methemalbumin is a pigment formed by the union of
20 o
methemalbumin. Clinical cyanosis occurs when there albumin in the plasma with hemin. This imparts a brown
S
is more than 1.5 g% of methemoglobin or 0.5 g% of color to the plasma. This is present when there is excessive
sulfhemoglobin. breakdown of the red blood cells, like hemolytic state or
extravascular accumulation of blood.
al
Methemoglobin
Pseudocyanosis
ic
Methemoglobin is the oxidized form of hemoglobin

Pseudocyanosis refers to a permanent bluish discoloration
(HbFe 3+ ), which is unable to transpor t ox ygen.
og
caused by deposition of blue pigments in the skin. In

Methemoglobin is usually reduced to deoxyhemoglobin
patients with pseudocyanosis, the mucous membranes of
by the NADH [nicotinamide adenine dinucleotide (NAD) +
the mouth are pink. Unlike cyanosis, in pseudocyanosis
hydrogen (H)] cytochrome b-5 reductase enzyme. Elevated
ol
pressure on the skin fails to blanch the abnormal color.

methemoglobin imparts a characteristic brownish hue to
This may occur after exposure to metals (argyria from
the skin, termed as chocolate cyanosis. When cyanosis
di
topical silver compounds; chrysiasis from gold therapy)

is noted in the absence of clubbing with minimal or
or drugs (amiodarone, minocycline, chloroquine, or
no cardiorespiratory symptoms, methemoglobinemia
ar
phenothiazines).
should be suspected. The saturation is abnormal in these
patients but the PaO2 is normal on blood gas analysis.
DIFFERENTIAL DIAGNOSIS OF CYANOSIS
C
Methemoglobinemia can be congenital or acquired.

The characteristic features of central cyanosis versus
peripheral cyanosis are described in Table 1. Clues to
Congenital Methemoglobinemia
differential diagnosis of central cyanosis are mentioned in
This rare disorder can be either autosomal recessive or Table 2.
autosomal dominant. The autosomal recessive variant
is caused by mutations in the CYB5R3 gene, resulting in Differential Cyanosis
deficiency of NADH cytochrome b-5 reductase enzyme. It
Differential cyanosis is the term used when one part of the
is of two types: Type I and II. In type I, there is an inherent
body is cyanosed while other parts are pink.
deficiency of the reducing enzymes limited to the red
blood cells, resulting in elevation of methemoglobin. They Upper limbs pink, lower limbs cyanosed:
have only mild symptoms such as headache, fatigue and Patent ductus arteriosus (PDA) with severe pulmonary
exertional dyspnea. Ascorbic acid or methylene blue is arterial hypertension (PAH) and right-to-left shunt
helpful to control the methemoglobin levels in this type. (Figure 2) 379
KG-46.indd 379 02-11-2018 16:55:45

SECTION
Table 1: Differentiating features between central and peripheral cyanosis
7 Central cyanosis Peripheral cyanosis
Mechanism Arterial destauration Increased peripheral utilization

Sites Skin, mucous membrane of oral cavity Only skin involved
Temperature Warm Cold clammy
Clubbing Present Absent
Secondary erythrocytosis Present Absent
On warming Cyanosis same Cyanosis reduces
a
Oxygen therapy Pulmonary cause can improve Cyanosis reduces
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Exercise Cyanosis worsens Cyanosis same or improves
In
Arterial blood gas pO2 low pO2 normal
of
Table 2: Clues to differential diagnosis of central cyanosis
Cyanotic heart defect Pulmonary diseases Pulmonary AV Methemoglobinemia
ty
malformations (PAVMs)
Onset of cyanosis Usually at birth or early Usually late Any age Congenital: from birth or
childhood 18 cie Can be sudden infancy;
Acquired: Any age
Clubbing Marked +++ ++ + Absent

20 o
Secondary Marked +++ + + Absent
S
erythrocytosis
Other features Cyanotic spells, squatting, Dyspnea, wheeze, etc. Cardiorespiratory symptoms Cardiorespiratory symptoms
dyspnea, etc. absent absent; neurological
al
signs in type II congenital

methemoglobinemia
ic
Auscultation Cardiac murmur Murmur usually absent; Continuous bruit in large Normal
lung signs present malformations; may be
og
absent in diffuse small

PAVMs
X-ray Abnormal cardiac silhouette Abnormal lung fields Large AVMs: opacity in lung Normal
ol
(either cardiomegaly or boot field noted; Diffuse small

shaped), decreased lung PAVMs- X-ray may be normal
di
vascularity
Echocardiography Abnormal heart Usually normal; may Contrast echo diagnostic- Normal
ar
show secondary PAH or contrast appears in left-

cor pulmonale sided chambers after 3 to 4
cardiac cycles
C
Arterial gas SpO2 and pO2 low SpO2 and pO2 low SpO2 and pO2 low SpO2 low, pO2 normal
Severe coarctation of aorta (CoA) with PDA shunting Upper limbs cyanosed, lower limbs pink (reverse differential
right to left. cyanosis):
Interruption of aorta with PDA shunting right to Transposition of great arteries (TGA) with coarctation
left. [However, most patients with interruption have of aorta

associated ventricular septal defect (VSD) which may TGA and severe PAH with PDA shunting right to left.
shunt bidirectionally due to PAH. Hence, cyanosis is
more often generalized].
In the above conditions, left upper limb may also be Cyanosis in one upper limb:
cyanosed when the left subclavian artery origin is close to Isolation of ipsilateral subclavian artery with pulmonary
or distal to the aortic insertion of PDA. hypertension.
380
KG-46.indd 380 02-11-2018 16:55:45

Cyanosis with Clinical Features of ASD CHAPTER
46
TAPVC
Unroofed coronary sinus
Streaming of inferior vena cava (IVC) flow to left atrium
Cyanosis in Adults
(LA) through patent foramen ovale (PFO)
Straddling of superior vena cava (SVC) in sinus
venosus ASD.
HEMOGLOBIN WORK-UP IN A CYANOTIC

PATIENT
a
Approach to a Cyanotic Patient
di
A detailed history and physical examination can help
in determining the underlying cause of cyanosis. The
In
Figure 2: Differential cyanosis in a child with patent ductus arteriosus
and severe pulmonary hypertension. Cyanosis and clubbing are
following four step-approach may help in most patients.
Timing of onset of cyanosis: The presence of cyanosis
characteristically present in the lower limbs while upper limbs are
normal. The ascending aortic and descending aortic saturation were at birth or early infancy suggests congenital heart
of
96% and 80% respectively on cardiac catheterization disease.
Courtesy: Nageswara Rao Koneti, Care Hospitals, Hyderabad, India Central or peripheral: Warming the extremities reduces
or abolishes the cyanosis in peripheral cyanosis. The
ty
Cyanosis with Continuous Murmur presence of other cardiorespiratory symptoms or signs
suggests central cyanosis.

atresia
TOF physiology with PDA
18 cie
Collaterals in tetralogy of Fallot (TOF) with pulmonary
Is there clubbing? Cyanosis associated with clubbing
occurs in right-to-left shunting at cardiac (congenital

heart disease) or intrapulmonary level (PAVMs) and
20 o
Total anomalous pulmonary venous connection
suppurative pulmonary disease (e.g. lung abscess).
(TAPVC)
S
Arterial blood gas analysis and pulse oximeter :

Pulmonary AV malformations
Clinicians should be wary while using pulse oximetry
Truncus arteriosus with branch pulmonary artery
in the cyanotic patient. Bedside pulse oximetry relies
al
stenosis
on the infra-red light absorption characteristics of oxy
Surgically created shunts.
and deoxygenated hemoglobin. Although it usually
ic
indicates hypoxemia in patients with central cyanosis,

Cyanotic Heart Disease with Cardiomegaly pulse oximetry may falsely indicate arterial hypoxemia
og
on X-ray in patients with peripheral cyanosis or those with

Unobstructed TAPVC abnormal hemoglobin. This can be circumvented
Truncus arteriosus by doing arterial blood gas analysis, as it readily
ol

TGA, double outlet right ventricle (DORV), single distinguishes deoxyhemoglobin from abnormal types
ventricle or tricuspid atresia with increased pulmonary of hemoglobin, and will demonstrate a low pO 2 in
di
blood flow central cyanosis.

Eisenmenger syndrome with atrial septal defect
ar

(ASD)/AV septal defect Investigations

Ebstein’s anomaly
The following investigations may be considered in a
C
Severe pulmonary stenosis (PS)/tricuspid regur-

cyanotic patient based on the clinical scenario. The
gitation/ASD.
investigations are done to establish the etiology, effects of
hyperviscosity and to rule out iron deficiency.
Cyanotic Heart Disease with Relatively Normal Complete blood count, mean corpuscular volume
Sized Heart on X-ray (MCV), mean corpuscular hemoglobin (MCH), mean

TOF corpuscular hemoglobin concentration (MCHC),
TGA, DORV, single ventricle or tricuspid atresia with peripheral smear
pulmonary stenosis Serum ferritin, transferrin and transferrin saturation
Obstructed TAPVC Serum electrolytes and creatinine
Eisenmenger syndrome with VSD/PDA/AP window Serum uric acid
Pulmonary AV malformations Liver function tests
Anomalous systemic venous drainage. Chest X-ray
381
KG-46.indd 381 02-11-2018 16:55:46

SECTION Electrocardiogram analysis machines give the value of methemoglobin
Echocardiogram including contrast echocardiography levels also.
7

Pulmonary function test
Computed tomography
Methemoglobinemia: The diagnosis is confirmed
by direct measurement of methemoglobin by
Simple bedside test: One approach for assessing multiple wavelength co-oximeter. Specific enzyme
the etiology of cyanosis is to obtain a heparinized assays (NADH cytochrome b-5 reductase) may be
arterial blood specimen. If the sample is dark red determined to diagnose inherited cases. Hemoglobin
and becomes bright red on shaking in air, it indicates electrophoresis and DNA sequencing of the globin
arterial hypoxemia consistent with central cyanosis. chain gene can be used to identify hemoglobin M.
One should perform blood gas analysis on another
specimen to confirm arterial hypoxemia. If the
TREATMENT STRATEGY
a
specimen obtained is brown and does not change
di
color on shaking in air, the plasma should be allowed If the cyanosis is due to a correctable lesion like tetralogy
to separate. If the plasma is brown, methemalbumin of Fallot, surgical correction is done. In conditions like
In
is likely to be present. If the plasma is clear, one Eisenmenger syndrome, where corrective surgeries are
should suspect the presence of methemoglobin not possible, palliative care and preventive measures are
or sulfhemoglobin. A bright red arterial specimen adopted to avoid complications due to cyanosis and its
of
obtained in a patient with generalized blue skin color secondary adaptive mechanisms.
should lead one to suspect deposition of non-heme Prevent and treat iron deficiency: The causes of
pigment in the skin (Figure 3). iron deficiency include dietar y insufficiency,
ty
Arterial blood gas analysis: It helps to differentiate repeated phlebotomies, hemoptysis, epistaxis, and
central cyanosis from peripheral cyanosis and those menorrhagia. Iron deficiency is an established risk
18 cie
with abnormal hemoglobin. Most arterial blood gas factor for cerebrovascular complications in cyanotic
20 o S
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ic
og
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ar
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Figure 3: Schematic representation of a simple bedside test for differential diagnosis of cyanosis
382
KG-46.indd 382 02-11-2018 16:55:47

heart defects. Hence, all cyanotic patients should be embolization of the aortopulmonary or bronchial CHAPTER
evaluated for iron deficiency and treated with iron vessels may be helpful.
supplementation. Iron deficiency should be assessed
by serum ferritin and transferrin saturation and not
Methemoglobinemia: Methylene blue along with 46
ascorbic acid and riboflavin is useful in autosomal
Cyanosis in Adults
by red blood cell indices alone. Iron supplementation recessive type of methemoglobinemia. High levels of
is required if serum ferritin ≤15 µg/L and transferrin methemoglobin which do not respond to methylene
saturation ≤15%. Inappropriate phlebotomies should blue are treated with hyperbaric oxygen and exchange
be avoided. Most often, correction of iron deficiency transfusion.
itself reduces the hyperviscosity symptoms in cyanotic
patients. Iron deficiency should be suspected when
CONCLUSION
hyperviscosity symptoms are present with a hematocrit
a
less than 65%. Multidisciplinary approach is required in evaluation and
di
Av oid dehydration: D ehydration can worsen management of cyanosed patients. History, complete
hyperviscosity symptoms. Hence, adequate hydration clinical examination, arterial blood gas analysis and
In
is advised in these patients, especially during fever, radiologic tests can clinch the diagnosis in most of them.
diarrhea, vomiting, and hot climate. Diuretics should Curative or palliative measures can be adopted based on
be used sparingly and with caution, when needed. etiologic diagnosis. Often, the complications in cyanotic
of
Phlebotomy: It is indicated only when erythrocytosis patients are due to the secondary adaptive mechanisms.
is associated with hyperviscosity symptoms such Iron repletion and avoidance of unwarranted phlebotomies
as headache, blurred vision, dizziness, fatigue, help in maintaining a balanced homeostasis in most of the
ty
paresthesia, and myalgia. Brain abscess should be palliated patients.
ruled out as a cause of headache. Phlebotomy should
18 cie
be carried out only in patients with hyperviscosity
symptoms when the hematocrit is >65. Any dehydration
SUGGESTED READING
should be corrected before assessing the need for 1. Blount SG Jr. Cyanosis: pathophysiology and differential
20 o
phlebotomy. The following formula guides to calculate diagnosis. Prog Cardiovasc Dis. 1971;13(6):595-605.
2. Braunwald E. Hypoxia and cyanosis. In: Harrison’s
S
the volume to be exchanged during venesection to

achieve a desired hematocrit: Principles of Internal Medicine. Kasper DL, Braunwald E,
Volume to be exchanged (mL) = Fauci AS, Hauser SL, Longo DL, Jameson JL (Eds). 16th ed.
al
New York: McGraw Hill. 2005. pp. 210-1.

Initial hematocrit – desired hematocrit 3. Broberg CS. Challenges and management issues in adults
ic
Initial hematocrit with cyanotic congenital heart disease. Heart. 2016;

× body weight (kg) × blood volume (mL/kg) 102(9):720-5.
og
Often, in adults, 500 mL of blood may be withdrawn 4. Noro L. On cyanosis. Acta Medica Scandinavica. Vol CXXII
fasc. I, 1945.
with simultaneous infusion of an equal volume of
5. Oechslin E. Management of adults with cyanotic congenital
isotonic saline over one hour. Routine prophylactic
ol
heart disease. Heart. 2015;101(6):485-94.

phlebotomies in asymptomatic patients with high
6. Snider HL. Cyanosis. In: Clinical Methods: The History,
hematocrit should be avoided as it may lead to iron
di
Physical, and Laboratory Examinations. Walker HK, Hall

deficiency.
WD, Hurst JW, (eds). 3rd edn. Boston: Butterworths; 1990.
Gouty arthritis: Oral colchicine for reduction of pain in
ar

pp. 236-8.
acute stage followed by allopurinol is the treatment for 7. Tandon R. Bedside Approach in the Diagnosis of Congenital
these patients. Asymptomatic hyperuricemia does not Heart Diseases, 2nd edn. New Delhi: Sitaram Bhartia
C
require any specific medication. Care should be taken Institute of Science & Research, 2011.
to avoid dehydration, aggravating factors in the diet 8. Thorne SA. Management of polycythaemia in adults with
and concomitant medications. cyanotic congenital heart disease. Heart. 1998;79(4):315-6.
Hemoptysis: Supportive measures, such as cough 9. Vongpatanasin W, Brickner ME, Hillis LD, et al. The
suppressants, volume replacement and iron Eisenmenger syndrome in adults. Ann Intern Med. 1998;
supplementation, are initiated. If hemoptysis persists, 128(9):745-55.
383
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Eisenmenger Syndrome:
CHAPTER 47 An Update
a
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INTRODUCTION EPIDEMIOLOGY
Congenital heart disease (CHD) is the most common With advances in early diagnosis and treatment of CHD,
In
congenital defect affecting approximately 8 of 1000 the incidence of ES has sharply fallen especially in the
live births.1,2 Pulmonary hypertensive vascular disease Western world by 50% in the last 5 decades.8 Although
of
(PHVD) associated with congenital heart disease (CHD) exact prevalence of ES is not known, historical data puts
is probably the most common cause of pulmonary it at 8% of all CHD with increase to 10–12% in patients
vascular disease worldwide. Eisenmenger syndrome (ES) with left-to-right shunt.9 Prevalence of PHVD associated
ty
represents the most severe form of PHVD associated with with CHD in French and Scottish registries is estimated
CHD. Although patients with ES frequently survive into at 1.6 to 12.5 cases per million with approximately 50%
18 cie
their third or fourth decade; progressive cyanosis, exercise
limitation and deteriorating quality of life are the hallmark
of the disease. For a long time, therapy has been limited
secondary to reversal of shunt. 10,11 A similar registry
from The Netherlands, reports the incidence of PHVD in
CHD at 4.25 cases per million with 58% associated with
ES.12 A recent Belgian registry specific for ES reported a
20 o
to symptomatic options or lung or combined heart-lung
transplantation. As new selective pulmonary vasodilators prevalence of 11 per million adults.13 The population of
S
have become available and proven to be beneficial in adults with CHD is growing at an acceleration rate of 5%
various forms of pulmonary arterial hypertension, this per year. In the USA, more than 1 million adults have CHD;
10% of the cases present with pulmonary hypertension
al
targeted medical treatment has been expected to show

(PH), 30% of them due to unrepaired defects. The ES
promising effects with a delay of deterioration also in
will develop in half of these patients with unrepaired
ic
Eisenmenger patients. Also, nearly one-third of the

cardiovascular defects.14 Unfortunately, limited data is
patients with ES maintain some degree of vasoreactivity
og
available about prevalence of disease in the less privileged

to inhaled nitric oxide (iNO), which along with reverse
part of the world, where most of the disease burden
remodeling of targeted therapy may vastly improve
is presumably located. Worldwide, it is estimated that
hemodynamics, exercise capacity, and quality of life and
ol
3.2 million children are at risk for the development

survival in this select subgroup.3,4
of PHVD associated with CHD. 15 Most of them do not
di
develop ES, particularly if cardiac repair is done within

DEFINITION AND CLASSIFICATION the first 2 years of life. However, due to inequality of
ar
In patients with CHD, PHVD is defined as mean pulmonary access to medical care, only a small percentage of
artery pressure (PAP) >25 mm Hg and pulmonary vascular patients (2–15%) undergo reparative surgery in the
resistance index (PVRI) >3 Wood units × m2 for biventricular developing world.15 The presence of PHVD is associated
C
physiology.4,5 The most severe form of pulmonary arterial with 4-fold increase in mortality in adult patients with
hypertension (PAH) related to CHD is called Eisenmenger CHD.2
syndrome (ES). In 1897, Victor Eisenmenger described
postmortem findings of ventricular septal defect in CLASSIFICATION
an adult patient who died of cyanosis and dyspnea on In the clinical classification of pulmonary hypertension
exertion.6 However, the exact pathophysiology was only (PH) proposed at Dana Point in 2009 and revised at the
described six decades later by Paul Wood who defined National Institute for Health and Care (NICE) in 2013
ES as ‘pulmonary hypertension at systemic level, due to (Table 1); PH associated with all CHD was clubbed
a high pulmonary vascular resistance (>800 dynes/cm5 in Group I. 16 The rationale for the same is the similar
or >10 Wood unit × m2), with reversed or bidirectional histological findings of plexiform lesions on light
shunt through any large communication between the two microscopy. However, the Dana Point classification with
circulations.’7 NICE modification do not always readily apply to PHVD
KG-47.indd 384 02-11-2018 16:55:33

Table 1: Updated clinical classification of pulmonary hypertension (NICE 2013) CHAPTER
47
1. Pulmonary arterial hypertension
1.1 Idiopathic PAH
1.2 Heritable PAH

1.2.1 BMPR2
1.2.2 ALK-1, ENG, SMAD9, CAV1, KCNK3
1.2.3 Unknown
1.3 Drug and toxin induced
1.4 Associated with:
1.4.1 Connective tissue disease
a
1.4.2 HIV infection
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1.4.3 Portal hypertension
1.4.4 Congenital heart diseases
In
1.4.5 Schistosomiasis
1’ Pulmonary veno-occlusive disease and/or pulmonary capillary hemangiomatosis
of
1’’ Persistent pulmonary hypertension of the newborn (PPHN)
2. Pulmonary hypertension due to left heart disease
2.1 Left ventricular systolic dysfunction
ty
2.2 Left ventricular diastolic dysfunction
2.3 Valvular disease
2.4 18 cie
Congenital/acquired left heart inflow/outflow tract obstruction and congenital cardiomyopathies
3. Pulmonary hypertension due to lung diseases and/or hypoxia
3.1 Chronic obstructive pulmonary disease
20 o
3.2 Interstitial lung disease
S
3.3 Other pulmonary diseases with mixed restrictive and obstructive pattern
3.4 Sleep-disordered breathing
al
3.5 Alveolar hypoventilation disorders

3.6 Chronic exposure to high altitude
ic
3.7 Developmental lung diseases

4. Chronic thromboembolic pulmonary hypertension (CTEPH)
og
5. Pulmonary hypertension with unclear multifactorial mechanisms

5.1 Hematologic disorders: Chronic hemolytic anemia, myeloproliferative disorders, splenectomy
5.2 Systemic disorders: Sarcoidosis, pulmonary histiocytosis, lymphangioleiomyomatosis
ol
5.3 Metabolic disorders: Glycogen storage disease, Gaucher disease, thyroiddisorders

di
5.4 Others: Tumoral obstruction, fibrosing mediastinitis, chronic renal failure, segmental PH
ar
associated with CHD. Arterial and venous hypertension vasodilators and constrictors ultimately leading to
are arbitrarily separated in the clinical classification, it has unfavorable vascular remodeling.19
C
been demonstrated that these frequently coexist in PHVD Four clinical variables have been suggested in
associated with CHD.17 Also, the proliferating endothelial influencing the development of pulmonary hypertensive
cells in PHVD associated with CHD are of polyclonal vascular disease in patients with CHD.20
origin as opposed to monoclonal in idiopathic/hereditary 1. Age of the patient
PAH.18 This has led to development of numerous sub- 2. Type of cardiac lesion
classifications in pediatric PH and PHVD associated with 3. Genetic and epigenetic factors
CHD (Tables 2 to 4).5 4. Environmental factors and comorbidities.
PATHOPHYSIOLOGY Age
Increase in pulmonary blood flow (PBF) and pressure The duration of shunt flow should be directly proportional
induce endothelial cell dysfunction, abnormal shear to the chance of developing irreversible disease.
stress, circumferential wall stretch and imbalance between Rabinovitch et al. demonstrated that even advance
385
KG-47.indd 385 02-11-2018 16:55:33

SECTION Table 2: Anatomic-pathophysiologic classification of congenital systemic-to-pulmonary shunts associated
with pulmonary arterial hypertension
7 Type Description
1. Type
1.1 Simple tricuspid shunt

1.1.1 Atrial septal defect (ASD)
1.1.1.1 Ostium secundum
1.1.1.2 Sinus venosus
1.1.1.3 Ostium primum
1.1.2 Total or partial unobstructed anomalous pulmonary venous return
a
1.2 Simple post-tricuspid shunts
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1.2.1 Ventricular septal defect (VSD)
1.2.3 Patent ductus arteriosus
In
1.3 Combined shunts (describe combination and define predominant defect)
1.4 Complex congenital heart disease
1.4.1 Complete atrioventricular canal defect
of
1.4.2 Truncus arteriosus
1.4.3 Single ventricle physiology with unobstructed pulmonary blood flow
ty
1.4.4 Transposition of great arteries with VSD (without pulmonary stenosis) and/or patent ductus arteriosus
1.4.5 Other
2.
2.1
2.1.1
Hemodynamic (specify Qp/Qs)
18 cie
Dimension (specify for each defect if >1 congenital heart defect)
Restrictive (pressure gradient across the defect)

20 o
2.1.2 Nonrestrictive
S
2.2 Anatomic
2.2.1 Small to moderate (ASD ≤ 2.0 cm and VSD≤ 1.0 cm)
2.2.2 Large (ASD> 2.0 cm and VSD > 1.0 cm)
al
3. Direction of shunt
3.1 Predominantly systemic to pulmonary
ic
3.2 Predominantly pulmonary to systemic

3.3 Bidirectional
og
4. Associated cardiac and extracardiac abnormalities

5. Repair status
ol
5.1 Unoperated
5.2 Palliated (specify type of operation, age of surgery)
di
5.3 Repaired (specify type of operation, age of surgery)

ar
pulmonary vascular changes could be reversed with Pretricuspid shunts result in volume overload on the
cessation of precipitating factors. However; there are pulmonary circulation without an immediate increase in
C
a certain group of patients who develop PHVD much pulmonary artery pressures. The development of PHVD in
earlier than the cut off criteria of 2 years as described pretricuspid shunt is determined by the size of the defect,
by Rabinovitch et al. Environmental factors such as right ventricular compliance as well as the presence of left
high altitude, genetic and epigenetic factors such as the ventricular dysfunction and left heart disease.3 Moreover,
presence of Down’s syndrome increase the likelihood of only 2% of the patients with pretricuspid shunt progress
developing PVHD earlier than previously described.21 to have ES.8 The presence of PHVD in adults with simple
pretricuspid shunt should initiate investigation into
Types of Cardiac Lesion other probable causes of PAH. Even in patients with post-
The wide spectrum of CHD presents a unique perspective tricuspid shunt, complex lesions such as transposition of
to development of PHVD. Not all CHDs have the same great vessels with a ventricular septal defect or a truncus
propensity to develop PHVD. Patients with post-tricuspid arteriousus develop PHVD earlier than simpler lesions
shunt, with increase in both flow and pressure develop such as ventricular septal defect (VSD), patent ductus
386 PHVD earlier that patients with pretricuspid shunt. arteriosus (PDA), and aortopulmonary window.
KG-47.indd 386 02-11-2018 16:55:33

Table 3: Clinical classification of congenital systemic-to-pulmonary shunts associated to PAH CHAPTER
47
A. Eisenmenger syndrome Includes all systemic-to-pulmonary shunts resulting from large defects and leading to
a severe increase in PVR and a reversed (pulmonary-to-systemic) or bidirectional shunt;
cyanosis, erythrocytosis, and multiple organ involvement are present

B. PAH associated with systemic-to- Includes moderate-to-large defects; PVR is mildly to moderately increased, systemic-to-
pulmonary shunts pulmonary shunt is still prevalent, and no cyanosis is present at rest
C. PAH with small defects Small defects (usually ventricular septal defects <1 cm and atrial septal defects <2 cm
of effective diameter assessed by echocardiography); clinical picture is very similar to
idiopathic PAH
D. PAH after corrective cardiac surgery Congenital heart disease has been corrected, but PAH is still present immediately after
surgery or recurs several months or years after surgery in the absence of significant
postoperative residual lesions
a
di
Table 4: The broad schema of 10 basic categories of pediatric pulmonary hypertensive vascular disease
In
Category description
1. Prenatal or developmental pulmonary hypertensive vascular disease
2. Perinatal pulmonary vascular maladaptation
of
3. Pediatric cardiovascular disease
4. Bronchopulmonary dysplasia
ty
5. Isolated pediatric pulmonary hypertensive vascular disease (isolated pediatric PAH)
6. Multifactorial pulmonary hypertensive vascular disease in congenital malformation syndromes
7.
8.
Pediatric lung disease
Pediatric thromboembolic disease
18 cie
9. Pediatric hypobaric-hypoxic exposure
20 o
10. Pediatric pulmonary vascular disease associated with other system disorders
S
Genetic and Epigenetic Factors hypobaric oxygen in prevention of development of PHVD

al
Wide variability in the development of PHVD in response associated with CHD has been suggested.27
ic
to similar stimuli leads to consideration of a genetic

link. Associations with trisomy 21 and the occurrence of Comorbidities
og
PHVD in children with syndromic and unusual genetic It is unknown how other factors, such as anemia,
defects reinforce this view. 5 The BMPR2 mutation has malnutrition, and infections such as tuberculosis, HIV and
been described in 6% of a cohort of children with CHD.22 schistosomiasis, would affect development of PHVD.28,29
ol
Mutation in BMPR2 with alteration in the gene encoding

the protein ALK1 are known to cause PAH. 22 Du et al. NATURAL HISTORY
di
reported a link between familial and acquired PH, and

Outcomes of patient with ES are better than that of other
molecular genetic contributions to abnormal septation,
causes of PH. In a study of 192 patients, 20-year survival
ar
PDA, and ASD continue to be elucidated.23 Limsuwan

in adults with ES was 87% as compared to 36% in the
et al. recently demonstrated protective effect of repeat
patients with operated CHD and idiopathic pulmonary
C
polymorphism of 5 UTR BMPR2 in development of PHVD

arterial hypertension (IPAH) (Figure 1).30,31 The larger
in children with CHD.24
REVEAL study demonstrated similar outcomes in patients
with PH associated with CHD including ES as compared
Environmental Factors and Comorbidities to IPAH.32 The prognosis also is dependent on the type
High altitude has a complex and profound effect on of CHD with complex CHD with ES such as transposition
normal neonatal transition of pulmonary hemodynamics, of great arteries and single ventricle physiology with
incidence of CHD as well as development of PHVD. 25,26 increased pulmonary blood flow having worse prognosis
However, the pulmonary vascular changes in the as compared to ES with simpler lesions such as VSD, PDA,
individuals staying at high altitude are reversible and and ASD (Figure 2). The actuarial survival rate is 80% at
decrease in PAP and PVRI has been demonstrated in 10 years, 77% at 15 years 42% at 25 years.31 Most Eisenmenger
such individuals after chronic exposure to sea level. Thus, patients die from sudden cardiac death, congestive heart
operability assessment and management decisions are failure, hemoptysis, cerebral abscesses, thromboembolic
different at high altitude. Probable protective effect of events, from complications during pregnancy, or due
387
KG-47.indd 387 02-11-2018 16:55:33

SECTION
7
a
di
In
Figure 1: Patients with Eisenmenger syndrome have better survival Figure 2: Prognosis in patients with simple defects with Eisenmenger
as compared to patients with idiopathic pulmonary hypertension or syndrome is better than patients with complex diseases like
persistent pulmonary hypertension post shunt closure transposition of great arteries and truncus arteriosus
of
Source: Barst, et al. Four- and seven-year outcomes of patients with Source: Diller GP, et al. Presentation, survival prospects, and predictors
congenital heart disease-associated pulmonary arterial hypertension of death in Eisenmenger syndrome: a combined retrospective and
(from the REVEAL Registry). The American Journal of Cardiology. case–control study. European Heart Journal. 2006;27(14):1737-42.
2014;113:147-55.
ty
18 cie
to noncardiac surgery. 33,34 A recent multicenter study
demonstrated age, presence of pretricuspid shunt, oxygen
saturation at rest, presence of pericardial effusion as
complex interaction between RBC mass and morphology,
aggregation and dispersion of blood cells, plasma viscosity,
temperature and shear stress.35 Compensated secondary
predictors of death in patient with ES.34 erythrocytosis has been demonstrated to produce little
20 o
or no symptoms even when hematocrit increases to
S
CLINICAL FEATURES 70%.36 Acute normalization of the hematocrit secondary

Dyspnea and effort intolerance occurs in 40% of the to isovolumic phlebotomy has been demonstrated to
al
patients followed by angina, syncope, hemoptysis, and decrease the hyperviscosity symptoms along with increase
congestive heart failure. Low cardiac output, abnormal in cardiac output in patients with chronic cyanosis
secondary to ES as well as other cyanotic CHD.37 However,
ic
oxygen delivery, abnormal rheology; systemic endothelial

dysfunction, peripheral myopathy, and deconditioning repeated phlebotomies can lead to iron deficiency, which
og
contribute to the development of symptoms in patients by itself is a risk factor for development of cerebrovascular
with ES. accidents as well as overall adverse outcomes in patients
On physical examination, central cyanosis with with ES. 38 Decompensated erythrocytosis also leads
ol
clubbing may be present. Right ventricular heave with to shear endothelial stress with imbalance between
prominent pulmonary component of second heart sound vasodilators and constrictors resulting in impaired
di
are often present. More advance cases may present with vascular function.39
peripheral edema and hepatosplenomegaly. In addition,
ar
patients may present with serious complications such Platelets

as cerebral abscess, cerebrovascular stroke, bacterial Platelet abnormalities in ES include both thrombocytosis
C
endocarditis, hemoptysis, or myocardial dysfunction as well as thrombasthenia. Both of which have been
with low cardiac output. Chronic hypoxia secondary to correlated to the increase in hematocrit levels.40
the right-to-left shunt is responsible for the multisystem
involvement in ES.
Abnormal Coagulation Factors
Erythrocytosis Decrease in vitamin K-dependent clotting factors (II, VII,
IX, and X), factor V, and large multimers of von Willebrand
Chronic cyanosis leads to erythrocytosis and increase
factor contribute to bleeding tendency in ES.41
in the red cell mass. An inverse relationship has been
established between baseline saturations and red blood
cell (RBC) count in iron replete patients with ES. This Thrombosis
helps in tissue oxygen delivery thus increasing the exercise In spite of the presence of platelet and coagulation
capacity.35 Maintenance of adequate blood viscosity is a abnormalities, laminated thrombi in the dilated
388
KG-47.indd 388 02-11-2018 16:55:35

pulmonary arteries have been demonstrated in as high RENAL FUNCTION AND URIC CHAPTER
as 30% of patients with ES. Older age, female gender, poor ACID CLEARANCE
functional class, ventricular dysfunction, and dilated
pulmonary arteries are all the risk factors associated
Both structural and functional renal abnormalities have 47
been described in patients with cyanotic heart diseases

with development of thrombi.42However, the presence of
including ES. However, moderate-to-severe decrease
these thrombi were not associated with adverse events in
in glomerular filtration rate (GFR) is associated with
patients with ES.43
mortality in patients with ES. 52 While renal plasma
flow is low, filtration fraction remains high presumably
CEREBROVASCULAR EVENTS secondary to efferent arteriolar constriction.53 Although
Cerebrovascular events ranging from transient ischemic not universally seen in all patients, isovolumic phlebotomy,
a
attack to complete infarct have been described in with a decrease in hematocrit to normal, does not affect
approximately 12% of the adult population with ES. The glomerular filtration rate but decreases filtration fraction.
di
etiology for these events could be multifactorial ranging The latter is associated with spontaneous diuresis. 54
from paradoxical emboli, endothelial dysfunction,
In
Additionally, inability to concentrate urine or inability to
rheological abnormalities, and iron deficiency. The excrete a water load is demonstrated in some patients.55
presence of risk factors, such as atrial arrhythmias and
Serum uric acid concentration is elevated in ES that
systemic hypertension, increase the chances of developing
of
may be related to reduced renal excretion with a small
these events.44
contribution of increased production in the setting of
tissue hypoxia and cell turnover.55,56 Oya and colleagues
PULMONARY DYSFUNCTION
ty
reported that elevated serum uric acid concentration was
Both obstructive and restrictive lung diseases have been associated with increased mortality [hazard ratio (HR) 1.6;
18 cie
described in patients with cyanotic CHD including ES.45,46
Moderate-to-severe lung function abnormality has also
been demonstrated to be an independent predictor of
95% CI, 1.3–2.7] independently of clinical factors and other
serum markers.56
20 o
mortality in these patients.45 In addition to pulmonary
vascular changes, scoliosis associated with approximately
OTHER MISCELLANEOUS ORGAN
S
10% of patients with CHD, enlarged cardiopulmonary INVOLVEMENT

ratio and enlarged central pulmonary arteries resulting Patients with ES have increase heme turnover secondary
al
in space-occupying lesion have been described as the to erythrocytosis. They are thus at risk of developing
potential mechanisms for lung function abnormalities.45 calcium bilrubinate gallstones complicated by acute
ic
Patients with ES have lowest exercise capacity among cholelithiasis. 57 Other systemic involvement would
all adults with CHD.47 In patients with ES; peak oxygen include hypertrophic osteoathropathy, retinal changes,
og
consumption (VO 2 ) is reduced, phase I response is immune dysfunction, and pheochromocytoma. 58-60
blunted and there is decrease in peripheral oxygen Immunologic dysfunction predisposes them to infective
saturation. Blunted augmentation of pulmonary blood endocarditis, chronic sinusitis, and cerebral abscess.
ol
flow during exercise secondary to PHVD, increased right-

to-left shunt and increased peripheral oxygen extraction
INVESTIGATIONS
di
lead to these abnormalities.47 Even at low levels of steady

work, patients with ES have to depend upon increase in
Laboratory Investigations
ar
heart rate for maintenance of cardiac output. Elevated

minute ventilation (VE), and elevated minute ventilation/ Hematological investigations including hematocrit,
platelet counts, iron stores, uric acid, and renal function
C
carbon dioxide clearance (VE : VCO 2) ratio have been

demonstrated in patients with ES.48 Despite these changes, are important prognostic markers in patients with ES.
patients with ES maintain normal arterial pH and partial A number of biomarkers including brain natriuretic
pressure of carbon dioxide (PCO2). peptide (BNP), N-terminal natriuretic peptide (NT-pro-
Decrease in oxygen saturation and partial pressure BNP), high sensitivity cardiac troponin T, atrial natriuretic
of oxygen, more in supine position in the absence of peptide, and more recently serum homocysteine and
obstructive sleep apnea, has been demonstrated in hydrogen sulphide have now been evaluated for usefulness
patients with ES.49 The frequency of nocturnal hypoxia in prognostication of patients with ES. 61,62 The BNP and
is correlated with the degree of hematocrit; however, the NT-Pro-BNP levels are predictive of right ventricular
iron status of these subjects was not known.50 However, a function and adverse events in patients with ES. Serum
2-year trial with nocturnal oxygen supplementation failed homocysteine and hydrogen sulphide levels are associated
to demonstrate any benefit in patients with ES.51 with retention of vasoreactivity in patients with ES.
389
KG-47.indd 389 02-11-2018 16:55:37

SECTION Exercise Testing Cardiac Catheterization
7
Exercise capacity is depressed in patients with ES. Cardiac catheterization with vasodilator testing is useful to
Both resting and postexercise saturations have been predict response to therapy and prognosis in patients with
demonstrated to have prognostic significance in patients ES. Higher mean right atrial pressure, lower cardiac output,
with ES. Six-minute walk test and/or cardiopulmonary and no response to vasodilator therapy are associated
exercise testing (CPET) with peak oxygen consumption can with poor prognosis in patients with ES (Figures 3A
be used for assessment of patients with ES. Six-minute walk and B).69,70
test is an easy, nonexpensive, and objective way to assess
daily functional capacity in patients with PHVD. Distance MANAGEMENT STRATEGY
walked in six minutes, post-test saturation, and Borg In the past, management of patients with ES was limited
a
dyspnea scale have been demonstrated to have prognostic to symptomatic therapy with heart lung transplant or lung
significance in patients with ES. 63 Similarly, decreased
di
transplant with repair of the intracardiac defect. However,
peak oxygen consumption in CPET has been shown to be in the past decade, considerable experience has been
associated with poor prognosis in patients with ES.64
In
gathered in the management of these patients with both
conventional and targeted therapies. Current guidelines in
Cardiac Imaging the management of patients with ES recommend regular
of
Normal right ventricular function and right ventricle to consultations with experienced physicians in CHD and PH.
pulmonary artery coupling is essential for favorable outcome
in patients with ES. Right ventricular function can be assessed Conventional Therapy
ty
using 2D and 3D echocardiogram with or without strain and
strain rate imaging. Tricuspid annular systolic excursion
Phlebotomy
18 cie
(TAPSE) and right ventricular fractional area change can
be easily obtained using M-mode and 2D echocardiogram.
Though secondary erythrocytosis in response to chronic
hypoxemia is the hallmark of ES, severity of secondary
A lower TAPSE, larger RA diastolic area, and right atrium/ erythrocytosis in itself does not increase the risk of stroke
20 o
left atrium (RA/LA) area ratio have been associated with and is not an indication for phlebotomy. 71 Repeated
phlebotomies can lead to iron deficiency and thus increase
S
poor prognosis in patients with ES. 65 The presence of

pericardial effusion in PAH without CHD is associated with risk for development of stroke and worsening symptomatic
poor prognosis. Although not infrequent, the presence of status secondary to decreased oxygen delivery. 71
al
pericardial effusion has not shown to be associated with poor Therapeutic phlebotomy should be restricted to relief of
prognosis in patients with ES.66 Right ventricular function moderate-to-severe symptoms of hyperviscosity in the
ic
can be more accurately assessed with cardiac magnetic absence of volume and iron deficiency in patients with ES.
og
resonance imaging (cMRI). Along with the RV function, cMRI

can also assess the cardiac output, quantum of pulmonary Iron Supplement
blood flow, and pulmonary artery distensibility, which can Iron deficiency is a common complication in patients with
ol
help predict outcomes in patients with ES.67,68 ES. ‘Relative anemia’ is often not recognized in cyanotic
di
ar
C
A B
Figures 3A and B: Lower mean right atrial pressure and higher cardiac output are associated
with better prognosis in patients with pulmonary hypertension
Source: Hopkins, et al. Comparison of the hemodynamics and survival of adults with
severe primary pulmonary hypertension or Eisenmenger syndrome. J Hear Lung Transplant. 1996;15(1 Pt 1):100-5.
390
KG-47.indd 390 02-11-2018 16:55:37

patients: an Hb concentration, which drops to levels that Infective Endocarditis Prophylaxis and CHAPTER
are normal for the general population, is often suboptimal Prevention of Infections
for cyanotic individuals. Iron supplementation to treat
Patients with ES are highly prone to infective endocarditis 47
iron deficiency (transferrin saturation <10–20% of normal and prophylactic therapy with antibiotics as well as

or serum ferritin <30 mg/L) is prudent in the management routine oral hygiene is strongly recommended for these
of patients with ES.72 patients. Similarly, they are also prone to lower respiratory
tract infections, which are responsible for approximately
Oxygen Therapy 7% of the deaths in patients with PAH. Hence, routine
The use of oxygen supplementation in patients with ES vaccination with pneumococcal and influenza vaccine is
is controversial. It has been shown to have no impact on strongly recommended in patients with ES.73
a
exercise capacity and survival in adult patients with this
OTHER CONVENTIONAL THERAPIES
di
condition.67 Some patients may benefit from nocturnal
supplementation for symptomatic relief, and oxygen may Other conventional therapies, such as diuretics, digoxin,
In
be useful in patients with advanced disease and in those anticoagulants, and antiarrhythmics, have been used in
awaiting heart–lung transplants. patients with ES without much mortality or morbidity
benefits.73
of
Exercise Conditioning
Supervised exercise including Yoga has been demons- TARGETED THERAPY
trated to improve functional capacity.73 Mild-to-moderate
ty
The primary goal of targeted therapy in patients with ES
aerobic activity and low-level resistance exercises can be is to improve tissue oxygen delivery, thereby reducing
18 cie
safely performed in most clinically stable patients. This
prompted elevation of recommendation to level 1 in the
updated treatment guidelines for PH.16 Highly isometric
symptoms, improving quality of life and survival.
Acute vasoreactivity testing with nitric oxide (NO) and
subsequent therapy with calcium-channel blockers
exercise (e.g. weight lifting) should be avoided. in responders is established in IPAH, but no evidence
20 o
is available in PAH-CHD. The use of calcium-channel
S
blockers is, in fact, discouraged in ES, as they may cause

Pregnancy and Contraception
significant peripheral vasodilatation and hypoxia.
Parturients with PAH have been described to experience Vasodilation of the pulmonary vasculature would
al
adverse outcomes as the added physiologic demands of decrease the right-to-left shunt across the defect, increase
pregnancy and parturition can precipitate right ventricular the pulmonary blood flow thereby increasing the systemic
ic
failure leading to maternal and/or fetal complications. saturations. However, except for inhaled therapy, all the
Very high maternal and fetal mortality rates (30–50%)
og
other pulmonary vasodilators are not specific and have

have been reported in parturients with PAH. 74 And, dilatory effects on the systemic vasculature as well. There
therefore, women with ES in the child-bearing age should are three groups of drugs now available for therapy in
ol
be counseled to avoid pregnancy.16 Many women with patients with ES.

ES are also often treated with pulmonary therapies, 1. Endothelin receptor antagonist (ERA)
di
which are teratogenic (ERAs), while cyanosis makes 2. Phosphodiasterase inhibitors (PDEI)
spontaneous abortions likely. Also, the expectant mother 3. Prostanoids
ar
with ES should be advised on the risk of transmission of 4. Combination therapy.

CHD to her offspring, varying from 3 to 5% compared
with 1% risk for the general population.70 However, there Endothelin Receptor Antagonist
C
is no consensus in the best contraceptive method in such Endothelin-1 plays an important role in pulmonary
patients. Pills containing only progesterone are effective vascular remodeling leading to structural and functional
and avoid the effect of estrogen used in earlier pills.75 abnormalities in the pulmonary vasculature and in
However, endothelin receptor antagonist may reduce the the development and progression of PAH. Beneficial
efficacy of oral contraceptives. Intrauterine devices can effects of oral nonselective ERA (bosentan) in improving
rarely cause vasovagal syncope; which is poorly tolerated functional class, oxygen saturation clinical status, and
in patients with PAH. 75 A combination of two or more pulmonary hemodynamics in ES were demonstrated in a
contraceptives may be used for effective prevention of double-blind, placebo-controlled Bosentan Randomized
pregnancy.73 Double contraception (with barrier methods) Trial of Endothelin Antagonist Therapy-5 (BREATHE-5)
is recommended, especially in patients on bosentan, study. Beneficial effect with minimal side effects was
due to the high teratogenicity and an interaction, which demonstrated in this study (Figures 3A and B).4 An open-
reduces the contraceptive efficacy. label extension study, demonstrated that these effects
391
KG-47.indd 391 02-11-2018 16:55:37

SECTION
7
a
di
Figure 4: Administration of Bosentan is associated with improved functional class
In
and six-minute walk distance in patients with Eissenmenger syndrome.
Source: Gaile, et al. Bosentan therapy in patients with Eisenmenger syndrome: a multicenter,
double-blind, randomized, placebo-controlled study. Circulation. 2006;114(1):48-54.
of
were sustained over a period of 24 weeks (Figure 4).76 A Significant improvement in functional class, resting
subgroup analysis did not reveal any significant difference oxygen saturation, and hemodynamics was observed
ty
in patients with ASD, VSD or both. 77 A recent meta- during two prospective open-label multicenter study
analysis of 8 studies has demonstrated beneficial effects of using sildenafil in CHD-associated PAH after 6-12 months
18 cie
bosentan on 6-min walk test distance (6MWTd) and resting
oxygen saturation with good tolerability.78 An open-label
single center observational study demonstrated beneficial
of therapy.82
Other small studies of PDE5Is, alone and in
combination with prostanoids, have shown improvements
effects of ambrisentan (selective endothelin receptor in exercise capacity, functional class, and hemodynamic
20 o
A antagonist) in improving resting and postexercise parameters without safety issues.83 Similar results were
S
saturation, 6MWTd, and hemoglobin levels in 17 patients obtained in a recent randomized double-blind placebo-
with ES.79 controlled trial using another PDE5I, tadalafil.84
Ambrisentan is a selective monoantagonist of the Riociguat is a relatively new drug in PAH. Unlike PDE5I
al
endothelin receptor type A (ETA) with a longer half-life that acts on the NO/cGMP pathway to slow down cGMP
allowing for once-a-day dosing. A retrospective study degradation, guanylate cycle stimulators (sGCs) enhance
ic
by Zuckerman et al. in patients with CHD showed the production of cGMP, a potent vasodilator. Rosenkranz
improvement in 6MWD without any adverse outcome in et al. explored the efficacy and safety of riociguat in the
og
arterial saturations or serious adverse events.79 There are subgroup of 35 patients with repaired CHD included in the
no randomized controlled trials (RCTs) or prospective PATENT-1 trial and its open-label extension, PATENT-2.
studies of ambrisentan in ES. They concluded that sGCs are well tolerated and improved
ol
Macitentan, similar to bosentan, is a dual ET receptor outcomes, including 6MWD, PVR, functional class, and
antagonist and has been evaluated in a large event- N-terminal pro–B-type natriuretic peptide.85,86
di
driven RCT on patients with PAH (not ES). The Study

with Endothelin Receptor Antagonist in Pulmonary
Prostanoids
ar
Arterial Hypertension to Improve Clinical Outcome

(SERAPHIN) compared macitentan to placebo and Prostanoids are prostaglandin analogs which cause
direct vasodilation of the pulmonary and systemic
C
showed macitentan reduced morbidity/mortality and

increased exercise capacity. A recent single center circulation as well as inhibit platelet aggregation. Data on
experience has demonstrated improvement in functional prostanoid therapy in patients with ES are limited to case
capacity and 6MWT in patients with PHVD and CHD.80 reports and small studies. 87,88 Continuous intravenous
Concurrently, the clinical study to evaluate the effects (IV) epoprostenol was reported to significantly improve
of macitentan on exercise capacity in subjects with ES; functional class, oxygen saturation, and exercise capacity
MAESTRO, an RCT, is underway with an aim to evaluate and to decrease PVR in 8 patients with ES after 3 months of
the effect of macitentan on 6MWD in patients with ES.81 therapy.89 However, epoprostenol is heat labile, has a very
short half-life (1-2 minutes), and has to be administered
Phosphodiasterase Type 5 Inhibitors via a continuous intravenous line with complications
The PDEIs inhibit inactivation of cyclic guanosine such as thrombosis, paradoxical embolism, infection, line
monophosphate (cGMP) thereby prolonging the blockage, and line breakage. More stable analogs, such as
vasodilatory effects of cGMP. Tadalafil and sildenafil treprostinil, are now available for use as IV, subcutaneous
392 selectively inhibit the phosphodiesterase type-5 enzymes. (SC), and more recently oral routes. However, its use in
KG-47.indd 392 02-11-2018 16:55:38

ES is limited. Iloprost, administered via inhalation, has physiological basis of creation of a atrial shunt/Potts shunt CHAPTER
been demonstrated to have beneficial effects on exercise to improve symptoms in patients with idiopathic PAH.98
capacity, quality of life, and right ventricular function in
a randomized control trial involving patients with ES. 90
Experimental data has demonstrated beneficial reversed
remodeling on vascular endothelium and smooth muscle
47

Beraprost is an orally active prostacyclin analog, currently cells.99 Hypothetically, this could allow corrective surgery
in use in Japan. In an RCT in 130 patients, improvements in some borderline patients with type B lesions in the
in exercise capacity at 6 months were observed, but pulmonary vasculature. As the optimal time of surgery
there was no hemodynamic improvement or long-term after vasodilatation is not defined, such an approach could
outcome benefits.91 paradoxically accelerate pulmonary vascular disease
Treprostinil is another stable prostacyclin, with a secondary to increase in flow. Furthermore, once this
longer half-life of 3 hours. It is currently available for SC defect is erroneously closed, an Eisenmenger physiology
a
and IV administration. Improvement in functional class, gets converted to IPAH physiology with worse prognosis.100
di
6MWT and NT-pro-BNP has recently been demonstrated Similarly, only anecdotal reports exist describing
in patients with PHVD and CHD.92 other potential surgical strategies including restriction
In
Selexipag is one of the latest pulmonary therapies to be of flow by pulmonary artery banding.101 and redirecting
tested in PAH. It is an orally available selective prostacyclin ventricular inflow (palliative Senning/Mustrad) 102 or
(IP) receptor agonist. An initial phase-2 proof of concept outflow (palliative arterial switch)103 in an effort to improve
of
pilot RCT examining the safety and efficacy of selexipag oxygenation.
in PAH patients showed a reduction in PVR after 17 weeks
of treatment. Recently, beneficial effects on selexipag on FUTURE TRENDS
ty
patients with ES was shown in a cohort of 4 patients.93 A greater understanding is required to analyze the
vast individual difference in development and clinical
Combination Therapy 18 cie
The ES is a progressive disease; although initial studies
presentation of PHVD in response to the same stimuli.
Availability of advanced medical therapy and the positive
response of ES to the same have opened a new can of worms.
have demonstrated beneficial effects of targeted therapy,
20 o
However, the data currently available for advocating this
it may be transient.94 Addition of another drug at this
treat–repair–treat strategy is scarce and restricted to case
S
point in time could be beneficial. A recent observational

reports. Similarly, it would be exciting to know the effects
single center study demonstrated plateauing of beneficial
of newer therapies (nitric oxide synthase stimulators, oral
effect of therapy at a median duration of 2.5 years. It also
al
prostanoids, antiproliferative drugs) on ES.

demonstrated beneficial effects of addition of one more
drugs in patients with ES.95
ic
REFERENCES
og
1. Marelli AJ, Mackie AS, Ionescu-Ittu R, et al. Congenital heart

SURGICAL MANAGEMENT
disease in the general population: changing prevalence and
Heart and Lung Transplant age distribution. Circulation. 2007;115(2):163-72.
2. Schwartz SS, Madsen N, Laursen HB, et al. Incidence and
ol
Currently, the overall 1-year, 5-year, and 10-year survival mortality of adults with pulmonary hypertension and
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di
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ar
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396
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CHAPTER 48
Adults with Repaired
Tetralogy of Fallot
Snehal Kulkarni
a
di
INTRODUCTION and will require competent pulmonary valve placement.
Amongst cyanotic congenital heart defects (CCHD), Some patients with previous shunt may have branch PA
In
tetralogy of Fallot (TOF) is the most common CCHD. The stenosis and may require rehabilitation of pulmonary
first surgical repair of TOF was done by Lillihei in 1955.1 arteries in future. In addition, residual ventricular
septal defects (VSD), tricuspid valve regurgitation, and
of
Since then, it is the most common surgery performed
for CCHD. With advances in surgical techniques and progressive aortic root dilatation are important issues
perioperative management, early postoperative outcomes in adult patients. In general, there is a wide spectrum of
right ventricular outflow tracts (RVOT) and PA anatomy
ty
have significantly improved in the last 25 years.
All patients are expected to survive into adulthood. in these patients. They need individualized approach for
management and follow-up on-long term.
18 cie
However, residual hemodynamic abnormalities and long-
term morbidity is a major concern on follow-up in adults.2
Over the period of time, the number of repaired adults SURGICAL REPAIR OF UNOPERATED TOF
with TOF will be more than the unoperated children. The IN ADULTS
20 o
risk of sudden death will be much more than the average Though most of the patients get surgical repair in
S
population which is approximately 0.3%/year. Several early childhood, delayed presentation of adults with
studies report satisfactory long-term survival in patients unrepaired TOF is not a rarity. Surgical repair of TOF in
al
with repaired TOF. Ten years and 30 years survival is adult is challenging owing to chronic hypoxia, myocardial
reported to be 95.8% and 90.55, respectively. At the same dysfunction, cerebral complications, and ventricular
ic
time, mortality increases from 0.123% per year in the first arrhythmias. These patients have chronic multisystem
15 years to 0.395% per year after 15 years.3 Regular periodic cellular hypoxia and compensatory polycythemia which
og
follow-up after the surgical repair is extremely important. predispose these patients to myocardial, neurological,
Survival beyond 3rd and 4th decades is substantially hematolo gical, and coagulation problems. The
lower than the age-matched normal population and hypertrophied and fibrotic right ventricular myocardium
ol
is often associated with significant sequel–progressive is prone to ventricular arrhythmias. As opposed to

exercise intolerance, arrhythmias, right heart failure, pediatric population, this tendency may persist even after
di
and death. Sudden cardiac death is well documented in surgical repair in adults.4
repaired TOF population with variable risk factors related
ar
to chronic right ventricular volume overload.

Intracardiac repair for TOF is usually performed
SUBSETS WHO DO BETTER ON LONG-TERM
FOLLOW-UP
C
between 6 months and one year of age with excellent short-

term outcomes. Some patients with TOF with pulmonary On long-term follow-up, patients with normal heart
atresia will require conduit connection between right size, absence of residual RVOT obstruction or VSDs,
ventricle and pulmonary artery (PA), and they will need RVOT patch in place of transannular patch, and
change of conduit over the period of time. Some of these absence of significant PR have better effort tolerance.
patients will have multiple aortopulmonary collaterals On echocardiography, patients having restrictive
and have undergone unifocalization procedures. There right ventricular (RV) morphology, and less PR have
may be narrowing at anastomotic site and may require better effort tolerance than patients with dilated hearts
multiple procedures to deal with the narrowing. Children and nonrestrictive RV physiology. PR besides being
with small-sized pulmonary valve annulus will require associated with chronic right ventricular dilatation and
correction with transannular patch. These children will reduced functional capacity, increases the risk of
eventually develop severe pulmonary regurgitation (PR) arrhythmias.
KG-48.indd 397 02-11-2018 16:55:23

SECTION ISSUES ON LONG-TERM FOLLOW-UP assessment and PA anatomy, enlargement of aortic
IN ADULTS root also needs to be assessed periodically. Patients
7 Pulmonary Regurgitation
with right aortic arch, pulmonary atresia with multiple
aortopulmonary collaterals, prior BT shunt surgeries,
Pulmonary regurgitation (PR) is the most common problem late age at the time of repair, and hypertension in
after surgical repair. It is secondary to transannular patch adults are the risk factors for progressive aortic root
placement with small-sized pulmonary valve annulus in dilatation. Only echocardiography may not provide
these patients. It is associated with exercise intolerance adequate surveillance and other imaging modalities,
and arrhythmias, and is a cause for sudden cardiac death either computed tomography (CT) or cardiac magnetic
in this subset. Many diagnostic methods are used for resonance (CMR) may need to be done periodically. There
assessment of right ventricle in these subsets after surgery. is no consensus at present on β-blocker administration for
a
Of late, cardiac magnetic resonance imaging (MRI) is prevention of progressive dilatation of the aortic root in
di
the diagnostic method of choice. It provides data on the repaired TOF, or regarding in which patients and at what
spectrum of PR, biventricular volume, mass and function. stage aortic root surgery should be considered. Aortic root
In
surgery may also be considered for patients with TOF and
Arrhythmias aortic root dilatation exceeding 55 mm, particularly when
the primary indication for surgery is pulmonary valve
of
Prevalence of atrial arrhythmias varies from 2.5 to 54%
implantation.
in various studies.5 Atrial arrhythmia itself is a serious
problem and leads to later development of ventricular
Other Cardiac Comorbidities
ty
arrhythmias, congestive heart failure, reoperations, and
stroke. Patients with operated TOF remain a high-risk group for
18 cie
Ventricular arrhythmias can occur between 7 and 15%
in various studies. Incidence of ventricular arrhythmias
increases with time from repair. Its association with QRS
infective endocarditis due to residual lesions, prosthetic
patches. They require lifelong antibiotic prophylaxis
for infective endocarditis. Some of the patients may
widening and adverse events is well documented. have cyanosis due to residual shunts. A small group
20 o
of patients have pulmonary hypertension due to large
S
Residual Ventricular Septal Defects aortopulmonary collaterals.
Significant numbers of patients with TOF have additional

Optimal Frequency of Clinical Follow-up
al
muscular ventricular septal defects (VSDs). Some of

these residual VSDs can cause significant hemodynamic Operated patients for TOF need life-long follow-up
ic
problems on long-term follow-up such as excessive throughout adulthood. Frequency of follow-up is typically
pulmonary blood flow or high pulmonary vascular annual. This may be modified depending on the severity
og
resistance. They may need additional surgery for and type of residual defects.
closure of these defects or certain VSDs can be closed by There are multiple recommendations for follow-up.
transcatheter techniques as well. Following algorithm helps in risk stratification and
ol
need for further interventions in adults.

Right Ventricular Outflow Tract Obstructions
di
Because of variable right ventricular outflow tract (RVOT) ECG

ar
anatomy, residual RVOT obstructions remain significant The ECG is important to measure QRS duration and
problem on long-term follow-up. Patients with pulmonary rate of change of duration (Figure 1). Patients with QRS
atresia, multiple aortopulmonary collaterals, nonconfluent duration of more than 180 ms are high risk for ventricular
C
pulmonary arteries with prior unifocalization operations tachycardia and sudden cardiac death. These patients
and patients who had prior Blalock–Taussig (BT) shunt are may need to be considered for implantable cardioverter-
at high risk for distortion of PA anatomy. These patients defibrillator (ICD) implantation.
need frequent imaging for assessment of pulmonary
arteries. They may develop right ventricular hypertension Echocardiography
and need frequent procedures—either surgical or
Acoustic windows in this age group are often poor for
transcatheter—to relieve the obstructions.
a detailed echocardiographic evaluation (Figures 2A
and B). Quantitative assessment of right ventricle is
Aortic Root Enlargement after TOF Repair extremely difficult.
Significant numbers of adults have aortic root enlargement The following parameters need to be assessed on
on long-term follow-up.6 In addition to right ventricular echocardiography:7
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CHAPTER
48

a
di
In
of
ty
Figure 1: ECG of an operated adult for tetralogy of Fallot (TOF).
It shows right bundle branch block (RBBB) pattern with prolonged QRS duration
18 cie
20 o S
al
ic
og
ol
di
A B
ar
Figures 2A and B: Echocardiopgraphy four-chamber (A) and short-axis (B) views of an operated patient with tetralogy of Fallot (TOF).
It shows significantly dilated right ventricle
C
RV end-diastolic cross-sectional area—20 cm2/m2— PR fraction—PR jet width/PV annulus

correlates to CMR end-diastolic volume (EDV) 170 PR deceleration time <0.77 suggests significant PR.
mL/m2
RV diameter at base and mid-ventricle PERIODIC HOLTER MONITORING
RV fractional area change—Normal >35%
Frequency of this test needs to be individualized.
Tei Index
Tricuspid annular plane systolic excursion (TAPSE)
Tissue doppler imaging (TDI) COMPUTED TOMOGRAPHY
RV diastolic function assessment Computed tomography (CT) is routinely used to delineate
Diameter of inferior vena cava with respiratory the right ventricular and PA anatomy and also for
variations assessment of ascending aorta in cases of significant aortic
Calculation of right atrial area root dilatation (Figures 3 to 5). The major advantage of
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SECTION
7
a
di
In
Figure 3: CT of an operated adult for tetralogy of Fallot (TOF). Figure 4: CT of an operated patient with calcification of conduit
There is significant narrowing at the distal end of the conduit with with distal narrowing
pulmonary artery bifurcation
of
ty
18 cie
20 o S
al
ic
Figure 5: CMR of operated patient with tetralogy of Fallot (TOF) Figure 6: CT of an operated patient with significant dilatation of
og
done to assess right ventricular volume. It shows significantly dilated ascending aorta
right ventricle with right ventricle end-diastolic volume (RVEDV) of
90 cc
ol
CT in patients with repaired TOF is its excellent spatial (Figure 6).8,9 There is no definite consensus regarding the
di
resolution. This advantage is particularly valuable for frequency of MRI on follow-up evaluation.
detailed evaluation of small blood vessels such as the The following parameters can be studied accurately on
ar
coronary arteries or the distal PA branches. Another MRI:

RV volume
advantage is the ability to perform CT in patients with
C
RV systolic function
pacemakers and defibrillators. Additionally, CT may
Severity of PR
allow successful imaging of structures that are obscured
Pulmonary arteries/ascending aorta
on CMR imaging by stainless-steel metallic artifacts. 7 Residual VSDs
Ionizing radiation with its repeated use on follow-up is Ventricular fibrosis: Late gadolinium enhancement is a
a major limiting factor. In addition, CT does not provide marker of fibrosed, scarred myocardium.
hemodynamic information on flow rate or velocity.
NUCLEAR SCINTIGRAPHY
MAGNETIC RESONANCE IMAGING
In the era of CT and CMR, its role has decreased
As echocardiographic imaging becomes difficult in adults, significantly. It is usually recommended for evaluation
magnetic resonance imaging (MRI) is seen as reference of differential pulmonary blood flow and regional lung
standard for evaluating operated patients on follow-up perfusion when CMR facilities are not available.
400
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CARDIAC CATHETERIZATION AND PREGNANCY IN PATIENTS WITH TOF CHAPTER
ANGIOGRAPHY
48
Pregnancy is not advised in unrepaired patients. It can
Diagnostic catheterization is rarely required for follow- be advised safely in repaired patients in the absence of
up assessment. Patients who have undergone surgical residual hemodynamic defects with good functional

procedures for unifocalizations at earlier age may require capacity. Pregnancy is even well tolerated with severe
assessment of pulmonary blood flow and resistance. PR but preserved right ventricular function. 13 There
RVOT obstruction and PA anatomy can be delineated is a possibility for increased fetal loss. Congenital
well on CT/MRI. Cardiac catheterization is required for abnormalities are common if the mother has e22 q 11
interventional purpose for balloon dilatation and stent deletion. Risk of fetus having CHD is 4–6% .
implantation in the RVOT or pulmonary arteries. It is
a
important to delineate coronary artery anatomy prior to PREDICTORS OF COMPLICATIONS ON
interventional procedures like percutaneous pulmonary FOLLOW-UP
di
valve implantation. There are some predictors for complications in adults
Residual VSDs can be well delineated on angiography.
In
on long-term follow-up. Patients with long-standing
Significance of residual VSDs can be assessed by palliative shunt and older age at the time of definitive
quantifying pulmonary blood flows and resistance. They surgery have high chances of developing distorted PA
of
can be closed effectively in catheterization laboratory if anatomy and abnormal RV hemodynamics. Patients with
required and are suitable for closure. prolonged QRS duration >170 ms, high-grade ectopy on
Residual atrial septal defects (ASD)/patent foramen Holter monitoring, inducible ventricular tachycardia at
ty
ovale (PFO) can be a cause for significant cyanosis after electrophysiology, VO 2 max of 20 + 6 mL/kg/min, and
surgical repair. Assessment of flow across the shunts and history of syncope are at risk of sudden cardiac death.
laboratory.
18 cie
their potential elimination is possible in catheterization Patients with right ventricular end-diastolic volume index
(RVEDVI) = 192 + 49 mL/m2, right ventricular ejection
fraction (RVEF) = 37 + 7%, and PR fraction: 38 + 12% on
SERIAL ESTIMATION OF BRAIN NATRIURETIC
20 o
MRI, are at risk of development of right ventricular failure
PEPTIDE and ventricular arrhythmias.
S
Serial estimation of brain natriuretic peptide (BNP)

is considered as an objective assessment to study the REOPERATIONS IN ADULTS WITH
al
right ventricular function.10 It has good correlation with REPAIRED TOF

right ventricular ejection fraction (EF) but not with right Complications after repaired TOF are results of deleterious
ic
ventricular end-diastolic volumes. effects of tricuspid and PR, RV dysfunction, VSD patch
leaks, RVOT obstruction, and stenosis of branch
og
ELECTROPHYSIOLOGY STUDY FOR RISK pulmonary arteries.

Hemodynamic abnormalities and cardiac arrhythmias
STRATIFICATION
are indications of late operations. Reoperations are also
ol
There are no specific recommendations and this test advised in cases of deterioration in patient’s clinical
should be individualized. Symptomatic patients with status, objective signs of RV dysfunction, and onset of
di
increasing QRS duration on ECG and history suggestive of ventricular arrhythmias. It is also advised for patients who
arrhythmias, decreasing VO2 max on exercise testing, and are free of symptoms, but need an optimal clinical status
ar
evidence of ventricular fibrosis on MRI should undergo to tolerate pregnancy. PR is a frequent consequence of
electrophysiology study.11 RVOT reconstruction in repaired TOF. However, chronic
C
right ventricular volume overload (RVVO) leads to

STANDARDIZED CLINICAL ASSESSMENT AND gradual dilatation and decline in function, exacerbated
MANAGEMENT PLANS by secondary TR. Atrial and ventricular arrhythmias are
The standardized clinical assessment and management very common on long-term follow-up. Pulmonary valve
plans (SCAMPs) are guidelines for outpatient follow- replacement in combination with atrial and/or ventricular
up of repaired patients with TOF. They are innovative cryoablation can be addressed together to adapt these
quality improvement strategies that actively collect data sequelae.14
on deviations from standardized algorithms in actual
practice. 12 A standardized algorithm for follow-up of PERCUTANEOUS PULMONARY VALVE
repaired TOF could be established, and then periodic REPLACEMENT/IMPLANTATION
analysis of patterns of deviation from the algorithm could Percutaneous pulmonary valve replacement (PVR)/
help identify subgroups of patients for targeted testing. percutaneous pulmonary valve implantation (PPVI)
401
KG-48.indd 401 02-11-2018 16:55:24

SECTION procedure has gained increasing attention of late. Optimal 7. Valente AM, Cook S, Festa P, et al. Multimodality imaging
timing of PVR has been the focus of considerable debate. guidelines for patients with repaired tetralogy of Fallot: a
7 PVR improves functional status attributable to PR, aids

RV remodeling and stabilizes QRS duration.15 The most
report from the American Society of Echocardiography:
developed in collaboration w ith the S ociety for
common indication is residual right ventricular tract lesion Cardiovascular Magnetic Resonance and the Society for
in adults—which can be either stenotic, regurgitant, or Pediatric Radiology. J Am Soc Echocardiogr. 2014;27(2):111-
41.
mixed. This procedure is usually advised in symptomatic
8. Davlouros PA, Kilner PJ, Hornung TS, et al. Right ventricular
patients with severe PR with RV dysfunction and/or
function in adults with repaired tetralogy of Fallot assessed
dilatation. Prior to the procedure, proper delineation of
with cardiovascular magnetic resonance imaging:
RVOT is required by CMR imaging. It not only provides
detrimental role of right ventricular outflow aneurysms or
important information about the spatial relationship of the
a
akinesia and adverse right-to-left ventricular interaction. J
conduit to its surrounding structures but also quantifies Am Coll Cardiol. 2002;40(11):2044-52.
di
lesions such as PR, right ventricular dilatation and 9. Babu-Narayan SV, Kilner PJ, Li W, et al. Ventricular fibrosis
dysfunction, and branch PA stenosis. Spatial relationship suggested by cardiovascular magnetic resonance in
In
of coronary arteries to the site of stent implantation is adults with repaired tetralogy of Fallot and its relationship
one of the most important factors in suspecting a risk of to adverse markers of clinical outcome. Circulation.
coronary compression. 2006;113(3):405-13. .
of
10. Koch AM, Zink S, Glöckler M, et al. Plasma levels of B-type
REFERENCES natriuretic peptide in patients with tetralogy of Fallot after
surgical repair. Int J Cardiol. 2010;143(2):130-4.
1. Lillehei CW, Cohen M, Warden HE, et al. Direct vision
ty
11. Khairy P, Aboulhosn J, Gurvitz MZ,et al. Arrhythmia burden
intracardiac surgical correction of the tetralogy of Fallot,
in adults with surgically repaired tetralogy of Fallot: a multi-
pentalogy of Fallot, and pulmonary atresia defects; report
18 cie
of first ten cases. Ann Surg. 1955;142(3):418-42.
2. Murphy JG, Gersh BJ, Mair DD,et al. Long-term outcome in
patients undergoing surgical repair of tetralogy of Fallot. N
institutional study. Circulation. 2010;122(9):868–75.
12. Rathod RH, Farias M, Friedman KG, et al. A novel approach
to gathering and acting on relevant clinical information:
Engl J Med. 1993;329(9):593-9. SCAMPs. Congenit Heart Dis. 2010;5(4):343–53.
20 o
3. Warnes CA. The adult with congenital heart disease: born 13. Warnes CA, Williams RG, Bashore TM, et al. ACC/AHA
S
to be bad? J Am Coll Cardiol. 2005;46(1):1-8. 2008 Guidelines for the Management of Adults with
4. Sadiq A, Shyamkrishnan KG, Theodore S, et al. Longterm Congenital Heart Disease: a report of the American College
functional assessment after correction of tetralogy of Fallot of Cardiology/American Heart Association Task Force
al
in adulthood. Ann Thorac Surg. 2007;83(5):1790–5. on Practice Guidelines (writing committee to develop
5. Gatzoulis MA, Balaji S, Webber SA, et al. Risk factors guidelines on the management of adults with congenital
ic
for arrhythmia and sudden cardiac death late after heart disease).. Circulation. 2008;118(23):e714-833.
repair of tetralogy of Fallot: a multicentre study. Lancet. 14. Oechslin EN, Harrison DA, Harris L, et al. Reoperations
og
2000;356(9234):975–81. in adults with repair of tetralogy of Fallot: indications and

6. Niwa K, Siu SC, Webb GD, et al. Progressive aortic root outcomes. J Thorac Cardiovasc Surg. 1999;118(2):245-51.
dilatation in adults late after repair of tetralogy of Fallot. 15. Khambadkhone S. Percutaneous pulmonary valve
ol
Circulation. 2002;106(11):1374-8.. implantation. Ann Pediatr Cardiol. 2012;5(1):53-60.

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Single Ventricle Pathway:
CHAPTER 49
Simplified
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INTRODUCTION A1. DILV with normally related great arteries—
The incidence of single ventricle (SV) among all congenital ‘Holmes heart ’ (15%)
In
heart diseases (CHD) is 7.7%.1 The term ‘single ventricle’ A2. DILV with right-sided hypoplastic subaortic right
has created confusion in the description of complex CHD ventricle (25%)
A3. DILV with left-sided hypoplastic subaortic right
of
either within or between institutions and hence, terms
such as single ventricle, common ventricle, univentricular ventricle (38%)
heart or functional single ventricle have all been used. 2 A4. DILV with left and posterior aorta—inverted
(<5%).
ty
Anderson et al. defined a ‘ventricle should consist of an
B. Single right ventricle (absence of left ventricular sinus/
inlet, trabecular and outlet portion’ based on several
inflow) which included double inlet right ventricle
18 cie
observations. 3,4 There should be fibrous continuity
between the inlet and outlet portions in the left ventricle,
whereas they are separated by the crista supraventricularis
(DIRV—5%).
C. Undivided ventricles (absent or rudimentar y
ventricular septum) akin to a large VSD amounting to
in the right ventricle. A chamber must have 50% or
20 o
SV (5%).
more of an inlet portion to be classified as a ventricle
D. Infundibulum only (failure of development of both
S
otherwise it is called a ‘rudimentary chamber’. There are

ventricular sinuses and the ventricular septum) truly
CHDs such as pulmonary atresia with intact ventricular
single ventricle (very rare).
septum, hypoplastic right heart or left heart syndrome
al
Ventricles are usually identifiable right and left

which have two unequivocally well-defined ventricles
separated by apical muscular septum. A true single
but hemodynamically behave like a single ventricle.
ic
ventricle is rare (seen in only 5% of Van Praagh’s series).

Similarly, some associated lesions, such as straddling
In DILV, the rudimentary right ventricle is carried on the
of atrioventricular valves, may produce unbalanced
og
anterosuperior shoulder of the dominant LV either right

ventricles that prevent them from being managed like a
superior (d-looped) or left superior (l-looped). When the
biventricular circulation. The ultimate aim is to decide
RV is dominant, the rudimentary LV is usually located
ol
either towards biventricular circulation or to proceed

posteroinferior and left of the RV (d-looped). Usually, the
towards univentricular path.
rudimentary LV does not have an outflow or inflow.
di
MORPHOLOGY
Ventriculoarterial (VA) Connection
ar
A ventricle consists of an inlet, outlet and trabecular

In DILV, discordant VA connections are more common
portion. The inlet portion of the ventricle extends from the
than concordant. When considering discordant VA
C
atrioventricular (AV) valve to the insertion of the papillary

connections, L-malposed aorta is more common than
muscles, the outlet portion includes the nontrabeculated
D-malposed aorta. Concordant VA connections and
portion above the crista supraventricularis and below the
normally related great arteries are not uncommon also
semilunar valve and the trabecular portion lies between
known as Holmes heart (15%).
the inlet and outlet portion. 2 There are three possible
AV connections: (i) SV with both the atrial chambers are
connected to a dominant ventricle with two separate AV Interventricular Communications
valves (double inlet ventricle), (ii) Common AV valve, and In DILV, irrespective of the type of AV connection that
(iii) Single inlet due to atresia of one of the AV valves.5 Van exists, the interventricular communication between the
Praagh et al. classified SV into four types:6 two chambers is completely muscular involving apical
A. Single left ventricle (absence of right ventricular sinus and outlet component of the septum. It has a tendency
or inflow) which included as double inlet left ventricle to become restrictive when associated with unprotected
(DILV—78%) pulmonary circulation.7 This communication is known as
KG-49.indd 403 02-11-2018 16:55:09

SECTION bulboventricular foramen (BVF) or outlet foramen. The Interatrial Communication
defect is known to decrease in size following pulmonary
7
Double inlet left ventricle (DILV) with right or left AV valve
artery banding due to muscular hypertrophy but
atresia and restrictive interatrial communication will have
association is yet to be proved.8 In the case of a dominant
systemic or pulmonary venous congestion respectively.
right ventricle, both the great arteries usually arise from

Atrial septectomy or balloon septostomy will reduce the
the dominant RV, hence the BVF is not an integral part of
congestion in these cases.
the circulation.
Pulmonary and Systemic Outflow

Associated Malformations
The clinical presentation of univentricular heart will
Interatrial communications are known to commonly
depend on the presence or absence of systemic or
a
exist in univentricular hearts. Interatrial communication
pulmonary outflow obstruction. The patient can present
is mandatory in SV associated with atresia of one of
di
with shock depending on severity when there is subaortic
the AV valves. The most significant associated lesions
obstruction or coarctation of aorta. Similarly, severe
are the outflow tract lesions which can be produced
In
cyanosis and hypoxia is seen in cases with pulmonary
by deviations of the outflow muscular septum either
atresia. Congestive cardiac failure and mild cyanosis is
anteriorly or posteriorly, this can produce either subaortic
seen in cases with unprotected pulmonary blood flow and
or subpulmonary obstructions depending on the VA
of
usually present between 2 and 6 weeks of age due to fall
connections and relationships of the great vessels. In
in neonatal pulmonary vascular resistance. Apart from
addition to this subpulmonary/subaortic stenosis, this
these presentations, balanced circulation with adequate
can also be produced by abnormal AV valve tissues or
ty
pulmonary stenosis (PS) may be seen in some late
chordal structures crossing the outflow tract. Patients with
presentation cases.
DILV with transposed great vessels and restrictive BVF are
18 cie
commonly associated with coarctation or interruption of
aorta. Abnormality of the systemic venous or pulmonary CLINICAL FEATURES
venous pathways and juxtaposed atrial appendages may Most patients with SV present between neonatal period
20 o
be associated with heterotaxy. to early infancy. Presentation essentially is due to
S
hemodynamics of the subset.

Conduction Axis i. Asymptomatic murmur: Optimal pulmonary blood
In DILV, the connecting AV node will be located flow
al
anterolaterally at the acute margin of the right AV valve ii. Cyanosis: Reduced pulmonary blood flow
orifice. After perforating the annulus of the right AV valve to iii. Shock: Systemic outflow obstruction
ic
enter the main LV chamber, the nonbranching bundle will iv. Heart failure: Unprotected pulmonary blood flow.
The mode and time of presentation depend on the
og
course along the right-sided rim of the bulboventricular

chamber to reach the crest of the septum. So, the course relative amounts of systemic and pulmonary blood flow.
of the bundle depends on the location of the rudimentary The SV associated with duct dependent pulmonary or
system circulation usually present with severe cyanosis
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right chamber. In the setting of DILV with L-malposed

great vessels, the right rim of the bulboventricular septum or shock at the time of ductal closure.10-12 Restrictive
interatrial communication in the presence of one of the AV
di
is separated from the AV node by the pulmonary artery,

so the nonbranching bundle has a long course around the valve atresia may cause low cardiac output. Patients with
PS will have progressive onset cyanosis and mimics other
ar
pulmonary artery; hence, these types of lesions are prone

for heart block.2 causes of VSD with PS physiology, clinical examination
may give clue to the diagnosis. In most of the cases, left
C
ventricular type of apex and great vessel pulsations either

HEMODYNAMICS
right or left parasternal due to ‘D or L’ malposed great
There is complete admixture of blood in the SV. The
vessels is appreciable. The second heart sound is usually
oxygen saturation of the patient depends on the amount
single and loud due to anterior position of aorta. There
of pulmonary blood flow. Rarely, some patients with DILV
is pulmonary ejection systolic murmur due to valvular or
either with d-looped or normally related great vessels
subvalvular pulmonary obstruction.
(Holmes heart) have unfavorable streaming due to the
proximity of the systemic venous blood to the rudimentary
chamber. For the same reason, patients with DILV and INVESTIGATIONS
l-looped ventricles and discordant VA connections Chest X-ray may be useful to assess the amount of
may have favorable streaming due to the proximity of pulmonary blood flow, the presence of cardiomegaly with
the pulmonary venous blood to the bulboventricular plethora signifies CCF due to increased pulmonary blood
chamber.9 flow. Cardiomegaly with reduced vascularity suggests
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atrioventricular regurgitation or ventricular dysfunction. function, the adequacy of bulboventricular foramen and CHAPTER
Patients with systemic outflow obstruction will show its location, the presence of any outflow tract stenosis,
signs of pulmonary venous hypertension depending on
the severity of obstruction. Oligemic lung fields suggest
the relationship of great vessels and the size of branch
pulmonary arteries. The suprasternal view is ideal for
49

pulmonary atresia in a neonate. On X-ray, the presence assessing the arch for coarctation, branch pulmonary
of a left upper cardiac border convexity suggests left artery sizes, and presence of bilateral superior vena cava.
and anterior bulboventricular chamber and l-malposed
aorta (Figure 1) while right heart border cut-off signifies Cardiac Catheterization
associated juxtaposed right atrial appendage.13-15 The main indication for cardiac catheterization is to
assess PA pressures, ventricular end-diastolic pressures,
Electrocardiogram transpulmonary gradient, and assessment of vascular
a
resistance. Systemic saturations above 85% and below
There is diversity in the ECG in univentricular hearts
di
75% indicate either increased or decreased pulmonary
due to their varied morphological types but certain
blood flow respectively.16 Pulmonary venous desaturation
clues can be obtained. Double inlet left ventricle with
In
followed by bidirectional Glenn surgery suggests
a left anterior bulboventricular chamber will show the
development of pulmonary arteriovenous malformation
QRS axis directed inferior and to the right away from the
due to lack of hepatic factors. Ventricular angiogram in
rudimentary chamber with clockwise depolarization.
of
anteroposterior and lateral views show SV and great vessel
Similarly, DILV with a right anterior rudimentary chamber
relationship (Figures 4A and B). Cardiac catheterization
will show the QRS axis directed leftward and superior
can serve as a diagnostic investigation or therapeutic
with counterclockwise depolarization. The presence of
ty
procedure before bidirectional Glenn (BDG) or total
stereotypical QRS complexes in the precordial leads from
cavopulmonary connection (TCPC). Pulmonary artery
V1-V6 or the presence of discordance between the frontal
18 cie
plane QRS axis and the precordial lead vectors (Figure 2)
should lead us to think towards the diagnosis of SV.13-15
anatomy can be demonstrated by Glenn shunt injection
(Figure 5). Demonstration of venovenous collaterals and
other venous structures may be useful prior to TCPC.
Closure of collaterals, stenosed pulmonary arteries,
20 o
Echocardiography or closure of antegrade flow is some of the common
S
A sequential segmental approach to define the atrial procedures prior to surgery.17-18

situs, AV and VA connections, relationship of great vessels
should be done on transthoracic echo. AV valve flows, Computed Tomography/Magnetic
al
obstruction at outflow tracts should be assessed by color Resonance Imaging

Doppler interrogation. The apical view is excellent for
ic
Computed tomography (CT) angiogram is routinely

determining the ventricular morphology (Figure 3), the being done whenever there is a doubt about pulmonary
og
AV connection, and the amount of straddling/overriding artery anatomy prior to surgery. Other indications are the
of the AV valves, and the presence/severity of AV valve presence of collaterals, abnormal pulmonary or systemic
stenosis or regurgitation. The parasternal long axis and veins. Magnetic resonance imaging (MRI) may be useful
ol
short axis views are excellent for assessing ventricular for flow calculation in the Glenn/Fontan pathways and
aortopulmonary collaterals. A recent development in MRI
di
is computational fluid dynamics to assess geometry and

power loss in the Fontan pathway. This can help in surgical
ar
planning of TCPC and individualize the type of conduit to

the patient to obtain maximum efficiency in Fontan flows
and minimize workload of the heart and energy losses.19
C
MANAGEMENT
The goal of management of SV is to prepare the patient
towards Fontan path. The anatomy and hemodynamics
should fulfill at least to meet the criteria for BDG
surgery during late infancy. Figure 6 describes a detailed
treatment of the various subset of SV patients are reaching
BDG.
Figure 1: Chest X-ray of a patient with single ventricle with Neonatal Period
pulmonary stenosis showing convexity of left heart border (thin The goal of management is to optimize the pulmonary
arrow) and l-malposed aorta (thick arrow). There is cut-off of right
blood flow. Neonate presents with features of duct-
heart border
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KG-49.indd 405 02-11-2018 16:55:16

SECTION
7
a
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In
of
ty
18 cie
Figure 2: Electrocardiogram of a child with double inlet left ventricle and pulmonary stenosis
showing rightward axis and left ventricular dominance (discordance pattern)
20 o S
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A B
ar
Figure 3: Transthoracic echocardiogram apical 4-chambered view Figures 4A and B: Ventricular angiogram in anteroposterior (A) and
showing double inlet left ventricle lateral (B) views showing single ventricle with d-malposed great
vessels
C
dependent circulation should be treated immediately. Patients present beyond neonatal period with
The SV associated with systemic outflow obstruction increased pulmonary blood flow should go for pulmonary
should go for repair of aortic arch and pulmonary artery artery banding between 4 and 8 weeks of age to prevent
banding to optimize the pulmonary blood flow. Patients development of pulmonary hypertension. The SV with
with restrictive bulboventricular foramen and hypoplastic PS are the good subset of patients and can go for elective
ascending aorta need Damus-Kaye-Stansel (DKS) palliative BDG after 6 months of age.
operation. Patients with pulmonary atresia with duct-
dependent pulmonary circulation may be stabilized with Superior Cavopulmonary Anastomosis
prostaglandin infusion and subsequently establishment or Glenn Shunt
of pulmonary blood flow either by stenting of the ductus This is usually carried out after 6 months of age when the
arteriosus or systemic to pulmonary shunt. pulmonary vascular resistance falls to its minimum. The
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CHAPTER
49

a
di
In
Figure 5: Right jugular sheath injection in anteroposterior projection showing
opacification of left bidirectional Glenn shunt and branch pulmonary arteries with good
arborization in a child with situs inversus totalis and single ventricle
of
ty
18 cie
20 o S
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ar
Figure 6: Treatment pathway for single ventricle

Abbreviations: SV, single ventricle; PS, pulmonary stenosis; BVF, bulboventricular foramen; COA, coarctation of aorta
C
end of the SVC is anastomosed to side of the pulmonary Glenn flows. There are some proponents for preserving
artery. Initially, the SV had to pump both the systemic the antegrade flow to the pulmonary arteries to improve
and pulmonary blood flow (300% of normal cardiac saturations and prevent the development of pulmonary
output). Glenn shunt will offload the ventricle as SVC arteriovenous malformations by allowing the ‘hepatic
contributes to 60% of the cardiac output and the saturation factor’ to pulmonary circulation.2
will increase to approximately 85%.22 Atrial septectomy
can be done in the same sitting in case of restrictive Total Cavopulmonary Circulation or Fontan
interatrial communication in the presence of AV valve Extracardiac total cavopulmonary connection (TCPC) can
atresia. There is a tendency to interrupt the pulmonary be performed after 3–4 years of age when child reaches
artery so that, the pulsatile flow does not interfere with the above 12 kg weight to have optimal size tube graft to
407
KG-49.indd 407 02-11-2018 16:55:17

SECTION route inferior vena cava (IVC) to pulmonary artery. As the REFERENCES
child becomes more active, the contribution of IVC blood
7
1. O’Leary PW. Prevalence, clinical presentation and natural
increases and the supra vena cava (SVC) will contribute history of patients with single ventricle. Prog Pediatr
only 30–40% of the cardiac output.20 Hence, the Glenn Cardiol. 2002;16(1):31–8.
shunt will not be able to maintain saturations. Previously, 2. Earing MG, Hagler DJ, Edwards WD. Univentricular
the 10 commandments of Choussat’s was essential to atrioventricular connection. ln: Allen HD, editor. Moss
satisfy before TCPC. But now mean pulmonary artery and Adams’ Heart Disease in Infants, Children, and
pressures <15 mm Hg, pulmonary vascular resistance Adolescents including the Fetus and Young Adult, 9th edn.
index <2.5 units, normal ventricular end diastolic pressure Philadelphia: Wolters Kluwer. 2016. p. 1217-37.
and good pulmonary artery anatomy are the essential 3. Anderson RH, Becker AE, Tynan M, et al. The univentricular
criteria to perform TCPC.21 atrioventricular connection: getting to the root of a thorny
a
Extracardiac TCPC became ver y popular and problem. Am J Cardiol. 1984;54(7):822–8.
commonly being performed due to fewer incidences 4. Anderson RH, Becker AE, Freedom RM, et al. Problems
di
of arrhythmia and energy losses after surgery during in the nomenclature of the univentricular heart.
follow-up. About 18–20 mm size conduit is anastomosed Herz.1979;4(2):97–106.
In
from the IVC to the pulmonary artery. The addition of a 5. Penny DJ, Anderson RH. Other forms of functionally
univentricular hearts. ln: Anderson RH, editor. Paediatric
fenestration from the conduit to the atrium is commonly
Cardiology, 3rd edn. Philadelphia: Churchill Livingstone.
being practiced in many centers (to serve as a pop-
of
2009. pp. 665-686.
off ). This will serve to maintain cardiac output at the
6. Van Praagh R, Van Praagh S, Vlad P, et al. Diagnosis of
expense of desaturation, if there is any adverse Fontan
the anatomic types of single or common ventricle. Am J
hemodynamics.
ty
Cardiol. 1965;15:345–66.
7. Bevilacqua M, Sanders SP, Van Praagh S, et al. Double-
LONG-TERM FOLLOW-UP OF FONTAN inlet single ventricle: echocardiographic anatomy with
18 cie
The overall 10-, 20-, 30-year survival after the Fontan
operation is 74%, 61%, and 43%, respectively.
emphasis on the morphology of the atrioventricular
valves and ventricular septal defect. J Am Coll Cardiol.
1991;18(2):559-68.
1. Protein losing enteropathy: About 5% of patients may
20 o
8. Nakanishi T. Cardiac catheterization is necessary before
develop edema, fatigue, and effusions due to systemic bidirectional Glenn and Fontan procedures in single
S
venous congestion. There is no definitive treatment. ventricle physiology. Pediatr Cardiol. 2005;26(2):159–61.
2. Arrhythmia: Atrial arrhythmias are common especially 9. Tharakan JA. Admixture lesions in congenital cyanotic
with lateral tunnel Fontan surgery.
al
heart disease. Ann Pediatr Cardiol. 2011;4(1):53-9.

3. Thromboembolism: Routine anticoagulant/antiplatelet 10. Franklin R, Spiegelhalter D, Anderson R, et al. Doubleinlet
regimes after TCPC have been institution specific. We ventricle presenting in infancy. Survival without definitive
ic
tend to give vitamin K antagonists such as warfarin repair. J Thorac Cardiovasc Surg. 1991;101(5):767–76.
11. Jacobs ML, Blackstone EH, Bailey LL. Intermediate survival
og
after TCPC and maintain international normalized

ratio (INR) between 2 and 2.5. in neonates with aortic atresia: a multi-institutional
study. The Congenital Heart Surgeons Society. J Thorac
4. Cyanosis and desaturation: Cyanosis may be due to
Cardiovasc Surg.1998;116(3):417–31.
ol
surgically created fenestration, undiagnosed abnormal

12. Fesslova V, Hunter S, Stark J, et al. Long-term clinical
systemic venous drainage to atrium or venovenous outcome of patients with tricuspid atresia. ‘‘Natural
di
collaterals to pulmonary veins and atrium. History’’. J Cardiovasc Surg. 1989;30(2):262–72.

5. Fontan failure: It can also be due to ventricular 13. Perloff JK, Marelli AJ. Hypoplastic left heart. ln: Perloff JK,
ar
dysfunction. Some studies have shown ventricular editor. Perloff ’s Clinical Recognition of Congenital Heart
dysfunction to be more in RV dominant vs LV dominant Disease, 6th ed. Philadelphia: Elsevier Saunders. 2012. p.
single ventricle. Other causes are arrhythmias, 522–529.
C
complete heart block, AV valve regurgitation or chronic 14. Perloff JK, Marelli AJ. Tricuspid atresia. ln: Perloff JK, editor.
hypoxia-induced ventricular dysfunction. Perloff’s Clinical Recognition of Congenital Heart Disease,
6th ed. Philadelphia: Elsevier Saunders. 2012. p. 439–453.
15. Perloff JK, Marelli AJ. Univentricular heart. ln: Perloff JK,
CONCLUSION editor. Perloff ’s Clinical Recognition of Congenital Heart
Disease, 6th ed. Philadelphia: Elsevier Saunders. 2012. pp.
Single ventricle requires early diagnosis, meticulous
454–471.
evaluation, and staged treatment which are varied 16. Lock JE, Keane JF, Fellows KE. The use of catheter
depending on age and hemodynamics. Current advances intervention procedures for congenital heart disease. J Am
in treatment have significantly prolonged the life of these Coll Cardiol.1986;7(6):1420–3.
patients. These patients need multidisciplinary long-term 17. Prakash A, Khan MA, Hardy R, et al. A new diagnostic
follow-up and care due to late functional problems. algorithm for assessment of patients with single ventricle
408
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before a Fontan operation. J Thorac Cardiovasc Surg. 20. Stumper S, Penford G. Catheter hemodynamic assessment CHAPTER
2009;138(4):917–23. of the univentricular circulation. Ann Pediatr Cardiol.
18. Yassin H, Bhat AN, Tysarowski P, et al. Noninvasive
evaluation of single-ventricle patients before Fontan
2017;10(2):167–74.
21. Stern HJ. Fontan “Ten Commandments’ revisited and
49
operation. Asian Cardiovasc Thorac Ann. 2015;23(4):

revised. Pediatr Cardiol. 2010;31(8):1131-4.
412-7.
19. Kutty S, Rathod RH, Danford DA, et al. Role of imaging in 22. Pundi KN, Johnson JN, Dearani JA, et al. 40-year followup
the evaluation of single ventricle with the Fontan palliation. after the Fontan operation: long-term outcomes of 1,052
Heart. 2016;102(3):174-83. patients. J Am Coll Cardiol. 2015;66(15):1700-10.
a
di
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of
ty
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CHAPTER 50 Fontan Circulation: Simplified
a
di
INTRODUCTION FONTAN PHYSIOLOGY
To achieve higher physiologic demands, the normal Fontan circulation is nothing but surgically created TCPC
In
blood circulation in mammals consists of two circuits, to divert blood from SVC and IVC to the pulmonary
pulmonary and systemic, connected in series. These arteries. The systemic venous blood directly reaches lungs
circuits are supported separately by the right ventricle (RV)
of
without going through the heart. In simple words, Fontan
and the left ventricle (LV). In some cardiac malformations, circulation bypasses the heart to divert the whole of the
however, there is only one functional ventricle. This systemic venous blood to the lungs for oxygenation. This,
ty
‘functionally single ventricle’ has to support both the in turn, abolishes right-to-left shunt and results in near
systemic and the pulmonary blood circulations, which normalization of the arterial saturation. In addition, the
18 cie
are no longer connected in series but are in parallel. Such
a circulation has two major disadvantages: admixture
of oxygenated and deoxygenated blood causing arterial
functionally single ventricle is saved from the volume
overload since the blood returning from systemic veins no
longer has to pass through the heart.
desaturation and chronic volume overload of the single As is evident, there is no ventricular pump to propel
20 o
ventricle. Over a period of time, this volume overload systemic venous blood to the lungs and the blood in the
S
gradually impairs ventricular function and reduces pulmonary circuit is driven by the pressure in the systemic
survival with only a few living beyond the fourth decade.1,2 veins. In doing so, the pressure head in the systemic veins
After initial animal experiments in the 1940s, William
al
has to overcome the resistance posed by the pulmonary

Glenn performed the first cavopulmonary connection in circuit. The resistance in the pulmonary circuit is the sum
1958, when he surgically connected superior vena cava of the resistance posed by cavopulmonary connections,
ic
(SVC) to the right pulmonary artery (RPA).3,4 This diverted pulmonary arteries, arterioles, pulmonary veins, and the
deoxygenated blood from systemic veins to the lungs.
og
cardiac chamber receiving the pulmonary venous return.

The diversion, however, was incomplete and resulted in The blood flow across the lungs is determined by the
only partial improvement in oxygen saturation as blood pressure gradient between the pulmonary artery and the
from the inferior vena cava (IVC) continued to reach
ol
pulmonary vein (transpulmonary gradient). Higher is the

systemic circulation without getting oxygenated. In 1968, pressure in the atrium receiving pulmonary veins, higher is
for the first time, the RV was surgically excluded from the
di
the pressure required in the systemic veins to pump blood

circulation by diverting blood from both the SVC and IVC across the Fontan circuit. It is conceivable, therefore, that
to the lungs and thus complete separation of systemic and
ar
any change in the characteristics of this pulmonary circuit

pulmonary circuits was achieved in three patients with and downstream ventricular chamber determines the flow
tricuspid atresia.5 The total cavopulmonary connection capabilities of this newly developed state of circulation,
C
(TCPC) thus created, produces unique circulation of devoid of a pumping chamber.7

blood and is commonly referred to as ‘Fontan circulation’
or ‘Fontan circuit’, paying a fitting tribute to the cardiac
surgeon Francis Fontan who first performed ‘Fontan INDICATIONS FOR FONTAN OPERATION
operation’.6 The procedure was later performed to palliate A Fontan repair can be considered in all cardiac
other cardiac malformations with functionally single malformations with single ventricle physiology. As is now
ventricle as well. Over the last four decades, multiple well known, a complete absence of one of the ventricles
techniques for achieving TCPC have been developed. is extremely rare and a heart with true single ventricle is
In clinical practice, Fontan circulation and TCPC are exceptional. Instead, most such hearts have ‘functionally
used interchangeably. In this chapter, we discuss various single ventricle’. Broadly, an absence or hypoplasia of one
indications and surgical techniques for creating Fontan of the atrioventricular valves, as in tricuspid and mitral
circulation. We then discuss hemodynamic effects of this atresia, and/or one of the ventricles, as in hypoplastic LV
unique form of blood circulation. or RV, result in a univentricular heart. For some complex
KG-50.indd 410 02-11-2018 16:55:01

CHAPTER
Table 1: Conditions representing ‘functionally single ventricle’
Absence of two adequate sized atrioventricular valves
zz Tricuspid atresia
50
Mitral atresia

zz
Hypoplasia of one of the ventricles

zz Single ventricle
zz Hypoplastic right or left ventricle
zz Double inlet left ventricle
zz Straddling of one atrioventricular valve
zz Unbalanced atrioventricular septal defect
a
Difficult biventricular repair
Congenital heart disease with large or multiple or nonroutable ventricular septal defects with unacceptable outcome with possible
di
biventricular repair
In
malformations, where the risk of biventricular surgical pulmonary artery pressure <15 mm Hg are nonmodifiable
repair is unacceptably high, Fontan operation offers factors. In a retrospective analysis of 406 patients, Hosein
of
palliation at much lower risk and a better clinical outcome. et al.10 found that only these two factors predicted the early
Table 1 enumerates common cardiac malformations that and late outcomes.
are treated as ‘functionally single ventricle’.8 In clinical practice, the aim is to identify patients with
ty
the most suitable hemodynamics so that the risk of Fontan
SELECTING A PATIENT FOR FONTAN failure can be minimized. An ideal candidate for Fontan is
OPERATION 18 cie
As there is no ventricle to pump systemic venous blood
a patient with good sized pulmonary arteries (preferably a
McGoon’s ratio >1.8), low pulmonary vascular resistance
across the lungs, the circuit can flow only with an (PVRI <2 WUm2), unobstructed pulmonary veins, no or
20 o
elevated pressure in the systemic veins. An acceptably mild atrioventricular valvar regurgitation and normal or
S
low transpulmonary gradient is vital for the functioning near-normal ventricular function. More are the number
of prospective TCPC. Any disturbance in the lung of parameters fulfilled, better are the chances of success
vasculature, lung parenchyma or the left-sided cardiac following Fontan surgery. In addition, it is important to
al
chambers can interfere with the flow across lungs and pay attention to certain other factors, such as obstruction
increase pressure in the systemic veins to nonphysiologic to the left ventricular outflow and aortopulmonary
ic
levels causing failure of Fontan circuit. Even in functioning collaterals, which indirectly affect the functioning of
Fontan circuit. While obstruction to the ventricular
og
Fontan circulation, chronic hypertension of the systemic

veins is deleterious in long term. It is, therefore, obligatory outflow or coarctation of aorta reduces the compliance
to identify patients who are at high risk of Fontan failure to of the ventricle, the aortopulmonary collaterals increase
pressure in the pulmonary arteries.
ol
improve outcomes.
In 1977, Choussat and colleagues proposed ‘Ten
PREPARING FOR FONTAN OPERATION
di
Commandments’ to identify a candidate suitable for

successful Fontan operation (Table 2).9 The aim of these The morphologic and physiologic conditions in a
ar
rather strict selection criteria was to identify low-risk functionally univentricular heart are widely variable. The
candidates. These traditional criteria are no longer used. hearts with an unrestricted flow to the lungs have elevated
C
Age younger than four is no longer a contraindication. pressure in the pulmonary arteries. The pulmonary artery
Systemic venous connections become irrelevant since pressure in patients with severe pulmonary stenosis,
these are dealt with during cavopulmonary connection. on the other hand, is low. As highlighted, the Fontan
Newer techniques of achieving TCPC obviate the need circulation is highly dependent on transpulmonary
of having a normal volume of the right atrium (RA). gradient and the most important factor determining
Similarly, atrioventricular valve regurgitation can be success is low pulmonary artery pressure. It is, therefore,
repaired and small or distorted pulmonary arteries can be imperative to protect the lungs for future cavopulmonary
dealt with surgical repair or percutaneous intervention in connections.
most cases. The rhythm abnormalities, both bradycardia The patients with functionally univentricular hearts are
and tachycardia, can be managed by implantation of a assessed in detail with an emphasis on identifying the status
pacemaker and antiarrhythmic treatment, respectively. of pulmonary artery pressure. A pulmonary artery band is
In effect, only two of the original 10 commandments: (i) performed in those with no obstruction to the pulmonary
preoperative ventricular function, and (ii) preoperative blood flow, while those with pulmonary stenosis are
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SECTION
Table 2: Ten commandments for successful Fontan operation9
7 Original 10 commandments
1.zAge >4 years
2.zSinus rhythm
3zNormal systemic venous return

4.zNormal right atrial volume
5.zMean pulmonary artery pressure <15 mm Hg
6.zPulmonary arteriolar resistance <4 Wood units/m2
7.zPulmonary artery-aorta ratio >0.75
8.zLeft ventricular ejection fraction 60%
9.zCompetent systemic AV valve
a
10.zAbsence of pulmonary artery distortion
di
followed medically. In patients with severe pulmonary it is advisable to leave a fenestration between the Fontan
In
stenosis and severe hypoxemia, an aortopulmonary shunt circuit and the atrium during surgery. It is also preferable
or stenting of patent ductus arteriosus is performed. It to perform fenestration in patients older than 10 years,
is also important to identify and treat associated lesions especially if they have not had a prior BDG and primary
of
that interfere with the flow of blood to the heart, in Fontan procedure is performed.11
the cardiac chambers and systemic circulation. The
surgery should aim at achieving an adequate interatrial TO STAGE OR NOT TO STAGE
ty
communication in cases with hypoplastic, absent or CAVOPULMONARY CONNECTION
obstructed atrioventricular valve to facilitate admixture
18 cie
of blood. In addition, lesions obstructing outflow to the
systemic circulation, such as aortic stenosis or coarctation
During the fetal life and prior to BDG, the ventricle is
volume overloaded as it handles both the systemic and
the pulmonary circulation. This chronic volume overload
of aorta, must be treated. The aim of this first step is
20 o
leads to ventricular hypertrophy and predisposes to future
to protect the pulmonary vasculature and prepare the
diastolic dysfunction. A practice of BDG operation initially
S
patient for future cavopulmonary connections.

and TCPC later, permits gradual unloading of the ventricle.
In the second stage of surgery, once the child is at
Direct or primary TCPC, on the other hand, causes an
least a few months’ old and PVR has fallen, a partial
al
acute volume reduction which results in sudden reduction

cavopulmonary connection is achieved surgically by in preload to a hypertrophied ventricle. Consequent
end-to-side anastomosis of SVC to the right pulmonary
ic
mismatch in preload and afterload predisposes to low

artery. This bidirectional Glenn (BDG) operation diverts cardiac output in the early postoperative period. Prior
deoxygenated blood returning from the upper half of the
og
BDG also promotes some growth of pulmonary arteries

body to directly reach the lungs. This improves oxygen particularly if flow across the pulmonary valve is not
saturation and allows time for the child to grow, to be completely obliterated. Also, since the blood flowing
ol
able to achieve completion of cavopulmonary connection through the lungs following BDG is lesser, it is tolerated
later. In addition, increased flow results in the growth of well even in patients with borderline suitability. The staged
di
pulmonary arteries. During surgery, once again, all efforts approach offers advantages in terms of cardiac function,
are made to treat associated lesions that might interfere arrhythmias, and long-term survival.12 In addition, the
ar
with future completion of cavopulmonary connection. staged approach allows room for interim intervention
In the next stage, IVC blood is also diverted to the like correction of atrioventricular valve regurgitation,
pulmonary arteries and cavopulmonary connection is
C
pulmonary arterial distortion and left ventricular outflow

completed. As highlighted before, Fontan circuit thus tract obstruction for better preparation for future Fontan
achieved flows well only if transpulmonary gradient is operation. It is currently recommended to perform BDG at
low and ventricular function is normal. While ventricular 6-12 months of age followed by TCPC at 4–5 years of age.13
function and the status of the atrioventricular (AV) valve In select cases older than 6 years of age, a single
can be assessed by echocardiogram in most instances, stage TCPC can be performed provided they have good
cardiac catheterization is performed to measure sized pulmonary arteries (McGoon’s ratio >2.0), normal
pulmonary artery pressure and calculate PVR. The final ventricular function, and low PVRI. On the other hand,
decision for completion of cavopulmonary connection in some cases, with borderline hemodynamics and/
is individualized; but, as a guiding principle, a patient or relatively small pulmonary arteries, BDG operation
is considered suitable only if mean pulmonary artery is the final palliative procedure. A brief outline of the
pressure is less than 15 mm Hg and indexed PVR is less management in patients with ‘functionally single ventricle’
than 2 WUm2. In those with borderline hemodynamics, is provided in Figure 1.
412
KG-50.indd 412 02-11-2018 16:55:01

KG-50.indd 413
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ar
di
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og
ic
al
20 o S
18 cie
ty
of
In
di
a
Figure 1: Algorithm for management of a patient with functionally univentricular heart
413
50
CHAPTER
02-11-2018 16:55:02
SECTION DIFFERENT TYPES OF FONTAN CIRCULATION In 1988, based on the extensive flow dynamics studies,
14 de Leval demonstrated the poor hemodynamics of
7
Rodbard and Wagner were the first to achieve the
atriopulmonary connections.17 The bloodstreams from the
right ventricular bypass in 1949 when they successfully
superior and the IVC were found colliding within the atrium
anastomosed the right atrial appendage (RAA) to the
leading to stasis and significant energy loss. Progressive

pulmonary artery and ligated the main pulmonary artery
dilatation of RA predisposed to atrial tachyarrhythmias
in dogs. In 1958, Glenn and colleagues performed the
and thrombosis. Based on these observations, de Leval
first successful cavopulmonary connection (SVC-to-
proposed the lateral tunnel (LT) variant of TCPC. The LT-
distal right pulmonary artery) in a 7-year-old child with
TCPC consists of three parts: (1) end-to-side anastomosis
a functional single ventricle. In 1968, Fontan and Baudet
of the SVC to the undivided right pulmonary artery; (2)
performed the ‘Fontan procedure’ in three adults with
construction of a composite intra-atrial tunnel using
tricuspid atresia.6
a
the posterior wall of RA, and (3) a prosthetic patch to
Fontan and colleagues or iginally per for med
channel the IVC to the orifice of the transected SVC that
di
atriopulmonary connection and the steps involved: (1)
is anastomosed to the main pulmonary artery (Figure 2).
end-to-side anastomosis of distal end of right pulmonary
Extra-cardiac conduit-TCPC (EC-TCPC) is yet another
In
artery (RPA) to superior vena cava (SVC); (2) end-to-end modification popularized by Humes and Marcelletti
anastomosis of RAA to proximal end of left pulmonary in 1990. 18,19 Instead of creating a tunnel in RA , a
artery (LPA) by means of an aortic valve homograft; (3) conduit is inserted between the transected IVC and the
of
closure of atrial septal defect (ASD); (4) insertion of a undersurface of the right pulmonary artery (Figure 2).
pulmonary valve homograft into IVC, and (5) ligation The conduits are made up of PTFE or are fashioned from
of main pulmonary artery (MPA) (Figure 2).15 A similar the pericardium. There is limited growth potential with
ty
operation was subsequently described by Kreutzer et al.16 polytetrafluoroethylene (PTFE) conduit; and therefore,
in which RA was anastomosed directly to the MPA with an a conduit usually larger than the diameter of the IVC
18 cie
interposed semilunar valve without Glenn anastomosis
and valve in IVC. Unlike the procedure described by
Fontan, the branch pulmonary arteries remained in
(conduit-to-IVC ratio >1.5) is chosen. Pericardial conduit,
on the other hand, has an advantage of growth and lower
risk of thrombosis and infection.
continuity with each other. Intuitively, a smooth conduit or tunnel in both these
20 o
During the decade following pioneering work by procedures allows laminar flow and, consequently, is
S
Fontan and Kreutzer, multiple modifications of the more energy efficient compared to an atriopulmonary
original procedure were reported. The initial procedures connection. In addition, there is minimal risk of
were based on the belief that RA being a pulsatile interference with the pulmonary venous drainage
al
chamber would augment pulmonary blood flow with the or atrioventricular valve. In contemporary practice,
assistance of two aortic or pulmonary valve homografts. atriopulmonary connection is no longer performed and
ic
In subsequent years, it became apparent that maintaining has been replaced by LT-TCPC or EC-TCPC. Overall,
the confluence of the pulmonary arteries is beneficial both lateral tunnel and extracardiac conduit approaches
og
and, hence, became the standard of care. Limited growth have similar early postoperative hemodynamics, and
potential and durability of conduits and valves also early to mid-term clinical outcomes. The lateral tunnel
became apparent. has an added advantage of growth and, therefore, can
ol
di
ar
C
A B C
Figure 2: Three forms of Fontan operation. (A) Atriopulmonary; (B) Lateral tunnel; (C) Extracardiac.
Adapted from Clift P, Celermajer D. Managing adult Fontan patients: where do we stand? Eur Resp Review 2016;25:438-450 (reference no. 15).
414
KG-50.indd 414 02-11-2018 16:55:03

be used in any age group. The extracardiac conduit, than 2%. Certain patients with mean pulmonary artery CHAPTER
on the other hand, has limited growth potential but is pressure >15 mm Hg, common atrioventricular valve and
technically simpler and can be easily reproduced in
complex malformations. In select cases, EC-TCPC can be
hypoplastic left heart syndrome, however, continue to
have relatively higher mortality and morbidity following
50

performed without cardiopulmonary bypass. In addition, surgery. Some patients develop state of low cardiac
almost no suture lines in the atriums and minimal output, pleural effusion and other signs of failure of Fontan
manipulation of atrial tissue during EC-TCPC minimizes circulation owing to a sudden reduction in preload to
the risk of arrhythmias. hypertrophied ventricle and preload-afterload mismatch.
In all patients with borderline hemodynamics and The postoperative course in such cases is stormy; although
doubtful suitability for TCPC, it is advisable to leave a in the majority, this can be managed by careful adjustment
fenestration between Fontan circuit and the atrium. of preload and afterload. In some cases, however, pleural
a
This fenestration permits flow of blood from the venous effusion remains challenging and warrants prolonged
di
circuit to the atrium in the event of elevated pulmonary chest tube drainage, infusion of somatostatin analog and/
artery pressure. This flow maintains cardiac output or pleurodesis. In a minority, pleural effusion is refractory
In
and thus helps in postoperative recovery.20 In a large and mandates interventional or surgical creation of
majority, the fenestration closes spontaneously. A patent fenestration.22,23
fenestration needs closure if there is unacceptable
of
hypoxemia postoperatively. Late Complications
Physiologically, Fontan circulation is inherently
CLINICAL EFFECTS OF FONTAN CIRCULATION disadvantageous. In addition, the ventricle is at risk of
ty
Fontan circulation corrects the functional abnormality of progressive functional deterioration. As a result, late
reduced pulmonary blood flow by directly diverting blood complications are not uncommon. Although there is often
18 cie
from systemic veins to reach pulmonary arteries. Following
TCPC, there is complete separation of pulmonary and
systemic circulations and the whole of the systemic
some overlap between the categories, the complications
are broadly related to ventricular dysfunction, systemic
complications of Fontan physiology, and chronic Fontan
20 o
venous return, except coronary sinus, reaches lungs for failure.
oxygenation. As a result, oxygen saturation is near normal.
S
Most of the carefully selected patients enjoy an improved Ventricular Dysfunction

quality of life. Despite improvement in surgical techniques, the
al
Nonpulsatile flow in the circuit, however, limits very nature of cardiac malformations predisposes to
exercise-induced recruitment of arterioles and reduction
progressive ventricular dysfunction initially due to volume
ic
in PVR. As a result, there is a limited increase in cardiac

overload and later due to chronic reduction in preload. In
output during exercise; and therefore, despite near
a cross-sectional study of 546 children following Fontan
og
normalization of arterial saturation at rest, patients

operation, 27% had systolic dysfunction and 72% had
with Fontan circuit have reduced exercise capacity. The
diastolic dysfunction.24 The prevalence of systolic and
functional capacity further declines over time as the
diastolic ventricular dysfunction increases with age,
ol
compliance of the ventricle is gradually reduced. Long-

particularly in those with morphologic RV functioning as
standing nonpulsatile flow causes adverse remodeling
systemic ventricle and previous ventriculotomy incisions.
di
of the pulmonary vasculature with increased intimal

The treatment options are largely empiric and are guided
thickness and reduced medial thickness of intra-acinar
by the evidence-based literature for heart failure in
ar
vessels leading to gradual increase in PVR.21

general. Existing literature has shown little impact on the
ventricular function of medications, such as inotropes,
C
LONG-TERM EFFECTS AND COMPLICATIONS afterload reducing agents, vasodilators, and beta blockers,
Chronic systemic venous hypertension and relatively fixed as these have no impact on the reduced preload, which is
cardiac output predispose to the development of unique the dominant limiting factor.
complications in patients with Fontan operation. Gradual
deterioration in ventricular function, both systolic and Systemic Complications
diastolic, also adds to the long-term morbidity and
z Growth restriction: The patients with Fontan circuit are
reduced survival.
at risk of growth restriction particularly in achieving
height potential. Inability to gain weight, on the other
Early Postoperative Complications hand, may be an early indicator of inadequate cardiac
In the modern era, with an improved patient selection, output. Significant growth failure should prompt a
a staged approach and better perioperative care, the thorough investigation of hemodynamic status with
mortality rate in the early postoperative period is less early efforts to optimize hemodynamic status.25
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SECTION z Cyanosis : Even after TCPC, the coronary sinus endobronchial lymph leakage. This leakage may be
continues to drain within the atrium and cause mild due to lymphatic trauma during surgery, adhesions
7 resting desaturation. In some cases, hepatic vein(s)
may remain outside the Fontan circuit and drain
and elevated central venous pressure. Majority of
patients who develop plastic bronchitis have significant
directly into the atrium. In patients with a fenestration hemodynamic derangements as a result of ventricular
in the Fontan circuit, right-to-left shunt results in dysfunction or refractory atrial arrhythmias and thus
persistent desaturation.24,25 have poor prognosis.29
z Arrhythmias: Atrial arrhythmias occur in up to 45% z Hepatic dysfunction: Progressive liver fibrosis is
patients in the 10 years following Fontan operation. universal after the Fontan operation. The degree of
The incidence is particularly higher in patients hepatic dysfunction has been correlated with time
with surgeries, with atrial manipulation, and suture from Fontan surgery, cardiac output, and extent of
a
lines in the atrium. As expected, arrhythmias are systemic venous hypertension. The pathogenesis of
di
most prevalent after conventional atriopulmonary liver fibrosis in the Fontan population is not well-
connection. Evidently, as there is minimal atrial documented. Prevailing understanding is that it relates
In
manipulation, arrhythmias are least frequent in to the chronic congestion associated with elevated
EC-TCPC. Other than atrial arrhythmias, patients venous pressure and diminished oxygen delivery
following Fontan completion are also at risk of sinus associated with the low cardiac output. Patients
of
node dysfunction, atrioventricular block, and sudden operated for more than 10 years should be closely
arrhythmic death. Ventricular arrhythmias are less followed to check for the onset of portal hypertension-
common, but they contribute to one-tenth of sudden related complications or hepatocellular carcinoma.
ty
death.24,25 Most experts recommend periodic screening and
z Thrombosis and thromboembolism : A low flow monitoring of liver function, although the optimal
18 cie
state, atrial scarring, arrhythmias, dehydration,
and a hypercoagulable state all increase the risk
radiological technique and interval are unknown.30,31
Diuretic therapy and optimization of hemodynamics
are the mainstay of therapy. Combined cardiac and
of thromboembolism. The incidence of thrombo-
20 o
embolism varies from 6%–20% across studies. There liver transplantation for a Fontan patient has been
is wide variability in the prophylactic strategies. performed successfully.25
S
Aspirin has been shown to reduce the incidence of

thromboembolic events from 18.6% to 8.6%. There is Chronic Fontan Failure
al
no added advantage of adding oral anticoagulants.26 Fontan physiology is characterized by a progressive

Oral anticoagulation, however, is preferred in those decrease in cardiac output and increasing central venous
ic
with high risk of thromboembolism. pressure over time. By mid-adolescence, exercise capacity
z Protein-losing enteropathy: Protein-losing enteropathy is typically reduced to approximately 66% of expected.
og
(PLE) is a rare complication with an estimated Beyond adolescence, exercise tolerance continues to
prevalence of 1–15% in patients with Fontan circulation. decrease at a rate of about 2.6% per year. By the third
It is characterized by excessive loss of protein from decade of life, exercise capacity crosses a threshold of
ol
serum into the intestinal lumen. It is usually seen late 45% of predicted values and hospitalization rates and
after Fontan palliation and is associated with significant symptoms increase significantly.32
di
morbidity and mortality. Manifestations include Conversion to EC-TCPC is shown to be successful

edema, ascites, immunodeficiency, malabsorption, in many patients with failed atriopulmonary Fontan
ar
hypocalcemia, and coagulopathy. The diagnosis is circulation. More than moderate regurgitation of AV
mostly clinical but can be confirmed by testing the valves is an indication for surgical repair or replacement
C
stool for trypsinogen. Treatment includes a diet low in of the valve. Patients with other residual obstructive
salt and high in calories, protein, and medium chain anatomic lesions in the pulmonary arteries, pulmonary
triglycerides. Corticosteroids, unfractionated heparin, veins, subaortic area, or aortic arch should be considered
and octreotide, a somatostatin analog are known to for early corrective surgery. Fontan failure related to
provide symptomatic relief in some individuals.27,28 ventricular dysfunction is the most challenging subset with
z Plastic bronchitis: It is a rare, potentially life-threatening limited options. Some reports have suggested a beneficial
complication with an incidence of 1–2%, in which large role of ventricular assist devices. Heart transplantation
and pale bronchial casts with rubber-like consistency is the final option for patients who have failed all other
develop in the tracheobronchial tree and cause airway treatment strategies. However, coexisting multiorgan
obstruction. The pathogenesis of plastic bronchitis dysfunction and prior human leukocyte antigen (HLA)
is not well understood. The proposed mechanism is sensitization during multiple surgeries makes it a less
the development of break in mucosal integrity and than an ideal treatment option. The early outcomes of
injury to the alveolar–capillary barrier which causes the heart transplant in patients with Fontan operation are
416
KG-50.indd 416 02-11-2018 16:55:03

suboptimal although medium and long-term mortality is 10. Hosein RB, Clarke AJ, McGuirk SP, et al. Factors influencing CHAPTER
comparable to other cardiac malformations.32 early and late outcome following the Fontan procedure
in the current era. The ‘Two Commandments’? Eur J
Cardiothorac Surg. 2007;31(3):344–52.
50
OUTCOME

11. Ro PS, Rychik J, Cohen MS, et al. Diagnostic assessment
Early mortality rates have decreased and long-term survival before Fontan operation in patients with bidirectional
has also improved significantly. Nevertheless, despite cavopulmonary anastomosis: are noninvasive methods
improvement in medical and surgical management, the sufficient? J Am Coll Cardiol. 2004;44(1):184–7.
survival among patients with Fontan operation remains 12. Norwood WI, Jacobs ML. Fontan›s procedure in two stages.
less than the population average. As per estimates from the Am J Surg. 1993;166(5):548–51.
Mayo clinic study, the survival following Fontan surgery 13. Saxena A. Working group on management of congenital
a
is 74%, 61%, and 43% at 10, 20, and 30 years follow-up.33 heart diseases in India. Consensus on timing of intervention
More recent estimates from the Australian-New Zealand for common congenital heart disease. Indian Pediatr.
di
Registry have documented better survival of 93%, 90%, and 2008;45(2):117–26.
14. Rodbard S, Wagner D. Bypassing the right ventricle. Proc
83% at 15, 20, and 30 years following Fontan operation.34
In
Soc Exp Biol Med. 1949;71(1):69.
15. Clift P, Celermajer D. Managing adult Fontan patients:
CONCLUSION where do we stand? Eur Resp Review. 2016;25:438-50.
of
The circulation of blood following TCPC or Fontan 16. Kreutzer G, Galíndez E, Bono H, et al. An operation for the
operation is largely dependent on low transpulmonary correction of tricuspid atresia. J Thorac Cardiovasc Surg.
gradient. Pulmonary artery pressure and ventricular 1973;66(4):613–21.
ty
17. de Leval MR, Kilner P, Gewillig M, et al. Total cavopulmonary
function are the most important determinants of success
connection: a logical alternative to atriopulmonary
of the Fontan circuit. Despite near normalization of arterial
18 cie
saturation, the patients continue to have suboptimal
exercise tolerance. Long-term survival is improving but is
significantly less than the general population.
connection for complex Fontan operations. Experimental
studies and early clinical experience. J Thorac Cardiovasc
Surg. 1988;96(5):682-95.
18. Humes RA, Feldt RH, Porter CJ, et al. The modified Fontan
20 o
operation for asplenia and polysplenia syndromes. J Thorac
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S
19. Marceletti C, Corno A, Giannico S, et al. Inferior vena

1. Gewillig M. The Fontan circulation. Heart. 2005;91(6):839–
cava-pulmonary artery extracardiac conduit: a new form of
46.
al
right heart bypass. J Thorac Cardiovasc Surg. 1990;100(2):

2. Gewillig M, Brown SC. The Fontan circulation after 45
228–32.
years: update in physiology. Heart. 2016;102(14):1081–6.
ic
20. Ono M, Boethig D, Goerler H, et al. Clinical outcome

3. Starr I, Jeffers WA, Meade RH Jr. The absence of conspicuous
of patients 20 years after Fontan operation—effect of
increments of venous pressure after severe damage to the
og
fenestration on late morbidity. Eur J Cardiothorac Surg.

right ventricle of the dog, with a discussion of the relation
2006;30(6):923–29.
between clinical congestive failure and heart disease. Am
21. Ridderbos FJ, Wolff D, Timmer A, et al. Adverse pulmonary
Heart J. 1943;26:291-301.
vascular remodeling in the Fontan circulation. J Heart Lung
ol
4. Glenn WW. Circulatory bypass of the right side of the heart. Transplant. 2015;34(3):404–13.
IV. Shunt between superior vena cava and distal right 22. Mascio CE, Austin EH 3rd. Pleural effusions following the
di
pulmonary artery; report of clinical application. N Engl J Fontan procedure. Curr Opin Pulm Med. 2010;16(4):362-6.
Med. 1958;259(3):117-20. 23. Talwar S, Agarwala S, Mittal CM, et al. Pleural effusions in
ar
5. Said SM, Burkhart HM, Dearani JA. The Fontan connections: children undergoing cardiac surgery. Ann Pediatr Cardiol.
past, present, and future. World J Pediatr Congenit Heart 2010;3(1):58–64.
Surg. 2012;3(2):171–82.
C
24. Mondésert B, Marcotte F, Mongeon FP, et al. Fontan

6. Fontan F, Baudet E. Surgical repair of tricuspid atresia. circulation: success or failure? Can J Cardiol. 2013;29(7):
Thorax. 1971;26(3):240–8. 811–20.
7. Goldberg DJ, Paridon SM. Fontan circulation: the search for 25. Deal BJ, Jacobs ML. Management of the failing Fontan
targeted therapy. Circulation. 2014;130(23):1999–2001. circulation. Heart. 2012;98(14):1098-104.
8. Rao PS. Fontan operation: indications, short and long term 26. Giglia TM, Massicotte MP, Tweddell JS, et al. Prevention
outcomes. Indian J Pediatr. 2015;82(12):1147–56. and treatment of thrombosis in pediatric and congenital
9. Choussat A, Fontan F, Besse P. Selection criteria for the heart disease: a scientific statement from the American
Fontan procedure. In: Paediatric cardiology,Anderson RH, Heart Association. Circulation. 2013;128:2622–703.
Shinebourne EA (eds.). Edinburgh, Scotland: Churchill 27. Rychik J. Protein-losing enteropathy after Fontan operation.
Livingstone.1977. pp. 559–566. Congenit Heart Dis. 2007;2(5):288-300.
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SECTION 28. Ryerson L, Goldberg C, Rosenthal A, et al. Usefulness 31. Téllez L, Rodríguez-Santiago E, Albillos A. Fontanassociated
of heparin therapy in protein-losing enteropathy liver disease: a review. Ann Hepatol. 2018;17(2):192-204.
7 associated with single ventricle palliation. Am J Cardiol.

2008;101(2):248–51.
32. Vaughn G, Moore J, Lamberti J, et al. Management of
the failing Fontan: medical, interventional and surgical
29. Costello JM, Steinhorn D, McColley S, et al. Treatment treatment. Prog Pediatr Cardiol. 2016;43:51–6.
of plastic bronchitis in a Fontan patient with tissue 33. Pundi KN, Johnson JN, Dearani JA, et al. 40-year followup
plasminogen activator: a case report and review of the after the Fontan operation: long-term outcomes of 1,052
literature. Pediatrics. 2002;109(4):e67. patients. J Am Coll Cardiol. 2015;66:1700–10.
30. Goldberg DJ, Surrey LF, Glatz AC, et al. Hepatic fibrosis 34. d’Udekem Y, Iyengar AJ, Galati JC, et al. Redefining
is universal following Fontan operation, and severity expectations of long-term survival after the Fontan
is associated with time from surgery: a liver biopsy procedure: twenty-five years of follow-up from the entire
and hemodynamic study. J Am Heart Assoc. 2017;6(5): population of Australia and New Zealand. Circulation.
a
e004809. 2014;130(11 Suppl 1):S32–8.
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KG-50.indd 418 02-11-2018 16:55:03

Ebstein’s Anomaly:
CHAPTER 51 What’s New?
a
di
INTRODUCTION occurs due to failure of delamination. The septal leaflet
Ebstein’s anomaly is a rare and intriguing malformation can be rudimentary or absent and represented by fibrous
In
of the heart that has a wide spectrum of pathologic and nodules. The valve can vary from severely regurgitant to a
clinical manifestation. It constitutes <1% of all congenital stenotic narrow orifice.4,5
heart diseases.1,2 The clinical and anatomic features were
of
Anterior Leaflet
first described in 1866 by Dr Wilhelm Ebstein in a cyanotic
patient who subsequently died.3 The clinical presentation The proximal attachment is at the normal position, but
there is varying morphology of distal attachment. There
ty
can vary from the critically ill neonate to an asymptomatic
adult. The primary abnormality is a right ventricular may be abnormal papillary muscle; and in severe cases,
they may be fused to form a linear shelf. The chordae
18 cie
cardiomyopathy with failure of delamination of tricuspid
valve. Surgery carries high risk in the neonate, but in late
childhood and adulthood has satisfactory outcomes.
tendinae may be thick and short or may be so small that
leaflet directly attaches to the papillary muscle. The leaflet
Late survival morbidity is dotted by atrial arrhythmias. instead of being entirely fibrous has varying amount of
20 o
Cone repair, the latest surgical technique achieves near muscle strands. Fenestrations, muscularization, tethering,
S
anatomic restoration of tricuspid valve (TV) anatomy. and redundancy occur to a varying extent. Rarely, the
Right ventricle (RV) dysfunction and surgery for recurrent entire leaflet may be in the form of an atretic membrane.
tricuspid regurgitation (TR) remain major challenges. Incomplete coaptation of anterior leaflet and multiple
al
fenestrations contribute to severe TR.4

ANATOMY
ic
Dilated Right AV Junction

The morphology is not a simple downward displacement
The right AV junction is 1.5 to 2 times the size of left AV
og
of the septal leaflet. The pathology involves all the three

junction.
leaflets, tension apparatus, and the RV myocardium.
The anterior leaflet is attached at the normal level of Enlarged Atrialized RV and Functional RV
ol
atrioventricular (AV) junction in the appropriate position.

The chamber between the true TV annulus and functional
Towards the membranous septum, the septal leaflet
orifice is the inlet portion of RV and is functionally an
di
attachment moves progressively downwards to meet the

posterior leaflet. Maximal displacement is seen at the atrium. This posterior wall is formed by this dilated
thinned out wall of RV. The wall is fibrous and has sparsely
ar
hinge point between the septal and posterior leaflets. The

attachment of the posterior leaflet then moves up to meet distributed muscle fibres. The dilated atrialized RV (aRV)
the anterior leaflet at the lateral aspect of the valve (Figure is thinned out and dyskinetic and forms a part of the
C
1A). Though traditionally the displacement is described wall of left ventricle (LV). This can lead to alteration of
as ‘downwards’ it is actually a rotation of the valvar orifice LV geometry and dyssynchronous contraction of LV. The
around the aortic root. There is anteroapical shift of TV functional RV (FRV) is formed by the trabecular and the
orifice towards right ventricular outflow tract (RVOT). The outflow components. This portion also progressively
normal TV orifice guards the inlet portion of the RV; but dilates over time due to TR. This can lead to LV compression
in Ebstein’s anomaly, it is positioned at the junction of and over time LV dysfunction.6,7
the inlet and the trabecular components of the ventricle.
The displacement exposes an area of the ventricular EMBRYOLOGY
wall to atria or the “atrialized ventricle”. Greater the The AV connections are first established followed by the
displacement, larger is the atrialized ventricle and smaller development of AV leaflets. The leaflets are formed by the
is the functional RV. The septal and the posterior leaflets process of undermining or delamination of ventricular
are thick, muscularized and have abnormal chordal myocardium. The subendocardial portion of the inflow
attachment and tethering to ventricular septum. Tethering develops fenestrations and spongy myocardium.
KG-51.indd 419 02-11-2018 17:04:01

SECTION
7
a
A B
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C
Figures 1A to C: (A) The maximal displacement seen between septal and posterior leaflet;
(B) Process of delamination and its failure; (C) Carpentier’s classification
20 o
(Courtesy: Dr Anand Matthew)
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Table 1: Carpentier’s classification (Figure 1C).8 Type D is the most difficult to correct. Type B
Functional RV volume ATL
and C are the most commonly occurring (Table 1).
al
A Good Large leaflet, no tethering

Associated Anomalies
ic
B Reduced FRV, large aRV, Abnormal chordae, normal

normal contractility mobility About 80–90% will have atrial septal defect (ASD) or
og
C Small FRV with dysfunction, Adhesions, restricted mobility, patent foramen ovale. The RVOT obstruction in the form
RVOT obstruction of pulmonary valve stenosis or atresia can be seen. Floppy
D Minimal FRV – only Extensive adhesions mitral valve, cleft leaflet, and parachute mitral valve are
infundibulum
ol
some rare associations.9,10 The grossly dilated RV may

Abbreviations: ATL, anterior tricuspid leaflet; RV, right ventricle; FRV, compress the LV into a crescent shape leading to LV
functional right ventricle; aRV, atrialized right ventricle; RVOT, right
di
ventricular outflow tract dysfunction.6 The Ebstein’s malformation of the TV can

occur in the setting of corrected transposition of great
ar
Continued process raises a flap-like muscular membrane arteries (CTGA). Patent ductus arteriosus, coarctation of
attached at the annulus. Progressive thinning and aorta, tetralogy of Fallot, atrioventricular canal defects,
aortic atresia are other rare associations.11
C
fibroblast ingrowth leads to formation of valve leaflets

(Figure 1B). The primary problem in this anomaly is
failure of delamination. The large right AV junction Coronary Arteries
which is found in all patients probably develops earlier
The origin and the course of the coronary arteries are
than leaflets. The large inlet into RV probably changes
normal. The course of the right coronary artery marks the
the hemodynamic pattern necessary for the process
true AV junction. During plication of atrialized RV, care
of delamination at the true AV annulus. Instead, the
should be taken not to distort the coronary artery.
undermining happens at the narrowest portion of the RV,
where the flow pattern facilitates this process. Deficiency
of sulcal tissue may be the cause of dilatation of the AV ARRHYTHMIAS
junction.4 Overall 15–20% of patients will have accessory pathways.
Carpentier et al. developed the first classification Most commonly occurring is right posterolateral
system in 1988. They classified based on the degree of pathway followed by posteroseptal pathway. Mahaim
420 tethering of anterior leaflet and amount of functional RV fiber tachycardia is also known to occur. The TV is an
KG-51.indd 420 02-11-2018 17:04:01

incomplete fibrous ring and allows direct muscular PATHOPHYSIOLOGY CHAPTER
connection between right atrium (RA) and RV. Muscle
51
The anatomic RA and atrialized RV contract sequentially.
strands are present in the anterior leaflet also. This forms The aRV balloons out during atrial contraction and acts
the substrate for the occurrence of multiple accessory as a passive reservoir. Impaired antegrade flow occurs

pathways. Ablation is recommended in the presence due to severe TR and reduced FRV. The consequences are
of accessory pathway with significant arrhythmias. congestive heart failure and cyanosis due to right-to-left
Recurrences may occur after ablation. If surgery is shunting across the atrial septum. In severe cases, the FRV
indicated, then surgical ablation of accessory pathway can is diminutive and unable to generate enough force to open
be carried out or perinodal ablation can be done for nodal the pulmonary valve resulting in functional pulmonary
re-entry tachycardia. No recurrence has been documented atresia. There is progressive dilatation of thinned out aRV
after surgical ablation.
a
and reduced cardiac output. The incompetent TV causes
Atrial flutter and atrial fibrillation occur with progressive regurgitation and dilatation of FRV. Massive
di
advancing age. By 50 years of age, around 30–40% will have dilatation and cardiac enlargement can occur in fetus
arrhythmias. They will require ablation during surgery in leading to hypoplasia of the lungs. Heart failure can occur
In
the form of right-sided maze or atrial isthmus ablation. in utero. Neonates with massive dilatation have a high
However, 29% of patients are known to have recurrence risk of mortality. Those who survive the neonatal period
after surgery.12 remain relatively asymptomatic in the first decade, after
of
which progressive decompensation can occur due to
ETIOLOGY AND GENETIC FACTORS progressive TR, RV and LV dysfunction.13,17,18
Most of the cases are sporadic. Mutation in MYH7 gene
ty
has been found to be associated with Ebstein’s anomaly NATURAL HISTORY
when associated with LV noncompaction.13 Occasional
18 cie
reports of familial clustering have been reported familial
clustering.14 Rare cases of cardiac transcription factor
Survival at the end of 1 year is 67%, and 59% at the end of
10 years. Neonatal presentation, higher echocardiographic
scores, cardiothoracic ratio more than 65%, and RVOT
NKX2.5 mutations, 10p13–p14 deletion, and 1p34.3–
20 o
obstruction are predictors of mortality. The annual
p36.11 deletion have been described in association with
risk of death was 36% in the first year of life, 4% in the
S
Ebstein’s malformation. 15 Syndromic association of

second year, and 1% in 2–10 years. It is 1.4% from 10–40
Ebstein’s malformation is rare. Maternal benzodiazepine
years of age. The natural history has been modified
use has been implicated as a causal factor for Ebstein’s
al
after development of improved surgical techniques, and

anomaly.1 Maternal use of lithium in the first trimester
improved management of arrhythmias.13
of pregnancy is associated with increased risk of cardiac
ic
malformations including Ebstein’s anomaly, but the

magnitude of affection is less than what was considered Sudden Cardiac Death
og
earlier.16 The risk of sudden death is around 0.2% per year with a
cumulative risk of death being 1.9%, 8.3%, and 14.6% on
DIFFERENTIAL DIAGNOSIS
ol
20, 50, and 70 years follow-up, respectively. Hemoglobin

Uhl’s anomaly: Diffusely thin and dilated RV and >15g/dL, heart failure, TV surgery, pulmonary stenosis,
di
biatrial maze, syncope, and prior episode of ventricular

grossly dilated RA with severe TR. The TV is situated at
tachycardia are predictors of sudden cardiac death.19
the normal position.
ar
Arrhythmogenic RV dysplasia: Dilated thinned RV with

fatty replacement of myocardium and patchy fibrosis. Presentation
C
Ventricular tachycardia and sudden death are known The presentation is bimodal with the first peak in the first
to occur. Septum and LV free wall also may be involved. year of life and the second peak after the first decade of
Dysplastic tricuspid valve: The valve leaflets are life. The neonate with severe Ebstein’s anomaly presents
thick, chordae tendinae may be fused, and there in a state of critical low cardiac output, shock, and duct-
may be tethering of leaflets. There is no downward dependant circulation. The baby is severely cyanosed
displacement of valve leaflets. There is severe TR and with huge cardiomegaly on chest X-ray. If the degree of
dilatation of RA and RV. It may be accompanied by involvement is not extreme, then the cyanosis gradually
pulmonary atresia. disappears as the pulmonary vascular resistance falls over
Unguarded tricuspid valve: Complete absence 2–4 weeks.
of leaflet tissue, chordae, and papillary muscle. During the later years, common symptoms are cyanosis,
Pulmonary atresia may be an association. This should arrhythmias, fatigability, and impaired exercise tolerance.
be differentiated from severe Ebstein’s anomaly with Progressive right heart failure occurs in advanced stages.
imperforate membrane.9 The child can be completely asymptomatic and have an
421
KG-51.indd 421 02-11-2018 17:04:02

SECTION incidental detected murmur or cardiomegaly. Majority 2D Echocardiography
of patients (43%) above 10 years of age present with an Apical displacement of septal leaflet >8 mm/m 2 is
7 episode of arrhythmia. Late hemodynamic deterioration
occurs due to the onset of RV dysfunction secondary to
diagnostic of Ebstein’s anomaly. This is best seen in apical
4-chamber view (Figure 3A). The degree of dilatation
progressive TR, right-to-left shunting and LV dysfunction. of right heart and the amount of functional RV have
Possible etiologies of LV dysfunction are paradoxical to be assessed. Points of tethering between leaflet and
septal motion, LV fibrosis, and chronic cyanosis. myocardium can be made out. Great Ormond Street Echo
Paradoxical embolism and infective endocarditis are (GOSE) score (Table 2) helps in predicting the prognosis
the other morbidities which can happen in the natural in the neonate. It is the ratio of the combined area of RA
history. Heart block can occur during catheterization or and atrialized RV to the sum of the area of FRV, left atrium
postoperatively.11,20 (LA) and LV (Figures 3C and D). The GOSE score greater
a
than Grade I predicts dismal survival. Grade III and Grade
di
EXAMINATION IV invariably have 100% mortality. The severity of the
regurgitation can be assessed using color Doppler across
In
Jugular venous distension and hepatic enlargement
the TV orifice. The atrial septum is best imaged in the
may be seen in advanced cases. The highly compliant subcostal coronal and sagittal planes for the presence of
RA limits these findings in most of the cases. Multiple ASD. Bidirectional or right to left across the ASD indicates
of
clicks can be heard due to a large mobile anterior leaflet. the presence of RV dysfunction (Figure 3B). Search should
The RV enlargement causes conduction delay resulting be made for associated lesions such as ventricular septal
in split S2. The TR murmur is soft and low intensity due defect (VSD), coarctation, and PDA, etc. It is important to
ty
to low velocity flow and early equalization of pressures assess LV function.11
across RA and RV. In chest X-ray, massive cardiomegaly
18 cie
is seen in severely symptomatic neonates. Ascending
aorta is small and inconspicuous, causing narrow pedicle.
3D Echocardiography
The advantage of the 3D imaging is it allows cropping and
Cardiomegaly is common with 60% of the patients ranging
reconstruction of the images and allows visualization of
20 o
from 60%–90%. The CT ratio more than 65% carries poor
the intracardiac structures from a clinically useful point
prognosis (Figure 2A).
S
of view, especially the ‘surgeons’ view. It is possible to

visualize the surface of the leaflets and know the exact
ECG location of the coaptation deficiency. The 3D matrix array
al
Tall P waves (71%), prolonged PR interval (34%), right probe helps in real-time 3D assessment (Figure 4A) of
bundle branch block (50%) are common features. the valve without the need for 3D reconstruction. It is
ic
Accessory pathway is seen in 15–20% patients. Atrial flutter possible to assess the coaptation planes, commissures,
and fibrillation is seen in older patients (Figure 2B).11 and entire valve apparatus to understand the mechanics of
og
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C
A B
Figures 2A and B: (A) Chest X-ray in an Ebstein’s anomaly patient showing cardiomegaly and right atrium enlargement, normal vascularity;
(B) ECG in a patient with Ebstein’s anomaly showing tall P waves and right bundle branch block
422
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CHAPTER
51

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20 o S
C D
al
Figures 3A to D: 2D echocardiogram in Ebstein’s anomaly. (A) Degree of displacement of septal leaflet; (B) Right-to-left shunt across the
atrial septum; (C) Area of left atrium and left ventricle; (D) Area of right atrium and atrialized right ventricle
ic
regurgitation (Figure 4B). The mutliplanar imaging helps can help in prognosticating the outcome of surgery.22 A
og
in viewing the valve in the three orthogonal plains at one novel index with the ratio of total right volume (RA + aRV
point of time. The degree of delamination can be assessed + FRV) to that of left volume (LA + LV) is correlated with all
well using 3D echocardiography. The regurgitant jet can parameters of heart failure such as severity of TR, degree of
ol
be accurately visualized and quantified. Quantification TV displacement, BNP, and peak oxygen consumption.23
of the effective volume of the RV is possible using 3D
The MRI has a lot of potential in assessing the anatomy and
di
echocardiography. This is required when the displacement

function and more studies are required.
is severe and the component of FRV appears very small for
ar
a successful biventricular repair.21 Cardiac catheterization is rarely required only if a

cavopulmonary shunt is planned. The hemodynamics
Magnetic Resonance Imaging including LV diastolic pressures and pulmonary vascular
C
resistance needs to be calculated.

Quantitative assessment of FRV size and function is possible
in a precise manner by magnetic resonance imaging (MRI).
The RV is a complex structure and complete assessment Fetal Echocardiography
is not accurately possible with echocardiography. The Diagnosis can be made as early as 16–20 weeks of
MRI is complementary to echocardiography in assessing gestation. Severe Ebstein’s anomaly can cause hydrops
the function and volume. This can help in planning
fetalis. It is important to assess for the presence of
the surgical procedure. The posterior leaflet adhesions
antegrade pulmonary flow as prostaglandin may be
and fenestrations are better appreciated in the MRI.
All the features of the valve anatomy including degree essential to maintain ductal flow in postnatal period.
of adhesions, amount of displacement, presence of Severe cardiomegaly, presence of hydrops, and pulmonary
fenestration and quantification of TR can be evaluated in stenosis are poor prognostic factors portending high
the different views of the MR scan (Figures 4C and D). Late mortality. Gross cardiac enlargement can cause pulmonary
gadolinium enhancement suggestive of myocardial fibrosis hypoplasia. 423
KG-51.indd 423 02-11-2018 17:04:03

SECTION
7
a
A B
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C D
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Figures 4A to D: (A) En-face of the tricuspid valve showing the incomplete coaptation in the center; (B) Inflow-outflow view of right ventricle
(RV) showing the anteroapical displacement of the orifice; (C) Axial section of MRI showing large dilated right atrium and atrialized RV;
(D) Sagittal section of MRI showing septal bowing due to dilated RV
(Courtesy: Dr Shivakumar/Dr PV Suresh)
20 o
Indications for Surgery
S
Table 2: Celermajer index/Great Ormond Street Echo score on

echocardiography (RA + ARV)/(FRV + LA + LV) The presence of severe cyanosis, inability to wean from
<0.5 Grade I ventilator, inotropes, and prostaglandin infusion, and the
al
0.5–0.99 Grade II GOSE score of III or IV with severe cardiomegaly >80% are
1.0–1.49 Grade III indications. Biventricular repair is preferred in most of the
ic
>1.5 Grade IV cases unless the functional RV is too small.24

og
TREATMENT RV Exclusion Approach (Starnes Procedure)

When the FRV is very small or if there is pulmonary atresia
ol
Neonate with small FRV, single ventricle pathway is preferable.

Reduced pulmonary flow occurs with type C or D of The tricuspid orifice is closed with fenestrated pericardial
di
Carpentier’s classification. The high pulmonary vascular patch to exclude the RV, enlargement of interatrial
communication is performed, and an aortopulmonary
resistance further comprises the pulmonary flow. This
ar
shunt is added. Right atrial reduction is performed in all

leads to cyanosis due to right-to-left shunting across ASD
types of surgeries.
and right heart failure. Mortality is near 100% when the
C
Biventricular repair was possible in 90% of patients. The

GOSE score is III or IV. Around 30–40% of neonates are TV repair with various techniques, RVOT reconstruction
symptomatic. Those with milder degrees of Ebstein’s with homograft, insertion of systemic to pulmonary artery
anomaly, with normal saturation, and no features of heart shunt in diminutive PAs, and correction of associated
failure do not require any intervention in neonatal period. anomalies are performed. Immediate survival was 78%
and 15-year-survival was 74%.
Management
Beyond Neonatal Period
Mechanical ventilation, prostaglandin infusion and
inotropes to control heart failure are necessary. Control Medical Management
of pulmonary vascular resistance will augment the Diuretics for heart failure
pulmonary flow. Control of arrhythmias
424
KG-51.indd 424 02-11-2018 17:04:03

CHAPTER
51

a
di
In
of
ty
18 cie
20 o S
A
al
ic
og
ol
di
ar
C
B C D
Figures 5A to D: (A) Surgeons sketch of cone repair detailing the different steps; (B) External appearance of grossly dilated right atrium;
(C) Rudimentary septal tricuspid leaflet, muscularized anterior tricuspid leaflet; (D) Delamination of anterior tricuspid leaflet
(Courtsey: Dr Jayanth Kumar)
Anticoagulation—paradoxical embolism and atrial Indications for Surgery

arrhythmias The indications for surgery are cyanosis, symptomatic
Endocarditis prophylaxis patients [Class III and IV New York Heart Association
Pregnancy counseling (NYHA)], uncontrolled arrhythmias, paradoxical
Definitive repair. embolism, RV dysfunction, and cardiothoracic ratio >65%.
425
KG-51.indd 425 02-11-2018 17:04:04

SECTION Once symptoms set in, the future can be rapid downhill As an alternative, atrial septal fenestration can be added
course.24. instead of the Glenn shunt to maintain cardiac output and
7 Danielson published the first repair of Ebstein’s
anomaly. It included plication of aRV, annuloplasty, and
decompress RV, especially in young patients. The trend
in the current era is towards early surgery in childhood
RA reduction and creation of monocusp valve using before deterioration of RV function. This should be done in
anterior leaflet. Sebening stitch was used to approximate centers which have consistent and predictable outcomes.
the anterior papillary muscle to septum causing coaptation The TV replacement is an option in older patients
of leaflet with muscular wall. Survival was 76% at 20 years. beyond 55–60 years of age and in situations with massively
Atrial arrhythmias were common on follow-up.7 dilated RV and tricuspid annulus and/or presence of RV
Carpentier developed another technique in 1988 dysfunction.
which involved reduction of aRV and RA, annuloplasty
a
with a ring, detachment of anterior and posterior leaflets, Outcome
di
and reattachment at true annulus. The 20-year survival Initial technique of surgeries had 10- and 20-year survival
was 82% with a significant reduction in atrial arrhythmias.8 of 84% and 71%, respectively.7
In
DaSilva from Brazil reported the cone repair in 2007 Cone repair in adults had immediate mortality of 1–4%
that gives the closest anatomic restoration of the valve with no late mortality. About 13% required repeat surgery.
architecture. The principle of cone repair is the complete Overall 97% remained in functional class I at 5-year follow-
of
surgical delamination and recruitment of all leaflet tissue. up.29
The anterior and posterior leaflets are detached from the In young patients <12 years operated at Boston
annulus and freed of all adhesions leaving only the apical children’s hospital with cone repair technique, immediate
ty
attachment. The valve is rotated clockwise and attached mortality was 1%; 80% had mild TR at discharge; and
to the true annulus. The septal aspect of the annulus is 10.5% required repeat surgery. At 4.3-year follow-up,
18 cie
also covered with leaflet tissue. Unlike earlier repairs,
this provides a central pathway for the diastolic flow with
full coaptation of leaflets in the 360° cone (Figures 5A
survival was 97% showing excellent outcomes in young
people with this technique.30
20 o
to D). The entire annulus has leaflet tissue guarding the
Arrhythmias
orifice and it is at its true AV junction. Before attachment
S
the annulus is plicated. In neonates, delayed sternal Cryoablation of cavotricuspid isthmus or right-sided maze
closure, and presence of an ASD, helps in the presence is done in the presence of flutter or paroxysmal fibrillation.
Left-sided maze or isolation of pulmonary vein can be
al
RV dysfunction in the postoperative period. Inhaled nitric

oxide can improve the pulmonary flow in the immediate performed for persistent atrial fibrillation. In the presence
of complete heart block, epicardial pacing is preferred to
ic
postoperative period. The atrialized RV is plicated from

annulus to apex. left ventricle.
og
Outcomes are superior when the surgery is done

before the development of RV or LV dysfunction. Operative Pregnancy
mortality ranges from 0–2.5% in best centers. Significant Marked increase in circulating blood volume, reduction of
ol
improvement in functional class and reduction of TR are systemic vascular resistance, and increase in pulmonary
seen. vascular resistance occurs. There may be worsening of
di
Relative contraindications to cone repair is old age, right heart failure, especially if RV dysfunction is pre-
absent septal leaflet, moderate pulmonary hypertension, existing. Increase in right-to-left shunting can occur with
ar
severe RV dilatation, extensive muscularization of anterior worsening of cyanosis. Management includes controlling
leaflet, and left ventricular ejection fraction (LVEF) <30%. the failure, avoiding sudden volume overload, and
C
In the presence of severe RV dysfunction (RVEF <10%), maintaining normoxemia with supplemental oxygen.
severe LV dysfunction (LVEF <25%), and severe ischemic Vaginal delivery is preferred. Patients with normal oxygen
mitral regurgitation, the best option would be cardiac saturation and no evidence of heart failure can have
transplantation.28 successful pregnancy outcomes. Cyanosis increases the
risk of miscarriage, low-birth weight and prematurity.
One-and-half Ventricle Repair Arrhythmias can be a complication during pregnancy with
Biventricular repair with reconstruction of TV is the norm due to increased sympathetic activity during labor.31
in majority of patients. If there is severe RV dysfunction
or a very small FRV, then 1.5 ventricle repair, where CONCLUSION
bidirectional cavopulmonary shunt is added along with Ebstein’s anomaly is an abnormal RV cardiomyopathy
TV repair is performed. It improves the preload on the with the involvement of the entire valve apparatus. The
LV and decompresses the RV. This reduces the chance of pathology can vary from mild to extreme forms leading
low cardiac output in immediate postoperative period. to various degrees of manifestation ranging from neonate
426
KG-51.indd 426 02-11-2018 17:04:05

to old age and asymptomatic to critically ill. Carpentier’s 14. Balaji S, Dennis NR, Keeton BR. Familial Ebstein’sanomaly: CHAPTER
classification helps as a guide to surgeons in planning a report of six cases in two generationsassociated with mild
surgery and GOSE score helps in prognostication in the
neonate. The 2D echo and 3D echo provide good imaging
skeletal abnormalities. Br Heart J. 1991;66:26-8.
15. Attenhofer Jost CH, Connolly HM, Dearani JA, et al. 51
Ebstein’s Anomaly.Circulation. 2007;115(2):277-85.

of the degree of displacement, tethering, regurgitation,
16. Patorno E, Huybrechts KF, Bateman BT, et al. Lithium Use in
and RV function. Cyanosis, heart failure, cardiomegaly, Pregnancy and the Risk of Cardiac Malformations. N Engl J
and paradoxical embolism are indications of surgery. Med. 2017;376(23):2245-54.
Arrhythmias are a common association and can be 17. Saxena A, Fong LV, Tristam M, et al. Late noninvasive e
congenital related to accessory pathways are acquired valuation of cardiac p er for mance in mildly symptomatic
to due to long-standing chamber dilatation. Complete olderpatients with Ebstein’s anomaly of the tricuspid valve:
biventricular repair is possible in most patients with role of radionuclideimaging. J Am CollCardiol. 1991;17:182-6.
a
18. Morray B. Preoperative physiology, imaging, and
cone technique and long-term follow-up has shown
management of Ebstein’s anomaly of the tricuspid valve.
di
good survival rates. Surgery should be considered before
Semin Cardiothorac Vasc Anesth. 2016;20(1):74-81.
ventricular dysfunction sets in. Cardiac transplantation 19. Attenhofer Jost CH, Tan NY, Hassan A, et al. Sudden death
In
is the only option in patients with severe ventricular in patients with Ebstein anomaly. Eur Heart J. 2018;39(21):
dysfunction with grossly enlarged hearts. 1970-7.
20. MacLellan-Tobert SG, Driscoll DJ, Mottram CD, et al.
of
Exercise tolerance in patients with Ebstein’s anomaly. J Am
REFERENCES
Coll Cardiol. 1997;29(7):1615-22.
1. Correa-Villasenor A , Ferencz, C, Neil C A, et al. Ebstein’s 21. Vettukattil JJ, Bharucha T, Anderson RH. Defining Ebstein’s
malformation of thetricuspid valve: genetic and malformation using three-dimensional echocardiography.
ty
environmental factors. The Baltimore-Washington Infant Interact Cardiovasc Thorac Surg. 2007;6(6):685-90.
Study Group.Teratology. 1994;50(2):137-47. 22. Nakamura I, Kotooka N, Komori Y, et al. Ebstein Anomaly
18 cie
2. Van Mierop LHS, Kutsche LM, Victoria BE. Ebsteinanomaly.
In: FH Adams, GC Emmanouilides, eds. Moss’ Heart
Disease in Infants, Children, and Adolescents. 4th ed.
by Cardiac Magnetic Resonance Imaging. J Am Coll
Cardiol. 2009;53(17):1568.
23. Hösch O, Sohns JM, Nguyen TT, et al. The total right/
Baltimore,Md: Williams and Wilkins; 1989. p.361-71.
left-volume index: a new and simplified cardiac magnetic
20 o
3. Mann, R. J. and Lie, J. T. (1979). The life story of Wilhelm
resonance measure to evaluate the severity of Ebstein
Ebstein (1836-1912) and his almost overlooked description
S
anomaly of the tricuspid valve: a comparison with heart

of a congenital heart disease. Mayo Clin Proc. 1979;54(3):
failure markers from various modalities. Circ Cardiovasc
197-204.
Imaging. 2014;7(4):601-9.
4. Anderson KR, Lie JT. Pathologic anatomy of Ebstein’s
al
24. Boston US, Goldberg SP, Ward KE, et al. Complete repair of
anomaly of the heart revisited. Am J Cardiol. 1978;41(4):739-
Ebstein anomaly in neonates and young infants: A 16-year
45.
ic
follow-up. J Thorac Cardiovasc Surg. 2011;141(5):1163-9.

5. Schreiber C, Cook A, Ho SY, et al. Morphologic spectrum
25. Warnes CA, Williams RG, Bashore TM, et al. ACC/AHA
of Ebstein’s malformation: Revisitation relative to surgical
og
repair. J Thorac Cardiovasc Surg. 1999;117(1):148-55. 2008 Guidelines for the Management of Adults with
6. Benson LN, Child JS, Schwaiger M, et al. Left venticular Congenital Heart Disease: a report of the American College
geometry and functionin adults with Ebstein’s anomaly of of Cardiology/American Heart Association Task Force
on Practice Guidelines (writing committee to develop
ol
the tricuspidvalve. Circulation. 1987;75(2):353-9.

7. Brown ML, Dearani JA, Danielson GK, et al. The outcomes guidelines on the management of adults with congenital
of operations for 539 patients with Ebstein anomaly. J heart disease). Circulation. 2008;118(23):714-823.
di
Thorac Cardiovasc Surg. 2008;135(5):1120-36. 26. da Silva JP, Baumgratz JF, da Fonseca L, et al. The
8. Carpentier, A , Chauvaud, S, Mace, L , et al. A new cone reconstruction of the tricuspid valve in Ebstein’s
ar
reconstructive operation for Ebstein’s anomaly of the anomaly.The operation: early and midterm results. J
tricuspidvalve. J Thorac Cardiovasc Surg. 1998; 96, 92-101. ThoracCardiovasc Surg. 2007;133:215-23.
9. Edwards WD. Embryology and pathologic features of 27. Anderson HN, D earani JA , Said SM, et al.Cone
C
Ebstein’s anomaly. ProgvPediatrvCardiol.1993;2(1):5-15. reconstruction in children with Ebstein anomaly: the Mayo
doi:https://doi.org/10.1016/1058-9813(93)90042-X Clinicexperience. Congenit Heart Dis. 2014;9(3):266-71.
10. Castaneda-Zuniga W, Nath HP, Moller JH, et al. Left-sided 28. Dearani JA, Said SM, O’Leary PW, et al. Anatomic repair
anomalies in Ebstein’s malformationof the tricuspid valve. of Ebstein malformation: lessons learned with cone
PediatrCardiol. 1982;3(2):181-5. reconstruction. Ann Thorac Surg. 2013;95(1):220-6.
11. Celermajer DS, Bull C, Till JA, et al. Ebstein’s anomaly: 29. Silva JP da, Silva L da F da, Moreira LFP, et al. Cone
Presentation and outcome from fetus to adult. J Am Coll reconstruction in Ebstein’s anomaly repair: early and
Cardiol. 1994;23(1):170-6. longterm results. Arq Bras Cardiol. 2011;97(3):199-208.
12. Khositseth A , Danielson GK , Dearani JA , et al . 30. Chávez Rodríguez M, Baird CW, Emani S, et al. Short Term
Supraventricular tachyarrhythmias in Ebstein anomaly: Outcomes of the Cone Procedure for Ebstein’s Anomaly in
Management and outcome. J Thorac Cardiovasc Surg. Young Pediatric Patients Are Comparable to Adult Patients.
2004;128(6):826-33. Circulation. 2017;136(Suppl 1).
13. Dearani JA, Mora BN, Nelson TJ, et al. Ebstein anomaly 31. Koutrolou-sotiropoulou P, Lima F V, Kapur A, et al. Ebstein
review: What’s now, what’s next? Expert Rev Cardiovasc anomaly in the adult : focus on pregnancy. J Cardiovasc
Ther. 2015;13(10):1101-9. Res. 2015. pp. 1-10. 427
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Total Anomalous Pulmonary
Venous Connection:
CHAPTER 52
An Overview
a
di
INTRODUCTION derived growth factor (PDGF) signaling pathways in the
Total anomalous pulmonary venous connection (TAPVC) pathogenesis of TAPVC.10 Though uncommon, TAPVC has
In
defines a group of congenital cardiac defects in which all been shown to occur as a part of genetic syndromes such
of the four pulmonary veins connect to systemic venous as Holt-Oram syndrome, Klippel-Fiel syndrome, Moebius
syndrome, and Alagille syndrome.11,12 Lead and pesticide
of
channels through persistent embryologic connections in
the splanchnic circulation. Often, one or more pulmonary exposure during pregnancy also have been attributed.4
veins drain anomalously resulting in partial anomalous
EMBRYOLOGY
ty
pulmonary venous connection (PAPVC). Many a times,
pulmonary veins can ‘drain’ anomalously into systemic The right common cardinal vein, which forms the right
18 cie
venous side in spite of normal ‘connections’ as can occur
in patients with malattachment of atrial septum. So both
the terms ‘drainage’ and ‘connections’ should not be used
horn of the sinus venosus, ultimately develops into
the right superior vena cava (SVC) and azygous vein.
Similarly, the left common cardinal vein, which forms the
interchangeably. left horn of the sinus venosus, ultimately develops into
20 o
left SVC and coronary sinus. The umbilicovitelline system
S
HISTORY evolves into the inferior vena cava (IVC), ductus venosus,
In 1798, the Philosophical Transactions of the Royal and portal vein.
al
Society of London, described an ‘unusual’ malformation During the initial phases of development, the
of the heart which was the first ever description of the intrapulmonary venous plexus do not communicate with
ic
anomaly.1 But, it was only in 1950, that the first clinical the left atrium (LA), rather they communicate with the
diagnosis of the congenital anomaly was made by cardiac paired common cardinal and umblicovitelline venous
og
catheterization.2 The first ever surgical repair was reported systems through the splanchnic plexus. At about 28 days
by Muller in 1951; and subsequently, there have been of gestation, the common pulmonary vein is formed as
multiple variations and classification systems of this an endothelial outpouching from the postero-superior
ol
anomaly reported in literature.3 wall of primitive LA. The common pulmonary vein then
establishes connection with the pulmonary venous
di
plexus by 30 days of gestation. The pulmonary veins

PREVALENCE AND ETIOLOGY
and tributaries form a common chamber, which gets
TAPVC is a rare congenital heart defect, representing
ar
incorporated into the LA, and the connections with the

nearly 1.5–2% of all cardiovascular anomalies. In the
cardinal and umbilicovitelline venous systems regress
Baltimore-Washington Infant study, TAPVC represented
C
progressively.
1.5% of all cardiovascular malformations, occurring
The TAPVC results when there is agenesis of the
once in 14,700 live births.4 The male to female ratio was
common pulmonary vein and persistence of one or more
18:23 in the group. Reports have suggested a strong male
of these primitive venous connections.
preponderance (3:1) for the infradiaphragmatic variety.5
As with other congenital heart diseases, most of these
cases occur sporadically, though there are a few case MORPHOLOGY
reports of TAPVC occurring in families.6,7 Bleyl et al. The right side of the heart including the atrium, ventricle,
have described a Scottish origin family, comprising of and pulmonary arteries are dilated, with diminished size
14 affected individuals, in whom the anomaly appeared of LA in all forms of TAPVC. The specific anatomic findings
to be inherited in an autosomal dominant pattern. 8 By depends further on the type.
linkage analysis, the susceptibility gene was mapped Darling et al. proposed a schema of classifying these
to centromere of chromosome 4. 9 The same author lesions based on the sites of anomalous drainage relative
has recently attributed abnormalities in platelet- to the heart, which has been widely accepted (Table 1).
KG-52.indd 428 02-11-2018 17:35:33

Table 1: Classification of total anomalous pulmonary venous common arrangement is of 3 + 1, where 3 pulmonary veins CHAPTER
connection according to the site of anomalous connection and form a confluence before draining and the fourth vein
potential sites of drainage
Supracardiac TAPVC:
draining separately.14
Obstruction is uniformly present in the infracardiac
52

zz Left brachiocephalic (innominate) vein* type and almost certain when the drainage is into
zz Right superior vena cava the portal veins, because of the resistance offered by
zz Azygos vein the hepatic sinusoids. Obstruction may also occur as
zz Left superior vena cava
the descending vein traverses the diaphragm or at its
junction with the portal vein. Obstruction may worsen
zz Hemiazygos vein
due to constriction of ductus venosus. Obstruction is
Cardiac TAPVC:
considered rare in the cardiac type, but a report suggests
a
zz Coronary sinus*
that obstruction is underestimated and may be present in
Right atrium
di
zz
22% of patients.15 Obstruction in supracardiac TAPVC can
Infracardiac TAPVC: be either intrinsic or extrinsic. Occasionally, the vertical
In
zz Portal venous system* vein may be compressed when it ascends posterior to the
zz Splenic vein left PA, secondary to the hemodynamic vice formed by
zz Splenic, superior mesenteric vein confluence left bronchus posteriorly and left PA anteriorly. Rarely,
of
zz Ductus venosus intrinsic narrowing occurs at pulmonary vein confluence
zz Hepatc veins
and vertical vein, or at the insertion of the vertical vein into
the innominate vein. Extrinsic compression also occurs in
Inferior vena cava
ty
zz
connections to right SVC, usually between right PA and
Abbreviation: TAPVC, total anomalous pulmonary venous connection
*Most common sites of drainage
trachea.16
Source: Adapted from reference 18 18 cie
They classified the defect into four types: supracardiac,
In any form of TAPVC, intrinsic narrowing of
individual pulmonary vein(s) can result in varying
degrees of obstruction. Obstructed TAPVC results in
20 o
cardiac, infracardiac, and mixed.13 TAPVC can further be underdevelopment of the small intrapulmonary arterioles,
classified as obstructive or nonobstructive. Except for the which may be responsible for the poor outcome in some of
S
mixed TAPVC and all pulmonary veins draining into right these patients.17
atrium (RA), all other types of TAPVC are characterized
al
by the pulmonary veins forming a common confluence ASSOCIATED LESIONS

directly behind the LA, which drains into the systemic An atrial level communication is always present in TAPVC
ic
venous system through an anomalous channel known as and is considered as a part of the TAPVC complex. A patent
vertical vein.
ductus arteriosus (PDA) is usually found in neonates. The
og
Supracardiac TAPVC is the most common type, where

TAPVC occurs as isolated lesion in two-thirds of patients
the confluence of pulmonary veins drains superiorly into
and occurs as part of a group of complex heart defects
the left innominate vein via a left-sided ascending vertical
in approximately one-third of patients. The TAPVC is
ol
vein. The vertical vein is related to the left pulmonary

commonly associated with asplenia or right isomerism,
artery (PA) and left main bronchus and passes anteriorly.
more so as these hearts lack a morphological LA and
di
Rarely, the vertical vein may drain into other supracardiac

coronary sinus.
locations such as azygous vein, or directly right- or left-
ar
sided SVC.
In the cardiac type TAPVC, the confluence drains into PATHOPHYSIOLOGY
C
the coronary sinus in the vicinity of the atrioventricular The TAPVC does not cause any hemodynamic problems
(AV) groove. Rarely, pulmonary venous confluence may in fetal life since the pulmonary blood flow is less.
drain directly into the RA usually near the midatrial After birth, with fall in pulmonary vascular resistance
septum, or individual pulmonary veins may connect (PVR), an obligatory left-to-right shunt is established.
directly into the RA. An unrestrictive right-to-left shunt, usually through
Infracardiac TAPVC refers to the anomaly where the an atrial septal defect (ASD) or patent foramen ovale
descending vertical vein from the confluence, traverses (PFO) is necessary for maintaining systemic flow and
the diaphragm through the esophageal hiatus, anterior therefore is a critical determinant of the hemodynamic
to the esophagus, and terminates infradiaphragmatically, and clinical presentation. During fetal life, there is only
most commonly into the portal venous system. Rarely, it minimal stimulus for development of large interatrial
drains into the ductus venosus, hepatic veins, or IVC. communication, resulting in a majority of patients
Finally, a mixed type of TAPVC occurs, where (70–80%) born only with a PFO. As the pulmonary venous
pulmonary veins drain at two or more levels. The most return increases after birth, the PFO becomes relatively
429
KG-52.indd 429 02-11-2018 17:35:34

SECTION restrictive, and along with increasing demand with age, adulthood is exceptional though the oldest reported
the systemic output is unable to be met. Hence, there patient underwent surgical repair at 66 years of age.21
7 is rise in right atrial pressure and congestion in both
systemic and pulmonary venous systems.18 CLINICAL FEATURES
The TAPVC with pulmonary venous obstruction

Patients of TAPVC with pulmonary venous obstruction
results in elevated pulmonary venous pressures, and
often present in neonatal period, whereas patients of
usually presents with pulmonary edema. Increase in
unobstructed TAPVC present later in life. Majority of
pulmonary lymphatic flow, opening up of broncho-
patients present in infancy. Neonates with obstructed
pulmonary venous anastomoses, and reflex pulmonary
TAPVC present with severe cyanosis and respiratory
vasoconstriction ensues as compensatory mechanisms all distress. Pulmonary edema and shock may ensue.
of which result in increased PA and right ventricular (RV)
a
Neonates with obstructed infradiaphragmatic TAPVC
pressures ultimately culminating in right heart failure. The have a stormy course with rapid development of severe
di
right-to-left shunting across the atrial septum increases, respiratory distress and acidosis in the first hours of life.
resulting in significant hypoxemia. Progressive hypoxia In c o nt ra st t o t h e a l a r m i ng c l i n i ca l c ou r s e,
In
leads to acidosis, shock, and multiorgan dysfunction. cardiovascular findings may be minimal in these children.
Hence, obstructed TAPVC in a neonate is characterized There is no evidence of right heart enlargement or
by decreased pulmonary blood flow, pulmonary edema,
of
heave. The second sound is often single or closely split,
pulmonary venous hypertension, and severe cyanosis. with loud pulmonary component. Murmurs are often
Unobstructed TAPVC produces complete admixture absent; however, a soft, mid-systolic flow murmur in the
of systemic and pulmonary venous blood in the RA,
ty
pulmonary area may be audible.
causing similar saturations in all the cardiac chambers In the presence of a restrictive ASD, symptoms of heart
18 cie
downstream. In the presence of adequate atrial level
communication, the shunt across it is determined by the
relative compliance of both atria, ventricles, which in turn
failure and mild cyanosis may be noticed from the first
month of life and progressively worsen. A pulsatile liver
may indicate restrictive communication at atrial septal
depends on relative vascular resistance of systemic and
20 o
level.
pulmonary vasculature. Cyanosis is mild in unobstructed TAPVC and infants
S
A low pulmonary vascular resistance, as seen in often present with tachypnea, feeding diaphoresis, and
infants, is associated with a compliant RV and significantly failure to thrive. The physical findings of unobstructed
al
increased pulmonary blood flow. Thus, mild cyanosis TAPVC generally resemble that of ASD except for mild
exists with increased pulmonary blood flow. There is cyanosis and earlier age of presentation. There are
ic
significant enlargement of RA, RV, and PA. Conversely, the features of RV volume overload. Tricuspid component
LA and left ventricle (LV) are small. of the first heart sound is loud and the second heart
og
Pulmonary artery hypertension develops in long- sound is wide and fixed split. A RV third heart sound can
standing unobstructed TAPVC secondary to medial be detected. Pulmonary and tricuspid flow murmurs
hypertrophy and intimal proliferation occurring in are heard frequently. Rarely, increased flow across the
ol
pulmonary arterioles resulting in decreased pulmonary vertical vein, innominate vein, and SVC, can result in a
blood flow and increased cyanosis. continuous murmur along the upper left sternal border,
di
more so if there is obstruction to flow. The murmur could

NATURAL HISTORY be differentiated from venous hum by the fact that the
ar
In the presence of obstruction, pulmonary edema and RV murmur is not accentuated during diastole, and does
failure ensues within a few days of birth. Most neonates not change with posture. As the pulmonary vascular
C
succumb in the initial few weeks of life, survival up to 3–4 resistance increases, the flow murmurs are attenuated.
months are exceptional.19 The course is unfavorable even The second heart sound split narrows or disappears
in children with unobstructed TAPVC, with up to 80% of with a loud pulmonary component. Pulmonary ejection
click, murmur of tricuspid regurgitation, and pulmonary
symptomatic infants not reaching 1 year of life.20 Heart
regurgitation may appear.
failure and infections are the major causes of mortality.
The minority who present after the first year of life are
those who have a low pulmonary vascular resistance X-ray
and a nonrestrictive ASD. In these patients, irreversible In neonates with obstructed TAPVC, chest radiographs
pulmonary vascular disease develops before third or reveal a reticulonodular, ground glass pattern fanning
fourth decade of life; however, more advanced intimal out from the hilum with no cardiomegaly (Figure 1).
lesions in the pulmonary arterioles have been described Meconium aspiration and hyaline membrane disease are
as early as 8 months of age. Unoperated survival into important differentials considered often.
430
KG-52.indd 430 02-11-2018 17:35:35

CHAPTER
Table 2: Goals of echocardiographic examination in total
anomalous pulmonary venous connection
zz To establish diagnosis 52
zz To image all the four pulmonary veins and their site of drainage

confirmed to common chamber (to avoid missing mixed TAPVC)
zz Size of individual pulmonary veins
zz Size of common chamber and its relation to left atrium
zz To trace the anomalous channel (vertical vein), its size, relation
to neighboring structures, exact site of connection to systemic
venous system
a
zz Presence of any stenosis from the pulmonary veins to the site of
drainage into systemic venous system, and if present, the exact
di
site and mechanism
zz Adequacy of interatrial communication
In
Figure 1: Chest X-ray of a neonate with obstructed total anomalous zz Associated cardiac lesions
pulmonary venous connection. Note the absence of cardiomegaly
and reticulonodular shadows suggesting pulmonary venous Abbreviation: TAPVC, total anomalous pulmonary venous connection
hypertension
of
Echocardiography
Echocardiography is diagnostic and the only imaging
ty
modality required in most patients with TAPVC (Table 2).
A sensitivity and specificity of more than 95% has been
18 cie reported for this modality to identify TAPVC.22,23 Enlarged

RA and RV, with small LA and LV, and the atrial level
communication shunting right to left are usually the initial
clues to the echocardiographer. Paradoxical septal motion
20 o
and bulging of Inter-atrial and inter-ventricular septum to
S
the left are usually seen. Pulmonary vein connections to

LA are not demonstrable. Subcostal long and short axis
views are best used to assess the ASD and the adequacy
al
of shunt across it. Pulmonary venous confluence could be

easily identified posterior to the LA. Individual pulmonary
ic
veins and their confluences are best identified in apical,

parasternal, and suprasternal views (Figures 3A to C).
og
Figure 2: Chest X-ray of an adolescent with supracardiac

total anomalous pulmonary venous connection showing the The individual pulmonary veins should be screened for
characteristic ‘figure-of-8’ or snowman appearance. The left heart
size and stenosis as these are shown to be an important
border is formed by dilated right ventricle, dilated pulmonary artery
ol
segment, and vertical vein. The right heart border is formed by independent predictor of survival in these patients.24 A
dilated right atrium and dilated superior vena cava phasic low velocity flow with brief flow reversal during
di
atrial systole is suggestive of unobstructive flow. Whereas

In unobstructed TAPVC, there is cardiomegaly with a turbulent flow with loss of phasic variation and increased
velocity usually >2 m/s suggests obstruction.25 Dilated
ar
enlarged RA, RV, and PA. In the supracardiac form of

TAPVC, figure-of-8 or snowman appearance is found, the venous channel should prompt search for any site of
dilated left vertical vein, innominate vein and right SVC, obstruction. Size and flow patterns across SVC, coronary
C
forming the upper portion of the figure (Figure 2). Dilated sinus, and IVC give clue towards potential site of drainage.
RV and atrium forms the lower portion. This distinctive Apical 4-chamber and subcostal views best identify the
appearance is usually not present at birth, but develops as dilated coronary sinus and the site of pulmonary venous
the child reaches 3–4 months. confluence drainage into the sinus in case of cardiac
TAPVC.
Electrocardiogram Infracardiac TAPVC is best identified in the subcostal
The electrocardiogram (ECG) in obstructive TAPVC view, which demonstrates a descending vertical vein
shows RV hypertrophy, qR complex in right chest leads. entering usually the portal veins or occasionally the
Right atrial enlargement is infrequent. However, ECG hepatic veins, IVC, or rarely ductus venosus. Dilated
in unobstructed TAPVC resembles that of an ostium hepatic sinusoids, with increased flow away from the heart
secondum ASD. The ECG usually shows right axis are valuable clues to infradiaphragmatic TAPVC. The
deviation and right atrial and ventricular enlargement descending vertical vein commonly traverses between
with incomplete right-bundle-branch pattern. IVC on the right and descending aorta on the left. Rarely, a 431
KG-52.indd 431 02-11-2018 17:35:36

SECTION
7
a
di
In
Figure 3A: Two-dimensional echocardiogram, 4-chamber view Figure 3B: Color Doppler evaluation showing predominantly right-
showing dilated right ventricle and atria, large atrial septal defect to-left shunting across the atrial septal defect and increased flow
and lack of identifiable pulmonary vein entry into left atrium across the tricuspid valve
of
physiology suggests identical saturation in all the cardiac
chambers, PA and aorta, but rarely selective streaming of
ty
venous return might result in blood with higher saturation
reach PA.27
18 cie Typical hemodynamic dataset of an adult with TAPVC
is shown in Box 1. Note should be made of the near
equalisation of oxygen saturation beyond the chamber
20 o
where mixing happens. In this example beyond SVC, all the
chambers have near identical saturation. The pressures in
S
the right and left atria are nearly similar suggesting a non-
obstructed ASD. There is moderate pulmonary arterial
al
hypertension, with no pulmonary venous hypertension.

Atrial septostomy offers excellent short- and
ic
intermediate-term palliation in selected patients.28 In

Figure 3C: Suprasternal view showing a large red color flow in the
TAPVC, atrial septostomy is technically challenging,
og
vertical vein which is seen entering into dilated left innominate vein,
which in turn draining into a dilated superior vena cava especially in the cardiac variety, due to small LA size
and absence of pulmonary venous connections. Atrial
ol
congested liver might compress on the descending vertical septostomy helps by increasing cardiac output, relieving
vein and preclude identification. systemic and pulmonary venous congestion, and reducing
di
PA pressures. These favorable hemodynamics lead to

Prenatal Diagnosis clinical stabilization and help in optimizing the timing
ar
Prenatal diagnosis of TAPVC is more challenging. In a of surgery.29 The absence of a pressure gradient between
large series, only 1.9% cases were identified in utero 24 the atria does not exclude a restrictive ASD. A pressure
C
and a French study reported a 10% prenatal diagnosis difference of ≥2 mm Hg between right and left atrium
rate, probably, because of very low pulmonary blood is more reliable in predicting a restrictive interatrial
flow in the fetus.26 The approach to diagnosis is not much communication; but too often, it might be seen even
different from that done postnatally. A high index of with adequate communication. A reliable method to
suspicion is, therefore, needed whenever one encounters measure the size of communication would be using a
right heart enlargement out of proportion to the LV and balloon catheter. In the current era, septostomy is rarely
aorta. Differentials include left-sided obstructive lesions, performed and is of no value when there is obstruction to
coarctation, and atriovenous malformations. the anomalous channel.
Balloon dilatation or stent placement is increasingly
Cardiac Catheterization performed to relieve obstruction in sick neonates
Indications for cardiac catheterization include atrial presenting with obstructed TAPVC.30,31 Palliative stenting
septostomy, or balloon dilation to relieve obstruction, PVR could be considered in extremely sick neonates as a
estimation, and reversibility in late presenters. Admixture method of preoperative stabilization.
432
KG-52.indd 432 02-11-2018 17:35:37

Box 1: Typical hemodynamic dataset of an adult with veins and the LA. The technique further depends on the CHAPTER
supracardiac TAPVC type of TAPVC. In the presence of common confluence
Chamber O2 Saturation Pressure (supra- and infracardiac TAPVC) with a common vertical
vein, an anastomosis between the confluence and the
52
Superior Vena Cava 88 —

Inferior Vena Cava 66 — LA is made. The vertical vein may be ligated. In cases
Right atrium 87 a6 v8 (6) where the pulmonary veins drain directly into the SVC,
an intracardiac baffle is made and blood from the RA, is
Right ventricle 89 50/6
redirected to LA across the atrial septum. In TAPVC to the
Pulmonary artery 88 45/14 (32)
coronary sinus, the common wall between the coronary
Left atrium 86 a7 v7 (6)
sinus and LA is excised, establishing pulmonary venous
Left ventricle 89 120/6
return to LA, and the coronary sinus ostium, ASD are
a
Femoral artery 88 130/80 (105)
closed. With this procedure, both pulmonary vein and
di
coronary vein flow returns to the LA.
Surgical outcomes have improved over the years.
OTHER IMAGING
In
In a recent multicenter study of 422 TAPVC surgeries,
Computed tomography angiogram (CTA) delineates
overall 3-year mortality was 15%; independent risk factors
the varied patterns of pulmonary venous drainage. The
for mortality been earlier age at surgery, hypoplastic/
of
CTA is shown to be superior to echocardiography, and
stenotic pulmonary veins, associated complex cardiac
has established itself as an invaluable imaging modality,
lesions, postoperative pulmonary hypertension, and
especially in patients with mixed and unusual forms of
postoperative pulmonary venous obstruction. Sixty (15%)
ty
TAPVC. 32 The CT angiography clearly establishes the
of these infants developed postoperative pulmonary
course of the anomalous vessel and also the presence or
venous obstruction; with a 3-year mortality of 41%
18 cie
absence of stenosis . One useful tip while imaging patients
with suspected supracardiac drainage, is to inject contrast
from below the heart and the converse be applied for
for this subgroup. Risk factors for the development of
postoperative pulmonary venous obstruction included
hypoplastic/stenotic pulmonary veins and the absence of
20 o
infracardiac connection, so as to enable differentiation of
vertical vein from other systemic venous structures such a common pulmonary venous confluence.35
S
as left SVC.
Magnetic resonance imaging (MRI), in addition, REFERENCES
al
provides functional data including flow quantifcation 1. Wilson J, Baillie M. A Description of a very unusual
and volumetric analysis. The MRI is especially useful formation of the human heart. By Mr James Wilson,
ic
in postoperative patients with residual pulmonary vein Surgeon. Communicated by Matthew Baillie, MDFRS
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og
2. Burroughs JT, Edwards JE. Total anomalous pulmonary

MANAGEMENT venous connection. Am Heart J. 1960;59(6):913-31.
Corrective surgery as early as possible is the standard 3. Muller WH. The surgical treatment of transposition of the
ol
of care. The role of medical management is only to pulmonary veins. Ann Surg. 1951;134(4):683-92.
optimize the general condition in sick neonates. 4. Correa-Villaseñor A, Ferencz C, Boughman JA, et al.
di
Preoperative stabilization includes correction of acidosis Total anomalous pulmonary venous return: familial and
and hypotension, fluid management and mechanical environmental factors. The Baltimore-Washington Infant
ar
ventilation; but many a times, complete stabilization Study Group. Teratology. 1991;44(4):415-28.
5. Gathman GE, Nadas AS. Total anomalous pulmonary
of the sick neonate might not be possible even. Hence,
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venous connection: clinical and physiologic observations

infracardiac obstructive TAPVC should be considered
of 75 pediatric patients. Circulation. 1970;42(1):143-54.
as a surgical emergency. Atrial septostomy and balloon
6. Paz JE, Castilla EE. Familial total anomalous pulmonary
dilation/stent placement across obstruction may be done
venous return. J Med Genet. 1971;8(3):312-4.
in select patients only. These procedures are no longer
7. Solymar L, Sabel KG, Zetterqvist P. Total anomalous
considered appropriate, when early surgery could be
pulmonary venous connection in siblings. Report on three
accomplished. Prostaglandin is generally known to be
families. Acta Paediatr Scand. 1987;76(1):124-7.
contraindicated in infradiaphragmatic TAPVC, but there
8. Bleyl S, Ruttenberg HD, Carey JC, et al. Familial total
are anecdotal reports demonstrating its usefulness by
anomalous pulmonary venous return: a large Utah-Idaho
opening up of ductus venosus.33,34
family. Am J Med Genet. 1994;52(4):462-6.
9. Bleyl S, Nelson L, Odelberg SJ, et al. A gene for familial
Surgery total anomalous pulmonary venous return maps to
The general principle of TAPVC surgery is to re-establish chromosome 4p13-q12. Am J Hum Genet. 1995;56(2):
a direct unobstructed pathway between the pulmonary 408-15. 433
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SECTION 10. Bleyl SB, Saijoh Y, Bax NA, et al. Dysregulation of the of 84 cases from 1 medical center. Medicine (Baltimore).
PDGFRA gene causes inflow tract anomalies including 2016;95(44):e5389.
7 TAPVR: integrating evidence from human genetics and

model organisms. Hum Mol Genet. 2010;19(7):1286-301.
23. Goswami KC, Shrivastava S, Saxena A, et al. Echocardio-
graphic diagnosis of total anomalous pulmonary venous
connection. Am Heart J. 1993;126(2):433-40.
11. Suvarna J, Bagnawar M, Deshmukh CT. Moebius syndrome

with total anomalous pulmonary venous connection. 24. Seale AN, Carvalho JS, Gardiner HM, et al. Total anomalous
pulmonary venous connection: impact of prenatal
Indian J Pediatr. 2006;73(5):427-9.
diagnosis. Ultrasound Obstet Gynecol. 2012;40(3):310-8.
12. TAPVR : A Cardiac Defect Associated with Alagille
25. Vick GW, Murphy DJ, Ludomirsky A, et al. Pulmonary venous
syndrome. [Internet]. [cited 2018 Sep 4]. Available from:
and systemic ventricular inflow obstruction in patients with
http://www.ashg.org/genetics/abstracts/abs06/f621.htm congenital heart disease: detection by combined two-
13. Craig JM, Darling RC, Rothney WB. Total pulmonary dimensional and Doppler echocardiography. J Am Coll
a
venous drainage into the right side of the heart; report Cardiol. 1987;9(3):580-7.
of 17 autopsied cases not associated with other major
di
26. Laux D, Fermont L, Bajolle F, et al. Prenatal diagnosis of
cardiovascular anomalies. Lab Investig J Tech Methods isolated total anomalous pulmonary venous connection: a
Pathol. 1957;6(1):44–64. series of 10 cases. Ultrasound Obstet Gynecol. 2013;41(3):
In
14. Chowdhury UK, Airan B, Malhotra A, et al. Mixed total 291–7.
anomalous pulmonary venous connection: Anatomic 27. El-said G, Mullins CE, Mcnamara DG. Management of
variations, surgical approach, techniques, and results. J total anomalous pulmonary venous return. Circulation.
of
Thorac Cardiovasc Surg. 2008;135(1):106-16.e5. 1972;45(6):1240-50.
15. Jonas RA, Smolinsky A, Mayer JE, et al. Obstructed 28. Ward KE, Mullins CE, Huhta JC, et al. Restrictive interatrial
pulmonary venous drainage with total anomalous communication in total anomalous pulmonary venous
ty
pulmonary venous connection to the coronary sinus. Am J connection. Am J Cardiol. 1986;57(13):1131–6.
Cardiol. 1987;59(5):431–5. 29. Mullins CE, el-Said GM, Neches WH, et al. Balloon atrial
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16. Kalantre AA, Champaneri B, Kottayil B, et al. “Hemodynamic
vice” of the right-sided ascending vertical vein in the
setting of supracardiac total anomalous pulmonary 30.
septostomy for total anomalous pulmonary venous return.
Br Heart J. 1973;35(7):752–7.
Ramakrishnan S, Kothari SS. Preoperative balloon
dilatation of obstructed total anomalous pulmonary
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venous connection in a neonate: Anatomic-embryological
venous connection in a neonate. Catheter Cardiovasc
correlation. Ann Pediatr Cardiol. 2017;10(1):104–6.
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Interv. 2004;61(1):128-30.
17. Maeda K, Yamaki S, Yokota M, et al. Hypoplasia of the small
31. Koneti NR, Kandraju H, Kanchi V, et al. Endovascular
pulmonary arteries in total anomalous pulmonary venous
stenting of the obstructed vertical vein in a neonate with
connection with obstructed pulmonary venous drainage. J
al
supracardiac total anomalous pulmonary venous return.

Thorac Cardiovasc Surg. 2004;127(2):448–56.
Ann Pediatr Cardiol. 2012;5(1):75.
18. C h o u d h a r y S, Ta l w a r S, R a m a k r i s h na n S. To t a l
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32. Oh KH, Choo KS, Lim SJ, et al. Multidetector CT evaluation

Anomalous Pulmonary Venous Connection. In: Pediatric
of total anomalous pulmonary venous connections:
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edition. Wiley-Blackwell; 2011. pp. 476–86. 39(9):950–4.
19. Infradiaphragmatic total anomalous pulmonary venous 33. Cirstoveanu C, Cinteza E, Marcu V, et al. Prostaglandin
return. Review of clinical and pathological findings and
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E1 on Infradiaphragmatic Type of Total Anomalous

results of operation in 28 cases. [Internet]. [cited 2018 Sep Pulmonary Venous Connection—a Case Report. Mædica.
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articles/PMC483289/ 34. Bullaboy CA, Johnson DH, Azar H, et al. Total anomalous
20. Keith JD, Rowe RD, Vlad P, et al. Complete anomalous pulmonary venous connection to portal system: A new
ar
pulmonary venous drainage. Am J Med. 1954;16(1):23-38. therapeutic role for prostaglandin E1? Pediatr Cardiol.
21. McMullan MH, Fyke FE. Total anomalous pulmonary 1984;5(2):115-6.
C
venous connection: surgical correction in a 66-year-old 35. Seale AN, Uemura H, Webber SA, et al. Total anomalous
man. Ann Thorac Surg. 1992;53(3):520-1. pulmonary venous connection: morphology and outcome
22. Zhang Z, Zhang L, Xie F, et al. Echocardiographic diagnosis from an international population-based study. Circulation.
of anomalous pulmonary venous connections: Experience 2010;122(25):2718-26.
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Pulmonary Arteriovenous
CHAPTER 53 Malformations
a
di
INTRODUCTION hepatic factors into the pulmonary circulation due to the
Pulmonary arteriovenous malformation (PAVM) is a rare neopostoperative connection. Other still rarer causes
In
clinical condition with abnormal direct communication include gestational trophoblastic disease and trauma.
between pulmonary artery and vein. Most PAVMs are The natural history shows a tendency towards
congenital, but rarely it can be acquired. The incidence of increased shunting and worsening cyanosis with age. This
of
PAVM is 2–3 per 100,000 population.1 Most of the clinical may be caused by an increasing number of intravascular
symptoms are due to right-to-left shunting across these communications, opening of previously unfilled channels
dilation of existing communications, or progressive
ty
abnormal channels. Transcatheter embolization of the
feeding vessel is the treatment of choice. polycythemia.
HISTORY
18 cie
The first reported case is of a 12-year-old boy who had
CLINICAL FEATURES
Majority of patients with PAVMs are asymptomatic. The
most common presenting symptoms include dyspnea on
20 o
episodes of epistaxis and hemoptysis and loud pulmonary
bruit. Postmortem examination showed bilateral multiple exertion, epistaxis, and hemoptysis. The classical triad of
S
PAVM (Churton, 1897). 2 Smith and Horton in 1939 dyspnea, cyanosis, and clubbing can be seen only 10%
clinically diagnosed PAVM in a 40-year-old male who of patients with PAVM. Relatively fewer patients present
with dyspnea unless there are significant coexisting
al
had cyanosis, clubbing, bruit, and polycythemia. 3 In

1942, Hepburn and Dauphine reported the first case of cardiopulmonary disease. Majority of cases are picked up
while being evaluated for some other unrelated symptoms
ic
successful surgical removal of a pulmonary hemangioma

with disappearance of polycythemia and clubbing in (Table 1).
og
the patient.4 Surgery was the treatment of choice until One of the characteristic findings of PAVM is
Taylor reported the first case of successful percutaneous orthodeoxia (orthostatic hypoxemia), which is attributed
embolization of a PAVM in 1978.5 to basal predominance of PAVMs. This term describes the
ol
tendency for greater hypoxemia when assuming the sitting

or standing position. Another clinical hallmark described
ETIOLOGY
di
is platypnea (improvement of dyspnea on reclining) is

Most of the congenital PVAM (80–90%) are associated associated with decreased blood flow through PAVMs in
with hereditary hemorrhagic telangiectasia (HHT) or
ar
the supine position. However, this is rarely demonstrable

Osler-Weber-Rendu disease. On the other hand, 15–35% of in patients.
HHT patients will present with PAVMs. It is an autosomal Th ou g h ra re, PAV M ca n l e a d t o h e m o p t y s i s
C
dominant disorder and the most common mutations are or hemothorax due to rupture of these thin-walled
in ENG, endoglin (HHT1), and activin type II-like receptor
kinase (ACVRL 1) gene (encoding for the activin receptor-
Table 1: Signs and symptoms of pulmonary arteriovenous
like kinase ALK 1) (HHTN2). The ENG and ACVRL 1 gene malformation
code for proteins of the transforming growth factor beta- Symptoms Signs
receptor, which is involved in blood vessel development.
Epistaxis Bruit
The second most common cause of single PAVMs
Dyspnea Clubbing
appears to be sporadic. Surgical treatment of cyanotic
Hemoptysis Cyanosis
congenital heart diseases palliated with bidirectional
Glenn shunt are also known to be associated with Chest pain Telangiectasia
development of PAVMs attributed to scanty supply of Polycythemia
KG-53.indd 435 02-11-2018 16:54:42

SECTION Table 2: Complications MANAGEMENT
7
Complication Etiology
Why do we Need to Close PAVMs?
Massive hemoptysis or Rupture of abnormal vessels
hemothorax There are no randomized studies showing the benefit of
Stroke, transient ischemic attacks Paradoxical embolization, closure, but there is evidence that PAVMs progressively
polycythemia enlarge over a period of time.9 Complication rate associated
Brain abscess with untreated lesions are nearly 50% and even more
Migraine
Myocardial infarction
during pregnancy.9 It may be prudent to give antibiotic
prophylaxis prior to dental or surgical procedures in
Hypoxemia Right-to-left shunting
these patients to reduce embolic abscess risks. Cerebral
Pulmonary hypertension Associated hereditary
complication rate is considered to be higher when the
a
hemorrhagic telangiectasia
feeding afferent artery size is larger in diameter and also in
di
patients with multiple PAVMs.
abnormal vessels. This is more commonly seen during
pregnancy 6 (due to hormonal changes) or if PAVMs
In
are perfused at systemic pressures (due to pulmonary How You do it?
hypertension or due to systemic arterial supply to PAVM Till the early 90s, surgical management was the accepted
modality for treatment which included pneumonectomy,
of
sac). Systemic arterial supply may be spontaneous but
more often develop after PAVM embolization.7,8 In patients lobectomy, segmentectomy, wedge resection, or vascular
with HHT, bleeding results from nasopharyngeal and ligation. Pulmonary transplantation may be offered to
ty
endobronchial telangiectasias. patients with diffuse lesions associated with respiratory
Neurological complications (Table 2) most often seen failure.
18 cie
include stroke, transient ischemic attacks, cerebral abscess,
migraine, and seizures. The most likely mechanism for
these neurological events are paradoxical embolism
But presently, the treatment of choice is transcatheter
coil or device closure. The transcatheter procedure
aims at occlusion of all the feeding arteries by selective
through the PAVM or due to a cerebral arteriovenous catheterization of pulmonary arteries. The CT scan helps
20 o
malformation in patients with HHT. in planning the catheterization procedure. It provides
S
the number, anatomy, location, and size of the feeding

INVESTIGATIONS vessel so that the interventional procedure can be better
planned. The type of device or coil can be planned well in
al
Chest radiography may reveal an abnormality in majority

of the cases with clinically significant PAVMs; but in about advance in most cases with the CT images.
Femoral venous access is the most commonly
ic
30–40% cases, it is reported as normal. Thus, the presence

of a normal chest X-ray does not exclude significant preferred route of approach while doing a transcatheter
og
malformations. The classic radiological features of PAVMs closure, followed by jugular approach. Once the feeding
are round or oval well-circumscribed lesions, mostly vessel is identified, selective pulmonary angiogram is
located in lower lobes (Figures 1A and B). done to further delineate the vessel and to confirm the
ol
Contrast echocardiography is a simple and minimally size and the landing zone available so that the device/
invasive tool for detection of PAVMs. Injection of agitated coil can be positioned without causing obstruction to
di
saline or contrast agent through peripheral vein in the normal pulmonary artery branches. Till recently,
normal individuals shows gradual disappearance of the using embolization coil was the cheaper and more easily
ar
contrast from the right-sided chambers as it gets trapped available option, but selection of coils and simultaneous
in the pulmonary circulation. In case of any right-to-left delivery of multiple coils needed more experienced hands
and can also be associated with more complication rates
C
shunting at the pulmonary level, the contrast will appear

in the left atrium after 2–5 cardiac cycles, whereas contrast including residual flows and distal embolization. 10 But
appearing immediately in both the atria/ventricles would with the availability of Amplatzer vascular plug (AVP; St.
be highly suggestive of an intracardiac shunt. JudeMedical, St. Paul, MN) the procedure has become
Contrast-enhanced computed tomography (CECT) safer and easier. Even large PAVMs can be easily tackled in
is considered as the gold standard investigation for the cath-lab and procedure time along with radiation has
diagnosing PAVMs. It is preferred to magnetic resonance come down considerably.11
imaging (MRI) because of its greater resolution. The CECT The AVP comes in four unique designs and is available
provides clear anatomic delineation of the malformation in a wide range of sizes from 3 mm to 22 mm. The first-
and helps in planning coil or device embolization of the generation AVP (range 4–16 mm) is best used for lesions
feeding afferent vessels (Figures 2A and B). It also helps with short-landing zone. Vascular plug II (3–22 mm) has
to rule out involvement of adjacent structures. It is useful more nitinol layers for better occlusion and is the one most
in follow-up imaging after embolization and to detect often used (Figures 3A and B). Smaller sizes (3–8 mm)
436 emergence of new lesions. can be deployed via a 4 F sheath or 5 F guide catheter
KG-53.indd 436 02-11-2018 16:54:42

CHAPTER
53
Pulmonary Arteriovenous Malformations

a
di
A B
In
Figures 1A and B: (A) Large pulmonary atrioventricular malformation in left lower lobe;
(B) Pulmonary arteriovenous malformation in right middle zone
of
ty
18 cie
20 o S
al
A B
ic
Figures 2A and B: Contrast-enhanced computed tomography showing pulmonary atrioventricular malformation in right lower lobe
og
ol
di
ar
C
A B
Figures 3A and B: Selective angiogram showing pulmonary arteriovenous malformation and the Amplatzer vascular plug in position
occluding the feeding vessel
which makes it quite accessible to most locations. Type III avoiding exchange of catheters. All present generation
vascular plug is utilized for high-flow situations. Vascular devices are MRI compatible.
plug 4 (range 4–8 mm) is so designed that it can be It can be technically challenging to embolize small
delivered even through a diagnostic catheter, which could diffuse atrioventricular (AV) malformations. Procedural
easily be tracked into any tortuous channels and, hence, complications that can occur include device migration,
437
KG-53.indd 437 02-11-2018 16:54:43

SECTION paradoxical embolization of thrombi, or air bubbles. But, 4. Hepburn J, Dauphinee JA . Successful removal of
usually, these complications are rare. Other complications hemangioma of lung followed by disappearance of
7 include pleurisy and pulmonary infarction. Delayed

pleurisy occurs 4–6 weeks after the procedure with fever,
polycythemia. Am J Med Sci. 1942;204:681-7.
5. Taylor BG, Codkerill EM, Manfredi F, et al. Therapeutic
chest pain, and infiltrates following closure of larger embolization of the pulmonary artery in pulmonary
PAVMs. Recanalization of embolized vessels can happen arteriovenous fistula. Am J Med. 1978;64:360-5.
rarely and is more often after coil closure. Follow-up CT 6. De Gussem EM, Lausman AY, Beder AJ etal. Outcomes
is recommended 1–5 years after the procedure to look for of pregnancy in women with hereditary hemorrhagic
telangiectasia. Obstet Gynecol. 2014;123(3):514-20.
late recanalization or regrowth of untreated PAVMs.
7. Sagara K, Myazono N, Inoue H. Recanalisation after
coil embolotherapy of pulmonar y arteriovenous
CONCLUSION
a
malformations: study of long term outcome and mechanism
Pulmonary AV malformations are a rare clinical problem for recanalization. Am J Roentgenol. 1998;170(3):727-30.
di
with a strong association with HHT. Chest radiography, 8. Brillet PY, Dumont P, Bouaziz N, et al. Pulmonary
contrast echocardiography, and CECT evaluation can help arteriovenous malformation treated with embolotherapy:
In
in identifying and delineating the lesions. Owing to the risk systemic collateral supply at multidetector CT angiography
of rupture and paradoxical embolism, it should be treated. after 2-20 year follow up. Radiology. 2007;242:267-76.
Percutaneous embolization is the treatment of choice for 9. Shovlin CL, Jackson JE. Pulmonary arteriovenous malfor
of
PAVMs. mations and other pulmonar y-vas cular abnormalities.
In: Mason B, Murray N, eds. Murray and Nadel’s textbook
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20 o
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CHAPTER 54 Systemic Effects of Cyanosis
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INTRODUCTION Vascular:
— Thrombosis
The word cyanosis is derived from the Greek word,
In
— Stroke
kuanos, meaning blue, it is defined as bluish or purplish
discoloration of mucous membranes and/or skin.
Renal problems
Rheumatological complications:
of
Description of cyanosis have been found in literature since
— Clubbing
the time of Hippocrates. De Senac (personal physician
— Hypertrophic osteoarthropathy
to King Louis XV) first described the pathophysiology of
Bacterial endocarditis
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cyanosis in 1749; and, subsequently, Christen Lundsgaard
classically quantified the amount of deoxygenated
Pulmonary:
— pulmonary hypertension
cyanosis.1
18 cie
hemoglobin 5 g/dL or more is required to produce clinical
Cyanosis is best appreciated in areas where the

— Hemoptysis
Gallstones
Ventricular dysfunction
overlying epidermis is thin and subepidermal vessels are
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Dental abnormalities
abundant such as the lips, nose, cheeks, ears, hands, feet,
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and mucous membranes of the oral cavity.

FAILURE TO THRIVE
Peripheral cyanosis or acrocyanosis: It involves lips,
Growth failure and poor weight gain are the common
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tongue, and sublingual tissues, as well as the hands and

feet, and occurs due to decreased oxygenation of blood. problem in cyanotic congenital heart diseases (CHDs).
Multifactorial etiology of growth failure is described
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Peripheral cyanosis or acrocyanosis: This condition is in patients with CHDs. Major causes of grow th
bluish discoloration of the fingers and toes or the nose
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failure in these children are decreased calorie intake,

which is because of increased content of desaturated malabsorption, increased metabolic demand and other
hemoglobin in stagnant blood. causes are swallowing dysfunction, gastroesophageal
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Pseudocynosis: It is bluish discoloration without increase reflux, immaturity of the GI tract, and genetic factors. The
in deoxygenated hemoglobin, e.g. methemoglobinemia, relative contribution of each of these factors depends
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metal exposure or cyanosis found during examination in upon the type and severity of the cardiac lesion, severity
fluorescent lightning, etc. of tissue hypoxia and degree of physiological adaptation.
ar
In general, acyanotic lesions are related to acute

Differential cyanosis: In this type of cyanosis, hands are
malnutrition, whereas cyanotic lesions are associated with
red or normal colored but feet are bluish. It can occurs in
chronic malnutrition.2 Along with growth, developmental
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patent ductus arteriosus (PDA) with reversal of shunt.

milestones such as sitting, crawling, standing, and walking,
In this section, we will be discussing the systemic
may also be effected adversly. Mild general cognitive
effects of cyanosis.
impairment and impairment of functions associated with
right-hemisphere can occur in children with CHD.3
SYSTEMIC PROBLEMS WITH CYANOSIS Inadequate caloric intake is leading cause of growth
Failure to thrive failure in CHD. Anorexia also accompanies malnutrition
Cyanotic spell and further compromises the patient’s condition. Chronic
Brain abscess hypoxia may lead to feeding difficulty. In early postnatal
Hematological: life, heart switches from carbohydrate metabolism
— Erythrocytosis/polycythemia to β-oxidation of fatty acids as main energy driving
— Hemostatic problems mechanism; and during hypoxia, it switches back to
— Iron deficiency anemia glycolytic metabolism leading to decreased energy
KG-54.indd 439 02-11-2018 17:04:12

SECTION production. Unmetabolized fatty acids exerts inhibitory during crying or agitation leads to Increased contractility
effect on glycolytic cycle causing decline in cardiac of right ventricle which in association with decreased right
7 contractility followed by poor oxygenation of organs
leading to delayed growth. Children with cyanotic
ventricular volume can trigger reflex hyperventilation and
peripheral vasodilatation which initiates a spell.6
heart disease and pulmonary hypertension have higher Cyanotic spells can occur in every variants of TOF
resting energy consumption and are known to be in a because of dynamic nature of left ventricular outflow tract
hypermetabolic state. It causes an increase in cardiac and obstruction (LVOTO) such as in cases of d-transposition of
respiratory work further diverting energy consumption. great arteries (D-TGA) with intact interventricular septum.
Delayed bone age is another common finding in Other cardiac conditions which can lead to cyanotic spells
children with CHDs. The presence of cyanosis with or are tricuspid atresia with PS, transposition of great vessels
without pulmonary hypertension further deteriorates with PS, Single ventricle physiology with PS or pulmonary
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growth failure and bone maturation.4 Some of the cyanotic atresia. A rare case of refractory cyanotic spell due to
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heart diseases are associated with syndromes, i.e. Down’s thrombus in right ventricular outflow tract in a patient of
syndrome, Turner syndrome and other genetic conditions, TOF has also been reported.7
In
so these children suffer with their respective consequences
including delayed physical and mental growth. Treatment
Management
includes dietary management based on individual
of
condition and requirement and interventions to restore The management of hypoxic spells is aimed at breaking
normal growth and development. the cycle by abolishing the hyperpnea, decreasing RVOTO
and/or increasing the systemic vascular resistance.
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CYANOTIC SPELL Traditional management of cyanotic spells is keeping
in knee-chest position, oxygen inhalation, intravenous
Also known as hypoxic, hypercyanotic, or ‘tet’ spells. It
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typically occurs in cyanotic CHD, i.e. tetrology of Fallot
(TOF) physiology. These spells are characterized by a
(IV) fluids (10–20 mL/kg up to 60 mL/kg), intravenous
morphine (0.1–0.2 mg/kg), correct acidosis (sodium
bicarbonate 1–2 mEq/kg), intravenous beta blockers, i.e.
paroxysm of hyperpnea, irritability or agitation, and
metaprolol (0.1 mg/kg followed by infusion of 1–5 µg/kg/
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prolonged crying, leading to worsening cyanosis and
min) and propranolol (0.1 mg/kg), IV phenylephrine (0.02
associated with decreased intensity of murmur. This
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mg/kg)/methoxamine (0.1 mg/kg). Knee chest position

may be precipitated by crying, urination, injections, and
compresses the femoral vesseles, which increases the
immunization, and usually seen in morning hours, if
afterload and decreases venous return from the lower limbs.
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not appropriately treated may lead to altered sensorium,

Correcting acidosis reduces the respiratory stimulation,
neurological complication and death. A spell mostly
morphine act by respiratory center suppression and
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occurs in pediatric population of less than two years of age

sedation thereby reducing hyperpnea. Propranolol
with cyanotic heart disease, but there is also a reported
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decreases cardiac contractility thus oxygen demand and

case of cyanotic spell in a 29- year-old man of TOF.5
also relieves infundibular spasm. Phenylephrine increases
SVR. Ketamine (0.25-1.0 mg/kg) have dual advantage
Pathophysiology
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of sedation and raising SVR can be used. In emergency

Degree of cyanosis and onset of cyanotic spell is dependent situations to sedate a child with difficult venous access,
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on the systemic vascular resistance (SVR) and severity intranasal midazolam can be used. A case of cyanotic
of pulmonary stenosis (PS) component. Explained spell in TOF managed by dexmedetomidine8 and fentanyl9
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mechanism of the cyanotic spells is that, it is the increase has also been reported. It is important to treat underlying
contractility of the infundibulum which enhances right precipitating cause, such as anemia and sepsis, to prevent
ventricular outflow tract obstruction (RVOTO) and in the recurrence of spell.
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association with low SVR causes right-to-left shunt. This

results in fall of arterial PO2, increase in PCO2 and fall in pH
(acidosis) which stimulate the respiratory center causing
BRAIN ABSCESS
hyperpnea. This hyperpnea causes increase in venous Brain abscesses are common in pediatric population
return and increased right-to-left shunt further aggravating with uncorrected or partially corrected cyanotic CHD
cyanosis which leads to vicious cycle of hyperventilation usually after 3 years of age. Cyanotic heart disease is
and hypoxia/cyanosis. If left untreated and the cycle the leading cause of brain abscess after complication
persists, the patient will become progressively more of otitis media and sinusitis. The common sites for
hypoxic and acidotic; it may lead to limpness, seizures, brain abscess are parietal, frontal and temporal lobes.10
neurological deficit and eventually cardiac arrest. Another Clinically, the patients usually present with vomiting,
mechanism described is stimulation of mechanoreceptor fever, headache, seizures, focal neurologic signs and
in the right ventricle. Increased catecholamine release eventually papilledema and coma.
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Pathophysiology polycythemia, shortened platelet survival and alteration CHAPTER
in clotting factors. An elevated prothrombin time (PT) and
54
The basis of pathophysiology is right-to-left shunting
of blood present in cyanotic cardiac conditions which APTT, decreased levels of factors V, VII, VIII, and IX have
allows passage of bacteria colonizing in airway to the been described along with qualitative and quantitative

cerebral circulation. Hypoxia and hyperviscosity are the platelet disorders. Thrombocytopenia may be due to
two important factors associated with brain abscess. reduced megakaryocytes fragmentation into platelets in
Hyperviscosity and presence of microcytic hypochromic the setting of right-to-left shunting. Erythrocytosis can
anemia cause micro- or macro-infarction and this with lead to bleeding diathesis in up to 20% of patients and
an infective source through the shunted blood results it can be mild (superficial) to moderate (epistaxis) to
in focal cerebritis followed by abscess.11 Polycythemia sever life-threatening with hemoptysis, or postoperative
leads to tissue hypoxia and ischemia which along with bleeding.15 Erythrocytosis well correlates with hemostatic
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hyperviscosity, creates a niche for the bacterial growth. defects. The management of bleeding diathesis depends
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Typical causative agents are Staphylococcus aureus and on the clinical circumstance and the abnormal hemostatic
Streptococcus group along with anaerobics. parameters.
In
Management Iron Deficiency Anemia
The management includes broad-spectrum IV antibiotic This is not an uncommon finding in cyanotic patients.
of
with anaerobic coverage for 6–8 weeks. Surgical drainage It can occur due to excessive utilization, excessive
is required in nonresolving or worsening symptoms, signs bleeding or phlebotomy. Typical indices of iron deficiency,
of raised intracranial pressure (ICP), abscess size more hypochromia and microcytosis may not be present so,
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than 2.5 cm or posterior fossa abscess. complete iron metabolism workup, including serum
ferritin and transferrin levels are reqired to make diagnosis.
HEMATOLOGICAL COMPLICATIONS
Erythrocytosis/Polycythemia
18 cie Microcytic hypochromic RBCs of iron deficient state are
less deformable compared to normal RBC which increases
blood viscosity may lead to symptoms of hyperviscosity
(Increased Red Blood Cells Count)
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at hematocrits level well below the 65%. Iron-deficient
Cyanosis leads to chronic hypoxemia and in response group also has an increased frequency of cyanotic spells.16
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body develop adaptive mechanisms to increase oxygen It should be treated in confirmed and symptomatic cases
delivery. This constitutes an increase in oxygen-carrying with oral elemental iron of 3–5 mg/kg/day.
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capacity, oxyhemoglobin dissociation curve shift to right

and increase in cardiac output.
VASCULAR COMPLICATIONS
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Pathophysiology Thrombosis
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Erythropoietin production is increasesd in response to Patients with cyanotic CHD have a high prevalence
hypoxemia which leads to erythrocytosis, which can lead of thrombosis despite their relatively young age and
to symptoms of hyperviscosity, i.e. headaches, dizziness, the absence of classical cardiovascular risk factors.
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faintness, fatigue, altered mentation, visual abnormalities, Historically, vessel wall integrity (endothelial injury),
paresthesias, tinnitus, and myalgias. These hyperviscosity blood composition (hypercoagulabality), and altered
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symptoms usually occur when hematocrit levels are blood flow (vascular stasis) were first recognized as the
more than 65% and its severity varies from mild to severe most important elements involved in thrombus formation
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depending upon hematocrit level, hydration status and by Rudolph Virchow known as the Virchow triad,17 which
iron repletion state. has formed the basis for understanding the pathogenesis
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of thromboembolism (TE) and is still widely used to assess

Management TE risk.18 Although exact pathogenesis is still not described
Phlebotomy to reduce hematocrit level provides but abnormalities in each of these three domains along
symptomatic releive, but it must be weighed against the with iron deficiency have been reported in patients with
risk of provoking iron deficiency. Therapeutic phlebotomy cynotic heart disease. 19 In cyanotic CHD, hypoxemia
is usually reserved for symptomatic cases of hyperviscosity either directly or through activation of neutrophils, which
with hemoglobin ≥20 mg/dL and hematocrit ≥65%.12 Few release vasoactive and chemotactic substances, causes
cases showed response to hydroxyurea but further studies endothelial injury and subsequent activation of platelets
are needed for its approval.13 and coagulation. 20 There is altered composition of
coagulation factors reported in cyanotic heart disease, i.e.
Hemostatic Problems increased FVIII levels, decreased protein C, antithrombin
Hemostatic complications are not uncommon in patients III, altered balance of these leads to hypercoagulable
with cyanotic CHD. 14 They are attributed to relative state. Microparticles, the sensitive marker of platelet
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KG-54.indd 441 02-11-2018 17:04:13

SECTION activation, play an important role in coagulability. Both leads to progressive kidney disease involving multiple
decreased platelet count and increased levels of platelet factors including podocyte injury.23
7 microparticles have been demonstrated in cyanotic CHD,
with levels proportional to the hematocrit.21 Polycythemia
Nephropathy in cyanotic CHD is well recognized entity
but its mechanism is poorly understood. Pathophysiology
and hyperviscosity leads to vascular stasis. may involves multiple factors, i.e. hyperviscosity due to
These cyanotic conditions have potential for shunting polycythemia, chronic hypoxia, changes in intraglomerular
(in either direction) and intracardiac mixing of systemic hemodynamics, altered autonomic regulation and
and pulmonary venous blood before going to lungs or neurohormonal activation. Hyperviscosity causes changes
systemic circulation, so thrombi can migrate to lungs in resistance of glomerular arteries, increased pressure
causing pulmonary embolism or to systemic circulation across the glomerulus, and raised filtration fraction
causing local mild ischemia to life-threatening stroke. leading to deranged function. It is described by dilatation
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Besides ischemic changes, these thrombi can cause of hilar arterioles and glomerular capillary engorgement
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additional problems as it may result in the inability to with red cell because of intraglomerular NO release
access an artery for an essential diagnostic or therapeutic through increased endothelial shear stress, which is
In
catheterization. It can cause complete occlusion of a associated with increased viscosity. 24 Neurohormonal
systemic-to-pulmonary artery shunt both native and derangements have also been described in patients with
operative (like Blalock–Taussig shunt), which is fatal cyanotic CHD, i.e. elevated level of atrial natriuretic
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unless immediately relieved. peptide, renin, aldosterone, and norepinephrine, which
may be associated with renal dysfunction. Chronic
Stroke hypoxia of local tissue due to cyanosis has been seen to
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play an important role in progression to CKD as it is well
The incidence of stroke is significantly higher in patients
proven in other diseases, i.e. diabetes, hypertension, and
with cyanotic heart disease compared to noncardiac
younger age.
18 cie
disease patients and also there is higher presentation at
cyclosporine toxicity.25
Clinical manifestation can be proteinuria, hyper-
uricemia, or renal failure. Hyperuricemia is common
An embolic material which originates in the venous
presentation and it is mainly due to the decreased
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compartment and reaches to systemic circulation after
reabsorption rather than to overproduction from
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bypassing the pulmonary capillary filter is known as

lysis of raised RBCs. Urate nephropathy and uric acid
paradoxical embolism. These paradoxical embolism
nephrolithiasis are rare conditions which can occur. Early
leading to stroke is well described as any venous thrombus,
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detection through screening programs is very crucial in

clot or any embolic substance from venous circulation long-term outcome.
goes directly to cerebral circulation leading to occlusion of Management of renal dysfunction involves optimizing
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blood flow results in stroke. In patients with erythrocytosis, renal perfusion pressure and oxygenation by maintaining
transient ischemic attacks may be related to rheological
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fluid and electrolyte balance, acid–base balance, adequate

problems of hyperviscosity or altered RBCs due to iron nutrition, and initiation of renal replacement therapy
deficiency as described above. when required along with treatment of underlying cardiac
As paradoxical embolism involves both a emboli and
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condition.
an abnormal anatomic communication, treatment should
be aimed at either preventing the formation of clots by
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using medication (antiplatelet agents, anticoagulants),

RHEUMATOLOGICAL COMPLICATIONS
or closing off the communication by surgery or device. Clubbing
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Importantly, conditions associated with hyperviscosity,

Digital clubbing, also known as drumstick fingers or
i.e. dehydration, iron deficiency should be promptly
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watch-glass nail, is condition described as focal bulbous

treated.
enlargement of the terminal segments of the fingers and/
or toes. It occurs because of proliferation of connective
RENAL PROBLEMS tissue between the distal phalanx and nail matrix. It results
Also termed as cyanotic nephropathy, is seen in significant in increase in both anteroposterior and lateral diameter
number of cases of cyanotic CHD. It effects both glomerular of the nails. This was first described by Hippocrates about
and tubular function, which results in proteinuria and 2,500 years ago in a patient of empyema and it is regarded
azotemia, which can lead to both acute kidney injury as the oldest sign in clinical medicine.26 Clubbing has been
and chronic kidney disease (CKD). It is found to be described in different grades from 1 to 5. Although it is a
directly related to duration of cyanosis and there is rising common finding in cyanotic heart disease, but the most
trend toward CKD and end-stage renal disease in adult common cause of clubbing is pulmonary pathology.
patients. 22 Another clinical condition named chronic Multiple hypotheses have been described over the
cardiorenal syndrome where chronic cardiac problems time to explain the pathophysiology of digital clubbing.
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The most promising is megakaryocytes or platelet the endocardium in these scarred areas, in suture lines CHAPTER
clusters lodged in the peripheral vasculature of the digits. or along the prosthetic material, formation of vegetation
Normally, megakaryocytes and large platelets clumps
got trapped in the pulmonary capillary vasculature
and/or abscess may occur on these areas, resulting in
IE.31 The microbiological findings and treatment of IE in
54

and get fragmented into platelets. In case of right-to- cynotic CHD patients is same to those in the overall IE
left shunt, these megakaryocytes and platelet clumps patients.
bypass the pulmonary capillary bed and got impacted
in distal peripheral circulation of digits. As a result of PULMONARY COMPLICATIONS
hypoxic stimuli, platelet-derived growth factors (PDGF)
are released along with vascular endothelial growth Pulmonary Hypertension
factor (VEGF), which leads to the increased vascularity, An estimated 4–15% of patients with CHD develop
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permeability, and connective tissue changes which are the pulmonary hypertension (PH), 32,33 it depends on the
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hallmark of clubbing.27 location and size of the shunt. PH due to CHD includes
a wide spectrum of conditions. Pulmonary arterial
Hypertrophic Osteoarthropathy
In
hypertension cases which are related to CHD are described
Hypertrophic osteoarthropathy (HOA) is a syndrome as precapillary PH and included in group I of the PH
which constitutes digital clubbing, periostitis with new classification according to the latest World Symposium
of
subperiosteal bone formation of long bones and arthritis. on Pulmonary Hypertension.32 This group includes vast
It is usually seen in children and young adults and can subset of condition ranging from transposition of the great
causes mild pain and swelling of effected part to disabling arteries (TGA), ventricular septal defect (VSD) physiology,
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symptoms severely affecting the routine life. It usually that will go earliest into eissenmengerization to various
involves long bones of lower limbs; but, in severe cases other conditions. Pressure overload in such conditions
18 cie
other bones like ribs, clavicles, scapulae, pelvis and malar
bones can also be involved. periostitis with new bone
formation in the subperiosteal region is typically seen on
with underlying hyperviscosity states (as described above)
leads to early PAH in cyanotic CHDs.
Segmental pulmonary perfusion is conditions of
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X-ray. inhomogeneous pulmonary perfusion, where areas of
VEGF is an important factor in the pathophysiology of ‘hyperperfused’ lung may develop pulmonary vascular
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HOA. In conditions of right-to-left shunt megakaryocytes disease (PVD) over the time. These PVDs may involve
and platelet clumps bypass the pulmonary capillary bed one part of lung rather than the entire lung vasculature,
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and get impacted distally in the peripheral circulation. leading to ‘segmental pulmonary hypertension’. Segmental
PDGF and VEGF are released on hypoxic stimuli, which pulmonary hypertension has been included in Group 5 of
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leads to vascular and bone stimulating effects such as the international PAH classification. Cardiac conditions
angiogenesis, increasing blood vessel permeability, and which can lead to segmental pulmonary hypertension are
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endothelial bone formation. It also activates osteoblast truncus arteriosus type 2 with stenosis of the left or right
formation and migration which contributes to HOA. 28 pulmonary artery or complex pulmonary atresia with
Management aims at symptomatic relieve with treatment multiple major aortopulmonary collateral arterie and/or
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of underlying cause. peripheral pulmonary artery stenosis (both are cyanotic

CHDs). There is no specific therapy described for PAH in
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BACTERIAL ENDOCARDITIS this condition.

The risk of infective endocarditis (IE) remains a major
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concern in patients with CHD, whether unrepaired, Hemoptysis

palliated, or corrected. Increased survival of children with
Hemoptysis is an important complication of CHD.
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CHD and the use of prostheses and conduits in surgeries

Possible etiologies include hemorrhage from enlarged
are the major contributors of increasing incidence of IE.29
tortuous bronchial arteries (MAPCAs), thrombotic lesions
Cyanotic CHD confers the highest risk for IE among the
in the small pulmonary arteries (as discussed above),
CHDs along with endocardial cushion defect, and left-
‘pseudofibrosis’ at the lung apices. Other causes which
sided lesions.30
need to be investigated and described in the literature
Persons with CHD have structural heart changes
include associated tuberculosis, hemoptysis associated
(native or postoperative) that creates turbulence and
with pregnancy or oral contraceptives and other systemic
sheer force in blood flow that disrupt the endocardium,
causes of bleeding.6
leaving the heart vulnerable by exposing subendocardial
collagen and extracellular matrix. During the healing
process, production of tissue factor, deposition of fibrin GALLBLADDER STONES
and platelet adherence lead to hemostasis and scar Increased red cell counts in cynosis increases bilirubin
formation. Pathogenic organisms may settle in and infect generation (by heme metabolism) which predisposes to
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KG-54.indd 443 02-11-2018 17:04:13

SECTION pigment gallstones. Gallstones are found to be twice as 5. Weng YM, Chang YC, Chiu TF, et al. Tet spell in an adult. Am
prevalent among cyanotic CHD compared to age-matched J Emerg Med. 2009;27(1):130.
7 acyanotic CHD. 34 Nature of cyanotic CHD, prolonged

cyanosis durations and low platelet counts have influences
6. Kothari SS. Mechanism of cyanotic spells in tetralogy of
Fallot–the missing link? Int J Cardiol. 1992;37(1).
7. Gupta SK, Saxena A, Anil OM, et al. Thrombus in right
on gallstone formation. Management is same as in general

ventricular outflow tract : unique cause of refractory
population, depends on symptomatic status.
cyanotic spell. Congenit Heart Dis. 2012;7(4):56-8.
8. Tsze DS, Vitberg YM, Berezow J, et al. Treatment of tetralogy
VENTRICULAR DYSFUNCTION of Fallot hypoxic spell with intranasal fentanyl. Pediatrics.
Ventricular dysfunction is important risk factor for 2014;134(1):266-9.
9. Senzaki H, Ishido H, Iwamoto Y, et al. Sedation of
morbidity and mortality in cardiac patients, specially
hypercyanotic spells in a neonate with tetralogy of Fallot
a
in surgical cases. It can be due to multiple causes, i.e.
using dexmedetomidine. J Pediatr (Rio J). 2008;84(4):
structural (aberrant left coronary artery from pulmonary
di
377-80.
artery, CoA), myocarditis/cardiomyopathy, sustained 10. Udayakumaran S. Forgotten? Not Yet. Cardiogenic Brain
arrhythmias and shunt overflow in post-surgical cases. Abscess in Children: A Case Series-Based Review. World
In
Hypoxia itself though scarcely recognized is an important Neurosurg. 2017;107:124-9.
cause of ventricular dysfunction. Many studies showed 11. Kumar K. Neurological complications of congenital heart
ventricular dysfunction due to chronic hypoxia by disease. Indian J Pediatr. 2000;67:287-91.
of
subcellular effects and few of them showed improvement 12. Giglia TM, Massicotte MP, Tweddell JS, et al. Prevention
after increasing oxygenation. Some studies on animals and treatment of thrombosis in pediatric and congenital
showed effect of hypoxia, but human studies in cyanotic heart disease: a scientific statement from the American
ty
Heart Association. Circulation. 2013;128:2622–703.
CHD for the same still lacking. Severe cyanotic spells
13. Reiss UM, Bensimhon P, Zimmerman SA, et al. Hydroxyurea
leading to acute hypoxia can cause ventricular dysfunction,
18 cie
which reverses rapidly after early management of spell.
Hypoxia due to cyanotic CHD is a strong reversible risk
therapy for management of secondary erythrocytosis
in cyanotic congenital heart disease. Am J Hematol.
2007;82(8):740-3.
factor for ventricular dysfunction. Polycythemia due to 14. Kurt M, Litmathe J, Roehrborn A, et al. Abdominal
20 o
chronic hypoxia have altered rheological properties which complications following open-heart surgery: a report
S
further exaggerebate this dysfunction. Total correction of of 12 cases and review of the literature. Acta Cardiol.
cyanotic condition results in correction of hypoxia which 2006;61:301–6.
leads to improvement in myocardial function.35 15. Perloff JK, Rosove MH, Child JS, et al. Adults with cyanotic
al
congenital heart disease: hematologic management. Ann

Int Med. 1988;109:406-13.
DENTAL ABNORMALITIES
ic
16. Mukharjee S, Sharma M. Iron deficiency anemia in

Higher incidence of dental problems in patients of children with cyanotic congenital heart disease and
og
cyanotic CHDs is well reported and are due to either effect on cyanotic spells. Med J Armed Forces India.
systemic manifestation of disease or effect of its treatment. 2017;74(3):235-40.
Among the various problems dental caries have high 17. Virchow R. Thrombosis. Gesammelte Abhandlungen zur
ol
incidence and significance, and are mainly due to enamel Wissenshaftlichen Medicin. Canton, MA: Science History
abnormalities of primary dentition as chronic hypoxia Publications; 1856. pp. 219-732.
di
18. Malone PC, Agutter PS. The aetiology of deep venous

in cyanotic CHD can cause abnormality in enamel
thrombosis.QJM. 2006;99(9):581-93.
formation and mineralization.36 Untreated caries can be
19. Kotby AA, Mamdouh NM, Eissa DS, et al. Risk factors for
ar
a contra-indication for heart surgery. Preventive dental thrombosis in children with cyanotic congenital heart
care and proper oral hygiene are important aspect in its disease. J Med Clin Res. 2016;4(10):13175-83.
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management along with addressing underlying cause. 20. McLeod KA, Martin P, Williams G, et al. Neutrophil
activation and morbidity in young adults with cyanotic
congenital heart disease. Blood Coagul Fibrinolysis.
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27. Atkinson S, Fox SB. Vascular endothelial growth factor 33. D ’A l to M , Merola A , Dimop ou l os K . Pulmo nar y
(VEGF)-and platelet-derived growth factor (PDGF) play a hypertension related to congenital heart disease: A
central role in the pathogenesis of digital clubbing. J Pathol. comprehensive review, Global Cardiology Science and
a
2004;203(2):721-8. Practice 2015:42 http://dx.doi.org/10.5339/gcsp.2015.42
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28. Olan F, Portela M, Navarro C, et al. Circulating vascular 34. Shiina Y, Toyoda T, Kawasoe Y, et al. The prevalence and
endothelial growth factor concentrations in a case of risk factors for cholelithiasis and asymptomatic gallstones
pulmonary hypertrophic osteoarthropathy. Correlation in adults with congenital heart disease. Int J Cardiol.
In
with disease activity. J Rheum. 2004;31(3):614-6. 2011;152:171-6.
29. Day MD, Gauvreau K, Shulman S, et al. Characteristics 35. Awasthy N, S Radhakrishnan, KS Iyer, et al. Reversible
of children hospitalized with infective endocarditis. ventricular dysfunction in cyanotic heart disease Indian
of
Circulation. 2009;119:865-70. Heart J. 2014;66(6):704-6.
30. Rushani D, Kaufman JS, Ionescu-Ittu R, et al. Infective 36. Jalevik B, Noren JG. Enamel hypomineralization of
endocarditis in children with congenital heart disease: permanent first molars: A morphological study and
ty
cumulative incidence and predictors. Circulation. 2013;128: survey of possible aetiological factors. Int J Paediatr Dent.
1412-9. 2000;10:278-89.
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Cardiomyopathy
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Outcomes of Dilated Cardiomyopathy in 2018
of
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Genetics of Cardiomyopathies: An Overview
Ajay Bahl
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Noninvasive Evaluation of Suspected Heart Muscle Disease
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Krishnam Raju, Chandramukhi Sunehra
Curable Forms of Ventricular Dysfunction
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Myocarditis: An Update
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Tachycardiomyopathy
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The Role of Cardiovascular Magnetic Resonance in
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Risk Stratification of Hypertrophic Cardiomyopathy

Martin S Maron
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Constrictive Pericarditis and Restrictive Cardiomyopathy: How to Differentiate?

V Jacob Jose
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Tubercular Pericarditis
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Surgery for Chronic Constrictive Pericarditis, Tuberculous Pericarditis

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and Effusive-Constrictive Pericarditis

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An Update on Restrictive Cardiomyopathy
8
Tropical Endomyocardial Fibrosis? A Vanishing Curious Disease
Cardiac Amyloidosis: Diagnosis and Management
Cardiac Sarcoidosis
Ajit Thachil
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Outcomes of Dilated
CHAPTER 55
Cardiomyopathy in 2018
a
di
INTRODUCTION nonuniform patient selection, extent of etiological
Dilated cardiomyopathy (DCM) refers to a group of work-up leading to discrepancies in classification and
In
disorders characterized by depressed ventricular systolic also adequate follow-up to ascertain irreversibility.
performance and ventricular dilatation in the absence The estimated prevalence of DCM in the United States
of hypertension, valvular, congenital or ischemic heart is around 40 cases per 100,000 population with an
of
disease.1 Either or both the ventricles get progressively annual incidence of 7 cases per 100,000 population.2 The
dilated and dysfunctional, eventually leading to pump incidence of DCM has been on a rise due to unknown
reasons, part of it being attributed to earlier and improved
ty
failure. End stage heart failure and sudden cardiac death
remain the two most common causes of death in DCM. detection. In Olmsted County, the incidence rose, almost
doubled from 3.9 to 7.9 cases per 100,000 person years
18 cie
Other important complications include conduction
abnormalities and thromboembolism. Risk stratification
remains essential to identify those at high risk of sudden
between 1975–79 and 1980–84. 3 However, DCM still
remains uncommon in other developed countries like
cardiac death to undertake preventive measures including Japan where estimated prevalence is 17 per 100,000
20 o
implantable cardioverter defibrillator (ICD) implantation. population. 4 The incidence of prevalence is typically
higher in developing and underdeveloped regions in the
S
Despite multitude of drug therapies being tried and

tested in the past two decades, the efforts have been world including India, Africa, and Latin America.5 This has
largely frustrating with only one new effective addition been linked possibly to nutritional deficiencies and some
al
in the form of angiotensin receptor-neprilysin inhibitor tropical cardiomyopathies including Takayasu arteritis
(ARNi) that has shown to improve outcomes over and and other infective causes.6 DCM continues to be the most
ic
above the conventional drug therapy. Drug therapies common cardiomyopathy in India.7
optimally work in the initial stages of left ventricular
og
(LV) dysfunction before the setting in of refractory end- Natural History

stage heart failure. Heart transplantation or mechanical The natural history of DCM is not well established due
circulatory support are often the only answers to end stage
ol
to the changing realm of the disease. Historical data

heart failure. Heart transplantation in itself is limited by is suggestive of a poor survival with 1 year and 5 years
availability of a donor heart, infections, graft rejection,
di
mortality rates up to 25-30% and 50%, respectively. 8

need for immunosuppressive therapy, and long-term Advances in the pharmacological and device therapies
complications including infections, allograft vasculopathy,
ar
have improved the prognosis of the disease in the past

and malignancies. With the grim scenario of treatment of two decades. This fact renders the natural history studies
end-stage heart failure, the focus is gradually shifting done in the pre-modern medicine era inapplicable. Also,
C
towards preventive measures and also early identification the prognosis of DCM (a highly heterogeneous group)
of LV dysfunction followed by early intervention to modify depends heavily on the particular etiology with each
the natural history of disease. having its different course of progression. The insidious
onset and slow progression of familial and idiopathic
EPIDEMIOLOGY AND NATURAL HISTORY DCM further complicates the situation. It introduces lead
time bias where a similar pathology may yield different
Epidemiology outcomes and survivals because of diagnosis being made
Even after being one of the most common causes of at different stages of the natural history of the disease.
heart failure and also cardiac transplant, defining the Thus, with earlier diagnosis based on familial screening
epidemiology of DCM accurately has been a daunting and implementation of optimal pharmacological and
task. Challenges include geographical variations, racial device therapies, the prognosis of DCM has improved
variations, variability in diagnostic criteria causing dramatically. A more contemporary study demonstrated
KG-55 (Sec-8).indd 449 03-11-2018 12:46:00

SECTION Table 1: Poor prognostic factors in DCM13 and endocrinological disorders like hypothyroidism.
New onset of heart failure should raise a suspicion of
8
z Left ventricular (LV) and right ventricular (RV) enlargement
z Reduced RV ejection fraction (EF) myocarditis and should be managed accordingly. If
z Moderate-to-severe mitral regurgitation detected in a pregnant or a postpartum female suspicion
Cardiomyopathy
z Pulmonary hypertension of peripartum cardiomyopathy should be borne in mind.

z Electrocardiographic findings of wide QRS duration Familial or genetically determined DCM constitutes an
z Recurrent ventricular tachycardia important part of the spectrum that is being increasingly
z Renal and hepatic dysfunction recognized. A genetic basis seems more likely after the
z Elevated levels of biomarkers [brain natriuretic peptide (BNP) or obvious acquired factors have been ruled out. Familial
NT-ProBNP (N-terminal ProBNP), cardiac troponins] screening involving three or four generations for the
z Peak oxygen consumption <12 mL/kg/min
disease helps to ascertain the genetic nature of disease
a
z Hyponatremia
and also to identify more cases in the asymptomatic
z Advanced NYHA (New York Heart Association) functional class
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stages who can be timely started on appropriate therapy.
z Elderly age group (>65 years)
z Myocytolysis on endomyocardial (EB) biopsy
A negative family history, however, does not rule out
In
the genetic nature of disease as sporadic forms do occur
due to de novo mutations. The proportion of patients
a survival free from death and transplantation up to 85% with genetic mutations is significantly underestimated
of
at 10 years.9 due to variable age, severity and clinical picture at
A few important observations regarding the prognosis presentation, and lack of specific phenotypes. Still
of the disease need to be noted. Spontaneous improvement the proportion has been estimated around 40% in
ty
may be seen in approximately 25% of the patients with a contemporary series of genetic testing in DCM. 14
recent-onset heart failure.10 But patients having persistent Autosomal dominant is the most common mode of
18 cie
symptoms for more than 3 months are unlikely to recover.10
Idiopathic DCM has a better prognosis than other causes
of DCM and also ischemic DCM. 11 Approximately two-
inheritance. Though relatively uncommon, X-linked,
autosomal recessive, and mitochondrial inheritance have
also been reported and are often associated with a more
20 o
thirds of the deaths are caused secondary to pump failure severe clinical disease. More than 50 candidate genes have
with the remaining one-third being attributable to sudden been identified till date. Out of these, TTN gene (encoding
S
cardiac death. 12 Poor prognostic factors for adverse for titin) is the most common culprit contributing to
outcomes in DCM are listed in Table 1.13 approximately 15–25% of familial DCM.15 A 25 base pair
al
deletion mutation in the gene encoding cardiac myosin-

ETIOLOGICAL CLASSIFICATION OF DCM binding protein C (MYBPC3) has been exclusively
ic
identified in patients with Indian subcontinental ancestry

The natural history and prognosis of the disease is affected
with a prevalence of up to 4% in Indian population. 16
by the etiology to a large extent. Thus, the importance of
og
MYBPC3 confers an increased risk of cardiomyopathy

adequate etiological work-up and classification of DCM
and heart failure with an odds ratio of 7.16 The diagnosis
cannot be overemphasized. DCM can be etiologically
of a specific mutation does not usually govern specific
classified as idiopathic, inflammatory, or secondary to
ol
therapy. However, it may influence management in terms

other causes (Figure 1). Only after ruling out a multitude
of familial screening, prognostication, and threshold for
of secondary causes, DCM should be labeled as idiopathic.
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primary prevention (implantation of a defibrillator as per

Looking for reversible causes of DCM is the clinical dictum
risk of arrhythmogenesis). For example, dystrophin gene
that should never be forgotten.
ar
(DMD) mutation is associated with poor prognosis with a

Idiopathic DCM accounts for approximately 20–30% of
shortened life span and lamin A/C gene (LMNA) mutations
all DCM associated with heart failure. The estimate varies
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are frequently associated with conduction disturbances

based on the extent of etiological work-up done. Treating
and also life-threatening ventricular arrhythmias.
the underlying cause in the secondary causes may affect
cure of inappropriately labeled DCM and thus completely
change the landscape of follow-up. The most common Myocarditis
reversible factors that are usually not missed include Myocarditis is inflammatory involvement of the heart
hypertension, valvular heart disease, and congenital leading to LV dysfunction and heart failure that can range
heart disease. Underappreciated reversible causes of from a completely recoverable syndrome to a chronic
LV dysfunction include tachyarrhythmias (persistent persistent disorder leading to DCM. Acute myocarditis
supraventricular arrhythmias or frequent ventricular may be defined as a clinical syndrome of acute heart
ectopics), substance abuse (e.g. alcohol, cocaine), cancer failure of less than 3 months duration associated with
chemotherapy, stress-induced LV dysfunction (Takotsubo unexplained elevation of troponins, new wall motion
cardiomyopathy), systemic autoimmune disorders (e.g. abnormalities on echocardiography, or tissue edema, or
sarcoidosis), coarctation of aorta, Takayasu arteritis, scarring noted on cardiac MRI. 17 Clinically, the disease
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Figure 1: Classification of DCM

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can be characterized by acute chest pain, heart failure, sarcoidosis, and tubercular myocarditis are the most
unexplained arrhythmias, unexplained cardiogenic important considerations pertaining to Indian scenario.
ic
shock, or a combination of these. Sudden cardiac death

has also been noted as a manifestation of myocarditis. EVALUATION OF DCM
og
Myocarditis has been attributed to be the third leading Table 2 enumerates the steps that are involved in
cause of sudden cardiac death among athletes in a US- the routine work-up of all DCMs. Cardiac MRI and
based registry data.18 The most common cause of acute
ol
endomyocardial biopsy7 have important role in evaluation

myocarditis is lymphocytic myocarditis secondary to viral and decision making in recent-onset heart failure where
di
pathogenesis. Common viral etiologies include parvovirus myocarditis is suspected and deserve special mention
B19, adenovirus, coxsackie B virus, human herpes virus (Figure 2). Cardiac MRI has the capability to differentiate
ar
6, and other enteroviral infections. 19,20 Bacterial and ischemic from nonischemic causes of cardiomyopathy.
protozoal infections may also be causative but are fairly The diagnostic cardiac MRI feature of acute myocarditis
uncommon. Besides infective causes, other causes include
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can vary from focal to a diffuse involvement that can

immune disorders, hypersensitivity reactions, and toxins. resolve with clinical resolution on clinical follow-up.
Myocarditis remains the most common cause of pediatric The presence of late gadolinium enhancement in the
DCM. Different clinical presentations with variable myocardium is a predictor of subsequent risk of ventricular
natural histories have been defined: fulminant, acute, arrhythmias and cardiovascular death. Thus, cardiac MRI
and chronic active and chronic persistent.21 However, the has an important role in diagnosis and risk stratification in
overall prognosis of patients with myocarditis remains cases of myocarditis. It may also help in gauging recovery.
similar to idiopathic DCM. In a recent case series of Endomyocardial biopsy has remained unpopular due
histopathologically confirmed myocarditis, 1 year and 5 to its invasive approach, poor sensitivity (only 10 to 22%
year survival rates were 79% and 56%, respectively.22 Other on the basis of gold standard histological Dallas criteria)
causes of inflammatory involvement of the heart include and uncertainty regarding the use of viral genome
infective and autoimmune involvement of the heart analysis and immonuperoxidase staining. However,
and rarely toxin induced. Of thes,e Takayasu arteritis, it may change prognosis or management in 20–25%
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SECTION
Table 2: Evaluation of DCM
8 Detailed history and physical examination
Biochemical evaluation
Cardiomyopathy
Routine blood investigations, creatine kinase, thyroid function tests, calcium and phosphate levels, HIV, antinuclear antibodies and iron
studies
Biomarker evaluation
BNP (brain natriuretic peptide), NT-ProBNP (diagnosis of acute heart failure, prognostic marker)
Cardiac troponin (prognostic marker)
Electrocardiogram
Specifically look for left bundle branch block (LBBB), myocardial ischemia and arrhythmias
Echocardiography (forms the cornerstone of diagnosis)
a
Rule out pressure overload and volume overload states
Look for ventricular size, mechanical dyssynchrony, mitral regurgitation, presence of intracardiac thrombus, speckling pattern in myocardium
di
(suggestive of infiltrative disorders)
Consider 3D echo and strain imaging to detect early LV dysfunction (especially when chemotherapy-induced cardiotoxicity suspected)
In
Holter monitoring (if indicated)
Screen for tachyarrhythmias when suspected
Look for burden of ectopic beats and atrial fibrillation
May help in risk stratification
of
Electrophysiological study (if indicated after Holter study)
Coronary angiography (Invasive or CT)

Consider in all patients >30 years of age to rule out coronary artery disease
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Endomyocardial biopsy
Consider in cases with acute fulminant heart failure or cases not responding to standard medical therapy for 3 months
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Helps identifying inflammatory cardiomyopathy and some secondary causes like amyloidosis
Limitations include lack of adequate facilities for pathological and virological testing
Specialized investigations
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Cardiac MRI: Very useful for initial evaluation of DCM (see text)
PET scan: Confirms inflammatory focus in myocardium, helps gauge treatment
S
Genetic testing: Consider in familial cases and specific conditions like storage disorders
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biopsy is a class I indication in the setting of acute fulminant

heart failure where a diagnosis of giant cell myocarditis or
ic
acute lymphocytic myocarditis is suspected.13 Biopsy may

prove useful in infiltrative disorders like amyloidosis and
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hemochromatosis.
MANAGEMENT OF DCM
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Optimal medical therapy forms the cornerstone of

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management of DCM. However, it remains disheartening

that only a few drug therapies exist which have any mortality
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benefit in heart failure, with only one major addition

to the list in the past decade. Drugs that can improve
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survival include angiotensin-converting enzyme (ACE)

inhibitors, angiotensin receptor blockers (ARBs), beta-
Figure 2: Role of cardiac MRI and endomyocardial biopsy in acute blockers, aldosterone antagonists, and now angiotensin
heart failure13 receptor-neprilysin inhibitor (ARNi). Diuretics and
Abbreviations: COR, class of recommendation; digoxin are added commonly for symptomatic relief.
LOE, level of evidence
The effect of ACE inhibitors is a class effect with clinical
data suggesting similar benefit with various agents. ARBs
of patients with unexplained DCM with high-grade have been shown to be effective in heart failure patients
heart block or ventricular tachyarrhythmias. Specific who fail to tolerate ACE inhibitors. Beta-blockers may be
forms of myocarditis including giant cell myocarditis, somewhat more effective with a meta-analysis of 21 trials
granulomatous and eosinophilic myocarditis that respond demonstrating a 39% reduction mortality over a median
well to immunosuppressive therapy can be readily treatment for 6 months (3.8 lives saved for 100 patients
diagnosed on endomyocardial biopsy.7 Endomyocardial treated over 1 year). 23 However, not all beta-blockers
452
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are equally effective with trials showing benefit only CHAPTER
with metoprolol succinate, bisoprolol, and carvedilol.
Out of these three agents, carvedilol remains the most
extensively studied. The question whether ACE inhibitor
55

or a beta blocker should be started first was addressed in
Cardiac Insufficiency Bisoprolol Study-III (CIBIS-III) trial
and both strategies were found to be similar.24 However,
the current guidelines recommend starting with an ACE
inhibitor followed by addition of beta blocker except in
patients who have tachycardia as a prominent clinical
feature. Mineralocorticoid receptor antagonists including
a
spironolactone and eplerenone have also been found to be
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effective with around 30% additional mortality reduction
in Randomized Aldactone Evaluation Study (RALES) and
In
Efficacy and Survival Study (EPHESUS) trials.25,26 The latest
addition to the armamentarium of mortality-reducing
agents is valsartan/sacubitril combination (ARNi) and
of
shows promise for further improvement in outcomes.
Figure 3: General medical management flowchart for DCM
In the Prospective Comparison of ARNi with ACEi to
Determine Impact on Global Mortality and Morbidity in
ty
Heart Failure (PARADIGM-HF) trial, ARNi reduced the Thus, there remains an unmet need of randomized
all-cause mortality by 16% in comparison to enalapril.27 prospective trials for evaluating the role of viral antigen
18 cie
However, in significant number of patients, because of
borderline blood pressure, the optimal doses of drugs
testing and immunosuppressive therapy in various forms.
Immunosuppressive therapy still remains strongly in
consideration in cases of giant cell myocarditis, cardiac
either could not be achieved or could be achieved only
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in a gradual sequential manner. Another drug which can sarcoidosis, and eosinophilic myocarditis.
be of help to control tachycardia after optimal dose of
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beta-blockers has been achieved is ivabradine. Although Device Therapy in Heart Failure
digoxin failed to produce any mortality benefit in heart Cardiac resynchronization therapy (CRT) targets
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failure in carefully conducted Digitalis Intervention ventricular dyssynchrony to improve outcomes. The
Group (DIG) trial, it did demonstrate morbidity benefit presence of ventricular dyssynchrony secondary to
ic
in terms of reduced hospitalizations. 28 However, it conduction delays is a mechanical disadvantage as it

remains notorious for narrow therapeutic window and worsens mitral regurgitation, ventricular filling, and
og
sudden cardiac death. Atrial fibrillation, ischemic stroke, paradoxical septal motion. About 20–30% of symptomatic
transient ischemic attack, and peripheral or pulmonary patients with DCM have significant dyssynchrony
embolism form the indications for oral anticoagluants. diagnosed with a QRS duration of more than 120 ms on
ol
Directly acting oral anticoagulants are now preferred over the electrocardiogram and may be candidates for CRT.
coumarin derivatives for this indication. Currently, left bundle branch block (LBBB) morphology
di
Role of immunosuppressive therapy in DCM due and QRS duration >150 ms form the most robust
to myocarditis remains controversial due to lack of indication for CRT.33 A 10% reduction in mortality with
ar
prospective randomized trials and mixed results from CRT over medical therapy has been demonstrated in
the retrospective analysis. Individual trials and a meta- cardiac resynchronization-heart failure (CARE-HF) trial.34
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analysis suggest that immunosuppression may not be including patients with narrower complexes (120–150
helpful for improving long-term outcomes in acute ms) and right bundle branch block (RBBB) morphology
lymphocytic myocarditis. 29 However, a recent Tailored is generally not useful. Among them, identifying patients
Immosuppression in Inflammatory Cardiomyopathy expected to have favorable outcomes with CRT remains an
(TIMIC) study trial, a combination of steroid and active area of research.
azathioprine was found to be effective in cases of acute Implantable cardioverter defibrillator (ICD) and its
myocarditis with virus negative inflammatory findings combination with CRT (CRT-D) help to reduce sudden
on biopsy.30 In our own experience of endomyocardial cardiac deaths. Patients with ejection fraction (EF) <35%
biopsy proven myocarditis, immunosuppressive therapy and New York Heart Association (NYHA) class II or III
was helpful in 16 out of 20 patients given this therapy symptoms with expected survival over 1 year are candidates
(Figure 3).31 The role of intravenous immunoglobulin for ICD. 33 The initial trials including Defibrillators in
(IVIg) therapy remains doubtful with a study of patients Nonischemic Cardiomyopathy Treatment Evaluation
with recent-onset DCM showing negative results. 32 (DEFINITE) and Sudden Cardiac Death in Heart Failure
453
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SECTION Trial (SCD-HeFT) in the DCM cohort showed mortality Mechanical Circulatory Support
benefit of ICD over medical therapy.35,36 However, with
8
Due to scarcity of donor hearts, the numbers of patients
application of contemporary optimal medical therapy awaiting heart transplant continue to rise. Mechanical
DANISH [Danish Study to Assess the Efficacy of ICDs circulatory support was introduced as a bridge to
Cardiomyopathy
(Implantable Cardioverter–Defibrillators) in Patients transplantation for short-term support in sick patients.

with Non-ischemic Systolic Heart Failure on Mortality] However, with realization of good survival and quality
trial failed to show improvement in all-cause mortality of life with ventricular assist devices (VADs), they are
with ICD raising doubts in its usefulness in patients with being increasingly used as destination therapy. 43 Latest
non-ischemic ventricular dysfunction.37 This has opened generation implantable VADs, such as HeartMate 3, have
a new domain of research for identifying patients at high demonstrated excellent results with 86.2% survival at 6
risk of sudden cardiac death where ICD would be most
a
months in clinical trials.44 The major obstacle for the use of
beneficial. Age more than 75 years, left ventricular ejection VADs in Indian setting remains its prohibitive cost.
di
fraction (LVEF) less than 20%, diabetes mellitus, chronic
kidney disease, and NYHA class III heart failure have
Regenerative Therapy
In
long been recognized as risk markers for sudden cardiac
death.38 Recently, mid-wall late gadolinium enhancement The majority of research for stem cell therapy has focused
on cardiac MRI has been found to be a robust risk marker onheart failure secondary to ischemic LV dysfunction.
of
for sudden cardiac death. Genetic markers are currently Even though the initial trials were encouraging, larger
being evaluated for risk assessment and may play an trials conducted lately have been dismal. An Indian
important role in future.39 study also failed to show benefit of stem cell therapy in
ty
post-acute ST elevation myocardial infarction patients. 45
A recent meta-analysis of 38 trials showed only low
Heart Transplantation
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Advanced heart failure with predicted 1-year survival
less than 50% forms the general indication for heart
quality evidence of some benefit of stem cell therapy in
ischemic heart failure.46 The DCM patients are different
from ischemic LV dysfunction in terms of lesser amount
transplantation. 40 Candidates for heart transplant
20 o
of scar and lesser amount of transmural involvement.
usually have severe symptoms (NYHA class III-IV Small open labeled randomized trials for efficacy of stem
S
dyspnea associated with significant fluid retention and cell therapy in DCM have shown encouraging results.47,48
recurrent episodes of acute decompensation requiring In a trial of 110 patients, intracoronary stem cell therapy
al
hospitalizations). Matching in heart transplantation with CD34 + cells (collected via peripheral blood after
is based on ABO compatibility. Advanced irreversible apheresis) conferred an increase in LVEF and a decrease
ic
damage of kidney, liver and lung parenchyma; severe in BNP levels which was sustained at 5 years as compared
irreversible pulmonary arterial hypertension; and other to placebo therapy. 47 Larger good quality randomized
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solid organ or hematologic malignancies are considered trials are awaited in this promising field and may change
absolute contraindications due to poor survival even after the landscape of management for heart failure secondary
successful cardiac transplantation.41 The first successful to DCM.
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heart transplant in India was done on 3rd August 1994

by Dr P Venugopal at All India Institute of Medical SPECIFIC CONSIDERATIONS FOR COMMON
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Sciences, New Delhi. Since then, it has been a slow journey

SECONDARY ETIOLOGIES
with around 400 transplants done in India up till 2016.
ar
There has been a recent spurt in transplant programs in A complete discussion of DCM due to specific etiologies is
India which will help tackle the dismal problem of end- beyond the scope of discussion of this chapter. Only a few
important conditions causing secondary DCM are being
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stage heart failure in future. The lack of a unified organ

briefly discussed.
transplant network in India, lack of physician awareness,
and poor availability of donor hearts have been rate
limiting for transplant programs. Survival at high-volume Chronic Alcoholism
centers have been reported to be at the tune of 82% at 1 Chronic alcoholism is one of the important causes of
year after transplantation.42 Although promising, heart DCM in the Western populations. It is characterized by
transplantation is not without complications and requires biventricular dysfunction associated with heavy alcohol
long-term follow-up with involvement of significant intake which is defined as >80 g alcohol per day for more
finances. The need of immunosuppressive therapy, than 5 years and until <3 months before diagnosis of LV
monitoring rejection with recurrent endomyocardial dysfunction.49 The prognosis of alcoholic cardiomyopathy
biopsies, risk of infections, risk of malignancies, and is generally better than idiopathic DCM if there is complete
cardiac allograft vasculopathy on long-term follow-up alcohol abstinence. Approximately two-thirds patients
form hurdles to success of transplant program. remain clinically stable, and half of these patients have a
454
KG-55 (Sec-8).indd 454 03-11-2018 12:46:01

good LV function recovery. The other one-third of patients Peripartum Cardiomyopathy CHAPTER
have poor prognosis leading to death or transplantation.50
55
Peripartum cardiomyopathy (PPCM) is defined as
In individuals who continue to drink, the prognosis is development of LV dysfunction in the last month of
poor with a mortality rate of up to 50% at 3–6 years. Lack pregnancy or within 5 months of postpartum period.

of abstinence, atrial fibrillation, QRS duration >120 ms, The entity is fairly uncommon with an incidence of
and lack of beta blocker use are poor prognostic markers.50 approximately 1 per 1000 live births.56 Advanced maternal
The importance of addressing nutritional deficiencies, age (>30 years), black race, pre-eclampsia, and multiple
especially folate and thiamine, cannot be overemphasized. fetal gestation are risk factors for developing PPCM.56 The
LVEF less than <30% at and LV end-diastolic diameter > 6.0
Anthracyclines cm are markers of poor prognosis.57 The risk of recurrence
a
Anthracyclines (doxorubicin, daunorubicin, mitoxan- with subsequent pregnancies remains significant which
trone, and epirubicin) are chemotherapeutic drugs that should be clearly avoided. The prognosis is variably
di
are commonly used in solid organ malignancies and reported from different regions of the world. In the
have a definite dose-related cardiotoxicity. At 400, 500 Investigations of pregnancy associated cardiomyopathy
In
and 550 mg/m 2 cumulative dose of doxorubicin, the (IPAC) study from the United States, approximately two-
probability of developing LV dysfunction is estimated at thirds of patients had complete recovery with only 13%
5%, 16%, and 26%, respectively.51 Thus, the conventional having major events.57 Registry data from Germany is also
of
cumulative dose limit for doxorubicin has been set at suggestive of recovery of LV function in up to on half of
400 mg/m2. However, there is no safe dose and highly the patients.58 However, in two studies from South Africa
and Turkey, there was complete recovery of LV function
ty
susceptible individuals can develop cardiotoxicity
even with the first dose or a lower cumulative dose. 52 in only 21% and 30% of the patients, respectively. 59,60
Research over the last decade has attributed risk of PPCM
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Historically, cardiotoxicity was usually detected at
later stages after development of heart failure and thus
was largely irreversible. With the regular screening in
to late gestational hormonal changes leading to vascular
dysfunction. A role of bromocriptine has been proposed
place, the large majority of patients facing cardiotoxicity for the management of PPCM. In a recent multicentric
20 o
have improvement in LV function with contemporary randomized trial, 1 week of bromocriptine therapy in
S
pharmacological therapy and prompt discontinuation of addition to standard heart failure therapy has shown to
cardiotoxic chemotherapy. An upcoming role of troponin improve outcomes in terms of complete recovery of LV
function.61 However, further studies are needed to clearly
al
being used for early detection of cardiac involvement in

postchemotherapy patients (especially anthracyclines) is define its role.
ic
being increasingly evaluated and deserves special mention.

According to a recent study, combining troponin level and Sarcoidosis
og
longitudinal strain imaging allowed better prediction of Sarcoidosis is an inflammatory disorder of unknown
cardiotoxicity in postchemotherapy patients.53 Pediatric etiology characterized by noncaseating granulomas
population is at higher risk of delayed development on histopathology. Lungs are the most common organ
ol
cardiotoxicity after many years. Efficient screening, early involved being affected in more than 90% of the cases.
detection, prompt discontinuation of cardiotoxic drug, Carefully ruling out tuberculosis before labeling a
di
and administration of optimal medical therapy (ACE diagnosis of sarcoidosis is essential. Clinical cardiac
inhibitors and beta-blockers) form the cornerstone of involvement is uncommon and is seen in only up to
ar
management of anthracycline cardiotoxicity. Preventive 5% of the cases. Asymptomatic cardiac involvement is

therapies include restricting dose of anthracycline, giving seen; however, in up to 25% of the cases.62,63 Conduction
C
it in divided doses, using infusions over boluses and disturbances, ventricular tachyarrhythmias, and heart
modifying pharmacokinetics with the use of liposomal failure are the three principal manifestations of cardiac
formulation.54 Desrazoxane is the only Food and Drug involvement. A suspicion should be borne in mind when
Administration (FDA)-approved agent for prevention of a young to middle-aged individual presents with heart
anthracycline-induced cardiotoxicity when higher doses failure associated with ventricular tachyarrhythmias or
are required. Small studies with short-term follow-up conduction disturbances. In the presence of systemic
have demonstrated benefit with beta-blockers and ACE involvement, the diagnosis can be usually made with
inhibitors. Although not widely used, a combination of beta the application of usual criteria. However, diagnosis may
blocker and ACE inhibitor may even be more beneficial remain elusive in a case of isolated cardiac sarcoidosis.
than individual agent when used in a preventive manner Cardiac MRI, PET scan and endomyocardial biopsy help
in patients at high risk of cardiotoxicity.55 However, these in forming a definitive diagnosis. In our experience of
findings need to be tested in larger randomized controlled seven patients with recent-onset heart failure associated
trial before definitive recommendations can be made. with ventricular arrhythmias, cardiac MRI followed by
455
KG-55 (Sec-8).indd 455 03-11-2018 12:46:02

SECTION intelligently done PET scan, CT scan, and endomyocardial adverse cardiovascular and cerebral events (MACCE) rate
biopsy helped to arrive at the final diagnosis.64 The role of of 9.9% at 1 year follow-up. At present, with no specific
8 high index of suspicion in such types of case holds the key
to further evaluation and diagnosis. Cardiac involvement
therapy for the condition, conservative management with
optimal medical therapy is all what can be offered. In a
Cardiomyopathy
is a common cause of death in sarcoidosis and prognosis retrospective analysis, the use of ACE inhibitors and not
of cardiac sarcoidosis is poor. In a historical case series, beta-blockers was associated with improved survival.68
survival was limited to approximately 2 years after the The role of medical therapy for improvement in long-
development of cardiac signs and symptoms.65 However, term prognosis remains to be prospectively studied in this
according to a more recent series of 250 patients, 44% difficult to manage subset of patients.
patients survived for more than 5 years after diagnosis of
cardiac sarcoidosis with proportion of 5-year survivors Tachycardiomyopathy
a
rising to 75% in the subgroup of 75 patients receiving
Tachycardiomyopathy is defined as ventricular dysfunction
di
corticosteroids. 66 Important predictors of mortality
secondary to rapid and/or asynchromous/irregular
include NYHA functional class, history of sustained
myocardial contraction, partially or completely reversed
In
ventricular tachyarrhythmia, and dilated LV cavity with
after treatment of the causative arrhythmia. 69 Factors
poor EF.67 Corticosteroids are the mainstay of treatment indicating a diagnosis include previously known normal
in sarcoidosis and other immunosuppressive agents EF, degree of LV dysfunction out of proportion to other
of
(e.g. methotrexate, azathioprine and mycophenolate comorbidities, ruling out other common causes of DCM,
mofetil) are required when there is steroid intolerance or relatively normal LV dimensions, and most importantly
dependence. reversal of LV dysfunction with treatment of arrhythmia.
ty
It is often difficult to ascertain whether the arrhythmia
Stress-induced Cardiomyopathy or Takotsubo is a cause or effect of myocardial dysfunction; and it is
Cardiomyopathy 18 cie
S t r e s s - i n d u c e d c a r d i o m y o p a t h y o r Ta k o t s u b o
not uncommon to make a diagnosis retrospectively after
control of arrhythmia. Tachycardiomyopathy can occur
cardiomyopathy refers to acute LV dilatation and at any age and may also involve a fetus. Atrial fibrillation
20 o
dysfunction triggered by acute intense emotional or is the most common cause, others being atrial flutter,
supraventricular tachycardias, frequent ventricular
S
physical stressors. It accounts for approximately 1–2% of

all cases of acute ST elevation myocardial infarction with a ectopics, asynchronous activation with an accessory
predilection towards female sex (sex ratio of 9:1) and elderly pathway, and also high burden of ventricular pacing
al
age group (mean age 66.8 years).68 Now more commonly after a permanent pacemaker implant. The minimal
recognized in intensive care units, it can be triggered ventricular ectopic burden that seems to be associated
ic
due to various acute medical illnesses including acute with tachycardiomyopathy is 10% and the likelihood
exacerbations of bronchial asthma, septic shock, acute increases as the burden increases. 70 In young children,
og
neurological states, and after major surgical procedures. supraventricular tachycardia particularly persistent
According to a contemporary registry data, approximately junctional reciprocating tachycardia (PJRT) and ectopic
atrial tachycardia (EAT) are known to be associated with
ol
one-third of the patients have physical triggers, another

one-third of patients have emotional triggers, and no tachycardiomyopathy. 71,72 Catheter ablation wherever
possible or rhythm control with antiarrhythmics have been
di
trigger could be identified in the remaining one-third of

patients.68 Diagnosis is established with demonstration of shown to effect complete reversal of LV dysfunction.72 The
importance of tachycardiomyopthy lies in its recognition
ar
regional wall motion abnormalities extending beyond a

as a reversible cause of DCM. Control of underlying
one coronary artery segment or a typical apical ballooning
arrhythmia is the treatment of choice and the condition is
with basal hyperkinesis picture, electrocardiographic
C
associated with a good outcome.

changes, elevated troponin, and most importantly no
significant obstructive coronary artery disease on coronary
angiogram. Patients who survive the initial phase of acute CONCLUSION
heart failure usually recover their LV function within four DCM with heart is a fairly common problem with a dreaded
weeks. Although better than acute coronary syndrome, prognosis. Ruling out secondary causes forms the basis of
the prognosis of Takotsubo cardiomyopathy is not as evaluation before labeling the disease idiopathic. The role
benign as previously contemplated. Serious in hospital of genetic studies is being increasingly recognized and
complications may be seen in around 20% of the patients may form an integral part of evaluation in future. Cardiac
including cardiogenic shock, ventricular tachycardia, MRI and endomyocardial biopsy have important role with
ventricular thrombus formation, ventricular rupture, and therapeutic implications in myocarditis and recent-onset
death.68 Older age, female sex, and emotional triggers heart failure with DCM. Although prognosis of DCM has
are associated with a better overall prognosis. Recent improved with principles of medical management, it still
456 long-term follow-up data also suggests a high major remains dismal. Further advances in medical management
KG-55 (Sec-8).indd 456 03-11-2018 12:46:02

are not much expected in the near future with multitude Council on Cardiovascular Disease in the Young; Council CHAPTER
of therapies failing to show benefit and only one new on Cardiovascular and Stroke Nursing; Council on
addition to the medical toolkit in the past 2 decades. The
focus has now shifted more towards preventive strategies
Epidemiology and Prevention; and Council on Quality
of Care and Outcomes Research. Current diagnostic and
55
treatment strategies for specific dilated cardiomyopathies:

rather than a therapeutic one. Outcomes of end-stage
a scientific statement from the American Heart Association.
heart failure continue to improve with application of
Circulation. 2016;134(23):e579-646.
device therapy and heart transplantation. Stem cell 14. Hershberger RE, Hedges DJ, Morales A . Dilated
therapy seems promising; however, it awaits scrutiny in cardiomyopathy: the complexity of a diverse genetic
larger trials before clinical application. architecture. Nat Rev Cardiol. 2013;10(9):531–47.
15. Jansweijer JA, Nieuwhof K, Russo F, et al. Truncating titin
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Genetics of Cardiomyopathies:
CHAPTER 56 An Overview
Ajay Bahl
a
di
INTRODUCTION induced cardiomyopathy, and Takotsubo cardiomyopathy.
Cardiomyopathies are heart muscle diseases usually The European Society of Cardiology (ESC) working group
In
associated with ventricular hypertrophy, dilatation or classification, though more clinically oriented, also gives
increased wall stiffness. They commonly have a genetic importance to genetics.
basis. The genetics, however, is complex with a large As stated earlier, a large number of mutations are
of
number of mutations spread across a number of cardiac responsible for causing cardiomyopathies. This great
sarcomeric and cytoskeletal protein-encoding genes. diversity in mutations is because of the founder effect.
A founder is an individual in whom a de novo mutation
ty
Large numbers of novel mutations are being regularly
reported. In view of the diverse mutation profile, it is occurs. Both mother and father of this individual have
a wild type genotype and do not carry the mutation.
18 cie
important to understand the general principles of genetics
in respect to disease pathophysiology as well as in its
clinical application in individual patients. This review will
This founder thus has a 50% chance of transmitting the
mutation to his or her offspring. With passage of time and
largely discuss the principles and highlight the common generations, this mutation may spread to involve a large
20 o
disease-causing genes. number of individuals, all being descendants of this one
founder. Sequence variations that have recent founder
S
(only a few generations) will have only a small number of

GENERAL PRINCIPLES carriers restricted to a single family, whereas those that
al
On genotyping, mutations are identified in 20–35% of occurred in the remote past may have a large number of
patients with dilated cardiomyopathy (DCM), 50–60% in carriers. This is best exemplified by a 25 base pair deletion
ic
hypertrophic cardiomyopathy (HCM), 33–66% of those in intron 32 of the cardiac myosin-binding protein-C gene
with idiopathic restrictive cardiomyopathy (RCM) and (MyBPC3). This deletion results in skipping of exon 33.
og
50–60% of those with arrhythmogenic right ventricular Though the role of this deletion in the direct causation of
cardiomyopathy (ARVC). In addition, Fabry disease, cardiomyopathies is not clear, it likely has a modulatory
Noonan syndrome, and left ventricular noncompaction effect. The risk of heart failure is increased in deletion
ol
are also genetic disorders. On the other hand, myocarditis, carriers with an odds ratio of 7. This deletion likely arose
peripartum cardiomyopathy, alcoholic cardiomyopathy, in a single individual around 23,000–33,000 years back.
di
and endomyocardial fibrosis are common nonfamilial Over hundreds of generations, this deletion has spread to
cardiomyopathies. Thus, majority of cardiomyopathies involve millions of individuals and is now present in over
ar
are genetic disorders that usually follow an autosomal 4% of the Indian population.
dominant pattern of inheritance. Genetic assessment Even though each individual cardiomyopathy is
C
forms an important part of patient management. commonly caused by mutations in a few specific genes,
The importance of genetics is reflected in the current the prevalence of individual mutations within a gene will
classifications. The American Heart Association (AHA) vary in different populations due to the founder effect.
classifies primary cardiomyopathies as genetic, mixed, Since there are a large number of founders, the spectrum
and acquired disorders. Genetic cardiomyopathies of mutations causing cardiomyopathies is also large. Due
are those that are purely genetic disorders and include to the founder effect, with each founder carrying a specific
HCM, ARVC, mitochondrial myopathies, left ventricular mutation, the spectrum of mutations varies in different
noncompaction, and glycogen storage disorders. Mixed population groups.
disorders are those which are due to genetic as well as Several mutations causing cardiomyopathies have
acquired causes. These include DCM and RCM. Acquired been reported in different population groups spread
cardiomyopathies include disorders that are purely across continents. The same mutations may occur
acquired and do not have a genetic basis. These include independently, just by chance in several unrelated
myocarditis, peripartum cardiomyopathy, tachycardia- individuals who would be founders for their own group.
KG-56.indd 460 03-11-2018 12:45:33

The same mutation would then spread independently in significance of most of these sequence variations has CHAPTER
different populations. There are several genetic hotspots not kept pace with the genotyping technology. Even if
in the genome that are prone to developing mutations.
Mutations are especially common at these hotspots.
we identify a sequence variation, we may not be certain
whether it is pathogenic or benign. One of the major
56

Another reason could be migration and thus intermingling reasons is the paucity of a large clinical database for most
of populations. of the sequence variations.There are several sequence
The HCM, DCM, and RCM can all be caused by variations that are clinically well characterized. For most
mutations in genes encoding sarcomeric proteins sequence variations, however, there are at the most a few
suggesting that these are overlapping disorders. However, case reports. It may not be possible base clinical decisions
there are differences between them. For example, on these sequence variations. This is best exemplified by
idiopathic RCM is most commonly due to mutations in the titin (TTN) gene. TTN is a huge gene which has 364
a
troponin I (TNNI3) and beta-myosin heavy chain (MYH7) exons. This is the largest number of exons in any gene.
di
genes with TNNI3 being reported in around half of the Screening TTN using conventional Sanger sequencing
patients in whom mutations are detected. In contrast, was cumbersome and time consuming. Thus, systematic
In
though TNNI3 mutations also cause HCM, they are screening of this gene in cardiomyopathy patients was not
reported in only 3% of HCM patients. MYH7 mutations, carried out earlier. With the availability of next generation
however, are common in both HCM as well as RCM. sequencing, TTN has been screened for mutations and has
of
Since cardiomyopathies commonly are inherited been found to be the most common gene responsible for
disorders, the management should involve not only DCM. Some of these sequence variations may be benign
the patient but the entire family. The patient should and not disease causing. Therefore, though we have been
ty
be counseled to discuss the disease with his family. All able to detect a large number of sequence variations, we
first-degree relatives should be offered counseling and are not clear about their pathogenicity and disease profile.
18 cie
screening. Clinical screening usually involves a detailed
history and examination, ECG, echocardiography, and
exercise testing. History alone is unreliable in picking up
Genotyping is most useful if it is used to answer
a specific clinically relevant question. For example, a
family has cardiomyopathy with a severe phonotype.
familial cardiomyopathy; for example, in DCM, a positive
20 o
The family wants to know if a young child will develop
family history can be elicited in only 2–6% patients. cardiomyopathy in future. The only way to answer this
S
Echocardiographic screening of first-degree relatives question is to identify the disease-causing mutation in

will identify at least one more affected family member this family. If this child does not carry the mutation, he
al
in as many as 20–35% patients. Clinical screening is the will not be at risk of developing cardiomyopathy in future.
simplest, but has its limitations. A normal clinical screen A few pitfalls need to be considered. Firstly, a definite
only indicates that the family member does not have
ic
disease-causing mutation needs to be identified in the

disease at the time of screening. Cardiomyopathies have family. Secondly, a possibility of a second disease-causing
og
an age-related penetrance with some patients developing mutation also has to be kept.
disease only in the seventh decade of life. A normal clinical There are a large number of genes in whom mutations
evaluation does not eliminate the risk of developing can cause cardiomyopathies. Most of these are rare.
ol
the disease in future. Thus, clinical screening needs to Some of the important genes involved in different
be repeated at regular intervals. Genotyping, however, cardiomyopathies are highlighted in Table 1.
di
is useful in predicting future risk. A few decades back,

genotyping involved conventional Sanger sequencing.
DILATED CARDIOMYOPATHY
ar
The disease-causing mutations were spread across

several genes. Thus, a large number of genes and exons Familial dilated cardiomyopathy (DCM) forms 20–35%
had to be screened. Sanger sequencing was, therefore, of nonischemic dilated cardiomyopathy and is caused by
C
time consuming and expensive. Recent availability of mutations in over 50 genes encoding sarcomere, Z band,
next generation sequencing technologies has allowed costamere, nuclear membrane and other proteins. These
rapid screening of a large number of genes for mutations are most commonly transmitted in an autosomal dominant
and has markedly brought down the cost of genotyping. pattern. The X-linked recessive mutations in dystrophin,
Screening 100 odd genes for mutations is now feasible in emerin, and tafazzin can also cause DCM. Rarely, DCM
a clinical setting and is available in India. Clinicians who may be due to mitochondrial mutations or transmitted
manage patients with cardiomyopathies must have an in an autosomal recessive pattern. Mutations inTTN
understanding of the available genotyping technologies. mutations are by far the most common and are reported
G e n o t y p i n g a l s o h a s i t s l i m i t a t i o n s. R a p i d in 18% of sporadic and 25% of familial DCM patients. Titin
advancements in technology has enabled us to reliably mutations are commonly protein-truncating mutations.
and rapidly screen a large number of genes for sequence This is unlike other genes where missense mutations are
variations. Unfortunately, our understanding of the by far the most common. Truncating TTN mutations are
461
KG-56.indd 461 03-11-2018 12:45:33

SECTION Table 1: List of genes that are commonly involved in causing cardiomyopathies. Although the list is long with mutations in over 50
genes causing DCM, only the common ones are highlighted in this table
8 Dilated cardiomyopathy
Titin (TTN)*
Idiopathic restrictive cardiomyopathy
Troponin I (TNNI3)*
Cardiomyopathy
Beta-myosin heavy chain (MYH7) Beta-myosin heavy chain (MYH7)*

Dystrophin
Lamin A/C
Hypertrophic cardiomyopathy Arrhythmogenic right ventricular cardiomyopathy
Beta-myosin heavy chain (MYH7)* Plakophilin 2 (PKP2)*
Cardiac myosin binding protein C gene (MyBPC3)* Desmoglein-2 (DSG2)
Troponin I (TNNI3) Desmocollin-2 (DSC2)
Troponin T (TNNT2) Desmoplakin (DSP)
Plakoglobin (JUP)
a
Transmembrane protein-43 (TMEM43)
di
*By far the most commonly involved genes.
In
much less common in patients with HCM suggesting that IDIOPATHIC RESTRICTIVE CARDIOMYOPATHY
these mutations predispose to the DCM rather than the Idiopathic restrictive cardiomyopathy (RCM) is a common
HCM phenotype. TTN mutations have also been reported
of
cause of RCM, especially in young individuals. There is an
in patients with ARVC. Other genes commonly involved in etiologic and morphological overlap between idiopathic
DCM are MYH7, dystrophin, and lamin A/C. Patients with RCM and HCM. Both are disorders of diastolic dysfunction
lamin A/C mutations are at high risk of arrhythmias and
ty
and histological features, such as myocardial fibrosis and
sudden death. myocyte disarray, are seen in both disorders. Genotyping
HYPERTROPHIC CARDIOMYOPATHY 18 cie

The diagnostic yield of genotyping in hypertrophic
identifies mutations in one-third to two-thirds of cases.
Though mutations in several sarcomeric genes and
titin cause RCM, these are commonly identified only in
2 sarcomeric genes—MYH7 and TNNI3. While MYH7
20 o
cardiomyopathy (HCM) patients is reported to be 30–60%
in different studies. Comprehensive screening using next mutations are also common in HCM, a high prevalence of
S
generation sequencing will identify mutations in over 50% TNNI3 mutations is a unique feature of idiopathic RCM.
cases. HCM is commonly caused by mutations in genes Desminopathies are a rare cause of RCM associated with
al
encoding cardiac sarcomeric proteins. Of these, mutations atrioventricular blocks and are caused by mutations in
in MYH7 and MyBPC3 genes are most common and desmin and alpha-B crystalline genes.
ic
account for 50% of HCM cases. Cardiac troponin T (TNNT2)

and TNNI3 mutations account for around 3% cases each. ARRHYTHMOGENIC RIGHT VENTRICULAR
og
In addition, mutations in genes encoding Z-disc proteins, CARDIOMYOPATHY

such as titin, muscle LIM protein (MLP), and myozenin 2,
Mutations are identified in around 50–60% of arrhyth-
account for a small number of HCM cases. There are some
mogenic right ventricular cardiomyopathy (ARVC)
ol
genetic storage disorders that mimic HCM. Most common

patients. The mutations most commonly occur in genes
among these is Fabry disease, an X-linked disorder caused
encoding desmosomal genes. Of these, mutations most
di
by mutations in the a-galactosidase gene and is thus far

commonly involve the plakophilin 2 (PKP2) gene.
more common in males. Glycogen storage disorders also
Mutations in other desmosomal genes—desmoglein-2
ar
mimic HCM. These are rare disorders caused by mutations

(DSG2), desmocollin-2 (DSC2), desmoplakin (DSP),
in the gamma subunit of adenosine monophosphate
and plakoglobin (JUP) also cause ARVC. Mutations
(AMP)-dependent protein kinase (PRKAG2) gene and the
C
in nondesmosmal genes, such as those encoding

lysosome-associated membrane protein 2 (LAMP2) gene.
transmembrane protein-43 (TMEM43) and transforming
The disease phenotype cannot be predicted simply
growth factor-β (TGF-β), are responsible for a small
from the identified mutation since the genotype-
number of cases.
phenotype correlation is often poor. A few generalizations
can be made about mutations in specific genes, but
these specific phenotypes may not be present in a large INDIAN CONTEXT
number of mutation carriers. These are late-onset disease The genes responsible for causing cardiomyopathies are
in MyBPC3 mutations, high risk of sudden death despite the same in Indians as in other ethnic groups. Due to our
mild hypertrophy in TNNT2 mutations, and restrictive own unique founders, however, frequencies of different
phenotype in TNNI3 and MYH7 mutations. MYH7 mutations will be different. Many mutations in Indians
mutations have a variable phenotype with some patients are novel in that they have not been previously reported.
having a benign course, while others are at high risk of Most mutations, however, will be the same as those in
462 sudden death. other populations. One of the unique sequence variations
KG-56.indd 462 03-11-2018 12:45:33

in Indians is a 25 base pair deletion in intron 32 of the prevalence and genotype-phenotype correlations. PLoS CHAPTER
MyBPC3. It is present in millions of Indians and involves One. 2017;12(1):e0169007.
the entire country except the north east and some ethnic 5. Herman DS, Lam L, Taylor MR, et al. Truncations of
titin causing dilated cardiomyopathy. N Engl J Med.
56
populations of Andaman Islands. This sequence variation

2012;366(7):619-28.
predisposes an individual to cardiomyopathies and heart
6. Kubo T, Gimeno JR, Bahl A, et al. Prevalence, clinical
failure.
sig n i f i ca n c e, a n d g e n e t i c b a si s o f hy p e r t ro p h i c
cardiomyopathy with restrictive phenotype. J Am Coll
CONCLUSION Cardiol. 2007;49(25):2419-26.
Mo s t c a rd i o my o p a t h i e s a re g e n e t i c d i s o rd e r s. 7. Maron BJ, Towbin JA, Thiene G, et al. Contemporary
Understanding the basic principles of genetics and current definitions and classification of the cardiomyopathies:
a
genotyping technologies is important for any clinician an American Heart Association Scientific Statement
from the Council on Clinical Cardiology, Heart Failure
who manages patients with cardiomyopathies.
di
and Transplantation Committee; Quality of Care and
Outcomes Research and Functional Genomics and
SUGGESTED READING
In
Translational Biology Interdisciplinary Working Groups;
1. Bahl A, Saikia UN, Khullar M. Idiopathic restrictive and Council on Epidemiology and Prevention. Circulation.
cardiomyopathy - perspectives from genetics studies. 2006;113(14):1807-16.
of
Is it time to redefine these disorders? Cardiogenetics. 8. Rai TS, Ahmad S, Ahluwalia TS,et al. Genetic and
2012;2:15-8. clinical profile of Indian patients of idiopathic restrictive
2. Dhandapany PS, Sadayappan S, Xue Y, et al. A common cardiomyopathy with and without hypertrophy. Mol Cell
ty
MYBPC3 (cardiac myosin binding protein C) variant Biochem. 2009;331(1-2):187-92.
associated with cardiomyopathies in South Asia. Nat Genet. 9. Richardson P, McKenna W, Bristow M, et al. Report of the
2009;41(2):187-91.
18 cie
3. Elliott P, Andersson B, Arbustini E, et al. Classification of the
cardiomyopathies: a position statement from the European
1995 World Health Organization/International Society
and Federation of Cardiology Task Force on the definition
and classification of cardiomyopathies. Circulation.
Society of Cardiology Working Group on Myocardial and 1996;93(5):841-2.
20 o
Pericardial Diseases. Eur Heart J. 2008;29(2):270-6. 10. Taylor MR, Fain PR, Sinagra G, et al. Natural history of
S
4. Franaszczyk M, Chmielewski P, Truszkowska G, et al. dilated cardiomyopathy due to lamin A/C gene mutations.
Titin truncating variants in dilated cardiomyopathy - J Am Coll Cardiol. 2003;41(5):771-80.
al
ic
og
ol
di
ar
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KG-56.indd 463 03-11-2018 12:45:33

Noninvasive Evaluation of
Suspected Heart Muscle
CHAPTER 57
Disease
Krishnam Raju P, Chandramukhi Sunehra
a
di
Heart muscle disease includes varied myocardial scarring/fibrosis or inflammation is suspected as the
disorders with structural and functional abnormalities of cause of myocardial disorder.
In
myocardium not contributory to hypertension, coronary The objectives of imaging modalities in cardiomyopathy
artery disease, valvular heart disease, or congenital heart are as follows:
disease. There has been substantial improvement in the Diagnosis: Evaluation of characteristic morphological
of
clinical identification and management of myocardial and functional features of cardiomyopathy and
disorders as a result of utilization of advanced cardiac defining the etiology and differential diagnosis
imaging modalities. The classification of a disorder Treatment: (1) Exclusion of reversible or treatable
ty
facilitates the clinical recognition and understanding causes of myocardial abnormalities (e.g. valvular
of the etiopathogenesis. Arbustini et al.1 proposed the heart disease, ischemia). (2) Detection of intracardiac
18 cie
MOGE(S) classification for cardiomyopathy in 2013. Each
letter in the MOGE(S) classification has well-defined
thrombus for anticoagulation. (3) Detection of severe
left ventricular systolic dysfunction for selection
subscripts, which provide details. In this classification M of candidates for intracardiac defibrillator (ICD)
20 o
indicates phenotype, e.g. dilated cardiomyopathy (DCM) implantation and cardiac resynchronization therapy
and restrictive cardiomyopathy (RCM), O indicates
S
(CRT). (4) Identification of candidates requiring heart

organ involvement (e.g. with/without extracardiac transplant
involvement), G indicates transmission (e.g. autosomal P ro g n o s i s : P ro g n o s t i c ma rke r s— ( 1 ) Ca rd i a c
al
dominant or recessive), E indicates pathogenesis (e.g. chamber dimensions—dilatation, (2) Systolic and
genetic with disease gene and mutation, if known), and diastolic function assessment, (3) Hemodynamic
ic
S indicates disease stage. WHO classified myocardial evaluation—intracardiac and pulmonary artery
diseases as primary and secondary cardiomyopathies.2 pressure assessment, stroke volume and cardiac
og
Primary cardiomyopathies include myocardial diseases output calculation, (4) Valvular function—regurgitant
which occur without any identifiable etiological agent, lesions, (5) Intracavitary thrombus, (6) Remodelling:
(e.g. idiopathic), and are related to a primary myocardial myocardial hypertrophy, scarring, thinning, regional
ol
abnormality. Secondary cardiomyopathies occur as a wall motion abnormalities, (7) Late gadolinium
result of systemic disorders which affect the myocardium. enhancement (LGE), (8) Nuclear imaging for the
di
Cardiac imaging plays a key role in the management assessment of radionuclide tracer uptake
of cardiomyopathies across all stages of the disease. Follow up: (1) Assessment of response to therapy. (2)
ar
Imaging is mandatory in the diagnosis and treatment of Assessment of functional parameters.

cardiomyopathy, assessment of the disease progression, Screening: Screening the family members in cases with
C
evaluation of response to therapy and screening the family

familial cardiomyopathy
members of the individuals with familial myocardial
disorder. Echocardiography is the basic fundamental
noninvasive imaging modality and offers cost effective, ECHOCARDIOGRAPHY
highly reproducible and comprehensive diagnostic tool. It Echocardiography, is a widely available and inexpensive
provides detailed morphological and functional analysis of basic imaging modality for diagnostic evaluation of patients
the myocardial disease. The advanced imaging modalities with suspected cardiomyopathy. Echocardiographic
like cardiac magnetic resonance imaging (CMR), cardiac evaluation of cardiomyopathy should include a compre-
computed tomography (CCT), and nuclear imaging hensive assessment utilizing two dimensional (2D)
provide additional information with incremental value imaging, motion (M) mode evaluation, color Doppler
that is complementary to echocardiography information. interrogation and Doppler assessment. In majority of
These advanced imaging modalities can be useful in patients 2D imaging and Doppler echocardiography
selected and more challenging cases where infiltration, can define the anatomic and functional characteristics
KG-57.indd 464 03-11-2018 12:45:12

that are diagnostic of dilated, hypertrophic, restrictive or risk group with a reduced event-free survival. PWD across CHAPTER
arrhythmogenic right ventricular cardiomyopathy. Newer left ventricular outflow tract (LVOT) is used to assess
echocardiographic techniques—tissue Doppler imaging
(TDI), strain rate imaging (SRI) and three-dimensional
the stroke volume and cardiac output. CWD across the
tricuspid regurgitation and pulmonary regurgitation gives
57

(3D) imaging can be aptly utilized for further refiningthe a measure of pulmonary artery pressure. Tissue Doppler
echocardiographic diagnosis. Various echocardiographic imaging derived velocities of the medial and lateral mitral
techniques for the evaluation of cardiomyopathy include annulus are important indices of diastolic function. LV
Two-dimensional echocardiography (2DE) filling pressure can be estimated from the ratio of early
M-mode evaluation diastolic mitral inflow velocity by PWD-E and the mitral
Color Doppler interrogation medial annular early diastolic velocity by TDI (e’), i.e.
Pulsed wave Doppler (PWD) and continuous wave average E/e’. Average E/e’ >14 is suggestive of high LV
a
Doppler (CWD) assessment filling pressure and diastolic dysfunction. The tricuspid
di
Tissue Doppler imaging (TDI) annular peak systolic velocity measured by TDI is a reliable
Strain rate imaging (SRI) index of right ventricular function. TDI for segmental
In
Three-dimensional echocardiography (3DE) myocardial tissue velocities helps in the assessment of
Contrast echocardiography regional ventricular function and it is also helpful in
differentiating specific cardiomyopathies. The various
of
Two-dimensional Echocardiography parameters assessed by TDI in the echocardiographic
It plays pivotal role in evaluation of left ventricular (LV) evaluation of cardiomyopathy include:
Average of mitral medial and lateral annular early
systolic function by Simpson’s biplane method with
ty
quantification of LV volumes. LV systolic function by left diastolic velocity (e’)—corresponding to early filling
ventricular ejection fraction (LVEF) measurement by of LV
18 cie
Simpson’s biplane method is most valuable parameter
indicating the prognosis and guiding the therapy. 2DE
Atrial contraction or medial mitral annular late
diastolic tissue velocity(a’)

Myocardial systolic velocity—a positive waveform(s’)
imaging also enables identification of hypertrophy and
20 o
Tricuspid annular peak systolic velocity (TAPSV).
myocardial scarring—which appears as bright, echodense
and thinned out areas. Valvular morphology can also be
S
assessed by 2DE. Intracardiac thrombus can be visualized. Strain Rate Imaging and Speckle Tracking
Left atrial volumes can be assessed which is important in Echocardiography
al
evaluation of diastolic function. The traditional echocardiographic parameter of

ventricular function—LVEF is insensitive to detect subtle
ic
M-mode Evaluation abnormalities in contractile function. Patients with

cardiomyopathy may have advanced disease stage by
og
LV internal diameter at end-diastole (LVIDD) and LV

internal diameter at end-systole (LVIDS) can be measured the time LVEF is impaired. Hence it is crucial to detect
in the transthoracic echocardiographic parasternal short- abnormalities in the initial stage of the disease and
ol
axis or long-axis view using either M-mode imaging or establish a diagnosis so that specific treatment can be
2D linear measurements, 1 cm distal to the mitral valve initiated. Strain and strain rate imaging allow accurate
understanding of the myocardial mechanics—contraction
di
annulus at the valve leaflet tips. These dimensions are

crucial in assessing the response to therapy. M-mode is also and relaxation (deformation imaging). Initially TDI-
derived strain and strain rate were used to quantify
ar
important in assessing the mitral systolic anterior motion

(SAM) in patients with HCM. Color Doppler interrogation myocardial deformation. But angle dependence and noise
enables the evaluation of valvular regurgitation and its interference make this method less desirable. Speckle-
C
severity. Spectral Doppler evaluation includes pulsed wave tracking echocardiography (STE) is an angle-independent
Doppler (PWD) and continuous wave Doppler (CWD) method for strain analysis. The advantages of STE
interrogation. PWD at the mitral inflow and the pulmonary compared with TDI derived strain are better 3D resolution,
vein is useful in the assessment of diastolic function. relative angle independence and lower interindividual
Acceleration or deceleration of the mitral regurgitant variability. The important clinical applications of STE are:
jet can be used as an analog of dP/dT (i.e. the change in 1. Detection of subclinical systolic dysfunction especially
LV pressure over time) and is an important prognostic in patients with chemotherapy-induced cardiotoxicity.
indicator. Kolias TJ, et al. 3 studied 61 patients with An approximate 15% reduction in average global
congestive heart failure and LVEF <50% and evaluated the longitudinal strain from baseline values predicts long-
utility of Doppler derived dP/dt and -dP/dt as a predictor term cardiac dysfunction after chemotherapy with a
of event free survival in patients with chronic congestive very high sensitivity and specificity. Baratta et al.4 had
heart failure (CHF). The study showed that dP/dT <600 studied 36 patients with breast malignancy who received
mmHg/sec and -dP/dT <450 mm Hg/sec identified a high trastuzumab or doxorubicin. Echocardiographic
465
KG-57.indd 465 03-11-2018 12:45:13

SECTION evaluation was performed at baseline, 2, 3, 4 and 6 abnormalities, and also evaluation of degree of myocardial
months after initiation of therapy. A decline of ≥15% perfusion. Contrast echocardiography enhances the LV
8 in the average global longitudinal strain at 3 months
had a very high sensitivity and specificity of 86% for
endocardial border delineation for precise estimation of
LV systolic function and segmental wall motion analysis,
Cardiomyopathy
detecting cardiotoxicity and is an indication for the particularly in patients with suboptimal 2D imaging.
modification of the chemotherapy regime. Contrast echocardiography improves imaging of LV apical
2. Differentiation of the HCM phenotype from LV anatomy, particularly in cases with suspected apical HCM
hypertrophy due to hypertension, athlete’s heart or and LV noncompaction. In apical HCM it aptly delineates
RCM, particularly amyloidosis. the hypertrophied apex and also aids in the imaging of the
3. Distinction of the athlete’s heart or initial stages of associated apical aneurysm/pouch and excludes apical
cardiac amyloidosis from HCM. thrombus. In cases with suspected LV noncompaction
a
contrast echocardiography clearly demonstrates the
di
Three-dimensional Echocardiography intertrabecular crevices and provides a clear distinction
Three-dimensional echocardiography complements between the compacted and noncompacted myocardium.
In
the traditional 2DE. Application of newer techniques for This enhances accurate measurements. Contrast
better endocardial border detection permits accurate enhanced echocardiography also facilitates the exclusion
assessment of LV volume, mass, and EF with 3DE. of normal LV trabeculations, which can be common
of
It enables appropriate selection of patients for ICD variants of the normal heart.
placement and CRT. Assessment of synchrony between
the left ventricular segments during the same cardiac CARDIAC MAGNETIC RESONANCE IMAGING
ty
cycle is possible with real-time 3DE. Assessment of left Cardiac magnetic resonance imaging (CMR) is rapidly
atrial volume by 3DE is accurate which is important gaining popularity as indispensable imaging modality to
18 cie
in evaluation of diastolic function. Patients with DCM
frequently develop functional mitral regurgitation due
aid in clinical diagnosis and treatment of cardiomyopathy.
CMR follows initial echocardiographic evaluation and
to distortion of valve morphology—annular dilatation, provides insights into the disease substrate. It helps
20 o
valve tenting, and tethering of the leaflets. The 3DE in differentiation of variants of cardiomyopathy and
facilitates the understanding of the pathophysiology of
S
predicts the outcome of the disease. CMR has very high

functional mitral regurgitation through identification of spatial resolution which enables accurate assessment of
changes in annular shape and the mitral valve apparatus. ventricular volumes, ventricular systolic function (ejection
al
3DE allows precise measurement of mitral annulus size, fraction), and wall thickness. It also provides information
tenting volume and 3D color Doppler allows accurate about the disease substrate and potential modifiable
ic
quantification of effective regurgitant orifice area and components of cardiomyopathy. A comprehensive CMR
regurgitant volume and accurate assessment of severity evaluation should include various imaging techniques.
og
of mitral regurgitation. Evaluation of right ventricular 1. T1- and T2-weighted sequences for tissue
(RV) morphology and function by 2DE is limited due to characterization
its asymmetric pyramidal shape which does not confirm 2. Cine functional analysis
ol
to any geometric assumptions. Thus, in patients with 3. Late gadolinium enhancement for infarct/fibrosis
predominant RV involvement, e.g. arrhythmogenic right assessment
di
ventricular dysplasia (ARVD), 3DE is especially valuable 4. Contrast-enhanced myocardial perfusion imaging
in the assessment of RV chamber shape, volumes, LGE also may be seen in ischemic as well as nonischemic
ar
and RV function assessment by fractional area change cardiomyopathies like HCM, RCM, sarcoidosis and
method. 3DE enables more accurate assessment of apical infiltrative cardiomyopathies. But the characteristic pattern
C
hypertrophic cardiomyopathy and LV noncompaction. of LGE helps in distinction of one form of cardiomyopathy
from the other. Ischemic cardiomyopathy: Usually
Contrast Echocardiography subendocardial LGE, but some degree of transmural LGE
2DE imaging with tissue harmonic echocardiography starting in the subendocardium and marching towards the
has limited ability for visualization of apical structures epicardium. Nonischemic cardiomyopathies : LGE occurs
due to noise, clutter, and reverberation artefacts in in a noncoronary distribution and may be heterogenous,
the near field where tissue harmonic signals are weak. with mid wall patchy, epicardial or global subendocardial
This limitation can be overcome with the utilization enhancement. Location of LGE can potentially identify
of contrast echocardiography. Contrast agents consist specific types of cardiomyopathies. Low-dose dobutamine
of microbubbles, with a gas core of high molecular CMR allows evaluation of myocardial perfusion and
weight gas. The myocardial contrast agents, which enables quantitative assessment of ventricular function
can traverse the pulmonary circulation, are used in and assessment of scar burden and viability assessment
delineation of the LV cavity, imaging of LV structural in vascular territory with fixed perfusion defects. Thus
466
KG-57.indd 466 03-11-2018 12:45:13

CMR facilitates prediction of left ventricular functional is the most preferred imaging modality for the evaluation CHAPTER
recovery following coronary revascularization with a of arrhythmogenic right ventricular dysplasia (ARVD)
very high sensitivity and specificity of 89% and 94%,
respectively. 5 In nonischemic cardiomyopathy LGE
enabling the detailed and accurate assessment of right
ventricular morphology and function.
57

indicates myocardial fibrosis due to various pathologies
and the presence of LGE strongly predicts adverse cardiac NUCLEAR CARDIAC IMAGING
events. In patients with nonischemic cardiomyopathy
Nuclear cardiac imaging utilizes intravenous injection of
with LVEF 35%, presence of LGE indicates a very high
radioactive tracers and includes multi-gated acquisition
risk of major adverse cardiac events—hospitalization
(MUGA) scans, stress testing with single-photon
for heart failure, arrhythmias, and cardiac death. Scar
emission computed tomography (SPECT) and positron
volume is also a very reliable prognostic indicator. T1 and
a
emission tomography (PET). Both MUGA and SPECT
T2 mapping CMR are novel techniques for quantitative
facilitate the assessment of right and left ventricular
di
myocardial tissue characterization. T1 and T2 mappings
volume, ejection fraction and wall motion abnormalities
are quantitative sequences, which provide tissue-specific
and used predominantly in patients with ischemic
In
T1 and T2 values and allow comparison with normal
reference values. T1 weighted CMR is evolving as a novel cardiomyopathy. PET imaging using new amyloid tracers
technique for detection of myocardial edema an indicator like the [11C]-labelled Pittsburgh Compound B (PiB)
or18F-Fluorodeoxyglucose [18F]FDG—enables direct
of
of recent infarction or myocarditis. Increased T1 signals
indicate myocardial edema due to increase in fluid in imaging of amyloid fibrils and are under investigation
tissue (recent infarction or inflammation) or increase in to quantify amyloid burden and identify early cardiac
involvement before overt cardiac structural changes.7 As
ty
interstitial space due to fibrosis either focal (infarction
scar, replacement fibrosis as in HCM) or diffuse (RCM and [18F] FDG accumulates in inflammatory cells in the heart,
PET is helpful in the diagnosis of cardiac sarcoidosis and
18 cie
DCM) or due to an infiltrative disorder like amyloidosis.
Reduced T1 signals are seen in myocardial diseases due
to lipid deposition (lipomatous metaplasia, Anderson–
myocardial tuberculosis. A meta-analysis of seven studies
reported that [18F]FDG PET has a very high sensitivity
Fabry disease) or iron deposition (hemochromatosis). of 89% and specificity of 78% for the diagnosis of cardiac
20 o
HCM patients have relatively increased T1 signals as sarcoidosis.8
S
compared to patients with mild hypertension and thus In patients with cardiac sarcoid focal perfusion
help discriminating HCM from hypertensive heart defects and [18F]FDG uptake indicates increased
riskof arrhythmias—ventricular tachycardia and death.
al
disease. T2 relaxation time is another biological parameter

which is a tissue specific time parameter utilized to Reduction in the intensity and extent of myocardial
differentiate between normal and abnormal myocardial inflammation on [18F] FDG PET was associated with
ic
tissues. Increase in the myocardial water content, i.e. improvement in LVEF, thus suggesting that serial PET scans
could be used to monitor efficacy of immunosuppressive
og
myocardial edema prolongs T2 relaxation times. T2

mapping sequences facilitate identification of myocardial therapy incardiac sarcoidosis 9 and therapy of myocardial
edema in conditions like acute myocardial infarction, tuberculosis.
ol
myocarditis, and sarcoidosis. T1 relaxation time is another

CMR parameter assessing the time duration required by CARDIAC COMPUTED TOMOGRAPHY
di
the nuclei to recover towards thermodynamic equilibrium. The cardiac computed tomography (CCT) achieves
Native T1 relaxation time is significantly prolonged excellent tissue characterization with its high-spatial
ar
in amyloid light chain and ATTR cardiac amyloidosis resolution and provides minute anatomical details.
as compared with to HCM. Native and postcontrast However, the associated radiation exposure is the main
T1 mapping aids in the estimation of extracellular
C
disadvantage. CCT has a high negative predictive value

volume and identification of abnormal expansion of
and can be used to rule out ischemia as a cause for
the extracellular space in the myocardium, as seen in
cardiomyopathy. The visualization of various extracardiac
amyloidosis and other infiltrative cardiomyopathies. 6
structures or indicators of numerous systemic diseases
CMR allows comprehensive evaluation of HCM right
(i.e. lymph nodes in sarcoidosis) is important as well.
from the diagnosis to the management and follow up of
When there is a dilemma between constrictive pericarditis
patients who have undergone therapeutic interventions.
and RCM, CCT can guide management decisions through
It helps in confirming or excluding the diagnosis when
confirmation or exclusion of constrictive pericarditis by
there is clinical suspicion of HCM but echocardiographic
identifying the thickened and calcified pericardium.
examination is negative or inconclusive. CMR facilitates
precise detection of apical or lateral wall and right
ventricular hypertrophy, mid-ventricular obstruction with DILATED CARDIOMYOPATHY
papillary muscles anomalies, or differentiation between Dilated cardiomyopathy (DCM) includes varied group
spongious and apical hypertrophic cardiomyopathy. CMR of myocardial diseases with ventricular dilation and 467
KG-57.indd 467 03-11-2018 12:45:13

SECTION inadequate myocardial performance which is not presentation is nonspecific and electrocardiographic
contributed to hypertension, valvular, congenital, or findings are diverse, hence noninvasive imaging plays a
8 ischemic heart disease.10
Echocardiography reveals dilated LV with normal wall
crucial role in the diagnosis and management of HCM
and understanding the pathophysiology in symptomatic
Cardiomyopathy
thickness, but increased mass (eccentric hypertrophy), patients. CMR is complementary to echocardiography and
decreased LV systolic function with reduced LVEF, stroke refines the information obtained by echocardiography.
volume, and cardiac output. Left atrial enlargement and CMR is also recommended when echocardiography is
less frequently RV dilation and RV dysfunction may be inconclusive in the diagnosis or exclusion of HCM and
present. The widely accepted criterion for LV dilatation also for differentiating HCM from other cardiomyopathies
in adults include LV internal diastolic dimension of as well as for risk stratification of HCM in selected
2.7 cm/m 2 of body surface area. LV volume is best patients. Current American College of Cardiology (ACC)
a
estimated using the biplane method of Simpson’s disks and American Heart Association (AHA) criterion for
di
summation technique. However, 3D echocardiographic diagnosis of HCM include the presence of a hypertrophied
assessment of LV volumes and LVEF is more accurate LV with wall thickness ≥15 mm in adults in the absence
In
and is recommended during standard echocardiographic of underlying cause.12 But there is wide variation in the
study. 3D echocardiographic LV volumes are larger than morphologic expression of HCM and it can affect any
2D echocardiographic values11 and corresponding upper portion of the LV. Asymmetric septal hypertrophy (ASH)
of
limits of the normal range are end-diastolic volume (EDV) is the most common form of HCM, and other variants
of 79 mL/m2 for men and 71 mL/m2 for women and end- include apical, symmetric or diffuse, midventricular,
systolic volume (ESV) of 32 mL/m2 for men and 28 mL/m2 mass-like, and non-contiguous HCM.
ty
for women. In DCM due to LV remodelling the mitral valve The comprehensive echocardiographic evaluation of
apparatus is distorted resulting in mitral annular dilatation, HCM should include:13,14
18 cie
apical displacement of the papillary muscles and tethering
of the leaflets. This resultsin inadequate coaptation of
leaflets and mitral regurgitation. The severity of mitral
1. Determination of extent and location of hypertrophy
(Figures 1B and C): Left ventricular hypertrophy
(LVH) > 1.5 cm, asymmetric septal hypertrophy with
regurgitation significantly affects the clinical course of the ratio of septal-to-posterior (inferolateral) wall
20 o
DCM. Mitral regurgitation severity can be appropriately thickness of 1.3:1, or focal LV hypertrophy.
S
assessed with various echocardiographic parameters like 2. Identification of the presence or absence of the left
vena contracta, proximal isovelocity surface area (PISA) ventricular outflow tract (LVOT) obstruction both
method—effective regurgitant orifice area and regurgitant
al
at rest and under physiologic provocation. Systolic

volume, or regurgitant fraction through volumetric anterior motion (SAM) is defined as systolic motion
method. CMR and PET can be utilized to exclude other
ic
of the anterior mitral leaflet or chordate into the LVOT

causes of LV dysfunction like inflammatory myocarditis or which can be very well appreciated on motion-mode
og
cardiac sarcoidosis. (M-mode) echocardiography (Figure 1A). SAM results

in turbulent systolic flow in the LVOT, appreciated
Echocardiographic Features as a mosaic pattern by color Doppler interrogation.
ol
of Dilated Cardiomyopathy 2D imaging assists in identification of level of LVOT

obstruction by identifying the area of the septal
Dilated LV and LA. LV systolic dysfunction
di
contact, i.e. SAM. Although LVOT obstruction in HCM

Global hypokinesia of LV
classically occurs at the basal septum, the chordal
Less frequently dilated RV and RV dysfunction
ar
SAM may result in the obstruction beyond LVOT into

Functional ischemic mitral regurgitation—assess the
the LV cavity. Midventricular obstruction can also
severity/anatomy/mechanisms
occur where hypertrophied papillary muscle abuts
C
Diastolic dysfunction of LV
the interventricular septum. SAM also interferes with
Pulmonary artery hypertension—assess with the help
the mitral leaflet coaptation with consequent mitral
of continuous wave Doppler of tricuspid regurgitation
regurgitation. The severity of LVOT obstruction is
jet
determined by measuring the peak LVOT velocity by
Estimation of right atrial pressure with the help of
continuous-wave Doppler. LVOT gradient >30 mm Hg
inferior vena cava size
is the hallmark of the diagnosis of obstructive HCM
Global strain and local regional strain of LV.
and is associated with an increased risk of sudden
cardiac death. Dynamic LVOT gradient should be
HYPERTROPHIC CARDIOMYOPATHY distinguished from fixed LVOT obstruction in the
Hypertrophic cardiomyopathy (HCM) is an autosomal form of subvalvular membrane. Concomitant aortic
dominant genetic disorder characterized by left ventricular valve disease with stenosis should also be excluded
hypertrophy (LVH) without any identifiable cause and the by careful examination of the aortic valve anatomy,
468 hypertrophy may be segmental or diffuse. The clinical including transesophageal echocardiography (TEE)
KG-57.indd 468 03-11-2018 12:45:13

CHAPTER
57

a
di
A B
In
of
ty
Figures 1A to C: (A) M-mode shows mitral SAM (indicated
by arrow) in patient with hypertrophic obstructive
18 cie cardiomyopathy with asymmetric septal hypertrophy
and severe LVOT obstruction; (B) Apical 4 chamber view
shows asymmetric septal hypertrophy involving the
basal and mid septum; (C) Apical 4 chamber view shows
20 o
hypertrophied LV apex and apical lateral wall in a patient
C with apical hypertrohic cardiomyopathy
S
al
if necessary. Combinations of HCM and aortic valve 7. Assessment of pulmonary hypertension.

disease or dynamic LVOT gradient are also possible. 8. Identification of right ventricular (RV) involvement;
ic
3. Evaluation of mitral regurgitation and its severity. look for RV outflow tract obstruction.
4. Characteristic abnormalities of the mitral valve in 9. TEE is crucial in guiding the therapeutic decision of
og
HCM include anterior displacement of papillary surgical myomectomy. Intraoperative TEE improves
muscles, unusual chordal attachments, elongated the safety and efficacy of surgical myomectomy.
anterior leaflet, or aberrant muscle bundles. MRin 10. During alcohol septal ablation or radiofrequency
ol
HCM is not always due to SAM but intrinsic mitral ablation of septum, myocardial contrast echocardio-
valvular abnormalities may be associated, suchas graphy is helpful to delineate strategic portion of
di
mitral annular calcification, mitral valve prolapse, septum (perfusion territory of target septal perforator).
chordal elongation or thickening, leaflet distortion
ar
secondary to injury from repetitive septal contact, Cardiac Magnetic Resonance Imaging
chordal rupture, and infectious etiologies. TEE may be in Hypertrophic Cardiomyopathy
C
required to assess the mitral valve apparatus. Typical CMR provides the comprehensive evaluation of patients
characters of MR jet like eccentric jet or central jet with HCM. The advantage of CMR is its superior spatial
also gives clue regarding the etiology of MR whether resolution with improved image quality, and inherent
it is due to SAM or due to primary organic mitral valve three-dimensional nature that allows the recognition of
disease. morphologic variants of HCM (Figure 2A), a few of which
5. Identify presence of anomalous or abnormal papillary can be missed by echocardiography. CMR imaging also
muscles, valve pathology or membranes. helps in differentiating HCM from closely resembling
6. Assessment of LV systolic and diastolic dysfunction, morphological cardiomyopathies like amyloidosis or Fabry
and left atrial dilation. SRI imaging is a better modality disease. CMR provides excellent demarcation between the
for the assessment of LV systolic dysfunction, which myocardium and blood pool, and allows the most accurate
can detect LV systolic dysfunction even before the assessment of LV mass and volumes. Velocity-encoded
diminution in LV ejection fraction. CMR imaging provides assessment of LVOT gradient and
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SECTION
8
Cardiomyopathy
A B C
a
Figures 2A to C: (A) CMR cine imaging clearly brings out asymmetric septal hypertrophy; (B) Late gadolinium enhancement imaging
shows discrete linear mid myocardial scar in the basal septum; (C) CMR cine imaging clearly brings out asymmetric septal hypertrophy and
di
associated apical hypertrophy is also very well appreciated with characteristic spade shape left ventricular cavity at end diastole
In
mitral regurgitation. CMR should be considered in all NONCOMPACTION CARDIOMYOPATHY
clinical scenarios of cardiomyopathies. LGE techniques Left ventricular noncompaction (LVNC) is characterised
may be used to identify patchy mid-wall myocardial
of
by three distinctive features: prominent LV trabeculae,
scarring (Figure 2B), particularly at the junctions of deep intertrabecular recesses, and the thin compacted
the interventricular septum and right ventricular free layer. It may be associated with systolic and diastolic
wall. In HCM, LGE is indicator of myocardial fibrosis/
ty
dysfunction and may be complicated by systemic embolic
replacement scarring, which is a substrate for ventricular events or arrhythmias.1
tachyarrhythmias and an independent prognostic marker
18 cie
for sudden cardiac death. Thus CMR helps in identifying
patients with HCM with appropriate indication for
Echocardiographic criteria for the diagnosis of LVNC
are:16
1. The presence of prominent LV trabeculations, pre-
implantable cardioverter-defibrillator. LGE ≥15% of LV dominantly identified in the apical and midventricular
20 o
mass doubles the risk of ventricular arrhythmias and is areas of both the inferior and lateral walls.
S
considered as indicator for primary prevention of sudden 2. Bi-layered appearance of the myocardium with
death with an implantable cardioverter-defibrillator in a thin, compacted outer (epicardial) layer and a
young patients even in the absence of other conventional thicker, noncompacted inner (endocardial) layer. The
al
risk markers. The absence of LGE indicates lower risk15 thicknesses of the two layers of the myocardium are best
for arrhythmias. In apical HCM LV apex may not be measured in short-axis views. 2D echocardiographic
ic
adequately visualized due to clutter and reverberation criterion is noncompacted/compacted ratio >2.0 in
artefacts in the near field in echocardiographic study. end-systole.
og
In these patients CMR imaging is helpful to confirm or 3. Multiple deep intertrabecular recesses communicating
exclude the diagnosis of apical HCM as the characteristic with the ventricular cavity, as visualized on color
“spade like” (Figure 2C) configuration of the LV cavity
ol
Doppler interrogation (Figures 3A and B).

at end-diastole is well appreciated on vertical long-axis 4. Systolic thickness of compacted myocardium 8 mm.
views. Also CMR is helpful in differentiating apical HCM
di
Contrast enhanced echocardiography facilitates

from LV noncompaction. CMR imaging is thus strongly the identification of noncompacted myocardium when
recommended as the optimal imaging modality for conventional echocardiographic images are poor or
ar
evaluation of apical HCM and also valuable test in all inconclusive.

patients with HCM. Cardiac CT and nuclear imaging CMR is particularly helpful in distinction of the two
C
have a limited role in evaluation of patients with HCM. layers—compacted outer (epicardial) layer and the
Cardiac CT is utilized when echocardiographic images noncompacted inner (endocardial) layer and precise
are inconclusive and when CMR is contraindicated, as measurement of the two segments and the ratio.
in patients with ICDs or pacemakers. In patients with Grothoff et al. 17 studied the value of CMR-derived
HCM with chest pain and less likelihood of coronary parameters to distinguish left ventricular non-compaction
artery disease, stress SPECT can be done. Computed cardiomyopathy from other cardiomyopathies and
tomographic angiography, is recommended in HCM controls. The investigators established quantitative
patients presenting with chest discomfort and having an CMR diagnostic criteria that facilitate differentiation
intermediate pretest probability of CAD. Fusion imaging o f n o n c o mp a c t i o n ca rd i o myo p at hy f ro m o t h e r
with merging of echocardiographic images with CT offers cardiomyopathies. The LV non-compacted myocardial
precise details of anatomy of septal arteries and their mass index, total LV myocardial mass index (LV MMI), and
distribution pattern which is very important during septal the percentage of LV non-compacted myocardium were
ablation in HCM patients. calculated.
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CHAPTER
57

A B
a
Figures 3A and B: (A) Two-dimensional echocardiography profiling apical 4 chamber view demonstrates the noncompacted myocardium at
di
left ventricular apex with multiple deep intertrabecular recesses; (B) Color Doppler interrogation demonstrating blood flow in the recesses
In
The four basic criteria for dioagnosis of noncompaction description of cardiac involvement with detailed
cardiomyopathy include: structural and hemodynamic assessment. Novel
1. Noncompacted LV myocardial mass >25%. echo techniques like tissue velocity imaging and
of
2. Total non-compacted LV myocardial mass index speckle tracking which analyze strain and strain rate
15 g/m2. provide information regarding ventricular myocardial
3. Noncompacted/compacted myocardium ratio ≥ 3:1 in properties and can detect the disease in its early
ty
at least one of the segments 1–3, 7–16, excluding the course. These techniques also help in differentiating
apical segment 17 and segments 4–6 of 17-segment RCM from chronic constrictive pericarditis.
model. 18 cie
4. The ratio of noncompacted/compacted myocardium
The characteristic echocardiographic features of RCM
include:
≥2:1 in segments 4 to 6 of 17-segment model. I. Two-dimensional echocardiographic features:
20 o
The diagnostic performance will be enhanced if 1. Normal or small ventricular cavity size with
CMR criteria are combined together and utilized for the
S
generally preserved or mildly reduced systolic

diagnosis. ventricular function (Figures 4A and B).
2. Biatrial enlargement (Figure 4B).
al
RESTRICTIVE CARDIOMYOPATHY 3. In RCM, wall thickness is typically normal,

RCM should be considered in the presence of heart failure though it may be increased with certain infiltrative
ic
symtoms with a nondilated, nonhypertrophied LV with processes (e.g. amyloidosis) or storage disease
(e.g. Fabry disease).
og
preserved contractility but abnormal diastolic function

and dilated atria. 4. Raised right atrial pressures as evidenced by
Echocardiography is the preferred imaging modality for dilated inferior vena cava.
5. Valve thickening, interatrial septal thickening
ol
assessing the morphological and functional characteristics

of RCM. or pericardial effusion may be present and are
suggestive of cardiac amyloidosis.
di
1. Electro cardiograhy: It may show nonspecific

abnormalities and include either large P waves 6. LV/RV apical obliteration is seen in endomyocardial
fibrosis.
ar
indicating enlarged atria or atrial fibrillation may be

present. ST-T wave abnormalities, premature atrial 7. RV free wall dimple is seen in RV endomyocardial
and ventricular beats, atrioventricular (AV) block, and fibrosis.
C
intraventricular conduction delay may be noticed. 8. Autocontrast may be seen in atria or inferior vena
2. Chest radiograph: It is usually characterized by cava.
significant atrial enlargement with pulmonary venous II. Doppler echocardiography:
congestion and pleural effusions. Endomyocardial Abnormal diastolic function, frequently with a
calcium may be found which is characteristic of restrictive LV filling pattern as evidenced by:
endomyocardial fibrosis. Sometimes radiological 1. Increased early diastolic filling velocity (E).
cardiac enlargement may be absent. 2. Decreased atrial filling velocity (A).
3. Echocardiogram : Echocardiogram is the most 3. E/A ≥ 1.5.
commonly performed and most useful imaging 4. Decreased deceleration time (Edt) 150 msec.
modality in the evaluation and management of patients 5. Decreased isovolumic relaxation time (IVRT).
suspected to have RCM. An integrated approach with 6. Significant decrease in the ratio of Systolic (S) and
combination of 2DE, M mode, Doppler evaluation diastolic (D) wave velocities in pulmonary venous
and color Doppler imaging gives a comprehensive flow, i.e. S/D ratio. 471
KG-57.indd 471 03-11-2018 12:45:15

SECTION
8
Cardiomyopathy
a
di
A B
In
Figures 4A and B: (A) Parasternal long axis view shows thickened interventricular septum and posterior wall with sparkling appearance
of myocardium, dilated LA and small posterior pericardial effusion; (B) Apical 4 chamber view shows normal size LV and RV, dilated atria,
thickened and sparkling interventricular septum
of
7. Augmented atrial reversal velocity in the pulmo- calcification on CCT favor constrictive pericarditis, though
nary venous flow. not conclusive.
ty
8. Pulmonary arterial hypertension which can be
evaluated by tricuspid regurgitation jet velocity Cardiac Magnetic Resonance Imaging (CMR)
18 cie
providing right ventricular systolic pressure
(RVSP) or pulmonary regurgitation velocity
CMR helps in the identification or exclusion of various
causes of RCM. LGE enables identification of myocardial
providing pulmonary arterial mean pressure and
fibrosis, scar, necrosis, or infiltration. Characteristic
20 o
pulmonary arterial diastolic pressure.
patterns of LGE help the diagnosis of certain characteristic
III. Tissue velocity imaging
S
disease processes. LGE in left atrium/interatrial

1. Markedly reduced mitral annular tissue velocities:
septum/valves and global LV distribution along with
Early diastolic medial mitral annular tissue velocity
classical gadolinium dynamics are diagnostic of cardiac
al
e’ and late diastolic medial mitral annular tissue

amyloidosis.LV inferolateral LGE is typical of Fabry’s
velocity a’ and systolic medial mitral annular
disease. In sarcoidosis, there is often patchy enhancement,
ic
tissue velocity s’ are all significantly reduced.

involving basal septum and basal inferolateral wall,
2. Evaluation of segmental myocardial tissue
frequently not consistent with any coronary artery
og
velocities of LV and RV show significantly

territory. Myocardial iron overload can be assessed by
reduced segmental myocardial tissue velocities.
cardiac T2 measurements. In addition, CMR-based
Tissue velocity imaging identifies the subclinical
tissue tracking can be used to differentiate restrictive
ol
ventricular dysfunction even before the reduction

cardiomyopathy from constrictive pericarditis.
in ejection fraction occurs. It also helps in
Nuclear imaging has a potential clinical role in two
di
distinguishing RCM from constrictive pericarditis,

forms of RCM: amyloidosis and sarcoidosis.
with a mitral annular diastolic velocity e’ ≤8 cm/s,
ar
a good discriminator for restrictive physiology

while constrictive pericarditis is characterized by IDIOPATHIC RESTRICTIVE CARDIOMYOPATHY
C
normal or elevated mitral annular tissue velocities. Echocardiographic features are those of restrictive
IV. 2D speckle tracking echocardiography: Strain and physiology usually with preserved LV systolic function,
strain rate imaging dilated atria, without ventricular hypertrophy or dilatation.
1. Markedly reduced global strain rate of left and Longitudinal function of LV may be decreased as brought
right ventricle. out by strain rate imaging. The right ventricle may be
2. Specific longitudinal strain rate pattern like involved. There is no ‘pathognomonic’ echocardiographic
reduced longitudinal strain rate with relative pattern diagnostic of idiopathic RCM.18 CMR with LGE
apical sparing as seen in amyloidosis. enables identification of infiltrative myocardial disease,
and is useful for ruling out a particular cause of RCM.
Cardiac Computerized Tomography (CCT)
It is especially helpful in excluding constrictive CARDIAC AMYLOIDOSIS
pericarditis which is a very deceptive mimic of restrictive Amyloidosis is a systemic disorder characterized by
cardiomyopathy. Evidence of pericardial thickening and extracellular deposition of insoluble fibrillar protein in the
472
KG-57.indd 472 03-11-2018 12:45:16

interstitial space in various organs like liver, kidney, heart, complexes on ECG are commonly seen in patients with CHAPTER
bowel, nerves, skin, and tongue. Cardiac amyloidosis is AL amyloidosis and less frequent finding in other forms of
the commonest cause of RCM. The three most common
types of amyloidosis, defined by their precursor proteins,
amyloidosis.
Echocardiography is the preferred noninvasive
57

are light-chain (AL) amyloidosis, familial or senile diagnostic imaging modality for the evaluation of
transthyretin related (ATTR) amyloidosis, and secondary cardiac amyloidosis. The characteristic features include
amyloid A (AA) amyloidosis. The frequency and severity increased ventricular wall thickness with “granular
of cardiac involvement varies among various types of sparkling” appearance of the myocardium, valvular
amyloidosis. Cardiac amyloidosis must be suspected when thickening with regurgitation, interatrial septal thickening
systemic features are present and patient has symptoms of , normal or decreased LV cavity size, dilated atria, and
congestive heart failure. small to moderate pericardial effusion. Tissue velocity
a
The diagnosis of cardiac amyloidosis is established imaging, myocardial strain and strain rate imaging are
di
by echocardiographic or CMR evidence of amyloidosis more sensitive. Strain rate imaging reveals markedly
and histologic confirmation of amyloid in noncardiac reduced global strain—both longitudinal and radial
strains of LV. 19 But the global strain may be reduced
In
tissue. Endomyocardial biopsy is the gold standard for the
diagnosis of cardiac amyloidosis. in other cardiomyopathies also. Phelan et al. 20 have
The various electrocardiographic abnormalities reported characteristic regional patterns in longitudinal
of
in patients with cardiac amyloidosis include Low strain (LS) using two-dimensional speckle-tracking
voltage complexes, large P waves due to biatrial echocardiography with regional variations in LS from base
enlargement, pseudoinfarction pattern, conduction to apex along with relative apical sparing. A relative ‘apical
ty
abnormalities—Intraventricular conduction delays or sparing’ pattern of LS is an easily recognizable, accurate
blocks like incomplete right bundle branch block or left and reproducible method of differentiating cardiac
18 cie
anterior fascicular block may be present, arrhythmia
atrial fibrillation—in advanced stage or fragmented
QRS complexes are also frequently seen. Low voltage
amyloidosis from other causes of LV hypertrophy (Figures
5A and B). This classic regional pattern of LS can be easily
identified on strain polar maps or ‘‘Bull’s eye’’ plots. It
complexes on ECG in a patient with preserved LV systolic typically displays marked decrease in LS in the basal- and
20 o
function and LV hypertrophy by echocardiography should mid-wall segments with relative apical sparring of LS and
S
raise the clinical suspicion of cardiac amyloid. Low voltage is typically called ‘cherry on the top’ (Figure 5C). In HCM,
al
ic
og
ol
di
ar
A B
C
Figures 5A to C: (A) Strain rate imaging in apical 4 chamber

view shows reduced longitudinal peak systolic strain; (B) Strain
rate imaging in apical 2 chamber view also shows reduced
longitudinal peak systolic strain of basal and mid segments.
Typically note that the mid and basal segments have low strain
rate as compared to the apical segments in the apical 4 chamber
and 2 chamber views and also apical segments in 2 chamber
view show normal strain of 20%. This is the characteristic relative
‘apical sparing’ pattern of longitudinal strain which is diagnostic
of cardiac amyloidosis; (C) Global longitudinal strain with Bull’s
eye plot shows apical sparing pattern typically called as ‘cherry
C on the top’
473
KG-57.indd 473 03-11-2018 12:45:18

SECTION there is preferential decrease in longitudinal strain at the specific CMR features. ATTR amyloidosis was associated
site of greatest hypertrophy. with significantly higher LV mass index, higher LV
8 This characteristic pattern of apical sparing in cardiac
amyloidosis was integrated into a relative apical LS
volumes, and lower LVEF compared with AL amyloidosis.
Myocardial and blood pool gadolinium kinetics and
Cardiomyopathy
formula as: uptake are unusual and typical for cardiac amyloidosis.
Relative apical LS = average apical LS/(average of basal Pleural and pericardial effusions were more common in
+ mid LS) cardiac AL amyloidosis.In cardiac ATTR amyloidosis, LGE
A score of 1 was associated with very high sensitivity was more extensive, with a higher prevalence of trans
and specificity of 93% and 82% respectively for the mural LV LGE as well as of RV LGE.21
diagnosis of cardiac amyloidosis.
NUCLEAR IMAGING IN CARDIAC
a
CARDIAC MAGNETIC RESONANCE AMYLOIDOSIS
di
IMAGING
Phosphonate-based tracers, including 99m Tc pyrophos-
The anatomical features diagnostic of cardiac amyloid phate (Tc-PYP) and 99mTc-3,3 diphosphono-1,2
In
on CMR cine imaging are biatrial enlargement, propanodicarboxylic acid (99mTc-DPD) Tc-DPD, have
thickened LV wall, reduced long-axis shortening, and been reported to localize amyloid in the heart 99mTc-DPD
pleural or pericardial effusion. Cardiac amyloidosis
of
scintigraphy is useful in differentiating ATTR amyloidosis
depicts a characteristic pattern of LGE—diffuse from AL amyloidosis. 99mTc-DPD uptake could be
circumferential subendocardial enhancement with characterized as moderate to severe with left ventricular
diffuse LV subendocardial or transmural enhancement
ty
or biventricular distribution in all patients with ATTR
(Figure 6) or bilateral septal subendocardial LGE, which
amyloidosis (Figure 7), and absent or mild and diffusely
may also involve the RV and atrial walls. This characteristic
18 cie
pattern of global transmural or diffuse subendocardial LGE
facilitates diagnosis of the disease in the early stage when
distributed in AL amyloidosis.22
CARDIAC SARCOIDOSIS
significant increase in LV wall thickness is not present
20 o
and it correlates with disease severity 20. Light chain (AL) It is a systemic inflammatory disorder characterized by
S
amyloidosis and hereditary transthyretin-associated noncaseating granulomas in lungs, spleen, lymph nodes,
(ATTR) amyloidosis can be distinguished with the help of skin, liver, parotid glands and heart. Cardiac involvement
al
ic
og
ol
di
ar
C
Figure 6: CMR with late gadolinium enhancement

images depicting diffuse transmural enhancement
of LV (as indicated by arrow) a diagnostic feature
of cardiac amyloidosis
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CHAPTER
57

a
di
Figure 7: Radionuclide imaging with 18F-fluorodeoxyglucose (FDG ): PET CT scan images in a patient with cardiac amyloidosis. It revealed
tracer uptake in thickened LV and RV myocardium. Patchy low grade uptake is seen in thickened wall of dilated RA
In
is patchy with the most common locations of granulomas 6. LV aneurysms.
found in the left ventricular free wall and basal ventricular 7. Valvular regurgitation.
of
septum, frequently affecting the conducting system.
CARDIAC MAGNETIC RESONANCE
ELECTROCARDIOGRAM
ty
CMR has a valuable role in the diagnosis of cardiac
An electrocardiogram (ECG) should be performed in sarcoidosis. It can detect both the active inflammatory
18 cie
every patient with sarcoidosis (systemic or cardiac)
to detect subtle or overt conduction or repolarization
abnormalities. Many patients may have splintered QRS
phase as well as the chronic phase of fibrosis and scarring
of cardiac sarcoidosis. CMR is currently the technique
of choice in the evaluation of sarcoidosis. CMR imaging
complexes, atrioventricular or intraventricular conduction reveals dilated LV with diffuse hypokinesis with LV wall
20 o
abnormalities. thinning and LV dysfunction.CMR uses T2-weighted
S
Ventricular tachycardia, complete heart block, bundle imaging and early gadolinium images to detect acute
branch blocks or first degree heart block occur very inflammation (edema). T1-weighted (cine) imaging
frequently in patients with sarcoidosis. In patients with illustrates wall motion abnormalities, hypertrophy due to
al
suspected or known cardiac sarcoidosis 24-hour ECG possible infiltrative disease, wall thinning, or heart failure.
monitoring should be performed to document and define LGE assesses fibrosis or scar and may represent
ic
subclinical rhythm disturbances that may be missed on chronic rather than active disease. 23 Typical patterns
ECGs, to aid risk estimation of sudden death. of enhancement on CMR are non-vascular in territory,
og
mid-myocardial, and sub-epicardial, although many

ECHOCARDIOGRAPHY patients have patterns in a coronary distribution with
ol
subendocardial involvement similar to myocardial

Echocardiography is basic imaging modality for the
infarction.
evaluation of cardiac sarcoidosis as it provides useful
di
information regarding the LV systolic and diastolic

function as well as the RV function. Characteristic POSITRON EMISSION TOMOGRAPHY (PET)
ar
echocardiographic findings are: 18F-fluorodeoxyglucose [(18F)FDG] PET detects active

1. Systolic function of the ventricles may be normal phase of cardiac sarcoidosis with high sensitivity. FDG
C
initially but it is usually severely impaired late in the PET is more sensitive than gallium-67 scintigraphy,
course of the disease when it usually comes to clinical thallium-201, or technicium-99m single-photon
attention due to symptoms of heart failure. emission computed tomography (SPECT).24 It can also
2. Global hypokinesia of LV or regional wall motion be combined with myocardial perfusion imaging to
abnormalities not consistent with vascular territory. detect fibrogranulomatous replacement. However, PET
3. Focal thinning, hyperechogenicity or scarring of is non-specific for sarcoidosis as uptake of 18F-FDG is
myocardium, usually basal septum is affected while seen in other inflammatory myocardial diseases also,
apex is spared (Figures 8A to C). e.g. myocarditis, cardiac amyloidosis, infection, cardiac
4. LV wall focal hypertrophy with localized thickening tuberculosis, and myocardial metastases causing focal
13 mm (due to granulomatous expansion). (18F)FDG uptake. The imaging protocol includes gated
5. Pulmonary involvement is frequently noted with cardiac (18F)FDG andwhole body images.25 A cardiac
resultant pulmonary arterial hypertension or right perfusion scan could be combined to compare [18F]
heart failure. FDG-PET and perfusion patterns. Serial (18F)FDG-PET/
475
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SECTION
8
Cardiomyopathy
a
A B C
Figures 8A to C: (A) Parasternal long axis view shows dilated LA and LV with hyperechoic and thinned out basal anterior septum;
di
(B) Parasternal short axis view of LV at the level of papillary muscles shows dilated LV with thinning of inferior and anterior septum; (C) Apical
4 chamber view show dilated all 4 cardiac chambers with focal thinning and hyperechogenicity of basal and mid inferior septum. This focal
In
thinning and hyperechogenicity is not consistent with any vascular territory and is diagnostic of cardiac sarcoidosis.
CT imaging is useful to assess the response to therapies.
of
Decreased (18F)FDG uptake in cardiac lesions following
therapy has been reported in case of corticosteroid
ty
treatment as well as immunosuppressive therapies. Thus
PET can be used in assessing the disease progression and
also the response to the therapy.
ANDERSON-FABRY DISEASE
18 cie
20 o
Anderson-Fabry disease is X-linked glycolipid storage Figure 9: Cardiac magnetic resonance imaging in a patient with
disease caused by deficient activity of alpha galactosidase Fabry disease shows scarring of the basal inferolateral segment
S
A enzyme. Clinical manifestations include cutaneous,

corneal, cardiac, renal, and neurologic manifestations.
endocardial layer subtended by a hypoechogenic
al
Cardiovascular manifestations of Fabry disease include

layer. Binary appearance reflects endomyocardial
hypertension, left ventricular hypertrophy, conduction
glycosphingolipids compartmentalization. However,
ic
abnormalities, valvular regurgitation, coronary artery

the binary appearance has a low sensitivity of 15–35%
disease, and dilation of aortic root.26 The right ventricle is
and specificity of 73–80% for the diagnosis of Fabry
og
also often hypertrophied. Among the affected individuals

female patients are more likely to present the cardiac disease.27
variant of the disease. 6. Aortic dimensions can be measured by 2DE and aortic
ol
root dilatation may be diagnosed

ECHOCARDIOGRAPHIC FEATURES
di
1. Unexplained left ventricular hypertrophy is the most

CARDIAC MAGNETIC RESONANCE IMAGING
characteristic finding. Concentric hypertrophy is LGE characteristically demonstrates the scarring of basal
ar
the most frequent manifestation, asymmetric septal and mid segments of the anterolateral and inferolateral
hypertrophy or eccentric hypertrophy can also occur. walls (Figure 9). Basal third of other LV walls may be
C
Rarely LV outflow obstruction may also occur. RV involved in severe cases. LGE in Fabry disease usually
hypertrophy may also be seen. spares the subendocardium, which helps distinguish it
2. In some cases the basal inferolateral wall becomes from the pattern seen with myocardial infarction.
thin and may exhibit hypokinesia due to myocardial
fibrosis and STE shows reduced longitudinal strain in
NUCLEAR IMAGING IN FABRY DISEASE
this segment.
3. The valves may be thickened with subsequent mitral, In patients with Fabry disease presenting with angina
aortic or tricuspid regurgitation. The regurgitant stress myocardial perfusion imaging reveals reversible
lesions are usually mild. defects consistent with ischemia, often accompanied
4. Usually LVEF will be preserved but STE demonstrates by fixed defects. These findings generally occur without
reduced strain rate. significant obstructive coronary disease and appear to be
5. Binary appearance of the myocardium on 2DE due to small vessel coronary disease with replacement
occurs as a result of a thickened hyperechogenic fibrosis surrounding severely stenosed intramural arteries.
476
KG-57.indd 476 03-11-2018 12:45:21

ENDOMYOCARDIAL FIBROSIS AND CARDIAC MAGNETIC RESONANCE IMAGING CHAPTER
LÖFFLER’S ENDOCARDITIS
57
CMR often provides additional diagnostic information
Endomyocardial fibrosis (EMF) occurs due to endocardial due to its ability to detect subendocardial fibrosis and
involvement with deposition of fibrous tissue in the its greater sensitivity for ventricular thrombus detection.

endomyocardium, endocardial calcification of LV or RV LGE imaging is capable of detecting myocardial fibrosis
or both, leading to restrictive physiology. It is endemic and inflammation. Overlying thrombus is identifiable as
in certain geographical areas like Asia, subtropical a low signal mass on the delayed enhancement images,
Africa and South America. EMF is a form of restrictive, which does not deform on tagged images. A characteristic
cardioobliterative cardiomyopathy characterized by three-layered image can be seen: a hypointense inner
fibrotic thickening and obliteration of either of the rim of thrombus adjacent to an hyperenhancement of
endocardium compared with the rest of the myocardium.
a
ventricles or both with selective involvement of the
ventricular apices and inflow region, sparing the outflow Despite the convincing diagnostic information available
di
tract. The cardiac involvement in EMF follows three from the noninvasive imaging modalities endomyocardial
stages: 28 (1) Acute necrotic stage, (2) Intermediate biopsy remains the diagnostic gold standard.30
In
phase—thrombotic stage and (3) Fibrotic stage.
Löffler’s endocarditis represents the third stage. It was ARRHYTHMOGENIC RIGHT VENTRICULAR
first described in 1936 by Wilhelm Löffler. He referred DYSPLASIA
of
to it as ‘fibroplastic parietal endocarditis with blood
Arrhythmogenic right ventricular dysplasia (ARVD) is an
eosinophilia’.29. It is a manifestation of hypereosinophilia
inherited cardiomyopathy characterized by structural
and morphologic abnormalities of eosinophils have been
ty
and functional abnormalities of the right ventricle. It
noted in patients with Löffler’s endocarditis. The most
is characterized by the fibrofatty replacement of RV
characteristic cardiac abnormality in hypereosinophilic
18 cie
syndrome is fibrosis and scarring of the ventricular
apex with resultant restrictive physiology. About 50
myocardium which eventually leads to progressive RV
dysfunction and life-threatening ventricular arrhythmias.
LV involvement has also been reported in later stages of
to 60% of patients with hypereosinophilic syndrome
the disease.
20 o
show cardiovascular manifestation. The patients with
The electrocardiographic diagnostic criteria of ARVD
Loffler’s endocarditis present with symptoms of heart
S
include Epsilon wave—electric potentials after the end

failure, intracardiac thrombus, myocardial ischemia or
of the QRS complex—a major diagnostic criterion and
arrhythmias and rarely pericarditis.
T wave inversions in V1 through V3, a minor diagnostic
al
criterion, but most common ECG abnormality.

ECHOCARDIOGRAPHY Transthoracic echocardiography (TTE) is the basic first
ic
The characteristic echocardiographic features of line imaging modality in the evaluation of a patient with
og
endomyocardial fibrosis include: suspicion of ARVD. The echocardiographic features of

Endomyocardial thickening with apical obliteration diagnostic ARVD are:31
due to thrombus formation without any regional wall RV dilation and hypokinesia
ol
motion abnormality. Endocardial calcium is seen as Dilatation of the right ventricular outflow tract
hyperechogenicity lining the apical endocardium. ≥32 mm on the parasternal long-axis view or ≥36 mm
di
Rarely focal involvement of other segments of LV can on parasternal short axis view – a major criterion for
be seen. diagnosis of ARVD
ar
Biatrial enlargement. Increased reflectivity of the moderator band
Mitral or tricuspid leaflet involvement with tethering of Prominent apical trabeculae
the leaflet and regurgitation. Focal aneurysms or sacculations of RV. Off-axis images
C
Doppler echocardiography can show diastolic should be obtained for appropriate visualization of
dysfunction often a restrictive left ventricular filling all segments of the RV free wall and identification of
pattern. localized RV aneurysms
Pericardial effusion may be present. Akinesis-dyskinesis of the inferobasal segment
Preserved LV systolic function (including the apex). RV function can be assessed by the estimation of
Tissue velocity imaging reveals significantly reduced the RV fractional area change (FAC) from the Apical
segmental tissue velocities of LV and RV. 4-chamber and it is decreased in individuals with
Thrombi may be found in left atrium or right atrium ARVD. FAC ≤ 33% is a major criterion
or both or the left atrial appendage or the right atrial TDI derived tricuspid annular peak systolic velocity
appendage. (TAPSV) and M-mode derived tricuspid annular plane

RV free wall dimple may be present in RV endo- systolic excursion (TAPSE) also are utilized in the
myocardial fibrosis. assessment of RV function.
477
KG-57.indd 477 03-11-2018 12:45:21

SECTION Myocardial performance index or Tei index is another Reversible cardiomyopathies have been shown
reliable parameter for assessment of RV function. Newer to have a transient impact on the heart. Significant
8 echocardiographic techniques like 3D TTE and strain
rate imaging of RV are now gaining popularity for the
improvement in cardiac function is seen if these reversible
cardiomyopathies are diagnosed promptly and treated
Cardiomyopathy
assessment of RV function. 3D TTE is an emerging tool appropriately.

for accurate estimation of RV volumes and RV ejection
fraction. Strain rate imaging provides assessment of global CHEMOTHERAPY AND RADIATION-INDUCED
and regional RV function. But both the techniques require CARDIOMYOPATHY
expertise and there is a steep learning curve.
Cardiac toxicity is one of the most concerning side
CMR represents the preferred imaging modality
effects of anti-cancer therapy. A baseline echocario-
in the diagnosis of ARVD and it gives accurate and
a
graphic evaluation of LV assessment, including LVEF
comprehensive assessment of RV morphology—RV wall
measurement, is mandatory before the initiation of
di
motion abnormalities: Akinesia and dyskinesia and
chemotherapy or radiotherapy. Chemocardiotoxicity
focal aneurysms and RV function.32 The CMR finding of
can manifest as impairment of myocardial systolic
In
regional RV akinesia or dyskinesia or dyssynchronous
function with resultant congestive heart failure during
RV contraction along with RV dilatation with indexed RV
or immediately after the initial infusion, although acute
end-diastolic volume (EDV) ≥110 mL/m2 in males or ≥ 100
cardiotoxicity occurs very rarely. Cessation of therapy
of
ml/m2 in females or RV ejection fraction ≤40% constitutes
usually improves myocardial function, though this
one of the major diagnostic criterion of ARVD. Other CMR
depends on the cumulative dose experienced by patients.
findings associated with ARVD include RV wall thinning,
Early cardiotoxicity can occur within 12 months of
ty
RV outflow tract enlargement, trabecular disarray,
treatment and late cardiotoxicity can occur beyond
fibrofatty replacement, ventricular dilation, and global or
12 months. The concomitant use of trastuzumab has
regional systolic dysfunction.
REVERSIBLE CARDIOMYOPATHIES
18 cie been shown to potentiate the cardiotoxic effects of
anthracyclines. Besides causing dilated cardiomyopathy,
anthracyclines can also cause endomyocardial fibrosis
20 o
Reversible cardiomyopathies are associated with a and diastolic dysfunction with restrictive filling pattern.
temporary reduction in contractile function leading to
S
Radiotherapy carries a very risk of diastolic cardiac failure.

reversible heart failure which improves when the root Chemocardiotoxicity can occur many years after the
etiological factor is addressed. chemotherapy and does not correlate with the dose.34 The
al
The two mechanisms responsible for reversible regular monitoring of heart function during chemotherapy
myocyte dysfunction are : acute inflammatory activation is of major importance for early detection of cardiotoxicity.
ic
in which cytokines depress myocyte function, and toxic Three-dimensional echocardiography has been validated
effects in which there is impairment of intracellular as the accurate echocardiographic modality for the
og
energetics. There are many etiological factors that can calculation of LV ejection fraction. Strain rate imaging
result in severe structural and functional dysregulation 33. has the ability to detect LV systolic dysfunction even
The various forms of reversible cardiomyopthies are before the decline in LVEF. Strain and strain rate imaging
ol
Inflammatory or infectious cardiomyopthy: Cardiac identify abnormalities in myocardial mechanics early

sarcoidosis, viral myocarditis, sepsis during cardiotoxicity, allowing the prediction of later
di
Metabolic: Thyroid disease–induced cardiomyopathy, overt systolic dysfunction. These parameters are useful
hypocalcemia induced lv dysfunction in identifying the patients treated with chemotherapy
ar
Sympathoexcitation-induced: Takotsubo cardio- who could benefit from alternate therapies, and thus
myopathy/catechol cardiomyopathy reduce the incidence of cardiotoxicity. Relative decline in
C
Cardiomyopathy of chronic diseases: Cirrhosis, global longitudinal strain 15% is indicates subclinical left
obesity, and uremia ventricular dysfunction and should prompt modification
Arrhythmogenic cardiomyopathy in chemotherapy dosage and initiation of cardioprotective
Autoimmune-mediated peripartum cardiomyopathy drugs.35 Exercise and pharmacologic stress testing has
Cardiomyopathy related to toxins: Alcohol, chemo- been studied as a way to unmask subclinical abnormalities
therapeutic drugs of LV function induced by chemotherapeutic agents.36
Nutritional deficiencies: Thiamine deficiency
The clinical scenario will indicate the etiology of CONCLUSION

reversible cardiomyopathy.
Echocardiography will remain the main screening method
Echocardigraphy assists in the diagnosis of LV systolic
in routine evaluation of cardiomyopathies.
or diastolic dysfunction. In few instances additional
Novel echocardiographic techniques of 3D echo-
imaging modalities like CMR or PET will be required for
cardiography and strain assessment supplement traditional
confirmation of the etiology.
478
KG-57.indd 478 03-11-2018 12:45:21

2D echocardiographic examination and provide important 10. Bozkurt B, Colvin M, Cook J, et al. Current Diagnostic and CHAPTER
information regarding etiology, cardiac mechanics, and Treatment Strategies for Specific Dilated Cardiomyopathies:
prognosis in patients with cardiomyopathy. CMR indeed
represents a standard method in diagnosis of ARVD
A Scientific Statement From the American Heart
Association. Circulation. 2016 ;134(23):e579-e646.
57
11. Lang RM, Badano LP, Mor-Avi V, et al. Recommendations

and certain restrictive cardiomyopathies (particularly
for Cardiac Chamber Quantification by Echocardiography
cardiac amyloidosis), myocarditis or persisting suspicion
in Adults: An Update from the American Society of
for hypertrophic cardiomyopathy with in conclusive
Echocardiography and the European Association of
echocardiography. Most important role of cardiovascular Cardiovascular Imaging. J Am Soc Echocardiogr. 2015;28:1-
CT in cardiomyopathies is distinguishing ischemic 39.
heart disease from DCM, and RCM from constrictive 12. Gersh BJ, Maron BJ, Bonow RO, et al. 2011 ACCF/AHA
pericarditis. PET imaging provides an effective method of Guideline for the Diagnosis and Treatment of Hypertrophic
a
assessing myocardial perfusion and inflammation. It plays Cardiomyopathy: a report of the American College of
di
an important role in distinguishing cardiac sarcoidosis Cardiology Foundation/American Heart Association Task
from other causes of cardiomyopathy and monitoring Force on Practice Guidelines. Developed in collaboration
with the American Association for Thoracic Surgery,
In
response of immunosuppressive therapy in patients with
cardiac sarcoidosis. American Society of Echocardiography, American Society of
Nuclear Cardiology, Heart Failure Society of America, Heart
Rhythm Society, Society for Cardiovascular Angiography
of
ACKNOWLEDGMENTS and Interventions, and Society of Thoracic Surgeons. J Am
Authors are thankful to Management of CARE HOSPITALS, Coll Cardiol. 2011;58(25):e212-60.
BANJARA HILLS, HYDERABAD; Dr . Johann, Mr. Shiva for 13. Nagueh SF, Bierig SM, Budoff MJ, et al. American Society
ty
providing MDCT and CMR images. of Echocardiography Clinical Recommendations for
Multimodality Cardiovascular Imaging of Patients with
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1. Arbustini E, Narula N, Tavazzi L, et al. The MOGE(S)
Hypertrophic Cardiomyopathy. J Am Soc Echocardiogr.
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14. Robinson A, Kramer CM. Imaging in Hypertrophic
classification of cardiomyopathy for clinicians. J Am Coll Cardiomyopathy. JACC Cardiovasc Imaging. 2016;9:1392-402.
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Cardiol. 2014;64(3):304–18. 15. Chan RH, Maron BJ, Olivotto I, et al. Prognostic value of
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2. Richardson P, McKenna W, Bristow M, et al. Report of the quantitative contrast-enhanced cardiovascular magnetic
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3. Kolias TJ, Aaronson KD, Armstrong WF. Doppler-derived and pathoanatomical characteristics of isolated left
dP/dt and -dP/dt predict survival in congestive heart ventricular non-compaction: a step towards classification
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failure. J Am Coll Cardiol. 2000; 36(5):1594-9. as a distinct cardiomyopathy. Heart. 2001;86(6):666–71.

4. Baratta S, Damiano MA, Marcheseet ML, et al. Serum 17. Grothoff M, Pachowsky M, Hoffmann J, et al. Value of
markers, conventional Doppler echocardiography, cardiovascular MR in diagnosing left ventricular non-
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and two-dimensional systolic strain in the diagnosis of compaction cardiomyopathy and in discriminating
chemotherapy-induced myocardial toxicity. Rev Argent between other cardiomyopathies. Eur Radiol. 2012;
Cardiol. 2013;81:151-5. 22(12):2699–709.
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5. Klem I, Heitner JF, Shah DJ, et al. Improved detection of 18. Habib G, Bucciarelli-Ducci C, Alida LP, et al. Imaging in
coronary artery disease by stress perfusion cardiovascular Restrictive Cardiomyopathies: An EACVI expert consensus
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magnetic resonance with the use of delayed enhancement document In collaboration with the “Working Group on
infarction imaging. J Am Coll Cardiol. 2006;47(8):1630-8. myocardial and pericardial diseases” of the European
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6. Jan MF, Tajik AJ. Modern Imaging Techniques in Society of Cardiology Endorsed by The Indian Academy of
Cardiomyopathies. Circ Res. 2017;121(7):874-91. Echocardiography. Eur Heart J Cardiovasc Imaging. 2017;
7. Antoni G, Lubberink M, Estrada S, et al. In vivo visualization 18(10):1090–121.
of amyloid deposits in the heart with 11C-PIB and PET. J 19. Phelan D, Collier P, Thavendiranathan P, et al. Relative
Nucl Med. 2013;54(2):213-20. ‘‘apical sparing’’ of longitudinal strain using 2-dimensional
8. Youssef G, Leung E, Mylonas I, et al. The use of 18FFDG PET speckle-tracking echocardiography is both sensitive and
in the diagnosis of cardiac sarcoidosis: a systematic review specific for the diagnosis of cardiac amyloidosis. Heart.
and meta-analysis including the Ontario experience. J Nucl 2012;98(19):1442-8.
Med. 2012;53(2):241-8. 20. Syed IS, Glockner JF, Feng D, et al. Role of cardiac magnetic
9. Osborne MT, Hulten EA, Singh A, et al. Reduction in resonance imaging in the detection of cardiac amyloidosis.
¹⁸F-fluorodeoxyglucose uptake on serial cardiac positron JACC Cardiovasc Imaging. 2010;3:155-64.
emission tomography is associated with improved left 21. Dungu JN, Valencia O, Pinney JH, et al. CMR-based
ventricular ejection fraction in patients with cardiac differentiation of AL and ATTR cardiac amyloidosis. JACC
sarcoidosis. J Nucl Cardiol. 2014;21:166-74. Cardiovasc Imaging. 2014;7:133-42.
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M, et al. Role of cardiac scintigraphy with ⁹⁹mTc-DPD in teosinophilie. Ein eigenartiges Krankheitsbild. Schweiz
8 the differentiation of cardiac amyloidosis subtype. Rev Esp

Cardiol (Engl Ed). 2012;65(5):440-6.
Med Wochenschr. 1936;66:817-20.
30. ten Oever J, Theunissen LJ, Tick LW, et al. Cardiac
23. Sharma S. Cardiac imaging in myocardial sarcoidosis involvement in hypereosinophilic syndrome. Neth J Med.
Cardiomyopathy
2011; 69(5): 240-4.

and other cardiomyopathies. Curr Opin Pulm Med. 2009;
31. Te Riele ASJM, Tandri H, Sanborn DM, et al. Noninvasive
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Multimodality Imaging in ARVD/C. J Am Coll Cardiol
24. Ishimaru S, Tsujino I, Tsukamoto E, et al. Combination Imaging. 2015;8(5):597–611.
of 18F-fluoro-2-deoxyglucose positron emission 32. Marcus FI, McKenna WJ, Sherrill D, et al. Diagnosis
tomography and magnetic resonance imaging in assessing of arrhythmogenic right ventricular cardiomyopathy/
cardiac sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis. dysplasia: proposed modification of the task force criteria.
2005;22(3):234-5. Circulation. 2010;121(13):1533-41.
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25. Skali H, Schulman AR, Dorbala S. (18)F-FDG PET/CT for 33. Morris PD, Robinson T, Channer KS. Reversible heart
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the assessment of myocardial sarcoidosis. Curr Cardiol failure: toxins, tachycardiomyopathy and mitochondrial
Rep. 2013;15(5):352. abnormalities. Postgrad Med J. 2012;88(1046):706-12.
34. Khawaja MZ, Cafferkey C, Rajani R, et al. Cardiac
In
26. Nagueh SF. Fabry disease: Clinical features, diagnosis, and
management of cardiac disease. Uptodate; 2018. complications and manifestations of chemotherapy for
cancer. Heart. 2014;100(14): 1133-40.
27. Kounas S, Demetrescu C, Pantazis AA, et al. The binary
35. Cardinale D, Colombo A, Sandri MT, et al. Prevention of
endocardial appearance is a poor discriminator of
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high-dose chemotherapy-induced cardiotoxicity in high-
Anderson-Fabry disease from familial hypertrophic risk patients by angiotensin-converting enzyme inhibitors.
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28. Brockington IF, Olsen EG. Löffler’s endocarditis and
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36. Cottin Y, L’Huillier I, Casasnovas O, et al. Dobutamine stress
Davies’ endomyocardial fibrosis. Am Heart J. 1973;85: echocardiography identifies anthracycline cardiotoxicity.
308-22. Eur J Echocardiogr. 2000;1(3):180-3.
18 cie
20 o S
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Curable Forms of Ventricular
CHAPTER 58 Dysfunction
a
di
INTRODUCTION ISCHEMIC CARDIOMYOPATHY (CORONARY
Ventricular dysfunction with subsequent heart failure ARTERY DISEASE)
In
(HF) constitutes the final common pathway for a number Coronary atherosclerosis is a common cause of ventricular
of cardiac disorders. Coronary artery disease (CAD) dysfunction, comprising 50–75% of patients with
of
or ischemic heart disease is the dominant cause of HF. ventricular dysfunction and HF. 1-3 Although the term
Other conditions which commonly lead to ventricular ‘ischemic cardiomyopathy’ has been used to describe
dysfunction and HF include hypertension, diabetes ischemic myocardial dysfunction, this is not supported by
ty
mellitus (DM), valvular heart disease, myocarditis, and the recent American Heart Association (AHA) or European
Society of Cardiology (ESC) cardiomyopathy classification
cardiomyopathies. Progressive HF decreases the quality
18 cie
of life and increases morbidity and mortality of patients
suffering from it. Incremental cost of hospitalizations, and
systems.
In some patients, persistent ventricular dysfunction
follows transient ischemia, even after the restoration
the expenses due to drugs, devices and other interventions
of coronary flow (myocardial stunning). Hibernating
20 o
results in significant economic burden to the society. In myocardium on the other hand is a state of persistently
S
this chapter, we will review some of the reversible causes of impaired ventricular dysfunction at rest due to chronically
ventricular dysfunction (Table 1) their pathophysiology, reduced coronary blood flow. This can result in HF
and management in brief. These conditions should and can be partially or completely restored to normal
al
probably be separated from cardiomyopathies and either by improving blood flow or by reducing oxygen
described as distinct entities. demand. Several tools, such as low-dose Dobutamine
ic
og
Table 1: Curable forms of ventricular dysfunction*

Common causes
ol
zz Coronary artery disease: Hibernating myocardium

zz Hypertensive heart disease
zz Diabetic cardiomyopathy
di
zz Valvular Heart disease

zz Obstructive sleep apnea
Tachycardiomyopathy (TCMP): Incessant tachycardias (both
ar
zz
zz supraventricular and ventricular tachycardias), frequent premature ventricular contractions (PVCs)

zz Drugs:** Chemotherapeutics agents (Anthracyclines, trastuzumab, cyclophosphamide), phenothiazines, clozapine, tricyclic
C
antidepressants, lithium, interleukins, 5-fluorouracil, antitubercular drugs, ionotropes, glitazones

zz Addictions: Alcohol, cocaine, amphetamines, etc.
zz Critical illness cardiomyopathy
zz Peripartum cardiomyopathy
zz Endocrine abnormalities: Hypothyroidism. hyperthyroidism, Hypoparathyroidism (hypocalcemia induced), growth hormone and/or
insulin-like growth factor 1 deficiency or excess, pheochromocytoma, Conn’s syndrome
zz Nutritional deficiencies: Thiamine, selenium, carnitine
zz Takotsubo cardiomyopathy
zz Infections: Viral myocarditis, Lyme’s disease, tuberculosis, Chagas disease, fungal infections, etc.
zz Autoimmune diseases: Systemic lupus erythomatosis (SLE), rheumatoid arthritis, Wegener’s granulomatosis, giant cell myocarditis,
sarcoidosis
zz Accessory pathway-induced cardiomyopathy: Conduction through accessory pathway causing dyssynchrony and cardiomyopathy
zz Uremic heart disease
Note:
* Although we tried to present a list of curable forms of ventricular dysfunction, some conditions may have been missed.
**Any drug used in clinical practice can cause myocarditis (immune-mediated)
KG-58.indd 481 03-11-2018 12:44:57

SECTION
8
Cardiomyopathy
a
di
In
of
B
ty
18 cie
20 o S
C
Figures 1A to C: Showing myocardial perfusion and metabolism studies with (A) Short-axis; (B) Horizontal-axis; (C) Vertical-long-axis slices.
al
Top rows in each A, B and C are a SPECT MIBI scan (perfusion) images and the bottom rows are 18-F FDG PET scan (metabolism) images. There
is significant perfusion mismatch demonstrating hibernating myocardium in the LAD territory
ic
Abbreviations: LAD, left anterior descending artery; SPECT, single-photon emission computed tomography; 18-F FDG PET-18, fluoro-2-
deoxyglucose positron emission tomography
og
stress echocardiography (DSE) and contrast-enhanced and structural abnormalities, such as fibrosis along with
ol
cardiac MRI, are helpful in identifying hibernating LVH, contribute to the development of HF with preserved
myocardium. Positron emission tomography (PET) has ejection fraction (EF). Systolic dysfunction usually follows.
di
shown that regions with abnormal wall motion, which are The mechanisms by which hypertension can cause
metabolically active, can improve after revascularization ventricular dysfunction and HF are depicted in Figure 2.
ar
(Figures 1A to C).4 Early left ventricular (LV) diastolic dyssynchrony may

Occult CAD is not an uncommon cause of dilated be associated with LV remodeling and contribute to LV
C
cardiomyopathy (DCM), it accounts for about 7% of diastolic dysfunction. The level of this dysfunction appears
otherwise unexplained cases.5 Significant coronary artery to correlate with increasing severity of hypertension.
stenosis causing ischemia in a large area of myocardium Abnormal early diastolic strain rate of the left ventricle may
can present as ventricular dysfunction (with or without be an independent factor contributing to the dysfunction.7
overt HF), and revascularization results in partial or Aggressive treatment of hypertension early in
the course of the disease may reverse the diastolic as
complete restoration of the contractile function of this
well as systolic dysfunction. In general, patients with
hibernating myocardium, and resolution of HF.
hypertension and HF with systolic dysfunction should
be treated with an angiotensin-converting enzyme (ACE)
HYPERTENSIVE HEART DISEASE inhibitor or an angiotensin receptor antagonist. Along
In persons with hypertension, ventricular relaxation with this, a beta-blocker and a mineralocorticoid-receptor
abnormalities are common. It is often accompanied by antagonist may be added if there is no contraindication.
left ventricular hypertrophy (LVH), coexistent CAD aging This results in improvement of their EF and reduction in
482
KG-58.indd 482 03-11-2018 12:44:59

CHAPTER
58

a
di
Figure 2: The pathways in the progression from hypertension to ventricular dysfunction and heart failure
1. Hypertension leading to concentric LVH. 2. Hypertension without LVH leading to decrease in LVEF with interval MI. 3. Hypertension
In
without LVH progressing to decrease in LVEF without interval MI. 4. Hypertension with LVH progressing to decrease in LVEF with interval MI.
5. Hypertension with LVH progressing to decrease in LVEF without interval MI. 6. Patients with concentric LVH developing heart failure with
a preserved LVEF. 7. Patients with decreased LVEF developing symptomatic heart failure6
Abbreviations: LVH, left ventricular hypertrophy; LVEF, left ventricular ejection fraction; MI, myocardial infarction
of
morbidity [stroke and chronic kidney disease (CKD)] and cardiovascular events in diabetic population.25-27 There are
ty
mortality. These agents have been shown to reduce LVH a growing number of trials assessing important favorable
and may be preferred agents in this subset of patients.8-12 cardiovascular health outcomes in patients taking
18 cie
The α-blockers, such as prazosin and doxazosin, are to be
avoided as the risk of HF increases with their use.13
sodium-glucose cotransporter-2 (SGLT2) inhibitors. 28,29
Peroxisome proliferator-activated receptor (PPAR)
agonists significantly increase the risk of HF30,31 and the
DIABETES MELLITUS risk of HF are intermediate with dipeptidyl peptidase-4
20 o
Heart failure is reported to be the ‘frequent, forgotten, and (DPP-4) inhibitors.32
S
often fatal complication of diabetes’.14

The role of elevated blood sugar in the causation of VALVULAR HEART DISEASE
al
various cardiovascular diseases has been investigated Valvular heart diseases, such as aortic stenosis, mitral
by several researchers.15-17 DM can cause structural and regurgitation, and pulmonary stenosis, can cause
ic
functional abnormalities of the myocardium independent ventricular dysfunction either due to pressure and/or
of atherosclerotic CAD resulting in adverse cardiovascular volume overload. These patients are managed initially with
og
events. 18 Chronic hyperglycemia in DM results in medical treatment. If valve surgery or interventions are
nonenzymatic glycation of tissue macromolecules, such performed in timely fashion, then ventricular dysfunction
as proteins, lipids, and deoxyribonucleic acid (DNA) to is reversible in some cases.33
ol
form advanced glycated end products. 19 Such products

accumulate in myocardium and subsequent fibrosis and
ALCOHOLIC CARDIOMYOPATHY
di
microangiopathy leads to structural changes.18,20,21 In the

diabetic heart, there is an increase in apoptosis leading Chronic alcohol intake in significant quantity may lead to
ar
to increased collagen deposition in a diffuse manner as biventricular dysfunction. Criteria for diagnosing alcoholic
a result of replacement fibrosis and connective tissue cardiomyopathy (ACM) include: (a) DCM phenotype, (b)
Absence of other known and detectable causes of DCM,
C
proliferation. Ultimately, there is decreased ventricular

compliance.22 Left ventricular diastolic dysfunction has and (c) Long history of heavy alcohol intake. The toxic
been proposed to be the first stage of the putative ‘diabetic effect is observed when daily alcohol consumption is over
cardiomyopathy’ which subsequently leads to systolic 80 g (three or more standard-sized drinks per day) lasting 5
dysfunction. 23 There are several mechanisms leading years or more before the onset or diagnosis.34-36 Thiamine
to HF among patients with DM,24 which are beyond the deficiency (beriberi) is no longer confused with this entity;
scope of this review. the former fully responds to thiamine administration,
Control of hyperglycemia in early stages of the whereas the latter does not.37 Although the evidence is
disease can reverse the ventricular dysfunction. Choice limited, genetic factors may predispose to ACM.38
of antidiabetic medications seems to be important. While Abstinence from alcohol is the most important aspect
all of them control the blood sugars, only some prevent of management; but ACM patients, who reduced their
or reverse the cardiac abnormalities. Metformin does alcohol intake to moderate levels, exhibited similar
not have adverse cardiovascular effects and decreases cardiac function recovery as abstainers.39
483
KG-58.indd 483 03-11-2018 12:45:00

SECTION COCAINE America. Clinically, it presents as acute myocarditis,
cardiac enlargement, tachycardia, and nonspecific
8
Cocaine abuse generally leads to coronary ischemia; but,
electrocardiogram abnormalities including right bundle
sometimes, it can lead to development of cardiomyopathy
branch block and premature ventricular contractions and
although the mechanism is not well understood. Cocaine
Cardiomyopathy
left ventricular apical aneurysms that are pathognomonic

abuse should be suspected when a young person presents
for this disease.
with cardiomegaly and otherwise unexplained HF.
Antitrypanosomal therapy is useful to treat patients
Direct toxic effect, cocaine-induced hyperadrenergic
with early chronic Chagas disease (CD). In patients with
state, and in parenteral cocaine abusers, concomitant
advanced DCM, the focus of management is supportive
infective endocarditis are possible mechanisms. Complete
care for HF, arrhythmia, and thromboembolism since
reversal of the myocardial dysfunction usually follows
antitrypanosomal therapy is unlikely to be effective in
abstinence.40,41
a
reversing established myocardial disease.47
di
MEDICATIONS Lyme Disease
Drugs can cause cardiomyopathy (see Table 1), significant
In
Lyme disease is usually manifested as a conduction
improvement can occur after discontinuation. The abnormality, but cardiac muscle dysfunction can
most extensively studied example is anthracycline- also occur; it is usually self-limited and mild, leading
of
induced cardiomyopathy. Trastuzumab is another to transient cardiomegaly or pericardial effusion on
chemotherapeutic agent associated with frequent echocardiogram or chest radiograph. However, occasional
cardiotoxicity particularly in patients also treated with an patients develop symptomatic myocarditis and DCM.
ty
anthracycline plus cyclophosphamide.42 Patients with Lyme carditis are treated with antibiotics
Early discontinuation of the culprit medication and to prevent later complications of Lyme disease and to
18 cie
supportive treatment reverses ventricular dysfunction.
INFECTIOUS CARDIOMYOPATHY
shorten the duration of the cardiac manifestations.48
Myocardial Tuberculosis
Although rare, myocardial tuberculosis can cause signi-
20 o
A variety of infectious organisms can lead to myocarditis
and ventricular dysfunction. ficant cardiovascular abnormalities, such as unexplained
S
VT, atrioventricular blocks, and cardiomyopathy, and even

Viral Cardiomyopathy sudden death. This is discussed in greater detail under
granulomatous myocarditis.
al
The most common cause of myocarditis is viral infection,

and this can lead to development of DCM. Causative
Trace Elements
ic
viruses include parvovirus B19, human herpesvirus 6,

coxsackievirus, influenza virus, adenovirus, echovirus, Trace elements play an important role in myocardial
og
cytomegalovirus, and human immunodeficiency virus metabolism and their excess, e.g. cobalt, arsenic or
(HIV).43 deficiency like selenium can lead to development in a
The degree of viremia is limited by the initial immune reversible form of DCM that is very similar to an idiopathic
ol
response early during infection and protects against cardiomyopathy.49-54

myocarditis. But, if this response is not sufficient, the virus
Peripartum Cardiomyopathy
di
may not be eliminated, and myocyte injury may ensue via

one or two mechanisms: (a) Receptor-mediated entry of Presenting in late pregnancy and the early postpartum
ar
the virus into cardiac myocytes causing direct cytotoxicity, period, peripartum cardiomyopathy (PPCM) is a rare
and (b) An adverse autoimmune response induced cause (0.1% of all pregnancies) of DCM. Despite many
attempts to uncover a distinct etiology of PPCM, the
C
by persisting viral genomic fragments that may not be

capable of replicating as intact virus. cause remains unknown and may be multifactorial.
If there is early recovery from the viral infection, Alterations in prolactin processing may contribute to the
then ventricular dysfunction reverses. Management of angiogenic imbalance, which can lead to development
myocarditis includes general nonspecific measures, such of PPCM.55 Diagnosis requires exclusion of other causes
as HF therapy, treatment of arrhythmias according to of cardiomyopathy. A variety of definitions have been
current guidelines, and if required anticoagulation. The proposed for this disorder.56 The LV may not be dilated,
efficacy of antiviral, immunosuppressive, and intravenous but the EF (EF) is always reduced below 45%.56 Ventricular
immune-globulin therapies are being investigated in these dysfunction recovers over a period. But recurrence rates in
patients.44-46 subsequent pregnancies are very high.
Chagas Disease Autoimmune Disorders

Protozoa Trypanosoma cruzi is the causative organism; it The DCM can be caused by autoimmunity, 57 and the
484 is the most common cause of DCM in Central and South presence of autoantibodies may identify family members
KG-58.indd 484 03-11-2018 12:45:01

of patients with DCM who are at a greater risk of developing factor-1 (IGF-1) can also cause reversible forms of CHAPTER
cardiomyopathy. DCM.64,65
Several cardiac autoantibodies have been identified
which target a variety of antigens. The following are some
58
Nutritional Deficiencies

of the examples: beta-1 adrenoceptor, alpha-myosin heavy
Deficiencies in thiamine, selenium, and carnitine have
chain, beta-myosin heavy chain, myosin light chain, and
been reported to produce ventricular dysfunction and
troponin. All these autoantibodies are sometimes referred
replacement therapy is curative.66,67
to as antiheart antibodies (AHAs). Therapy should be
Thiamine is very important in normal oxidative
directed towards the underlying disease. Treatment
phosphorylation and myocardial energy production.
options, such as immunoadsorption, can reverse the
Its deficiency initially presents as a high output state
ventricular dysfunction.58
a
secondary to vasodilation; this is followed by depression of
myocardial function and the development of a low-output
Systemic Lupus Erythematosus
di
state.66
Systemic lupus erythematosus (SLE) commonly involves Selenium (Se) deficiency causes increased free radicals
In
the heart. Valvular, pericardial, coronary disease or that are toxic to cardiac myocytes due to decrease in
myocarditis can develop. Myocarditis can present with the activity of glutathione peroxide. The development
resting tachycardia disproportionate to body temperature,
endemic cardiomyopathy that affects children and women
of
electrocardiographic abnormalities (such as ST-T
of childbearing age in areas of China known as Keshan
wave abnormalities), and unexplained cardiomegaly.
disease has been linked to Se deficiency. 68 Keshan disease
Immunosuppressive therapy occasionally leads to
is associated with local diets, which are nearly devoid of Se
ty
improved myocardial function in this setting.
in these geographical areas.
Carnitine deficiency results in lipid accumulation in
Celiac Disease 18 cie
As many as 5% of patients with autoimmune myocarditis
the myocyte cytoplasm due to impaired oxidation of fatty
acids. This can be reversed by carnitine supplements.
or idiopathic DCM can be caused by celiac disease,
20 o
which is often clinically unsuspected.59,60 The disease
Obstructive Sleep Apnea
can be subclinical presenting only as iron deficiency
S
anemia refractory to iron replacement.59 Cardiac function Obstructive sleep apnea can contribute to the impairment
improves following a gluten-free diet with or without of left ventricular dysfunction. A history of snoring,
al
immunosuppressive therapy. daytime somnolence, and obesity should alert the

It is premature to screen all patients with otherwise clinician to the diagnosis. Effective therapy, as with
ic
unexplained cardiomyopathy for celiac disease. Still, it is nasal continuous positive airway pressure during sleep,
reasonable to elicit history of gastrointestinal complaints can lead to a significant improvement in left ventricular
og
or refractory iron deficiency. dysfunction.69
Endocrine Dysfunction Tachycardiomyopathies

ol
Thyroid dysfunction, excess sympathetic activity in In routine clinical practice, arrhythmias are a common
cause of cardiomyopathy which is potentially reversible
di
pheochromocytoma, and rarely Cushing’s syndrome and

growth hormone (GH) excess or deficiency can cause but often overlooked. Practically, any kind of incessant
tachycardia can lead to tachycardiomyopathies (TCMP)
ar
cardiac dysfunction, which can usually be reversed by

correction of the endocrine disorder.61-64 including: atrial tachycardia (AT), atrial fibrillation (AF),
The exact mechanisms of thyroid dysfunction leading atrial flutter, atrioventricular re-entrant tachycardia,
C
to DCM are not known. Preload, afterload, heart rate, atrioventricular nodal re-entrant tachycardia, junctional
and contractility of heart are altered by thyroid hormone ectopic tachycardia, ventricular tachycardia (VT), frequent
each of which may contribute to cardiac dysfunction. premature ventricular contractions (PVCs) and right
Experiments have also shown that excess triiodothyronine ventricular pacing.70-84
(T3) causes myocyte hypertrophy and changes in specific When patients present with tachyarrhythmia and
protein synthesis.61 unexplained DCMP, it may be difficult to know whether
Excess sympathomimetic amines in pheochromo- HF is the cause or effect of tachycardia. 85 Thus, while
cytoma leads to focal direct myocyte injury followed managing these cases, we should focus on treatment of
by inflammation, downregulation of beta-receptors, HF and control of arrhythmia. The presence of tachycardia
ultimately leading to net reduction of viable myofibrils.62 may limit the therapy for HF. In cases like atrial tachycardia,
As many as 10% of patients with newly diagnosed radiofrequency catheter ablation (RFCA) should be
acromegaly have HF due to high cardiac output. 63 considered early, as it has a curative potential and is
Deficiency of growth hormone or interleukin growth associated with high success rate (Figures 3A and B). 485
KG-58.indd 485 03-11-2018 12:45:01

SECTION
8
Cardiomyopathy
A(I) B(I)
a
di
In
of
A(II) B(II)
Figures 3A and B: (A) 12-lead ECG of a patient who presented with tachycardiomyopathy: A(I) Focal atrial tachycardia. A(II) Sinus rhythm ECG
ty
of same patient after radiofrequency ablation of atrial tachycardia; (B) Chest X-ray of same patient B(I) Chest X-ray at the time of presentation
B(II) Chest X-ray one week after radiofrequency catheter ablation
catheter ablation.86
18 cie
Ventricular dysfunction due to TCMP can be cured by underlying inflammation along with antiarrhythmic drugs
and standard treatment of HF (Figures 4A and B).94-97
20 o
There are two categories of TCMP: (a) first where Corticosteroids are the first line of therapy in sarcoidosis.
arrhythmia is the cause of cardiomyopathy (arrhythmia- However, methotrexate can be used as a steroid sparing
S
induced) which completely reverses once tachycardia agent for long-term suppression of ongoing inflammation.
is taken care of, and (b) where arrhythmia exacerbates Similarly, in CTB, left ventricular function and HF can
al
the underlying ventricular dysfunction in a patient with improve with antitubercular therapy and short course of
known myocardial disease (arrhythmia mediated). 82 steroids.98
ic
TCMP as a cause of HF can only be evident once sinus

rhythm is restored. Accessory Pathway-induced Cardiomyopathy
og
The mechanism of myocyte dysfunction in TCMP is not In the current era, any symptomatic patient with HF and
completely defined, but includes oxidative mitochondrial left bundle branch block (LBBB) (QRS ≥150 ms) in sinus
damage, subclinical ischemia and calcium overload.85,87,88 rhythm on guideline-directed medical therapy (GDMT)
ol
A timely recognition and treatment of culprit arrhythmia is considered for cardiac resynchronization therapy
is important, in view of potential for complete recovery of (CRT).99However, it is prudent to evaluate such patients for
di
ventricular dysfunction. the underlying etiology before implanting CRT.

Accessory pathways cause pre-excitation of small part
ar
Granulomatous Myocarditis of the ventricular myocardium. Incessant tachyarrhythmia

Granulomatous myocarditis (GM) mainly comprising of in patients with Wolff–Parkinson–White (WPW) syndrome
C
cardiac sarcoidosis (CS) and cardiac tuberculosis (CTB) is can result in TCMP. However, the possibility of accessory
prevalent but under-recognized in India. Diagnoses of these pathway-induced dysynchrony must not be ignored.
entities have more often been made at autopsy highlighting Patients with right-sided accessory pathways (type
the difficulty in diagnosing.89-93 Cardiomyopathy with or B WPW syndrome) have wide QRS pattern similar
without HF may be one of the initial clinical presentations. to LBBB which can cause LV dyssynchrony-induced
Paucity of constitutional symptoms and lack of awareness cardiomyopathy. Such patients have a gratifying outcome
results in delayed diagnosis. Besides routine clinical following radiofrequency ablation (RFA).100-104 In general,
evaluation and laboratory tests, cardiac MRI, CT chest and the indication of RFCA in patients with WPW syndrome is
FDG-PET (Fluorine-18 fluoro-2-deoxyglucose positron frequent episodes of tachycardia with or without medical
emission tomography) help in evaluation of GM. therapy.105 However, in some patients, RFA is performed
The optimal treatment modality for GM with HF is not for tachyarrhythmias but to restore LV synchrony
not well defined. Left ventricular function can improve and normalize the LV function, as a treatment for HF
significantly with disease-specific therapy of the (Figures 5A and B).
486
KG-58.indd 486 03-11-2018 12:45:02

CHAPTER
58

B(I)
a
A B(II)
di
Figures 4A and B: (A) FDG-PET CT of a patient who presented with heart failure showing diffuse heterogeneous uptake in LV with maximum
uptake in apicolateral segment; (B) 12-lead ECG of same patient B(I) Baseline ECG at the time of presentation showing LBBB. B(II) ECG six
In
months after disease specific therapy (immunosuppressant) showing normalization of LBBB
Abbreviations: LBBB, left bundle branch block; FDG-PET CT, fluorine-18 fluoro-2-deoxyglucose positron emission tomography and computed
tomography; LV, Left ventricle.
of
ty
18 cie
20 o S
A(I) A(II)
al
ic
og
ol
di
ar
C
B(I) B(II)
Figures 5A and B: 1. 12-lead ECG of a patient who presented with WPW syndrome with LV dysfunction: A(I) Showing LBBB type of pre-
excitation (type B WPW syndrome); A(II) ECG after radiofrequency catheter ablation of pathway (B) Fluoroscopy (AP view) of the same patient.
B(I) White arrow showing ablation catheter at the site of RFCA. B(II) Contrast injection (white arrow) at the site of successful catheter ablation
for accessory pathway, which is right atrial appendage
Abbreviations: AP, anteroposterior; LV, left ventricle; RFCA, radiofrequency catheter ablation; LBBB, left bundle branch block; WPW, Wolff–
Parkinson–White
Left Apical Ballooning Syndrome to a balloon-like appearance of the distal ventricular

The left apical ballooning syndrome, or Takotsubo walls in systole. It mimics acute coronary syndrome in
cardiomyopathy, is characterized by transient hypo- the absence of CAD or spasm. It is most prevalent in
contractility of the mid and apical segments of the LV older women exposed to emotional or physical stressors.
associated with hyperkinesis of the basal walls. This leads This can present atypically such as reversed and right
487
KG-58.indd 487 03-11-2018 12:45:03

SECTION ventricular Takotsubo and global hypokinesis.106,107 It is 4. Tillisch J, Brunken R, Marshall R, et al. Reversibility of
generally associated with increased levels of circulating cardiac wall-motion abnormalities predicted by positron
8 catecholamines, especially epinephrine. Sometimes, it

does not follow obvious physical or emotional stress;
tomography. N Engl J Med. 1986;314(14):884-8.
5. Felker GM, Thompson RE, Hare JM, et al. Underlying causes
and long-term survival in patients with initially unexplained
Cardiomyopathy
superadded, it may carry significant early and late serious

cardiomyopathy. N Engl J Med. 2000;342(15):1077-84.
complication risks. Concomitant subcritical CAD may be
6. Drazner MH. The transition from hypertrophy to failure:
present; and cardiovascular risk factors can be present.107 how certain are we? Circulation.2005;112(7):936–8.
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to emotional stress, is largely reversible, and carries a in relation to left ventricular remodeling and function in
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a
morphologic LV abnormalities and remodeling that enalapril on mortality and the development of heart failure
di
characterize DCM. in asymptomatic patients with reduced left ventricular
ejection fractions. N Engl J Med. 1992;327(10):685-91.
In
9. Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/ AHA
Uremic Cardiomyopathy
guideline for the management of heart failure: executive
Chronic renal diseases can get complicated by developing summary: a report of the American College of Cardiology
uremic cardiomyopathy and is considered a risk factor for
of
Foundation/American Heart Association Task Force on
morbidity and mortality.109 Approximately 50% of deaths practice guidelines. Circulation. 2013;128(16):1810-52.
in patients with CKD occurs due to CAD, LV hypertrophy 10. Sakata Y, Shiba N, Takahashi J, et al. Clinical impacts of
additive use of olmesartan in hypertensive patients with
ty
and congestive HF. Proper etiology is unclear but uremic
toxins, renin-angiotensin-aldosterone system activation, chronic heart failure: the supplemental benefit of an
angiotensin receptor blocker in hypertensive patients with
18 cie
sympathetic nervous system activation, anemia, calcium
phosphate imbalance, and inflammation are emerging
as factors involved in the pathogenesis of cardiac disease
stable heart failure using olmesartan (SUPPORT) trial. Eur
Heart J. 2015;36(15):915-23.
11. Pitt B, Zannad F, Remme WJ, et al. The effect of
in CKD.110, 111 Frequent hemodialysis (nocturnal home
20 o
spironolactone on morbidity and mortality in patients with
hemodialysis, short daily hemodialysis, and peritoneal severe heart failure. Randomized Aldactone Evaluation
S
dialysis) optimizes the ultrafiltration rate with minimal Study Investigators. N Engl J Med. 1999;341(10):709-17.
reductions in intravascular volume and cooling the 12. Pitt B, Remme W, Zannad F, et al. Eplerenone, a selective
dialysate as compared with conventional hemodialysis
al
aldosterone blocker, in patients with left ventricular

(3 days per week); this reduces dialysis-induced dysfunction after myocardial infarction. N Engl J Med
myocardial stunning and intradialysis hypotension. 2003;348(14):1309-21.
ic
Uremic cardiomyopathy can be reversed after kidney 13. Major cardiovascular events in hypertensive patients
randomized to doxazosin vs chlorthalidone: the
og
transplantation and it confers a significant survival

Antihypertensive and Lipid-Lowering Treatment to Prevent
advantage over hemodialysis.112 Early diagnosis of uremic
Heart Attack Trial (ALLHAT): ALLHAT Collaborative
cardiomyopathy contributes to risk stratification and
Research Group [published correction appears in JAMA.
ol
decisions about proper type of dialysis therapy.113

2002;288(23):2976]. JAMA. 2000;283(15):1967–75.
14. Bell DS. Heart failure: the frequent, forgotten, and often fatal
di
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Clinical evaluation patients of ventricular dysfunction with 41.
ar
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C
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it. Treatment of these correctable factors helps to reverse
2005;15(4):635–40.
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16. Kannel WB, Hjortland M, Castelli WP. Role of diabetes
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Electrophysiologic studies in patients with persistent atrial
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acromegaly. Am J Med.2002;112(8):610-6. Neurohormonal, structural, and functional recovery
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64. Frustaci A, Perrone GA, Gentiloni N, et al. Reversible dilated pattern after premature ventricular complex ablation
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cardiomyopathy due to growth hormone deficiency. Am J is independent of structural heart disease status in
Clin Pathol.1992;97(4):503-11. patients with depressed left ventricular ejection fraction:
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insulin-like growth factor I and risk for heart failure 2013;62(13):1195–202.

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66. Abelmann WH, Lorell BH. The challenge of cardiomyopathy. 2015;66(15):1714–28.

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cardiomyopathy: prevalent, under-recognized, reversible. J
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86. Hanumandla A, Kaur D, Shah M, et al. Epicardial ablation
accuracy of NT-proBNP ratio (BNP-R) for early diagnosis of
of focal atrial tachycardia arising from left atrial appendage
tachycardia-mediated cardiomyopathy: a pilot study. Clin
Res Cardiol. 2011;100(10):887–96. in children. Indian Pacing Electrophysiol J. 2014;14(4):199-
71. Allen HW. Auricular fibrillation. Cal State J Med. 202.
1913;11:435–40. 87. Morris PD, Robinson T, Channer KS. Reversible heart
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cardiomyopathy. Circ J.2007;71(6):936–40. myocarditis. Tex Heart Inst J. 2003;30(1):76-9.
73. Pizzale S, Lemery R, Green MS, et al. Frequency and 89. Roberts WC, McAllister HA Jr, Ferrans VJ. Sarcoidosis of
predictors of tachycardia-induced cardiomyopathy the heart. A clinicopathologic study of 35 necropsy patients
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91. Veinot JP, Johnston B. Cardiac sarcoidosis--an occult cause
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cardiomyopathy in children with ventricular preexcitation:
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the location of the accessory pathway is predictive of this
Forensic Sci. 1998;43(3):715-7. association. J Electrocardiol. 2010;43(2):146-54.
92. Wallis PJ, Branfoot AC, Emerson PA. Sudden death due to 104. Nakabayashi K, Sugiura R, Mizuno Y, et al. Successful catheter
myocardial tuberculosis. Thorax.1984;39(2):155-6. ablation as a substitute for cardiac resynchronization
93. Rose AG. Cardiac tuberculosis. A study of 19 patients. Arch therapy in patient with an accessory pathway-induced
Pathol Lab Med. 1987;111(5):422–6. cardiomyopathy. Intern Med. 2017;56(16):2165-9.
94. Banba K, Kusano KF, Nakamura K, Morita H, Ogawa A, 105. Page RL, Joglar JA, Caldwell MA, et al. 2015 ACC/ AHA/
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and disease activity in cardiac sarcoidosis. Heart Rhythm. supraventricular tachycardia: a report of the American
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abnormalities. J Cardiovasc Electrophysiol. 2009;20(5):578- Takotsubo cardiomyopathy. Circ J.2014;78(9):2119-28.
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MA. Impact of early initiation of corticosteroid therapy cardiomyopathy: clinical characteristics and outcomes.
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on cardiac function and rhythm in patients with cardiac
sarcoidosis. Int J Cardiol. 2017;227:565-70. 109.
Rev Cardiovasc Med. 2015;16(4):244-52.
Alhaj E, Alhaj N, Rahman I, t al. Uremic cardiomyopathy:
98. Mohan A, Thachil A, Sundar G, Sastry BK, Hasan A, an underdiagnosed disease. Congest Heart Fail.
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Sridevi C, et al. Ventricular tachycardia and tuberculous 2013;19(4):E40-5.
lymphadenopathy: sign of myocardial tuberculosis? J Am 110. Chinnappa S, Hothi SS, Tan LB. Is uremic cardiomyopathy
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Coll Cardiol. 2015;65(2):218-20. a direct consequence of chronic kidney disease? Expert Rev
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Coats AJS, et al. 2016 ESC Guidelines for the diagnosis 111. Gansevoort RT, Correa-Rotter R, Hemmelgarn BR, et
and treatment of acute and chronic heart failure. Rev Esp al. Chronic kidney disease and cardiovascular risk :
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in Wolff-Parkinson-White syndrome: a possible cause of 112. Zolty R, Hynes PJ, Vittorio TJ. Severe left ventricular systolic
dilatative cardiomyopathy. Int J Cardiol.2008;123(2):e31-4. dysfunction may reverse with renal transplantation:
101. Tomaske M, Janousek J, Rázek V, et al. Adverse effects uremic cardiomyopathy and cardiorenal syndrome. Am J
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of Wolff-Parkinson-White syndrome with right septal or Transplant. 2008;8(11):2219-24.

posteroseptal accessory pathways on cardiac function. 113. Hassanin N, Alkemary A. Early detection of subclinical
Europace. 2008;10(2):181-9. u re m i c ca rd i o myo p at hy u s i ng t w o - d i m e n s i o na l
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102. Iwasaku T, Hirooka K, Taniguchi T, et al. Successful speckle tracking echocardiography. Echocardiography.
catheter ablation to accessory atrioventricular pathway as 2016;33(4):527-36.
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CHAPTER 59 Myocarditis: An Update
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INTRODUCTION CLASSIFICATION OF MYOCARDITIS
Myocarditis is an inflammatory disease of heart muscle Myocarditis can be of various types based on etiology,
In
diagnosed by established histological, immunological histology (lymphocytes, eosinophils, giant cells,
and immunohistochemical criteria.1,2 It has infectious and granulomatous, etc.), immunohistology and clinical
noninfectious etiology. It usually presents with nonspecific status (acute, fulminant or chronic). Viral myocarditis has
of
symptoms and signs. Myocarditis may have a fulminant histological evidence of inflammatory infiltrates in the
course with high morbidity and mortality or may present myocardium as per Dallas criteria associated with positive
ty
with chronic course of left ventricular dysfunction (LVD), viral polymerase chain reaction (PCR).
dilated cardiomyopathy (DCM), chronic heart failure, Autoimmune myocarditis has histological evidence
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conduction disturbances, ventricular arrhythmias, and
sudden death. Due to these varied presentations and
outcomes, a high degree of suspicion early in the course of
of myocarditis with negative viral PCR with or without
serum cardiac autoantibodies. There can also be a clinical
scenario with histological evidence of myocarditis, positive
disease is essential for the clinical diagnosis of myocarditis. viral PCR and positive serum cardiac autoantibodies.
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The incidence of biopsy proven myocarditis in adults Patients presenting with acute onset and fulminant
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with nonischemic DCM is reported to be 3–16% in the clinical course with development of recurrent ventricular
Western literature. However, there is paucity of data from tachycardia, high-grade atrioventricular block or failure to
our country. show response to optimum heart failure treatment may be
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suffering from giant cell myocarditis. This subgroup has

ETIOPATHOGENESIS poor prognosis. Early endomyocardial biopsy (EMB) can
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help in the histological diagnosis and guide appropriate

The most common cause of myocarditis is due to various
therapy.
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infectious agents. Hypersensitivity or toxic reaction to

Cardiac sarcoidosis is suspected in patient presenting
drugs and autoimmune mechanism also initiate the
with chronic heart failure, dilated cardiomyopathy,
process of myocardial inflammation in a susceptible host.3
new onset ventricular arrhythmia, and high-grade
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Table 1 enumerates some of the common etiological

atrioventricular block not responding to conventional
agents in the pathogenesis of myocarditis.
treatment.
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The progression from acute tissue injury to chronic

dilated cardiomyopathy passes through three phases
CLINICAL FEATURES
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(Figure 1).4,5 In the rodent model and isolated cell system

studies of molecular basis of myocardial inflammation, Myocarditis commonly presents with nonspecific
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virus enters myocardial cells through specific receptors symptoms of palpitation, malaise, exertional
and coreceptors. The virus after gaining entry into the cell breathlessness, fatigue, chest pain and syncope. Chest pain
has cytopathic effect in the initial weeks post infection. An may mimic myocardial ischemia but coronary angiography
innate humoral and cellular immune response consisting shows normal coronaries.7 Acute fulminant myocarditis
of macrophages, CD4+ and CD8+ T lymphocytes is has symptoms of acute heart failure, tachyarryhthmia,
started through toll-like receptors and pattern recognition syncope, and cardiogenic shock. There may be preceding
receptors in patients with tissue injury to remove the history of viral exanthema or exposure to new drug or
invading infectious agent. However, inflammation may toxin. Also, some patients of systemic autoimmune
damage cardiac myocytes with the release of hidden disorder may present with symptoms of myocarditis. In
antigens from cells (troponins) and generation of India, rheumatic carditis, tubercular myocarditis and viral
autoantibodies. This leads to further myocardial damage, infection, such as dengue and chickungunya, as causes
LVD and dilatation. Genetic predisposition may play a role of myocarditis are also reported.8-10 A clinicopathological
in the development of viral and autoimmune myocarditis correlation helps in prognosticating and planning line
in susceptible humans.6 of management including advanced life support and left
KG-59.indd 492 03-11-2018 12:44:29

Table 1: Causes of myocarditis2 CHAPTER
59
1. Infectious myocarditis
Bacterial Staphylococcus, Streptococcus, Pneumococcus, Meningococcus, Gonococcus, Salmonella, Corynebacterium
diphtheriae, Haemophilus influenzae, Myobacterium (tuberculosis), Mycoplasma pneumoniae, Brucella
Spirochaetal Borrelia (Lyme disease), Leptospira (Weil disease)
Fungal Aspergillus, Actinomyces, Blastomyces, Candida, Coccidioides, Cryptococcus, Histoplasma,
Mucormycoses, Nocardia, Sporothrix
Protozoal Trypanosoma cruzi, Toxoplasma gondii, Entamoeba, Leishmania
Parasitic Trichinella spiralis, Echinococcus granulosus, Taenia solium
Rickettsial Coxiella burnetti (Q fever), R. rickettsia (Rocky Mountain Spotted fever), R. tsutsugamuschi
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Viral RNA viruses: Cox sackie viruses A and B, echo viruses, polio viruses, influenza A and B viruses, respiratory
syncytial virus, mumps virus, measles virus, rubella virus, hepatitis C virus, dengue virus, yellow fever
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virus, Chikungunya virus, Junin virus, Lassa fever virus, rabies virus, human immunodeficiency virus-1
DNA viruses: Adenoviruses, parvovirus B19, cytomegalovirus, human herpes virus-6, Epstein-Barr virus,
varicella-zoster virus, herpes simplex virus, variola virus, vaccinia virus
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2. Immune-mediated myocarditis
Allergens Tetanus toxoid, vaccines, serum sickness
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Drugs: Penicillin, cefaclor, colchicine, furosemide, isoniazid, lidocaine, tetracycline, sulfonamides,
phenytoin, phenylbutazone, methyldopa, thiazide diuretics, amitriptyline
Alloantigens Heart transplant rejection
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Autoantigens Infection-negative lymphocytic, infection-negative giant cell
Associated with autoimmune or immune-oriented disorders: Systemic lupus erythematosus, rheumatoid
arthritis, Churg-Strauss syndrome, Kawasaki’s disease, inflammatory bowel disease, scleroderma,
3. Toxic myocarditis
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polymyositis, myasthenia gravis, insulin-dependent diabetes mellitus, thyrotoxicosis, sarcoidosis,
Wegener’s granulomatosis, rheumatic heart disease (rheumatic fever)
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Drugs Amphetamines, anthracyclines, cocaine, cyclophosphamide, ethanol, fluorouracil, lithium,
catecholamines, hemetine, interleukin-2, trastuzumab, clozapine
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Heavy metals Copper, iron, lead (rare, more commonly cause intramyocyte accumulation)
Miscellaneous Scorpion sting, snake and spider bites, bee and wasp stings, carbon monoxide, inhalants, phosphorus,
arsenic, sodium azide
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Hormones Phaeochromocytoma, vitamins: beri-beri

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Physical agents Radiation, electric shock

*Reprinted from Carforia ALP, et al. Position statement of the European Society of Cardiology working group of myocardial and pericardial
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diseases, Eur Heart J. 2013;34:2636-48, with permission from Oxford University Press and the European Society of Cardiology.
INVESTIGATIONS
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Electrocardiogram
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The sensitivity of electrocardiogram (ECG) in the diagnosis

of myocarditis is low. 2 ECG may show the following
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abnormalities in acute myocarditis:

Sinus tachycardia
Generalized ST-T segment elevation/depression, T

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wave inversion
Atrioventricular(AV) block
QRS prolongation, left bundle branch block (LBBB),
pathological Q waves, ventricular tachycardia,

Figure 1: Pathophysiological process of virus myocarditis fibrillation, supraventricular tachyarrythmia.11 These
ECG findings may indicate poor prognosis.
ventricular assist devices. In known patients of dilated
cardiomyopathy, hypertensive heart disease or chronic Echocardiography
heart failure, unexplained deterioration in clinical status
Two-dimensional echocardiography helps to rule out other
despite optimum medical therapy should raise suspicion
causes of cardiac dysfunction like valvular heart disease. It
of associated myocarditis.
also helps to monitor the progression of disease. There
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KG-59.indd 493 03-11-2018 12:44:30

SECTION may be biventricular chamber dilatation, global LVD or
regional wall motion abnormality. Valvular regurgitation
8 and evidence of pulmonary hypertension may be seen.
Increased sphericity of LV with increased volume suggests
Cardiomyopathy
acute myocarditis.12,13 In fulminant myocarditis, smaller

LV cavity size with increased ventricular wall thickness
due to edema and decreased contractility is observed.
Tissue Doppler and strain rate imaging are the new
modalities to assess myocardial function in suspected
myocarditis.
A B
a
Biomarkers
Figures 2A and B: Cardiovascular magnetic resonance image.
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Inflammatory markers like C-reactive protein (CRP) and Short-axis cardiac magnetic resonance imaging of a patient with
erythrocyte sedimentation rate (ESR) are elevated. acute myocarditis. (A) T2-weighted image, showing regional edema
In
Elevated biomarker of myocardial injury like troponin of the lateral left ventricle predominantly subepicardial involvement
I is highly specific (89%) but of limited sensitivity (34%). (arrow); (B) Late enhancement image, demonstrating high signal
intensity in the epicardial region of the lateral wall of the left
However, it is more sensitive than creatine kinase levels.14
ventricle (arrow)
of
Others like circulatory cytokines and brain natriuretic Source: Used with permission from Oxford University Press
peptide may also be elevated. However, positive viral
serology has limited diagnostic utility. etiology and type of inflammation. At least three biopsy
ty
Serum cardiac autoantibodies to cardiac and muscle samples (1–2 mm size) should be obtained from either
specific autoantigens have been evaluated in research ventricle or biventricular sites.2
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laboratories but not yet available for commercial use.15
Cardiovascular Magnetic Resonance Imaging

Dallas histopathological criteria ares useful to arrive at
the diagnosis. It defines active myocarditis as inflammatory
infiltrate with necrosis and/or degeneration of adjacent
Cardiovascular magnetic resonance imaging (CMR) helps
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myocytes not typical of ischemic damage.20 However,
in myocardial tissue characterization noninvasively. It can there is large interobserver variability in pathological
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detect inflammation, edema, necrosis and fibrosis within interpretation. It does not detect noncellular inflammation
myocardial tissue.16 It should be considered before an and the diagnostic yield is only 10–20%. 21 Therefore, a
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EMB in suspected patients of myocarditis who are stable. combination of histopathology, immunohistochemistry
Var ious imaging s e quence provide different and molecular detection of viral genomic sequence in
information. 17,18 T2-weighted imaging can detect
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diseased myocardium improves the diagnostic yield.

myocardial edema and tissue hyperemia which is surrogate Immunohistological evidence of inflammatory
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of inflammation (Figures 2A and B). Contrast imaging infiltrates is associated with risk of death and need for
with Gadolinium can show early capillary leakage on the cardiac transplantation.22 Persistence of viral genome in
basis of T1-weighted early Gadolinium enhancement. myocardium has shown to progress to end-stage dilated
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Late Gadolinium enhancement (LGE) is diagnostic of cardiomyopathy (DCM).23

myocardial necrosis and fibrosis. LGE in myocarditis can Therefore, EMB may help to select the mode of therapy
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have two types of presentation: in a patient. Biopsy specimen showing specific human
1. Intramural rim-like pattern involving septum
leukocyte antigen (HLA) markers with the absence of
ar
2. Patchy epicardial distribution on lateral LV free wall.

infectious agent (PCR-negative for viral genome) may be
An international consensus group on CMR diagnosis of
candidate for immunosuppressive therapy.24,25
myocarditis have developed certain criteria (Lake Louise
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criteria). If two of the three criteria are positive, it has

sensitivity of 67%, specificity of 91%, positive predictive NATURAL COURSE OF DISEASE
value 91%, and negative predictive value of 69%.19 Acute myocarditis resolves in 50% cases within 2–4 weeks.
However, CMR has some limitations like it is less Twenty-five percent will develop persistent cardiac
sensitive in borderline myocarditis, inability to provide dysfunction. Twelve to twenty five percent deteriorate
information of degree of inflammation and it does not acutely and may not survive or develop end-stage DCM
identify specific forms of myocarditis (viral, bacterial, (Figure 3). 2 Survival in giant cell myocarditis is even
granulomatous or eosinophilic, etc.).4 worse.
This subgroup of fulminant progressive myocarditis,
Endomyocardial Biopsy especially in children, may be candidates for ventricular
Endomyocardial biopsy (EMB) is confirmatory in the assist device, extracorporeal membrane oxygenation
diagnosis of myocarditis. It helps in identifying the (ECMO) and cardiac transplantation.
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CHAPTER
59
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Figure 3: Evolution of acute viral myocarditis
Abbreviation: DCM, dilated cardiomyopathy
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Box 1: Current recommendations for immunosuppressive therapy
z
z
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Immunosuppression should be started only after ruling out active infection on EMB by PCR.
Based on experience with noncardiac autoimmune disease, consideration of immunosuppression in proven autoimmune (for example,
infection negative) forms of myocarditis, should be made if no contraindications to immunosuppression are present, including giant-cell
myocarditis, cardiac sarcoidosis, and myocarditis associated with known extracardiac autoimmune disease.
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z Steroid therapy is indicated in cardiac sarcoidosis in the presence of ventricular dysfunction and/or arrhythmia and in some forms of
infection negative eosinophilic or toxic myocarditis with heart failure and/or arrhythmia.
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z Immunosuppression can be considered, on an individual basis, in infection negative lymphocytic myocarditis refractory to standard
therapy in patients with no contraindications to immunosuppression.
Follow-up EMB can be required to guide the intensity and the length of immunosuppression.
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z
Abbreviations: EMB, endomyocardial biopsy; PCR, polymerase chain reaction

Source: Reprinted with permission from Oxford University Press and the European Society of Cardiology.
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MANAGEMENT Immunosuppressive Therapy

Guidelines directed management of heart failure and Corticosteroids, azathioprine and cyclosporine have been
arrhythmia is recommended. Therapy directed towards studied in various combinations in acute autoimmune
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specific etiology of myocarditis may be considered. Acute virus-negative myocarditis with mixed result. The role
fulminant cases of myocarditis in cardiogenic shock would of corticosteroids in myocarditis due to sarcoidosis is
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require extracorporeal membrane oxygenator (ECMO) or established. Various prospective randomized controlled
ventricular assist device as bridge to recovery or cardiac
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trials of immunosuppression and immunomodulation

transplantation. Patients of giant cell myocarditis not therapy is shown in Table 2.
responding to optimal medical therapy may be candidates Th e n ove l c o n c e p t o f i m mu n oa d s o r p t i o n o f
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for cardiac transplantation. Immunomodulation therapy autoantibodies that can cause damage to myocardium,
directed towards maladaptive immune response against
requires testing in a large prospective study.
myocardium triggered by viral infection may be potentially
beneficial.
Antiviral Therapy
Intravenous immunoglobulin (IVIG) is useful in
antibody-mediated autoimmune disease. At present, no antiviral therapy is approved in the
In pediatric age group, high-dose IVIG in acute management of acute myocarditis. Larger randomized
myocarditis has shown improvement in left ventricular prospective trials are required to establish the role of
function and recovery in patients. However, in adults with antiviral treatment for acute myocarditis.
biopsy proven myocarditis, benefit of IVIG still needs Since no definitive guidelines are available to manage
to be established. Selection of suitable candidates for myocarditis, a practical algorithm to help decision making
immunosuppressive therapy is listed in Box 1. is proposed by Pollack et al (Figure 4).4
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8
Cardiomyopathy
SECTION
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Table 2: Prospective randomized, controlled trials of immunosuppression and immunomodulation in myocarditis
Authors Design Primary end point Results
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Parrillo, et al26 Randomized, controlled trial of 102 patients with a history of idiopathic DCM Improved LVEF at 3 months or reduced LV Mean LVEF increased 4.3 ± 1.5% in the prednisone
to compare prednisone with placebo end-diastolic dimensions group compared with 2.1 ± 0.8% in the control group
(p <0.054)
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Mason, et al27 Randomized, controlled trial of 111 patients with biopsy-proven myocarditis LVEF at 28 weeks No difference in LVEF or survival between the two
(unknown etiology) to compare prednisone plus cyclosporin or azathioprine groups (p = 0.96)
with conventional therapy
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Wojnicz, et al28 Randomized, controlled trial of 84 patients with inflammatory DCM (unknown A composite of death, heart No significant difference in primary end point (22.8%
S
etiology, increased HLA expression on EMB) to compare prednisone plus transplantation, and hospital readmission for the immunosuppression group vs 20.5% for the
azathioprine with placebo over 2 years placebo group)
Frustaci, et al29 Randomized, controlled trial of 85 patients with inflammatory, virus-negative LVEF at 6 months Significantly improved LVEF and decreased LV
20 o
DCM to compare prednisone plus azathioprine with placebo dimensions in immunosuppressive group
McNamara, et al30 Randomized, controlled trial of 62 patients with recent-onset unexplained Change in LVEF at 6 months and 12 months Both groups had similarly improved LVEF at 6 months
DCM (≤6 months) to compare IVIG with placebo and 12 months
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Gullestad, et al31 Randomized, controlled trial of 40 patients with chronic DCM to compare IVIG Change in LVEF at 6 months Improved LVEF at 6 months in IVIG group (LVEF
with placebo increased from 26 ± 2% to 31 ± 3%, p <0.01) compared
ty
with placebo. Marked increase in plasma levels of anti-
inflammatory mediators in IVIG group
Abbreviations: DCM, dilated cardiomyopathy; EMB, endomyocardial biopsy; IVIG, intravenous immunoglobulin; LV, left ventricle; LVEF, LV ejection fraction
Source: Reprinted from Pollack A et al, Viral Myocarditis, Nat Rev Cardiol. 2015;12:670-80, with permission from Macmillan Publishers Limited.
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Figure 4: Diagnostic and clinical algorithm for myocarditis

Abbreviations: ECG, electrocardiogram; EMB, endomyocardial biopsy; LV, left ventricle.
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*Used with permission from Macmillan Publishers Limited.

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FUTURE DIRECTIONS Production of human mature cardiomyocytes from

Development of novel imaging agent that identifies induced pluripotent stem cells (IPSC). This will help
in future in vitro studies of complete pathogenesis of
active inflammation on CMR.
myocarditis in humans.33
Use of inert perflurocarbons to detect areas of
Study to evaluate genetic susceptibility in general
inflammation on CMR.4
population to develop myocarditis after viral exposure
Gadolinium conjugated monoclonal antibody directed
and to develop preventive strategies.
against antigen in viral capsid.
Use of two-dimensional speckle tracking derived
segmental peak systolic longitudinal strain to CONCLUSION
diagnose early myocardial dysfunction in suspected Myocarditis is caused by various infectious and toxic
myocarditis.32 agents. Abnormal post viral autoimmune response to
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KG-59.indd 497 03-11-2018 12:44:34

SECTION myocardium plays a role in the pathogenesis of this 14. Lauer B, Niederau C, Kahl U, et al. Cardiac Troponin T in
disease. It has variable presentation from mild self- patients with clinically suspected myocarditis. J Am Coll
8 resolving condition to rapidly progressive course ending
in heart failure, arrhythmias and death. In some patients, it
Cardiol. 1997;30:1354-9.
15. Lauer B, Schannwell M, Kühl U, et al. Antimyosin
Cardiomyopathy
may have a chronic indolent course ending in nonischemic autoantibodies are associated with deterioration of systolic
dilated cardiomyopathy. EMB is the gold standard to & diastolic left ventricular function in patients with chronic
confirm the diagnosis along with immunohistochemistry myocarditis. J Am Coll Cardiol. 2000;35:1106-10.
and viral PCR. There is emerging role of CMR in 16. Yilnaz A, Ferreira V, Klingel K, et al. Role of cardiac magnetic
diagnosing myocarditis. Immunomodulation and resonance imaging (CMR) in the diagnosis of acute and
immunosuppression therapy is useful in selected patients. chronic myocarditis. Heart Fail Rev. 2013;18:747-60.
Nonresponders to acute management of heart failure 17. Abdul-Aty H, Boye P, Zagrosek A, et al. Diagnostic
a
are candidates for mechanical assist device as bridge to performance of cardiovascular magnetic resonance in
patients with suspected acute myocarditis:comparison of
di
recovery or cardiac transplantation.
different approaches. J Am Cardiol. 2005;45:1815-22.
18. Mahrhold H, Wagner A, Deluigi CC, et al. Presentation,
In
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1. Richardson P, Mckenna W, Bristow M, et al. Report of the myocarditis. Circulation. 2006;114(5):1581-90.
1995 World Health Organization/International Society 19. Freidrich MG, Sechten U, Schulz- Menger J, et al.
of
& Federation of Cardiology Task Force on the definition Cardiovascular magnetic resonance in myocarditis: a JACC
& classification of Cardiomyopathies. Circulation. white paper. 2009;53:1475-87.
1996;93:841-842.
ty
20. Aretz HT, Billingham ME, Edwards WD, et al. Myocarditis:
2. Caforio AL , Pankuweit S, Arbustini E, et al. Current state of A histopathologic definition and classification. Am J Cardio
Knowledge on etiology, diagnosis, management & therapy Pathol. 1985;1:1-10.
18 cie
of myocarditis: a position statement of the European
Society of Cardiology working group of Myocardial&
Pericardial diseases. Eur Heart J. 2013;34:2636-48.
21. Kindermann I, Barth C, Mahfoud F, et al. Update on
Myocarditis. J Am Coll Cardiol. 2012;59:779-92.
22. Dennert R, Crijns HJ, Heymans S. Acute Viral Myocarditis.
20 o
3. Magnani JW, Dec W, Myocarditis: Current trends in
Eur Heart J. 2008;29:2073-82.
diagnosis & treatment. Circulation. 2006;113:876-90.
S
23. Kinderman I, Kinderman M, Kandolf R, et al. Predictor

4. Pollack A, Kontorvich AR, Fuster V, et al. Viral Myocarditis-
of outcome in patients with suspected myocarditis.
diagnosis,treatment options & current controversies. Nat
Circulation. 2008;118(6):639-48.
al
Rev Cardiol. 2015;12:670-80.

24. Leone O, Veinot JP, Angelini A, et al. Consensus statement
5. Cooper LT Jr. Myocarditis.NEJM. 2009;360:1526-38.
on endomyocardial biopsy from the association for
6. Caforio AL, Mahon NG, Baig MK, et al. Prospective Familial
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European Cardiovascular Pathology and the society for

asessment in dilated cardiomyopathy,Cardiac auto
cardiovascular Pathology. Cardiovasc Pathol. 2012;21:
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antibodies predict disease development in asymptomatic

245-74.
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25. Herskowitz A, Campbell S, Deckers J, et al. Demographic
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features and prevalence of idiopathic myocarditis in
ol
mimicking acute myocardial infarction. J Am Coll Cardiol.

1992;20:85-9. patients undergoing endomyocardial biopsy. Am J Cardiol.
8. Cowley A, Dobson L, Kurian J, et al. Acute Myocarditis 1993;71:982-6.
di
secondary to cardiac tuberculosis; A case report. Echo Res 26. Parrillo JE, Cunnion RE, Epstein SE, et al, A prospective,
Pract. 2017;4(3):K25-K29. randomized controlled trial of prednisone for dilated
ar
9. Mirabel M, Vignaux O, Lebon P, et al. Acute Myocarditis cardiomyopathy. N Eng J Med. 1989;321:1061-8.
due to Chikungunya virus assessed by contrast enhanced 27. Mas o n J W ,O ’con nel JB , H e rskow i t z A , et al. A clinical
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magnetic resonance imaging. 2007;121:e2-e8. trial of immunosuppressive therapy for myocarditis. The
10. Ya c ou b S, We r t h e i m H , Wi l i s R . Ca rd i ova s c u la r Myocarditis Treatment Trial Investigators.N Eng Med.
manifestations of the emerging dengue pandemic. Nat Rev 1995;333:269-75.
Cardiol. 2014;11:335-45. 28. Wojnicz R, Nowalany-Kozielska E, Wojciechowska C, et
11. Ukena C, Mahfoud F, Kindermann I, et al. Prognostic al. Randomized, placebo controlled study for immuno-
electrocardiographic parameters in patients with suspected s u p p re s s i v e t re a t m e n t o f i n f l a m m a t o r y d i l a t e d
myocarditis. Eur J Heart Failure. 2011;13:398-405. cardiomyopathy: two year follow up result.Circulation.
12. Pinamonti B, Alberti E, Cigalotto A, et al. Echocardiographic 2001;104:39-45.
findings in myocarditis. Am J Cardiol. 1988;62:285-91. 29. Frustaci A,Russo MA, Chimenti C. Randomized study on
13. Felker GM, Boehmer JP, Hruban RH, et al. Echocardiographic the efficacy of immunosuppressive therapy in patients with
findings in fulminant and acute myocarditis. J Am Coll virus negative inflammatory cardiomyopathy.The TIMIC
Cardiol. 2000;36:227-32. study.Eur Heart J. 2009;30:1995-2002.
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30. Mcnamara DM, Holubkov R, Starling RC, et al, Controlled identifies regional myocardial involvement in patients with CHAPTER
trial of intravenous immunoglobulin in recent onset dilated myocarditis and normal global left ventricular systolic
cardiomyopathy. Circulation. 2001;103:2254-9.
31. Gullestad L, Aass H, Fjeld JG, et al. Immunomodulating
function.Pedtr Cardiol. 2015;36(5):950-9.
33. Sharma A , Marceau C ,Hamaguchi R , et al Human
59
therapy with intravenous immunoglobulin in patients with induced pluripotent stem cell derived cardiomyocytes as
chronic heart failure. Circulation. 2001;103:220-5. an in vitro model for Cocksackie B3 induced myocarditis
32. Uppu SC,Shah A,Weignad J,et al,Two dimensional speckle and antiviral drug screening platform. Cir Res. 2014;115:
tracking derived segmental peak systolic longitudinal strain 556-66.
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CHAPTER 60 Tachycardiomyopathy
a
di
INTRODUCTION ventricular conduction (rate 130 bpm) (Figure 1). The left
Tachycardiomyopathy (TCMP) or tachycardia-induced ventricular ejection fraction (LVEF) on echocardiogram
In
myopathy is a condition that results from long-standing was found to be 20%. The patient was subjected to
tachyarrhythmia that causes deterioration in left electrophysiological study (EPS), which revealed left atrial
ventricular (LV) function.1 Ventricular and atrial ectopy tachycardia (Figure 2). Tachycardia terminated to sinus
of
that promotes dyssynchrony can induce TCMP. It is rhythm during radiofrequency ablation (RFA) (Figure 3).
important for physicians to recognize TCMP because it The patient remained tachycardia-free during her hospital
is potentially reversible. Further, intercepting TCMP can stay and was discharged from the hospital with guideline-
ty
improve prognosis and reduce morbidity as well. Usually, directed medical therapy. She was regularly followed up
cardiac function recovers after rate or rhythm control with in the outpatient department. She remained arrhythmia-
18 cie
drug or catheter ablation therapy. The following cases
illustrate the importance and impact of prompt diagnosis
free. Her chest X-ray showed normal cardiac size, and
the LVEF improved to 62% on a follow-up visit after three
months. She is currently asymptomatic since her RFA and
and treatment.
20 o
does not require any heart failure medications.
Case 1
S
A 9-year-old girl was admitted with chief complaint Case 2

of dyspnea, orthopnea, and palpitations of 2 months A 45-year-lady with previous mitral valve replacement
al
duration. Chest X-ray revealed marked cardiomegaly. Her (MVR) with omniscience valve presented with sudden
electrocardiogram (ECG) revealed atrial flutter with 1:1 worsening of her functional status. The chest radiograph
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Figure 1: 12-lead ECG recorded at presentation: (Details in the text)
KG-60.indd 500 03-11-2018 12:44:13

CHAPTER
60
Tachycardiomyopathy
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Figure 2: Electrograms (EGMs) recorded during the EPS
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20 o S
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Figure 3: Atrial tachycardia (2:1 conduction) reverted to sinus rhythm during RFA (arrows)
ar
angiogram was normal (Figures 6A and B). She was

prescribed an amiodarone infusion and reverted to sinus
C
rhythm (Figure 7). The patient was discharged from the

hospital with guideline-directed medical therapy. She was
regularly followed up in the outpatient department. She
remained asymptomatic and arrhythmia-free. Her chest
Figure 4: ECG at presentation shows AF
X-ray showed resolution of cardiomegaly and serial echo
showed improvement in LV function on a follow-up visit
revealed marked cardiomegaly with a prosthetic valve after three months. Currently, her LVEF is 55% (Figure 8).
at the mitral position. Her electrocardiogram (ECG)
revealed atrial fibrillation (AF) with a fast ventricular DEFINITION
rate (Figure 4). Left ventricular ejection fraction (LVEF) T C M P i s a s t a t e w h e r e l e f t v e n t r i c u l a r ( LV )
on echocardiogram was 30% with Echo showing global dysfunction occurs, due to recurrent ventricular or
LV hypokinesia and good prosthetic valve function atrial tachyarrhythmias or ventricular ectopy. 2, 3 The
with no paravalvular leak (Figure 5) and her coronary chief characteristic of this condition is its potential
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SECTION
8
Cardiomyopathy
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Figure 5: Echocardiogram showed dilated LV with good prosthetic valve function
of
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20 o S
A B
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Figures 6A and B: (A) Coronary angiogram revealed normal coronaries (Note the mechanical prosthetic valve at mitral position); (B) Still
frame from a Cine recording, showing good prosthetic valve opening (arrow)
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Figure 7: ECG at the time of discharge shows sinus rhythm
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be countered in HF models by LV pacing. The potential CHAPTER
to reverse distorted ventricular function through the
management of primary tachycardia is a significant reason
to diagnose and treat TCMP as soon as possible.
60
Tachycardiomyopathy
CLINICAL FEATURES
TCMP may be diagnosed on the basis of clinical history in
a patient with LV dysfunction. The presence of recurrent
or continuing PVCs or tachycardia points to a diagnosis
of TCMP. 13 Typically, TCMP presents with signs and
a
symptoms of dilated cardiomyopathy and congestive
HF.14 Arrhythmia may not always be present at the time
di
of presentation, so the clinician needs to maintain
a high suspicion index to make a positive diagnosis.
In
Figure 8: Latest echo with normal LV function Echocardiography may also help in diagnosis before the
onset of clinical signs and symptoms following progressive
for full or partial reversibility following arrhythmia HF. Tachycardia lasting for more than 10–15% of a day
of
management. TCMP is divided into two classes. The first may result in LV dysfunction.15 The exact ventricular rate
category termed arrhythmia-induced TCMP includes that results in TCMP is unclear. However, ventricular rates
those situations where arrhythmia is the sole cause of exceeding 100 bpm are usually implicated in TCMP.10 In
ty
ventricular dysfunction. The second class of TCMP termed cases of AF or PVCs asynchronous LV contraction and
arrhythmia-mediated TCMP is characterized by pre- increased heart rate may contribute to LV dysfunction.
18 cie
existing ventricular dysfunction or HF that is aggravated
by arrhythmia.3 The process of ruling out any undisclosed
Few other factors that should lead to the suspicion
of TCMP include; occurrence of LV dysfunction in a
structural cardiac disease is complicated and direct patient with previously normal ejection fraction, LV
20 o
attribution is difficult to ascertain. dysfunction without any obvious cause, absence of left
ventricular hypertrophy or non-ischemic cardiomyopathy,
S
normal LV end-diastolic dimension, reversibility of LV

EPIDEMIOLOGY
function following management of tachycardia (through
al
The prevalence and incidence of TCMP are uncertain. cardioversion, rate control or radiofrequency ablation
TCMP appears an under-recognized disease.2 10 to 50% within 1 to 6 months). Rapid deterioration of LV ejection
ic
of cases with HF present with atrial fibrillation. Further, fraction after recurrence of tachycardia, in a person who
several patients with AF and cardiomyopathy show has recently recovered from cardiomyopathy can also help
og
deterioration in functional status and LV function only make the diagnosis of TCMP.
because of ventricular rates that are not well controlled.
The incidence of TCMP in adult patients with atrial
Arrhythmias Responsible for TCMP
ol
tachycardia (AT) is 8.3-0% 4,5 whereas 28% of pediatric

patients with AT may develop TCMP.7 TCMP is seen in Numerous studies have documented the several forms of
di
9 to 34% patients presenting with nonsustained ventricular arrhythmias that play a role in TCMP. These arrhythmias
tachycardia or recurrent premature ventricular complexes include incessant supraventricular tachycardia (SVT), AF,
ar
(PVCs). 7-9 ventricular tachycardia (VT), PVCs and atrial flutter.16-19
PATHOPHYSIOLOGY Supraventricular Arrhythmias

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The pathophysiology of TCMP is unclear but has been Persistent AF is a chronic arrhythmia linked to TCMP. It
found to comprise of energy metabolism defects, calcium shows a high prevalence and has also been shown to result
overload, redox stress, and subclinical ischemia as well.10-11 in an elevated risk of developing HF. Rhythm or rate control
Animal models involving ventricular or atrial pacing have strategy to control the ventricular rate can help improve
shown that ventricular impairment is linked to alterations LV function. The AATAC-AF trial involving 203 subjects
in myocardial electrophysiology such as ventricular with persistent AF were recruited and randomized for
arrhythmia and prolongation of the action potential. It treatment with catheter ablation or amiodarone. The
has also been seen that left bundle-branch block can lead ablation strategy was shown to be of greater efficacy with
to lateralization of gap junctions followed by apoptosis 70% of subjects showing significant improvement (p <
and anisotropy.12 Such cellular and molecular deviations 0.001) in quality of life, with reduced hospitalization, and
can result in adverse ventricular modeling and changes mortality rates. Patients treated with ablation also showed
in chamber geometry. These unfavorable changes can greater improvement of LVEF of 9.6%±7.4% as compared
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SECTION to 4.2%±6.2% in patients receiving amiodarone.20 LV the onset of rapid pacing. The next event is the elevation
function recovery is enhanced, if sinus rhythm can be of the pulmonary artery and filling pressures with a
8 achieved and sustained on a long-term basis. One study
has demonstrated that 25% of subjects with AF showed
decrease of systemic arterial pressures may be observed
after one week. Cardiac output and volume, and EF show
Cardiomyopathy
LV dysfunction. This points to the implication of AF in a declining trend over the next three to five weeks. The
the pathophysiology of TCMP because 57% of patients rate and duration of events determine the recovery rate of
in this study showed improvement following ablation.16 TCMP. Ejection fraction (EF) improves slowly over several
TCMP may also be caused by incessant atrial tachycardia weeks, and contractile dysfunction may be observed
due to an automatic focus.21-23 Once the atrial tachycardia as long as four weeks following rate and/or rhythm
is managed, concomitant LV function improvement is control. Long-term alterations such as end-diastolic and
seen. One rare cause of TCMP may be re-entrant SVTs end-systolic volumes may remain high up to 12 weeks
a
such as atrioventricular reentrant tachycardia (AVRT), following the cessation of pacing. However, persistent
di
and atrioventricular nodal reentrant tachycardia (AVNRT) contractile function abnormalities may occur in some
that are paroxysmal in nature. 24-26 LV dysfunction may cases without normalization of EF. In studies on human
In
occur due to a form of incessant AVRT called persistent subjects, rapid improvement in clinical presentation is
junctional reciprocating tachycardia (PJRT). seen. Human studies have shown that there is usually a
rapid clinical improvement. Almost complete recovery
of
of LV contractility and clinical symptoms may be seen by
Ventricular Arrhythmias
about three months following successful management of
Idiopathic ventricular arrhythmias are implicated in the tachycardia.34-36
pathophysiology of TCMP and can lead to reversible LV
ty
dysfunction.27,28 LV dysfunction usually originates from the
right ventricular outflow tract. A PVC burden of more than
CONCLUSION
18 cie
10,000 up to 25,000 PVCs per day and of more than 10–24%
of total heartbeats per day is considered high.29,30 TCMP
TCMP may occur due to many different types of arrhythmias
and show wide variability in clinical symptoms. This
may develop, if a threshold level of about 10,000 PVCs per makes it challenging to diagnose TCMP. However, the
20 o
day is achieved. One study determined a threshold level of potential for reversibility of TCMP is an important reason
for its timely diagnosis and management. A proactive
S
13% which is equivalent to a PVC burden of about 30,000

per day. Absolute increase of LVEF could be predictably strategy is best utilized to treat TCMP effectively utilizing
determined with a specificity of 85% and sensitivity of rate or rhythm control as needed. Cardiac imaging is
al
100% on ablation of more than 13% of baseline PVC now at an advanced level and can be very useful for early
burden independent of evidence of structural heart identification of persons showing reversible etiological
ic
disease on imaging. Many factors such as higher PVC reasons for cardiomyopathy. DC cardioversion for AF
coupling interval dispersion, lack of symptoms, elevated combined with anti-arrhythmic treatment can also be a
og
body mass index, male gender, the presence of retrograde practical approach to manage TCMP by minimizing the
P waves, and interpolated PVCs have been found to burden of arrhythmia.
ol
contribute to LV dysfunction. One of the most important

contributing factors may be a QRS width more than 150 REFERENCES
di
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In
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The Role of Cardiovascular
Magnetic Resonance in Risk
CHAPTER 61 Stratification of Hypertrophic
Cardiomyopathy
Martin S Maron
a
di
INTRODUCTION significant increase in future potentially life-threatening
ventricular tachyarrythmias.1,2
Hypertrophic cardiomyopathy (HCM) is a complex and
In
Echocardiography can also overestimate maximal
heterogeneous genetic heart disease with prevalence in
LV wall thickness compared with CMR due to including
the general population of up to 1: 200, with over 2,000
a right ventricular (RV) muscle structure (i.e. crista
of
mutations in at least 11 genes encoding proteins of the
supraventricularis) which originates in the RV apex and
cardiac sarcomere responsible for this disease. While
transects the cavity to insert on the basal ventricular
HCM is compatible with extended longevity and excellent
septum. 5 With high spatial resolution imaging with
ty
quality of life in the majority of patients, an important
CMR, the crista muscle structure can be seen on certain
subset of patients remain at-risk for adverse disease-
short-axis slices to separate from the septum in diastole
18 cie
related events, including sudden death.1-3
Over the last 50 years, advances in cardiovascular
imaging have been responsible for transforming our
exposing the epicardial border of the ventricular septum
allowing one to more accurately measure LV wall thickness
(Figures 1E and F). In some HCM patients, the crista
understanding of HCM diagnosis and management.4,5
20 o
can be particularly prominent, resulting in significant
Most recently, cardiovascular magnetic resonance (CMR) overestimation in LV wall thickness by echocardiography,
S
has emerged as particularly powerful imaging modality potentially leading to unnecessary recommendation for
for HCM, given its high spatial resolution with complete implantable cardioverter-defibrillator (ICD) therapy when
al
ventricular coverage and the opportunity to characterize wall thickness measurements exceed 30 mm or more
myocardial tissue following gadolinium injection. These when erroneously including crista into reported maximal
ic
important advancements with CMR have resulted in wall thickness. For this reason, CMR has the potential to
improved management strategies for HCM, including avoid some unnecessary ICDs by providing a more reliable
og
more reliable diagnosis and improved detection of at-risk measurement of maximal LV wall thickness by excluding
patients.3-9 For this reason, it is important to review the RV cristae in septal measurement (Figures 1E and F).1,5
current impact of CMR on risk stratification in HCM.
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LEFT VENTRICULAR APICAL ANEURYSM:

CARDIOVASCULAR MAGNETIC RESONANCE HIGH-RISK SUBGROUP
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CHARACTERIZATION OF LEFT VENTRICULAR The increasing penetration of CMR into HCM clinical
HYPERTROPHY AND IMPACT ON RISK
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practice over the last decade has resulted in increased

ASSESSMENT identification of a previously under-recognized subgroup
of HCM patients with thin wall, fibrotic apical aneurysm
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The CMR imaging provides reliable measurements

of left ventricle (LV) wall thickness due to the high (of varying size).10 This phenotype is commonly associated
spatial resolution imaging and sharp delineation of the with mid-to-distal hypertrophy, often producing a
myocardial borders resulting from the stark contrast distinctive hourglass shape to the LV chamber, which
can produce mid-ventricular obstruction due to mid-
produced between bright blood and dark myocardium.3,5-7
systolic apposition of hypertrophied septum and free wall.
In particular, the anterolateral wall, posterior septum, and
Apical aneurysm, particularly if small, may be missed
apex are regions of the LV chamber where maximal wall
with echocardiography due to issues of foreshortening or
thickness may be underestimated with echocardiography limiting acoustic resolution from thoracic or pulmonary
compared with CMR (Figures 1A to D). 5-7 This is an parenchyma (Figures 3A to C).10
important issue since maximal LV wall thickness is an Recent observational studies have demonstrated that
important marker of increased risk for sudden death HCM patients with LV apical aneurysm are at increased
in HCM, even in the absence of other risk factors, with risk for adverse events, including sudden death, stroke,
massive hypertrophy of ≥30 mm associated with a and heart failure and in contrast to the subgroup of HCM
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CHAPTER
61
The Role of Cardiovascular Magnetic Resonance in Risk Stratification of Hypertrophic Cardiomyopathy

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Figures 1A to F: Advantage of cardiovascular magnetic resonance (CMR) compared to 2-dimensional echocardiography (2DE). (A) 2DE.
Anterolateral left ventricle (LV) free wall is 18 mm; epicardial border and adjacent extracardiac structures are not well defined (asterisks); (B)
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CMR in the same patient shows well-delineated border of anterolateral LV wall (arrowheads) which is massively thickened (35 mm), creating
a sudden death (SD) risk factor; (C) 2DE. Posterior ventricular septal (VS) thickness is 21 mm (asterisk); (D) CMR in the same patient; massive
hypertrophy (41 mm) (asterisk); creating a SD risk marker. (Reproduced with permission from Maron MS et al.5); (E) 2DE. Maximal anterior
ventricular septal thickness is considered 34 mm (solid line), suggesting increased risk for SD based on massive LV hypertrophy; (F) CMR in the
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same patient, crista supraventricularis muscle identified (hashed yellow line) and excluded from ventricular septal measurement of 23 mm.
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patients with hypertrophy confined to the apex (i.e. apical and 3).1,10 Furthermore, the mid-cavitary gradients noted
HCM) (Figures 2A to J).10 The scarred aneurysm rim is in these patients appears unlikely to be responsible for
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considered to represent an additional focus for re-entry limiting heart failure symptoms and there is no evidence
ventricular tachyarrhythmias as well as a structural nidus that the aneurysm are at risk of rupture. For these
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for the formation of thrombus (even in patients in normal reasons, there does not appear to be a compelling role for
sinus rhythm) (Figures 3A and B). In a large single center surgical resection of myocardium to relieve mid-cavitary
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series of 93 HCM patients with apical aneurysm followed obstruction or to resect the aneurysm itself.1,10
for an average of 4 years, the rate of HCM-related deaths
combined with adverse disease-related events was 3-fold
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CMR TISSUE CHARACTERIZATION IN HCM

greater than in HCM patients without aneurysms.10 Of note,
in 13 patients, who experienced recurrent monomorphic The CMR also provides the opportunity with intravenous
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ventricular tachycardia (VT) requiring multiple ICD gadolinium injection to image abnormal myocardial
shocks, VT recurrence was effectively mitigated in 6 with substrate, predominantly LV myocardial fibrosis. 8,9,11
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endocardial and/or epicardial radiofrequency ablation Gadolinium contrast is deposited in areas of expanded
(Figures 3A and B). In addition, nonfatal thromboembolic extracellular space within the HCM myocardium and
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events occurred in 5 patients not taking anticoagulation imaged as increased signal intensity [i.e. late gadolinium
therapy, while no embolic events occurred in patients with enhancement (LGE)]. Areas of LGE can be visualized as
apical clots and on anticoagulation. Although aneurysm well as quantified by third-party offline software to express
size varies from <2 cm diameter to >8 cm, there is no the amount of fibrosis in total grams or as a % of LV mass.
consistent relationship between the size of the aneurysm Areas of LGE in HCM are considered to represent
and risk for future adverse HCM-related event.10 myocardial fibrosis. This observation is supported by
For this reason, management recommendations for histopathologic studies in which LGE is seen on CMR
HCM with apical aneurysm including consideration studies done before myectomy correlated to myocardial
for important therapeutic interventions for this high- fibrosis assessed by histological examination on resected
risk subgroup including primary prevention ICD for septal muscle. 12 In addition, fibrosis identified on
sudden death prevention and anticoagulation for stroke explanted HCM hearts correlates strongly to areas of LGE
prophylaxis, independent of both aneurysm size and on pre-transplant CMR.13 Although the precise mechanism
of traditional sudden death risk factors (Figures 2 for LGE in HCM remains not well characterized, fibrosis
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Cardiomyopathy
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Figures 2A to J: Morphologic abnormalities of the LV apex more reliably identified by contrast echocardiography and CMR in patients with
HCM, implications for management. A to E. Lower-risk apical hypertrophy; (A) Abnormal 12-lead ECG pattern; (B) 4-chamber echocardiogram
shows normal LV wall thickness; (C) In the same patient, opacification of LV chamber with echocardiographic contrast demonstrates regional
area of increased wall thickness at apex of 16 mm (asterisks); (D) High-resolution CMR imaging confirms apical hypertrophy (asterisks) and the
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absence of late gadolinium enhancement (LGE); (E) Contrast CMR images show no LGE, consistent with the absence of myocardial scarring,
associated with lower risk for sudden death events. (F to J) Higher-risk LV apical aneurysm; (F) Abnormal 12-lead ECG pattern; (G) 4-chamber
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echocardiogram shows increased LV wall thickness at mid-LV level but no apical aneurysm; (H) In the same patient, opacification of LV
chamber with echocardiographic contrast demonstrates medium-sized thin-wall apical aneurysm (arrowheads) with associated hourglass-
shaped LV chamber with regional area of increased wall thickness at mid-LV level of 16 mm (asterisks); I. high-resolution CMR imaging
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confirms apical aneurysm (arrowheads); (J) Contrast CMR images show transmural LGE of aneurysm rim (arrowheads) with contiguous
extension into the inferior (short arrow) and anterior LV walls (long arrow), a potential nidus of monomorphic VT. In addition, marked signal
intensity contrast between the bright aneurysm rim and hypointense mass (yellow arrow) confirms the presence of a thrombus in the apical
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aneurysm which was not seen on echocardiography, raising consideration for stroke prophylaxis with anticoagulation. (Reproduced with
permission from Maron MS et al.5)
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Abbreviations: LA, left atrium; LV, left ventricle; RV, right ventricle
resulting from abnormal myocardial blood flow due LATE GADOLINIUM ENHANCEMENT AND
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to abnormal small vessel disease may be an important SUDDEN DEATH RISK

contributing mechanism for LGE formation in this disease.
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Currently, the US and Canadian AHA/ACC (American

The LGE is present in approximately 50% of HCM Heart Association/American College of Cardiology)
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patients occupying an average of 9% of the overall LV guidelines rely on the presence of a number of noninvasive
myocardial volume, with no difference with respect to the risk factors to identify HCM patients at increased
prevalence and extent of LGE with respect to gender or age risk for sudden death (Figure 5). 1 More recently, the
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of the patient.8 The LGE does not correspond to a coronary European Society of Cardiology (ESC) has promoted a
vascular distribution in HCM; and therefore, given the risk score to estimate 5-year sudden death risk based on
diffuse nature of fibrosis throughout the LV myocardium, a formula which takes into account numerous clinical
any pattern, distribution, and location of LGE can be variables. 2 However, not all at-risk HCM patients are
currently identified with these risk stratification strategies,
observed in HCM including transmural extent in some
emphasizing the potential role of additional risk markers
LV segments (Figures 4A to F). The only consistent and
to more reliably identify high-risk patients, for which LGE
reliable LGE pattern observed in HCM is LGE located in
has been promoted.1,2
both the ventricular septum and free wall although this In this regard, a number of cross-sectional studies
pattern is not specific for HCM as it can also be seen in have shown a strong relationship between the presence
other cardiovascular diseases and even in normal patients of LGE and ventricular tachyarrhythmias on ambulatory
(Figures 4A to F).14 Rarely, LGE can be seen in the RV-free 24-hour Holter ECG in HCM, with LGE generally
508 wall and papillary muscles.3,5 conferring up to 7-fold increased risk for ambulatory
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61

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Figures 3A to C: Expanded risk stratification and management implications in HCM patients with high-risk apical aneurysms. (A and B)
High resolution imaging with CMR for reliable identification of LV apical aneurysms. Echocardiogram (A) in 4-chamber view shows normal
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apical contour without evidence of apical aneurysm (arrowheads), while in the same patient CMR (B) demonstrates medium-sized thin-wall
apical aneurysm (arrowheads) with associated hourglass-shaped LV chamber; (C) In different patient, contrast-enhanced CMR image shows
transmural LGE of aneurysm rim (arrowheads) with contiguous extension into the inferior (short arrow) and anterior walls (long arrow), with
marked signal intensity contrast between the bright aneurysm rim and hypointense mass (yellow arrow) reliably confirming the presence of
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a thrombus in the apical aneurysm. Below images B and C, illustrate management considerations and the effect of treatment interventions
applied to high-risk apical aneurysm patients, including ICD therapy for primary prevention of sudden death and radiofrequency ablation
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of arrhythmic focus in or near scarred aneurysm rim for treatment of recurrent monomorphic VT. Stroke prophylaxis with anticoagulation
therapy can protect against thromboembolic events. (Modified with permission from Rowin E et al.10)
Abbreviations: CMR, cardiovascular magnetic resonance; Echo, echocardiography; ICD, implantable cardioverter-defibrillator; LA, left atrium;
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LV, left ventricle; RA, right atrium; LGE, late gadolinium enhancement
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nonsustained ventricular tachyarrhythmias compared death event.9 In the largest of these studies by Chan et al.
to HCM patients without LGE (Figure 6).15 These initial extensive LGE occupying ≥15% of LV represented a 2-fold
cross-sectional studies provided the initial enthusiasm for increase in sudden death risk compared to HCM patients
LGE as a potential risk marker in HCM, since regions of without LGE (and without any conventional risk factors)
structurally abnormal myocardium with fibrosis appeared (Figures 6A and B).8 Of note, no LGE is associated with
to be a structural nidus for the generation of ventricular low risk and a reassuring finding for patients. These data
tachyarrhythmias. suggested that the results of contrast-enhanced CMR with
Following these initial cross-sectional studies, a extensive LGE may provide the opportunity to identify a
number of longitudinal investigations have now been subset of young HCM patients who are at increased risk
completed evaluating LGE as a CMR-imaging marker of but for whom without CMR would not be considered
risk. Together, these studies have demonstrated a strong candidates for sudden death prevention therapy with ICD
relationship between extent of LGE and risk of a sudden (Figure 5).3,5,8 In addition, for patients who reside in an
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Cardiomyopathy
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Figures 4A to F: Late gadolinium enhancement (LGE) patterns in hypertrophic cardiomyopathy are heterogeneous. (A) Predominantly
mid-myocardial LGE of the ventricular septum (arrows); (B) Localized area of LGE in the basal anterior septum extending to the anterior wall
S
(arrows); (C) Transmural LGE confined to the posterior lateral wall (arrows); (D) Focal mid-myocardial LGE of the septum and posterior wall; (E)
Extensive, diffuse LGE of basal ventricular septum (arrows); (F) LGE confined predominantly to the anterior and posterior insertion areas of the
right ventricle wall and ventricular septum (arrows)
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ambiguous or ‘gray area’ with respect to risk stratification,

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extensive LGE can act as an arbitrator to resolve decision

making regarding ICDs with extensive LGE swaying toward
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a decision of ICD and no or minimal LGE potentially away

from device therapy (Figure 5).3,5,8
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PATTERN OF LATE GADOLINIUM

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ENHANCEMENT
The pattern of LGE in HCM is incredibly diverse, with
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varied location and distribution throughout the LV

myocardium. The lack of a consistent and reliable LGE
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pattern in HCM makes it impossible to predict clinical

outcomes, like sudden death events, based on LGE
Figure 5: Risk stratification model currently used to identify HCM distribution. The only potential exception is LGE confined
patients at the highest sudden death risk who may be candidates to areas of confluence between RV and septum, which has
for ICDs and sudden death prevention. Primary risk markers and
emerged as the only reproducible LGE pattern noted in
potential arbitrators appear in boxes at the left. (Reproduced with
permission from Maron MS et al.5) HCM (Figures 7A to C).14 When confined to the insertion
*Extensive LGE while a primary risk marker, can also be used as an area of the RV wall and the anterior or posterior ventricular
arbitrator when conventional risk assessment is ambiguous. septum, the total amount of LGE is limited in size and
Abbreviations: CAD, coronary artery disease; EF, ejection fraction;
does not have the same clinical prognostic significance
ICD, implantable cardioverter-defibrillator; LV, left ventricular; LGE,
late gadolinium enhancement; LVH, left ventricular hypertrophy; as do larger areas of LGE elsewhere in LV wall. The LGE
NSVT, nonsustained ventricular tachycardia; SD, sudden death; VT/ confined the RV insertion areas likely does not represent
VF, ventricular tachycardia/ventricular fibrillation replacement myocardial fibrosis but rather an expanded
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Figures 6A and B: Relationship between late gadolinium enhancement and sudden death risk in HCM. (A) NSVT on 24-hour Holter ECG
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is 7-fold more common in HCM patients with LGE as compared to those without LGE (Modified with permission from Adabag et al.15);
(B) Relation between extent of LGE and sudden death events in 1,293 patients with HCM. (Modified with permission from Chan et al.8)
Abbreviations: NSVT, nonsustained ventricular tachycardia; LGE, late gadolinium enhancement; HCM, hypertrophic cardiomyopathy
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Figures 7A to C: (A) LGE confined to inferior insertion area (thin

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arrow); (B) LGE confined to anterior and inferior insertions area (thick
arrow); (C) Kaplan-Meier event-free survival curves comparing 134
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HCM patients with LGE confined to the RV insertion areas compared

with 745 HCM patients without LGE from HCM-CMR registry.
(Modified with permission from Chan et al.8)
Abbreviations: LV, left ventricle; RV, right ventricle; VS, ventricular
septum; HCM, hypertrophic cardiomyopathy, CMR, cardiovascular
C magnetic resonance; LGE, late gadolinium enhancement
extracellular space due to confluence of intersecting LV ADDITIONAL CMR METHODS OF TISSUE

and RV myofibrils. For this reason, LGE confined to only CHARACTERIZATION
RV insertion areas appears to be associated with lower
A number of relevant limitations with LGE-based
risk for sudden death, similar to patients with no LGE
techniques have been raised, including the requisite
(Figures 7A to C).14
that signal from regions of normal myocardium must be
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SECTION completely nulled.16 However, in diseases, such as HCM, by a process of accelerated myocardial fibrosis, often
fibrosis is often diffuse; and, therefore, no region of the diffuse and transmural, responsible for the adverse LV
8 LV myocardium is completely normal, an issue which
makes it possible that LGE methods may underestimate
remodeling. In a large cross-sectional HCM cohort studies,
a strong inverse relationship is observed between the extent
Cardiomyopathy
total amount of fibrosis. For this reason, novel techniques of LGE and EF, with end-stage patients demonstrating
have emerged which propose to directly assess burden the greatest amount of LGE. 23 More recently, extensive
of myocardial fibrosis by evaluating the expanded LGE ≥20% has been identified as a predictor for future
extracellular space within the myocardium. Extracellular development of systolic dysfunction.8 Therefore, it may
volume (ECV) fraction has emerged as a promising be reasonable to consider closer longitudinal follow-up of
measure of the extracellular matrix and is calculated by HCM patients with extensive LGE and preserved systolic
measuring longitudinal relaxation (T1) of the myocardium function in order to ensure timely recognition of decreases
a
before (native T1) and after injection of gadolinium.16 in EF that could impact management. End-stage HCM
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To date, T1 mapping has been applied to HCM as a patients should be considered for traditional heart failure
tool to aid in differentiating this heart disease from other drug therapies [e.g. angiotensin-converting enzyme
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cardiovascular disease. For example, compared to patients inhibitors (ACE-I) or aldosterone inhibitors] and primary
with LV hypertrophy secondary to cardiac amyloidosis prevention ICD therapy since decreased systolic function
or Fabry disease, ECV values are significantly higher in is associated with increased risk for life-threatening VT/
of
HCM patients.17 In addition, ECV values are noted to be ventricular fibrillation (VF).1,2,22
increased in HCM family members, who carry a disease-
causing mutation without LV hypertrophy.18 This raises REFERENCES
ty
consideration that T1 mapping techniques may also
1. Gersh BJ, Maron BJ, Bonow RO, et al. 2011 ACCF/AHA
identify affected family members, including those at
guideline for the diagnosis and treatment of hypertrophic
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risk for developing a clinical diagnosis of HCM with LV
hypertrophy. However, in the absence of clinical outcome
studies, there is currently no clinical role for T1 mapping
cardiomyopathy: a report of the American College of
Cardiology Foundation/American Heart Association
Task Force on Practice Guidelines. Circulation.
in risk assessment. Further clarification of a number of
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2011;124(24):2761-96.
these CMR-based issues in HCM will emerge from the 2. Elliott PM, Anastasakis A, Borger MA, et al. 2014 ESC
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international multicenter Hypertrophic Cardiomyopathy Guidelines on diagnosis and management of hypertrophic

Registry (HCMR) study.19 cardiomyopathy:the Task Force for the Diagnosis and
Management Of Hypertrophic Cardiomyopathy of the
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European Society of Cardiology (ESC). Eur Heart J.

QUANTIFICATION OF LATE GADOLINIUM 2014;35(39):2733-79.
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ENHANCEMENT 3. Maron MS, Maron BJ. Clinical Impact of Contemporary

Cardiovascular Magnetic Resonance Imaging
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Currently, there is no expert consensus agreement on

i n Hy p e r t ro p h i c C a rd i o m y o p a t h y . C i rc u l a t i o n .
the best method to quantify LGE in HCM. A number of
2015;132(4):292-8.
techniques have been applied in prior studies including
4. Maron BJ, Maron MS. The Remarkable 50 Years of
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higher gray-scale thresholds (5 or 6 SD above mean Imaging in Hypertrophic Cardiomyopathy and How it
of nulled myocardium or manually adjusted to define Has Changed Diagnosis and Management: From M-Mode
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areas of visually identified LGE) and full width at half Echocardiography to CMR. JACC: Cardiovasc Imaging.
maximum (FWHM).20,21 In one study, higher gray-scale 2016;9(7):858-72.
ar
thresholding methods best represented total fibrosis 5. Ma ro n M S, Row i n E S, Ma ro n BJ. How t o I mag e
burden as demonstrated by histopathologic analysis Hypertrophic Cardiomyopathy. Circ Cardiovasc Imaging.
of ventricular septal tissue removed in HCM patients 2017;10(7):e005372.
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undergoing surgical myectomy. In the Chan et al. a 6. Moon JC, Fisher NG, McKenna WJ, et al. Detection of
manual threshold was used correlating well with a 6 SD apical hypertrophic cardiomyopathy by cardiovascular
threshold, with excellent reproducibility.8 magnetic resonance in patients with non-diagnostic
echocardiography. Heart. 2004;90(6):645-9.
7. Rickers C, Wilke NM, Jerosch-Herold M, et al. Utility of
LATE GADOLINIUM ENHANCEMENT cardiac magnetic resonance imaging in the diagnosis of
AND SYSTOLIC DYSFUNCTION hypertrophic cardiomyopathy. Circulation. 2005;112:855-
61.
A small subgroup of HCM patients will develop 8. Chan RH, Maron BJ, Olivotto I, et al. Prognostic value of
systolic dysfunction often associated with adverse LV quantitative contrast-enhanced cardiovascular magnetic
remodeling with septal thinning and cavitary dilation resonance for the evaluation of sudden death risk in
defined by ejection fraction (EF) <50% assessed with patients with hypertrophic cardiomyopathy. Circulation.
echocardiography or CMR.22 This phase of HCM is driven 2014;130(6):484-95.
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9. Weng Z, Yao J, Chan RH, et al. Prognostic Value of LGE- extracellular volume in health and disease. Heart. CHAPTER
CMR in HCM: A Meta-Analysis. JACC Cardiovasc Imaging. 2012;98(19):1436-41.
2016;9(12):1392-402.
10. Rowin EJ, Maron BJ, Haas TS, et al. Hypertrophic
17. Sado DM, White SK, Piechnik SK, et al. Identification and
assessment of Anderson-Fabry disease by cardiovascular
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Cardiomyopathy with Left Ventricular Apical Aneurysm:
Implications for Risk Stratification and Management. J Am Circ Cardiovasc Imaging. 2013;6(3):392-8.
Coll Cardiol. 2017;69(7):761-73. 18. Ho CY, Abbasi SA, Neilan TG, et al. T1 measurements
11. Ismail TF, Jabbour A, Gulati A, et al. Role of late gadolinium identify extracellular volume expansion in hypertrophic
enhancement cardiovascular magnetic resonance in the cardiomyopathy sarcomere mutation carriers with and
risk stratification of hypertrophic cardiomyopathy. Heart. without left ventricular hypertrophy. Circ Cardiovasc
Imaging. 2013;6(3):415-22.
2014;100(23):1851-8.
19. Kramer CM, Appelbaum E, Desai MY, et al. Hypertrophic
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12. Moravsky G, Ofek E, Rakowski H, et al. Myocardial fibrosis
Cardiomyopathy Registry: The rationale and design of
in hypertrophic cardiomyopathy: accurate reflection of
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an international, observational study of hypertrophic
histopathological findings by CMR. JACC Cardiovasc cardiomyopathy. Am Heart J. 2015;170(2):223-30.
Imaging. 2013;6(5):587-96. 20. Harrigan CJ, Peters DC, Gibson CM, et al. Hypertrophic
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13. Moon JC, Reed E, Sheppard MN, et al. The histologic basis cardiomyopathy: quantification of late gadolinium
of late gadolinium enhancement cardiovascular magnetic enhancement with contrast-enhanced cardiovascular MR
resonance in hypertrophic cardiomyopathy. J Am Coll imaging. Radiology. 2011;258:128-33.
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Cardiol. 2004;43(12):2260-4. 21. Flett AS, Hasleton J, Cook C, et al. Evaluation of techniques
14. Chan RH, Maron BJ, Olivotto I, et al. Significance of Late for the quantification of myocardial scar of differing etiology
Gadolinium Enhancement at Right Ventricular Attachment using cardiac magnetic resonance. JACC Cardiovasc
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to Ventricular Septum in Patients with Hypertrophic Imaging. 2011;4(2):150-6.
22. Harris KM, Spirito P, Maron MS, et al. Prevalence, clinical
Cardiomyopathy. Am J Cardiol. 2015;116(3):436-41.
profile, and significance of left ventricular remodeling
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15. Adabag AS, Maron BJ, Appelbaum E, et al. Occurrence and
frequency of arrhythmias in hypertrophic cardiomyopathy
in relation to delayed enhancement on cardiovascular 23.
in the end-stage phase of hypertrophic cardiomyopathy.
Circulation. 2006;114(3):216-25.
Olivotto I, Maron BJ, Appelbaum E, et al.Spectrum and
magnetic resonance. J Am Coll Cardiol. 2008;51(14):
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clinical significance of systolic function and myocardial
1369-74. fibrosis assessed by cardiovascular magnetic resonance
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16. Sado DM, Flett AS, Banypersad SM, et al. Cardiovascular in hypertrophic cardiomyopathy. Am J Cardiol.
magnetic resonance measurement of myocardial 2010;106(2):261-7.
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Constrictive Pericarditis and
CHAPTER 62
Restrictive Cardiomyopathy:
How to Differentiate?
V Jacob Jose
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INTRODUCTION Dissociation of Intrathoracic and
About 50% of patients who presented with clinical Intrapericardial Pressures
In
heart failure have normal ejection fraction (EF), an The difference between pulmonary capillary wedge
entity termed as ‘heart failure with preserved ejection pressure (PCWP) and left ventricular (LV) diastolic
fraction’ (HFpEF). Hypertension is the single most
of
pressure (LV filling gradient) remains constant during
common cause of HFpEF worldwide. However, in about the respiratory cycle in normal conditions. In CP,
10–15% of cases, such a clinical presentation can be due the inspiratory reduction in intrathoracic pressure is
ty
to restrictive cardiomyopathy (RCM). The most frequent
transmitted to the extracardiac pulmonary veins, but
clinical differential diagnosis of the latter is constrictive
not to the encased left atrium (LA) and left ventricle
pericarditis (CP) (Table 1).1 It is essential to differentiate
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between these two because CP is potentially curable,
whereas treatment options are limited for RCM. Both RCM
(LV), leading to a reduction in LV diastolic filling with
inspiration. This failure of transmission of intrathoracic
pressure to the LV results in less filling of the LV during
and CP present signs of predominantly right-sided heart
20 o
failure with normal left ventricular systolic dysfunction. In inspiration (Figures 2A and B).
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this article, we provide stepwise algorithms, one based on

echocardiography and the other based on multimodality Exaggerated Ventricular Interdependence
imaging, for differentiating them.
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As the total heart volume is fixed by the constricting

pericardium, there is an interdependence of volume
PATHOPHYSIOLOGY OF CONSTRICTION
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between the left ventricle (LV) and right ventricle

It is essential to understand the unique pathophysiology (RV). With the inspiratory decrease in LV filling and
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of constriction (Figure 1) as this forms the basis of diastolic volume, right ventricular filling is increased in a
differentiating it from RCM. The key mechanisms of CP compensatory manner. Since the inferior vena cava (IVC)
are as follows. is subject to variations in intrathoracic pressure, most flow
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Table 1: Diagnostic approach when the patient presents with heart failure with preserved ejection fraction
Normal LV wall thickness
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1 Restrictive cardiomyopathy Idiopathic restrictive cardiomyopathy

(Normal LV chamber volumes, biatrial enlargement and increased LV Iron overload cardiomyopathy
filling pressures)
C
Radiation induced cardiomyopathy

Endomyocardial fibrosis
2 Constrictive pericarditis
(thickened pericardium and ventricular interdependence)
3 High output heart failure
Increased LV wall thickness
1 Hypertensive heart disease
2 Hypertrophic cardiomyopathy
3 Infiltrative cardiomyopathy Amyloidosis
Glycogen storage disorders (e.g. Fabry’s disease)
Abbreviation: LV, left ventricle

Source: Modified from Pereira N et al. Spectrum of restrictive and infiltrative cardiomyopathies: Part 1 of a 2-Part Series. JACC 2018; 71(10)1
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Figure 1: Hemodynamic alterations in pericardial constriction
Source: Adapted from IHJ. 2015;67:175–82
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Figures 2A and B: Inspiratory decrease in flow to the left side of the heart results in septal shift
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Source: Modified from Figure 6 of Garcia et al. JACC. May 3rd, 2016
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to the high-pressure right atrium (RA) during inspiration can be more accurately assessed using transesophageal
arrives from the inferior vena cava, which is also assisted echocardiography. The ventricular interdependence is
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by increased inspiratory intra-abdominal pressure. seen as septal bounce on 2D echo. In septal bounce,
In contrast to the above mechanism, pericardial the septum shifts towards the LV in inspiration and
compliance is normal in RCM, and the respiratory variation towards the RV in expiration. The other names for this
in intrathoracic pressures is normally transmitted to all the phenomenon are ‘septal shudder’ and ‘diastolic checking.’
cardiac chambers. This is one of the most specific signs of constriction.
Another crucial differentiating feature is the
ECHO DOPPLER SIGNS2 respiratory variation in the chamber filling seen with
Echocardiography is the initial imaging modality of Doppler flow across the mitral and tricuspid valves and
choice for this group of patients (Figures 3 and 4). pulmonary and hepatic veins. These variations are seen
Since systemic venous congestion is the main feature, only in patients with constriction and not in restrictive
both IVC and hepatic veins are dilated. Pericardial physiology. The degree to which this abnormality is
thickness can be measured using transthoracic echo, but seen is related to the degree of constriction and volume
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Figures 3A to E: Echo in constriction. (A) Mitral inflow Doppler

variation more than 25%; (B) Hepatic vein shows prominent
ar
diastolic reversal in expiration; (C and D) Mitral e prime showing

that medial is more than the lateral; (E) Classical septal notch in
E diastole in M-mode Echo
C
status of the patient. However, it is important to note that the lateral e’ is more than the medial e’. This is called
respiratory variation is seen only in two-thirds of patients annulus reversus. Quantification of the annulus reversus
of CP; hence, the lack of respiratory variation cannot be can be done using the ratio cut-off of 0.91. Of all the
used to exclude the diagnosis of CP.3 echocardiographic signs listed, the most useful one is the
Tissue Doppler is another handy echo tool for tissue Doppler. If the e’ velocity is more than eight, it will
differentiating constrictive from restrictive physiology. The exclude RCM.
mitral e’ velocity is usually nine or more in constriction. With speckle tracking echocardiography, it has
This sign is present even if there is no respiratory variation become easier to measure the strain, and it has been
in mitral flow. The lateral e’ is often less than the septal found to be significantly different in constriction versus
e’ in CP because the thickened pericardium constrains restriction. Deformation of the LV is constrained in the
the lateral wall. This is unlike normal hearts, where circumferential direction in CP and the longitudinal
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CHAPTER
62

A B
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of
C D
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Figures 4A to D: (A) A thick ventricle due to amyloid deposition; (B) The typical strain pattern called cherry red spot of amyloid; (C and D)
18 cie
Tissue Doppler shows that e’ is reduced both in medial and lateral wall of this patient
direction in RCM. Subsequent early diastolic recoil of LV is only if cardiac magnetic resonance imaging (MRI) is
20 o
also attenuated in each of the two directions, respectively, not available or contraindicated.
uniquely differentiating the abnormal diastolic restoration
S
mechanics of the LV seen in CP and RCM.4 The echo signs CARDIAC MAGNETIC RESONANCE (CMR)7
are summarized in Tables 2 and 3. A combination of Pericardial thickness: Normal pericardial thickness
al
echocardiographic signs provides better sensitivity and

is 2 mm or less. On blood pool anatomical CMR, more
specificity (Table 3).
than 4 mm thickness is considered abnormal.
ic
An algorithm has been suggested based on echo Left atrium enlargement: The LA is enlarged more
features by the American Society of Echocardiography
than the RA in CP. A ratio of more than 1.32 is highly
og
(ASE) and European Association of Echocardiography

suggestive of CP.8
(now European Association of Cardiovascular Imaging Cine MR : Increased ventricular coupling with
[EACVI]) for the differentiation of constriction versus
inspiratory flattening of the septum. This can be
ol
restriction (Figure 5).5 This utilizes the following five echo

quantified in the short axis images in expiration versus
Doppler features: inspiration. If the septal excursion is more than 12%, it
di
1. Mitral inflow E/A ratio more than 0.8 with dilated IVC is very specific for the diagnosis of CP.
as the first step Tagged cine MR: Nonadherence of visceral and
ar

2. Look at the ventricular septal motion – Septal bounce parietal pericardium throughout the cardiac cycle.
3. Medial tissue Doppler e’ Delayed hyperenhancement (DHE) of the peri
C
4. Medial e’ versus lateral e’ cardium: If seen in constriction, it indicates pericardial

5. Hepatic vein reversal in expiration versus inspiration. inflammation.9
CARDIAC COMPUTED TOMOGRAPHY MULTIMODALITY IMAGING

Cardiac computed tomography (CT) is a useful
Using a combination of echo, CT, and cardiac MRI, we
tool in the assessment of pericardial thickness and
can systematically diagnose and differentiate between
calcification. Thick pericardium of 4 mm or more is
constriction and restriction. We start with echo Doppler
suggestive of CP. However, CP can be present without
pericardial thickening in less than 20% of cases. and use cardiac MRI in cases of doubt. Cardiac CT is
CT can give additional anatomical information on reserved for cases in which we cannot do an MRI, or
chamber size, IVC size, and pericardial effusion. cardiac MRI is not available (Figure 6). An expert
ECG-gated images can identify the septal bounce consensus document has been published about the
as well. 6 However, it cannot assess the respiratory multimodality imaging in restrictive cardiomyopathies by
variation of the flow; hence, CT is used for diagnosis the ESC, which is useful for further reading.10 517
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SECTION
Table 2: Echo Doppler signs of constriction
8 Echo Doppler signs of constrictive pericarditis

z Septal bounce/Septal shudder
Cardiomyopathy
z Mitral Inflow variation of more than 25%

z Mitral e’ >9 cm/sec
z e’ ratio of medial to lateral >0.91
z Hepatic vein – expiratory diastolic reversal ratio >0.79
z Transesophageal echocardiography (TEE) pericardial thickness > 4 mm
z Strain: Longitudinal strain preserved and circumferential strain is reduced
a
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Table 3: Echo signs of constrictive pericarditis—Mayo clinic criteria: Diagnostic sensitivity and specificity
In
Sensitivity (%) Specificity (%) PPV (%) NPV (%)
1 Septal shift 93 69 92 74
2 Inspiratory change in mitral velocity 84 73 92 55
of
3 Medial e’ >9 cm/sec 83 81 94 57
4 Medial e’/lateral e’ >0. 91 75 85 95 50
ty
5 Hepatic vein diastolic reversal velocity / forward 76 88 96 49
velocity in expiration >0.79
6
7
8
1 and 3
1 with 3 or 5
1 with 3 and 5
18 cie 80
87
64
92
91
97
97
97
99
56
65
42
20 o
Abbreviations: PPV, positive predictive value; NPV, negative predictive value
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Figure 5: Algorithm based on Echo for differentiating constrictive and restrictive physiologies
Source: Adapted from ASE guidelines for diastolic dysfunction. JASE. April, 2016
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20 o S
18 cie
ty
of
In
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Figure 6: Algorithm for the use of multimodality imaging in differentiating constriction from restriction
519
62
CHAPTER
03-11-2018 12:43:54
SECTION
Table 4: Invasive hemodynamic criteria for constriction—sensitivity and specificity
8 Criteria Sensitivity (%) Specificity (%) PPV (%) NPV (%)
Resting hemodynamics
Cardiomyopathy
1 LVEDP-RVEDP <5 mm Hg 46 54 58 44
2 RVEDP/RVSP >1/3 93 46 73 66
3 PASP <55 mm Hg 90 29 47 25
4 LVRFW ≥7 mm Hg 45 44 62 42
Respiratory changes
a
5 Respiratory change in RAP <3 mm Hg 93 48 58 92
di
6 Dynamic respiratory PCWP/LV respiratory 93 81 78 94
In
gradient ≥5 mm Hg
7 LV/RV interdependence 100 95 94 100
8 Systolic area index 97 100 100 95
of
Abbreviations: PPV, positive predictive value; NPV, negative predictive value; LVEDP, left ventricular end-diastolic pressure; RVEDP, right
ventricular end-diastolic pressure; RVSP, right ventricular systolic pressure; LVRFW, left ventricular rapid filling wave; RAP, right atrial pressure;
PCWP, pulmonary capillary wedge pressure, LV, left ventricle; RV, right ventricle
ty
18 cie
20 o S
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A B
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Figures 7A and B: (A) The RA pressure is high with rapid Y descent; (B) The classical square root sign
di
INVASIVE HEMODYNAMICS RV diastolic to RV systolic pressure ratio: The RV

ar
(CARDIAC CATHETERIZATION) diastolic pressure is more than one-third of the RV

systolic pressure.
Before the Doppler era of hemodynamics, invasive
C
Elevated RV and PA systolic pressures: As the diastolic

cardiac catheterization (cardiac cath or heart cath) data
pressures are elevated, the systolic pressure gets
remained the standard method to confirm the diagnosis elevated modestly to maintain the forward flow. The
of constriction. The cath-derived criteria are summarized RV and PA systolic pressures, being more than 45-
in Table 4 and Figures 7 and 8. 50 mm Hg, are unusual in constrictive pericarditis.
Diastolic pressure plateau (equalization of diastolic
LV rapid filling wave (LVRFW): LV filling is rapid in the
pressures): In normal hearts, the diastolic pressures of early part of diastole, and this is reflected in the filling
the ventricles vary according to the phases of respiration. wave of 7 mm Hg or more.
In constriction, there is a failure of transmission of the Lack of respiratory variation of RA pressure: RA
intrathoracic pressure variation into the ventricles; pressure is elevated and does not vary with respiration.
hence, an equal contact pressure is applied on all the The variation is usually less than or equal to 3 mm Hg.
chambers. Hence, the diastolic pressures are the same Respiratory variation of the RV and LV systolic pressures
in the RV and LV within a 5mm range. (LV and RV interdependence): With inspiration, the RV
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CHAPTER
62

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20 o
B
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Figures 8A and B: (A) The ventricular interdependence of the RV and LV pressures in constriction;
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(B) Absence of this finding in restrictive cardiomyopathy

Source: Adapted from Figure 2 of Geske et al. JACC. 2016;2329–47.
ic
systolic pressure increases and the LV systolic pressure REFERENCES

og
decreases. 1. Pereira NL, Grogan M, Dec GW. Spectrum of restrictive and

The ratio of RV to LV systolic area during inspiration infiltrative cardiomyopathies: Part 1 of a 2-Part Series. J Am
and expiration: This is an alternative method of Coll Cardiol. 2018;71(10):1130–48.
ol
demonstrating ventricular interdependence. This 2. Welch TD, Ling LH, Espinosa RE, et al. Echocardiographic
systolic area index had a sensitivity of 97% and diagnosis of constrictive pericarditis: Mayo Clinic criteria.
di
specificity of 100% for the identification of patients Circ Cardiovasc Imaging 2014;7(3):526–34.
with surgically-proven constriction. 11 This is the 3. Ha JW, Oh JK, Ommen SR, et al. Diagnostic value of mitral
ar
most specific cardiac catheterization finding for annular velocity for constrictive pericarditis in the absence
differentiating restrictive and constrictive physiologies. of respiratory variation in mitral inflow velocity. J Am Soc
Echocardiogr. 2002;15(12):1468–71.
C
4. Sengupta PP, Krishnamoorthy VK, Abhayaratna WP, et al.

CONCLUSION Disparate patterns of left ventricular mechanics differentiate
CP is characterized by a rigid shell of the pericardium, which constrictive pericarditis from restrictive cardiomyopathy.
results in abnormal diastolic filling. Echocardiography JACC Cardiovasc Imaging. 2008;1(1):29–38.
is the first line of diagnostic imaging. An abnormal 5. Nagueh SF, Smiseth OA, Appleton CP, et al. Recommen-
dations for the evaluation of left ventricular diastolic
ventricular septal motion with respiration is a useful
f u n c t i o n by e c h o c a rd i o g ra p hy : a n u p d at e f ro m
starting point. A preserved or even accelerated mitral
the American Society of Echocardiography and the
annular velocity, and annular reversus, should add to this
European Association of Cardiovascular Imaging. J Am Soc
process of diagnosis. Addition of CT or MRI to measure the
Echocardiogr. 2016;29(4):277–314.
thickness of the pericardium can give further confirmation 6. Ghersin E, Lessick J, Litmanovich D, et al. Septal bounce
of the diagnosis. When a comprehensive transthoracic in constrictive pericarditis. Diagnosis and dynamic
echo features are diagnostic of constriction, there may not evaluation with multidetector CT. J Comput Assist Tomogr.
be a need to do an invasive cardiac catheterization. 2004;28(5):676–8.
521
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SECTION 7. Karamitsos TD, Francis JM, Myerson S, et al. The role 10. Habib G, Bucciarelli-Ducci C, Caforio ALP, et al.
of cardiovascular magnetic resonance imaging in heart Multimodality imaging in restrictive cardiomyopathies:
8 failure. J Am Coll Cardiol. 2009;54(15):1407–24.
8. Cheng H, Zhao S, Jiang S, et al. The relative atrial volume ratio
an EACVI expert consensus document In collaboration
with the “Working Group on myocardial and pericardial
and late gadolinium enhancement provide additive infor-
Cardiomyopathy
diseases” of the European Society of Cardiology Endorsed

mation to differentiate constrictive pericarditis from restrictive
by The Indian Academy of Echocardiography. Eur Heart J
cardiomyopathy. J Cardiovasc Magn Reson. 2011;13:15.
9. Zurick AO, Bolen MA , Kwon DH, et al. Pericardial Cardiovasc Imaging. 2017;18(10):1090–121.
delayed hyperenhancement with CMR imaging in 11. Talreja DR, Nishimura RA, Oh JK, et al. Constrictive
patients with constrictive pericarditis undergoing surgical pericarditis in the modern era: novel criteria for diagnosis
pericardiectomy: a case series with histopathological in the cardiac catheterization laboratory. J Am Coll Cardiol.
correlation. JACC Cardiovasc Imaging. 2011;4(11):1180–91. 2008;51(3):315–9.
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CHAPTER 63 Tubercular Pericarditis
a
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INTRODUCTION CLINICAL FEATURES
Tuberculosis is one of the most common infection in India. The symptoms of tuberculous pericarditis are initially
In
It is not uncommon to see patients with disseminated nonspecific and constitutional features such as fever,
tuberculosis in Indian subcontinent. Pericardial weight loss, and night sweats generally occur early.
involvement in tuberculosis is an important complication.
of
Symptom severity varies upon the stage of infection and
The diagnosis of tuberculosis can be difficult or delayed degree of extrapericardial tuberculous disease. They
in many cases which may lead to further complications usually have findings typical of pericarditis or cardiac
in form of constrictive pericarditis and heart failure. In
ty
tamponade. Common symptoms include cough, dyspnea
advanced disease management options are limited, so and orthopnea, pleuritic type of chest pain and weight
early identification is key to successful management.
EPIDEMIOLOGY
18 cie loss. Right upper abdominal pain can also occur due to
liver congestion. Sometimes patients present in the late
stages of disease with congestive heart failure due to
Pericardial involvement occurs in about 1–2% cases of constrictive pericarditis.
20 o
pulmonary tuberculosis. Autopsy studies from developed Examination findings include fever, tachycardia,
S
countries have shown tuberculous pericarditis in 1% of increased jugular venous pressure, hepatomegaly, ascites,
unselected autopsies, 2.5% to 8% of tuberculosis deaths, and pedal edema. A pericardial friction rub and distant
and 6%–11% of persons dying of pericarditis. To the heart sounds may sometimes be appreciated. Cardiac
al
contrary, in low income countries like India, tuberculosis tamponade occurs in almost 10% cases with tuberculous
remains the most common cause of large pericardial pericarditis. But none of these findings differentiates
ic
effusion accounting for around 60% cases. In recent times,

tuberculous etiology of pericarditis from other causes. The
due to increased prevalence of HIV infection, there has
og
complications include constrictive pericarditis, effusive

been an increase in the cases of pericardial tuberculosis.
constrictive pericarditis, myopericarditis and cardiac
tamponade.
PATHOGENESIS
ol
Constrictive pericarditis is usually seen in 30–60%

Routes for spread of tuberculous infection to pericardium of cases despite prompt treatment and steroid therapy.
include extension of infection from the lung or
di
Physical examination findings may include Kussmaul’s

tracheobronchial tree, mediastinal lymph nodes, thoracic sign (lack of an inspiratory decline in jugular venous
bony cage or via miliary spread. Pathologically, four
ar
pressure), distended neck veins with a prominent Y descent

stages of tuberculous pericarditis have been described:
and a pericardial knock. Effusive constrictive pericarditis
Fibrinous exudation, serosanguinous effusion, resolution
is another important complication which often becomes
C
of effusion with pericardial thickening and constrictive

apparent during pericardiocentesis in patients initially
scarring. Commonly, the earliest recognizable phase is
thought to have tamponade. Despite pericardial drainage,
the second phase consisting of lymphocytic effusion; the
the elevated right atrial pressure persists in association
inflammatory process likely reflects a hypersensitivity
reaction to tubercular protein. Without treatment, effusion with the development of prominent Y descent and
resorbs with resolution of symptoms over 2–4 weeks in impaired respiratory variation. Concurrent myocardial
approximately half of the cases. Subsequently, the course involvement can occur and may be diagnosed in a patient
of disease is variable and may or many not progress to with tuberculous pericarditis having concurrent abnormal
constriction. Effusive constrictive pericarditis may also cardiac ejection fraction and elevated cardiac enzymes.
develop in which there is concurrent pericardial effusion Patients with tamponade or constriction may present with
and pericardial constriction. The occurs due to visceral only ascites and may be misdiagnosed as liver cirrhosis.
pericardial thickening (due to healing with fibrosis and The main feature to the diagnosis of tamponade is
calcification) leading to constriction, and the pressure of elevation of JVP which is not a common feature of cirrhosis
pericardial fluid leading to cardiac tamponade. unless patient has tense ascites.
KG-63.indd 523 03-11-2018 12:43:32

SECTION DIAGNOSIS assay. CT and/or MRI thorax may demonstrate pericardial
effusion, pericardial thickening, and lymphadenopathy
8
Any patient with a prolonged course of pericarditis should
(Figures 1A to C). Electrography findings usually include
have a suspicion of TB as etiology. The definite diagnosis
non-specific ST-T wave changes. A positive tuberculin
is usually established by demonstration of TB bacilli on
Cardiomyopathy
skin test may be considered as a supportive feature of TB

pericardial fluid examination or pericardial fluid culture
though a negative TST does not exclude TB as etiology.
as well as by caseating granuloma on histopathological
Pericardiocentesis is required for routine evaluation
examination of pericardium. Diagnosis is suggested by
of suspected tuberculous pericarditis while cardiac
presence of tuberculosis elsewhere in the body, elevated
tamponade is an absolute indication for pericardiocentesis.
levels of adenosine deaminase (ADA) level and clinical
The pericardial fluid should be sent for cell count, protein
response to antituberculous therapy.
and glucose levels, lactate dehydrogenase concentration,
a
Essential investigations include chest radiograph and acid-fast smear/culture, Gram stain and bacterial culture,
echocardiography. Further investigations are guided by
di
adenosine deaminase concentration, and cytology. These
preliminary findings. Pericardiocentesis is required in effusions are typically exudative, lymphocytic and have
most cases with isolated pericarditis. Additional imaging
In
high protein content. The yield of pericardial fluid AFB
includes contrast CT scan of thorax and cardiac MRI. smear and culture is about 40–60% for the diagnosis
Evidence of pulmonary tuberculosis may be present of tuberculous pericarditis. Utility of GeneXpert is not
of
in 30–70% of cases on chest radiograph. Cardiac shadow well studied. One study including 176 extrapulmonary
enlargement or pericardial calcification may also be specimens that included pericardial fluid samples as
observed. Sometimes pleural effusion can also be seen, well, demonstrated sensitivity and specificity to be 52
ty
exudative in case of tubercular involvement of pleura and 100% respectively which suggests it may be a useful
and transudative due to heart failure in patients with adjunct diagnostic test. Pericardial ADA level assessment
18 cie
constriction physiology. Echocardiography can non-
invasively establish the presence of a pericardial effusion
and detect features of tamponade. Sputum smear should
is also helpful but the cut-off levels suggestive of TB varies
ranging from 30–60 units/L. Lower ADA levels may be
seen in HIV-infected patients with severe CD4 lymphocyte
be examined for acid-fast bacilli and sent for GeneXpert depletion.
20 o S
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A B
ar
C
Figures 1A to C: CT thorax demonstrating (A) Heterogenous

mediastinal lymphadenopathy; (B) Anterior pericardial
effusion; (C) Posterior pericardial effusion with pericardial
thickening. The diagnosis of TB was achieved by
endobronchial ultrasound guided transbronchial needle
aspiration from the mediastinal lymph node demonstrating
C necrotizing granulomatous inflammation
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Pericardial biopsy is required in a minority of cases. significant effect of adjunctive corticosteroids on the CHAPTER
In areas with high prevalence of TB, antituberculous primary composite efficacy outcome of death, cardiac
therapy may be started empirically while in non-endemic
areas biopsy is usually indicated for patients with illness
tamponade requiring pericardiocentesis, or development
of constrictive pericarditis. However, it led to decrease in
63
Tubercular Pericarditis
lasting more than 3 weeks. Biopsy specimen should the incidence of constrictive pericarditis. Corticosteroids
be sent for mycobacterial staining and culture as well also hasten clinical improvement, reduce the need for
as histopathological examination. The sensitivity of pericardiectomy and decrease reaccumulation of fluid.
pericardial biopsy for diagnosis of pericardial TB is Patients at high risk of constrictive pericarditis include
suboptimal and ranges from 10-64%. Yield of pericardial those with large effusions, high levels of inflammatory
biopsy is reported to be higher in effusive stage. cells in the pericardial fluid, or having early features
of constriction. The commonly used steroid regimen
a
includes prednisolone 60 mg/day for 4 weeks, followed by
DIFFERENTIAL DIAGNOSIS 30 mg/day for 4 weeks, 15 mg/day for 2 weeks, and 5 mg/
di
The list includes pericarditis due to other infectious (such as day for one week. In children, steroid dose should always
viral, bacterial and fungal) as well as non-infectious causes be weight based starting from 1 mg/kg body weight with
In
(such as malignancy, radiation, trauma and sarcoidosis). In gradual tapering over 10–12 weeks.
TB endemic areas, tuberculous pericarditis is an important Pericardiectomy is required in the setting of
cause of heart failure especially in younger population. persistent constrictive pericarditis despite appropriate
of
antituberculous therapy. The timing of surgery is
controversial. Some favor pericardiectomy for all patients
TREATMENT
with constrictive pericarditis once antituberculous
ty
ATT dramatically reduces mortality from 80–90% to therapy has been started while others favor reserving
8–10% in patients with pericardial TB. It also reduces the pericardiectomy for patients who do not respond to
18 cie
likelihood of development of constrictive pericarditis.
Antituberculous therapy has also been shown to reduce the
likelihood of constrictive pericarditis. In TB endemic areas,
antituberculous therapy. Pericardiectomy, in general, is
required for patients in whom hemodynamics that fail to
improve or hemodynamics that deteriorate after four to
ATT can be started empirically on clinico-radiological eight weeks of ATT. Earlier intervention is usually reserved
20 o
basis pending definitive diagnosis. Clinical response to for patients with pericardial calcification which suggests a
S
ATT serves as a support for the diagnosis of tuberculous chronic disease.

pericarditis. The antitubercular drugs in common use are
shown in Table 1.
SUGGESTED READING
al
Table 1: First-line antitubercular drugs 1. Cegielski JP, Devlin BH, Morris AJ, et al. Comparison of PCR,
ic
culture, and histopathology for diagnosis of tuberculous

Drug Dose/kg (Usual adult dose)
pericarditis. J Clin Microbiol. 1997;35(12):3254-7.
Isoniazid 5 mg/kg (300 mg)
og
2. Cherian G. Diagnosis of tuberculous aetiology in pericardial

Rifampicin 10 mg/kg (600 mg) effusions. Postgrad Med J. 2004;80(943):262-6.
Pyrazinamide 25 mg/kg (1,500 mg) 3. Komsuoğlu B, Göldelï O, Kulan K, et al. The diagnostic and
Ethambutol 15 mg/kg (1,000 mg) prognostic value of adenosine deaminase in tuberculous
ol
pericarditis. Eur Heart J. 1995;16(8):1126-30.

A total of 6 months duration of therapy is recommended. 4. Official American Thoracic Society/Centers for Disease
di
The treatment regimen has two phases: intensive phase of Control and Prevention/Infectious Diseases Society of
2 months and continuation phase of 4 months. During America Clinical Practice Guidelines: Treatment of Drug-
ar
intensive phase four first line drugs (Isoniazid, Rifampicin, Susceptible Tuberculosis. Clin Infect Dis. 2016;63(7):147-95.
5. Sagristà-Sauleda J, Permanyer-Miralda G, Soler-Soler
Pyrazinamide and Ethambutol) are used on daily basis
C
J. Tuberculous pericarditis: ten year experience with a

while during continuation phase, pyrazinamide is
prospective protocol for diagnosis and treatment. J Am Coll
discontinued and rest of the drugs are continued. If a
Cardiol. 1988;11(4):724-8.
patient is diagnosed as drug resistant tuberculosis on
6. Strang JI, Nunn AJ, Johnson DA, et al. Management of
GeneXpert or mycobacterial culture, therapy needs to
tuberculous constrictive pericarditis and tuberculous
be individualized accordingly and a tuberculosis expert pericardial effusion in Transkei: results at 10 years follow-
should be consulted. up. QJM. 2004;97(8):525-35.
Administration of corticosteroids for patients with 7. Wiysonge CS, Ntsekhe M, Thabane L, et al. Interventions
constrictive tuberculous pericarditis and patients at for treating tuberculous pericarditis. Cochrane Database
high risk of constrictive pericarditis is usually done. Syst Rev. 2017;9:CD000526.
Steroids do not appear to be beneficial in the setting of 8. Z e k a A N, Ta sb a k a n S, Cav u s o g l u C . Ev a l u at i o n
pericardial TB that is not constrictive. A large randomized of the GeneXpert MTB/RIF assay for rapid diagnosis
trial including 1400 adults with definite (approximately of tuberculosis and detection of rifampin resistance
25%) or probable tuberculous pericarditis (with 2/3rd in pulmonary and extrapulmonary specimens. J Clin
having concomitant HIV infection) demonstrated no Microbiol. 2011;49(12):4138-41. 525
KG-63.indd 525 03-11-2018 12:43:32

Surgery for Chronic Constrictive
Pericarditis, Tuberculous
CHAPTER 64 Pericarditis and Effusive-
Constrictive Pericarditis
a
di
INTRODUCTION infections are the causative factors for 20–25% of purulent
Although chronic constrictive pericarditis (CCP) was pericarditis. In the remaining 80% of cases, one or more
In
designated as “concertio cordis” more than 300 years predisposing factors namely, chronic renal failure,
ago, it still eludes the clinicians. It mimics restrictive malignancy, recent thoracic surgery, HIV infection and
cardiomyopathy, cardiac failure, endomyocardial other immunosuppressive disorders are responsible for
of
fibrosis and chronic liver disease.1 CCP has a country- this disease entity.
specific pathology.2-6 Unlike rheumatic heart disease, The incidence of hospital-acquired infections have
increased and fungal pathogens have become more
ty
endomyocardial fibrosis and aorto-aortitis, CCP does
not show a declining trend despite socioeconomic common (up to 20%) in patients with a predisposing factor
development.2-6 including hyperalimentation, steroid administration,
18 cie
Chronic constrictive pericarditis is a heterogenous
disease. It is the end stage of a chronic inflammatory and
prolonged antibiotic therapy, malignancy, burns,
immunosuppression and following cardiac surgery.5,6,8,9,11
non-inflammatory process that results in a thick, fibrotic, Iatrogenic causes include pacemaker insertion, coronary
20 o
constricting and sometimes calcific pericardium causing interventions, and catheter ablation.3 The prevalence of
idiopathic CCP varies from 24% to 61% in India.6,12-15
S
impedance to diastolic filling leading to heart failure,

manifested as systemic congestion. However, there is no
inherent correctness to the above definition. Constrictive CLINICAL CHALLENGE AND DIAGNOSTIC
al
pericarditis mostly postsurgical and post-irradiation can DILEMMA OF CCP

occur in around 18% of patients with normal pericardial
ic
This condition has posed a diagnostic dilemma since it

thickness, where-in microscopic examination revealed was first recognized. All cases of constrictive pericarditis
focal fibrosis, focal calcification or inflammation.7
og
cannot be diagnosed using an isolated criterion. An

individualized diagnostic approach is recommended for
ETIOLOGICAL SEARCH each patient. In some patients, the diagnosis may be made
ol
An extensive etiological MEDLINE search and hospital on the basis of the history, physical examination and chest
admission for all cases of pericardial effusion reveals radiography. However, in the majority echocardiography,
di
varying causes of pericarditis and the clinicians are cardiac catheterization and visualization of the
required to identify causes that require targeted pericardium may all be required. The most important
ar
therapies.2-9 diagnostic tool is the clinical suspicion of constrictive

The major specific causes to be ruled out are tubercular pericarditis in a patient with signs and symptoms of right
C
pericarditis, neoplastic pericarditis and autoimmune sided heart failure that are disproportionate to pulmonary
pericarditis, each having a frequency of around 5%. 3,5 or left-sided heart disease.
The etiology of CCP also has changed during the past few Clinically, it is necessary to differentiate cons-
decades leading to diagnostic uncertainties. Tuberculosis trictive pericarditis from other causes of right sided
continues to be the leading cause of CCP in developing heart failure, such as mitral stenosis, pulmonary
countries with a reported incidence of 38% to 83%.2-10 Due hypertension, pulmonary embolism, right ventricular
to the emergence of drug-resistant strains of tuberculosis infarction and left ventricular systolic dysfunction.1,5,6,9,16
in association with AIDS, the prevalence has increased to Hepatosplenomegaly occurs early and may lead to an
>90%.10 Like other etiologies of CCP, tubercular pericarditis erroneous diagnosis of cirrhosis of liver. Kussmaul’s
also present with dense fibrosis without direct evidence of sign may be positive but it lacks specificity, as it is
the same. Mediastinal radiation and previous open heart also seen in patients with restrictive cardiomyopathy,
surgery are the etiological causes in developed countries.5,9 right ventricular failure, endomyocardial fibrosis and
Presently, staphylococcal, pneumococcal, strepto- tricuspid stenosis. 1,5,6,9,16 Evidence of pulsus paradoxus
coccal, Haemophillus influenzae and L egionella is found in the majority of patients. Published literature
KG-64.indd 526 03-11-2018 12:43:21

does not document one exact cause of ‘ascites precox’, were clinical features of constriction with supportive CHAPTER
i.e. the appearance of ascites followed by pedal edema. echocardiographic and hemodynamic criteria. 6,20 A
Disproportionately high right atrial pressures, protein
losing enteropathy causing hypoalbuminemia, increased
pericardial thickness of 3 mm or more on TEE was 95%
sensitive and 86% specific for detection of thickened
64
Surgery for Chronic Constrictive Pericarditis, Tuberculous Pericarditis and Effusive-Constrictive Pericarditis
capillary permeability, cardiac cirrhosis, impedance to pericardium. A constrictive pattern was defined as 25%
lymph flow and disproportionately high atrial natriuretic or greater increase in mitral E-velocity and hepatic
peptide have been variously implicated as the causative venous flow reversal during expiration compared with
factors for ascites precox.3,5,11,17 A diastolic lift (pericardial inspiration.6,20,21-24
knock) that coincides with a high-pitched early diastolic Speckle tracking echocardiography demonstrates
sound and sudden inspiratory splitting of second heart limited left ventricular mechanics in circumferential
sound (Vogelpoel-Beck sign) are specific clinical signs direction in CCP in contrast to longitudinal direction in
a
found in 21% and 36% of patients with CCP respectively.6,8-11 restrictive cardiomyopathy. 21-27 However, echocardio-
di
Among the laboratory parameters, ESR may be graphy was of limited value in the evaluation of pericardial
raised. Plasma protein levels are reduced for the reasons thickening anterior to the right ventricle and near the right
In
mentioned above. The ECG shows nonspecific changes atrioventricular groove.6,20-27
such as low voltage QRS complex, ST-T abnormalities, Computed tomography (CT) and magnetic resonance
P-mitrale (19 to 37% patients) and atrial fibrillation imaging (MRI) are superior imaging modalities for
of
(one-third of cases). Unusual ECG findings include right detection and distribution of pericardial thickness,
ventricular hypertrophy as a sequel of fibrous band pericardial masses, pericardial calcification, loculated
obstructing the right ventricular outflow tract.5,6,9,11,14 pericardial effusions and asymmetric pericardial
ty
Although chest radiography as a single noninvasive thickening and are helpful in determining the optimal
imaging modality are not helpful in the diagnosis of CCP, surgical approach for pericardial resection.28,29
18 cie
certain findings suggest the existence of CCP.13 In a typical
patient with CCP, the cardiac silhouette is not enlarged
except with co-existing pericardial effusion or extracardiac
The normal pericardium is 1–2 mm thick, whereas
in constrictive pericarditis, the thickness of parietal
pericardium ranges between 4 and 20 mm. Computed
mass. Eggshell calcifications or cocoon calcifications or tomography has the advantage of detection of pericardial
20 o
amorphous calcification in the atrioventricular grooves calcification but has the following limitations: (i) in the
S
strongly suggests constrictive pericarditis in patients presence of minimal/mild pericardial effusion, the exact
with heart failure. 6,18-20 Pericardial calcification may pericardial thickening cannot be measured, and (ii) unless
be revealed over the right atrium and ventricle and gated, computed tomography cannot show functional
al
atioventricular groove on lateral chest X-ray.6,18-20 M-mode changes associated with constriction.28,29
echocardiography reveals pericardial calcification, In cases of diagnostic dilemma, cardiac magnetic
ic
pericardial thickening, abnormal pericardial filling, resonance imaging (CMR) is the investigation of
og
abnormal septal motion, flattening of the left ventricular choice with its ability to define both morphological
posterior wall endocardium and premature opening of the (left atrial, superior and inferior vena cava dilatation,
pulmonary valve.21 ventricular elongation, myocardial atrophy and fibrosis)
ol
The role of 2D-echocardiography in the introductory and functional changes (constriction septal bounce)
phase was to rule out other causes of right heart failure unlike nongated computed tomography (CT) which
di
such as pulmonary hypertension, right ventricular demonstrates only morphological changes.28-30

infarction, pulmonary embolism or valvular heart On cine sequences, CMR shows ventriculo-ventricular
ar
disease.21-23 In constrictive pericarditis, patients usually interaction with evidence of a flattened interventricular
have normal ventricular dimensions with normal ejection septum or its convexity towards left ventricle in end-
fraction, although ejection fraction may be impaired in diastole, suggesting high right ventricular pressure. During
C
mixed constrictive-restrictive disease. Two-dimensional deep inspiration, there is an increased venous return to
echocardiographic findings suggestive of CCP include: right heart and in the presence of constrictive pericarditis,
(i) abnormal ventricular septal motion, (ii) dilatation and the left ventricular filling reduces and the septum flattens
absence of collapse of the inferior vena cava and hepatic or becomes convex towards left ventricle. On deep
veins, (iii) preserved or increased medial mitral annulus expiration, there is reversal of this phenomenon.28-30
early diastolic e′ velocity and (iv) increased hepatic As stated by Hurrell, “a thickened and calcified
flow reversal with expiration reflecting the ventricular pericardium does not necessarily cause constriction”.
interaction and the dissociation of the intracardiac and Similarly, patients with normal pericardial thickness
intrathoracic pressures.21-24 on CT and MRI may still have constrictive physiology. 30
The diagnostic accuracy for constrictive pericarditis Therefore, clinical evidence of impaired diastolic filling
has increased since hemodynamic changes and mitral along with pericardial thickening and/or calcification
annulus motion were identified. In our study, CCP was and other associated morphological findings such as
considered to be hemodynamically significant when there dilated superior and inferior vena cava, dilated left atrium, 527
KG-64.indd 527 03-11-2018 12:43:21

SECTION flattened interventricular septum, elongated ventricles bypass.32-37 The efficacy of pericardiocentesis in preventing
with or without pleural effusion on CT/CMR should be CCP in pericardial effusion (serous/or hemorrhagic)
8 used to diagnose CCP.28-30
Despite the difference in pathophysiologic mechanisms
has been inadequately investigated. 37 The terms “total”,
“complete”, “extensive”, “radical”, “partial”, “subtotal” and
Cardiomyopathy
of restriction and constriction, considerable overlap is “near-total” pericardiectomy have been variably used to
seen in the parameters of these entities. Increased atrial describe the procedure, often without precise definition of
pressures, equalization of end-diastolic pressures, and the limits of pericardial resection.32-37
dip-and-plateau or square root sign of the ventricular Published reports attest to the unpredictable and
diastolic pressure have traditionally been considered variable pattern of CCP and lend support to radical
hemodynamic features typical of CCP. However, identical decortication. In 2005, to define the limit of pericardial
hemodynamic pressures traces can be obtained in resection, total pericardiectomy was defined as wide
a
patients with restrictive cardiomyopathy. excision of the pericardium with the phrenic nerves
di
Although the findings of cardiac catheterization may defining the posterior extent, the great vessels including
not be diagnostic of constrictive pericarditis, Vatikus and the intrapericardial portion of superior vena cava and
In
Kussmaul demonstrated overall predictive accuracy of superior vena cava—right atrial junction defining the
three major hemodynamic criteria in the diagnosis of superior extent, and the diaphragmatic surface, including
constrictive pericarditis. A difference between right- and the inferior vena cava—right atrial junction defining the
of
left-ventricular end-diastolic pressure of 5 mm Hg or inferior extent of the pericardial resection.6 Constricting
less, a right ventricular systolic pressure of 50 mm Hg or layers of the epicardium were removed whenever possible
less and a ratio of right ventricular end-diastolic pressure and the atria and venae cavae were decorticated in all
ty
to right ventricular systolic pressure of >1.3 carry 85%, cases in this study group. Pericardiectomy was considered
70% and 76% sensitivity, respectively for diagnosing partial if both ventricles could not be decorticated
18 cie
constrictive pericarditis. Presence of all three criteria is
diagnostic of constrictive pericarditis in more than 90%
of patients.30,31 Thus, patients with CCP have symptoms
completely because of dense myopericardial adhesions
or calcification.6 Radical pericardiectomy was defined as
removal of the entire pericardium over the anterolateral,
20 o
and signs of right heart failure disproportionate to left diaphragmatic surfaces of left ventricle, portion of
ventricular dysfunction or valvular heart disease. The pericardium posterior to the phrenic nerve and the left
S
challenge is to determine whether abnormalities are ventricle and the anterior and diaphragmatic surfaces of
caused by pericardial restraint, myocardial restriction, or RV until the atrioventricular groove leaving behind intact
al
both.30,31 left and right phrenic pedicles.6

Secondly, the importance of unrecognized constricting
Timing of Operation, Selection of Surgical
ic
epicardial peel was described by Harrington in 1944

Approach, Extent of Decortication, and successful pericardiectomy requires removal of
og
Requirement of Cardiopulmonary Bypass and all constricting layers including decortication of the
Postoperative Low Cardiac Output Syndrome ventricular epicardium.33 In a study, Kolster and associates
Pericardiectomy is the only accepted treatment for CCP. Its demonstrated normalization of pressure volume loop as
ol
origin dates back to 1898, when DeLorme first suggested an indicator of operative success of pericardiectomy.38
it. However, the German group Rehn and Sauerbruch in In 2005, we compared two surgical approaches
di
1913 performed successful pericardial resection for CCP used for the treatment of CCP, i.e. median sternotomy
through a left anterolateral thoracotomy approach. 32 and conventional left anterolateral thoracotomy in 395
ar
Other surgical approaches for pericardiectomy include patients. The surgical approach was primarily based on
Churchill’s approach, left anterolateral thoracotomy, surgeon’s preference and remained uniform.6 However,
C
bilateral anterolateral thoracotomy, median sternotomy the median sternotomy approach was preferred in the
(Holman and Willett’s approach) and a U-shaped incision following conditions: (i) annular CCP, (ii) presence of a
with the base of “U” at the left sternal border (Harrington’s gradient between the superior or inferior venae cavae
approach).33-34 and right atrium of 2 mm Hg or greater, (iii) calcific
Despite the experience spanning over 100 years, there is pericardial patch compressing the RA and right ventricular
no fool-proof formula in the published literature to decide outflow tract, (iv) extracardiac intrapericardial mass, (v)
the optimal approach for a given patient. The literature previous open heart surgery, (vi) circumferential ‘cocoon’
is rife with descriptions of pericardiectomy by either left calcification of the pericardium, and (vii) recurrent CCP
anterolateral thoracotomy or median sternotomy. Despite after partial pericardiectomy.6 We demonstrated that the
the effectiveness of surgery, there are disparate opinions maximum benefit occurs after total pericardiectomy,
regarding the role of corticosteroids in treating tuberculous which is best achieved through a median sternotomy and
pericarditis, timing of operation, surgical approach, extent is very difficult through a conventional left anterolateral
of decortication and requirement of cardiopulmonary thoracotomy.6,20
528
KG-64.indd 528 03-11-2018 12:43:21

The institution of cardiopulmonary bypass for effusive advanced NYHA symptoms on late survival, presumably CHAPTER
or inflammatory pericarditis depends on how the patient because of young patient population and timely institution
tolerates cardiac manipulation. It is justified to use
cardiopulmonary bypass in order to facilitate complete
of chemotherapy and surgery.6,20,39,40
Although the median sternotomy approach allowed
64
pericardiectomy as it has more favorable long-term a more radical clearance of pericardium overlying the
functional outcome compared to partial pericardiectomy.35 right atrium and venae cavae including the cavo-atrial
Although routine use of cardiopulmonary bypass to junctions, these areas usually are of little hemodynamic
achieve total pericardiectomy is an issue of debate, significance in the majority of patients. Furthermore, it
it requires to be employed in special circumstances, is impossible to excise the portion of the pericardium
namely (i) inadvertent damage to a cardiac chamber, posterior to the phrenic nerve using this approach.6,20,39,40
(ii) concomitant intracardiac surgical procedures, (iii)
a
previous partial pericardiectomy, (iv) presence of calcific
Criterions for Decision-Making and Selection
pericardial “cocoon” encompassing all cardiac chambers,
di
(v) pericardiectomy following mediastinal irradiation and
of Surgical Approach for Patients Undergoing
(vi) coexistent cardiac lesion.6,18-20,35,39,40 Radical Pericardiectomy via Left Anterolateral
In
However, a left anterolateral thoracotomy was the Thoracotomy without Cardiopulmonary
preferred approach in cases of purulent pericarditis and Bypass (UKC’S Modification)
effusive constrictive pericarditis because of the presence
of
As enunciated above, the median sternotomy approach
of concomitant pyothorax and the concerns of sternal was the preferred option of the author (UKC) in the
infection.6,20,39,40 selected heterogenous group of patients undergoing
ty
pericardiectomy.6,20 In an effort to decrease the hospital
Criterions for Decision-Making on the mortality rates and postoperative LCOS, the author
Timing of Operation and Selection of
Pericardiectomy
18 cie
Surgical Approach for Patients Undergoing
proceeded to perform several technical modifications of
the conventional left anterolateral thoracotomy approach
to achieve further radical excision of the pericardium
posterior to the phrenic nerve and diaphragmatic
20 o
The clinical course of constrictive pericarditis is usually
pericardium without utilizing cardiopulmonary bypass.39,40
progressive and it is extremely difficult for the cardiologist
S
to delineate the degree of pericardial constriction and Thus, there were seven forces driving our decision-making
myocardial restriction. The result of pericardiectomy are towards improvement of the results after pericardiectomy
via modified anterolateral thoracotomy.
al
poor with dominant myocardial involvement and better

The desire to obtain improved operative exposure of
with dominant constrictive element.
the RV and RA by developing a new dissection plane
ic
Early pericardiectomy is beneficial for patients with

a central venous pressure between 12 and 15 mm Hg, between the posterior surface of the sternum and
anterior surface of the pericardium.
og
RA pressure >24 mm Hg, hepatic dysfunction, renal

The desire to dissect the pericardium posterior
dysfunction and massive ascites. Survival of patients with
CCP following pericardiectomy is higher than without to the phrenic nerve overlying the left atrium and
ol
surgery.5,6,19,20,39,40 posterolateral surface of the left ventricle.

The desire to develop a new cleavage plane between
In our previous study, we compared the outcomes
di
after total versus partial pericardiectomy. Our study the diaphragmatic pericardium and diaphragm.
The desire to minimize cardiac manipulation at
demonstrated that total pericardiectomy was associated
ar
with lower operative mortality and low cardiac output the time of dissection by dividing the anterior and
syndrome, abbreviated hospitalization, and better long- posterior pericardial flap in two halves respectively.
The desire to minimise postoperative autotransfusion
term survival than partial pericardiectomy. Ascites, renal
C
dysfunction, hyperbilirubinemia, high preoperative RA by inserting a peritoneal dialysis catheter before

pressure (>24 mm Hg), atrial fibrillation, low ejection surgical incision and placing it on gravity drainage
fraction (0.40 or less), pericardial calcification, tricuspid intraoperatively.
The desire to maintain oxygenation and hemodynamic
regurgitation, mitral regurgitation, partial pericardiectomy,
thoracotomy approach and postoperative LCOS stability during pericardiectomy via left anterolateral
negatively affected survival. 6 In this study, the risk of thoracotomy by placing an intercostal chest drain
death was 4.5 times higher (95% CI: 2.05 - 9.75) in patients on the opposite side in case of right-sided significant
undergoing partial pericardiectomy compared to total pleural effusion.
pericardiectomy.6 The desire to keep both groins prepared at the time
Despite total pericardiectomy, the operative mortality of pericardiectomy via modified left anterolateral
rate was 7.6% in our series and 6% to 19% in several large thoracotomy in case of inadvertent injury to the
series published after 1985.2-6,18-20,39,40 Unlike others, there cardiac chambers and/or great vessels and urgent
was no correlation with age, tuberculous etiology and institution of cardiopulmonary bypass.
529
KG-64.indd 529 03-11-2018 12:43:21

SECTION SURGICAL TECHNIQUES AND RESULTS Despite improved diagnostic accuracy with echo-
The step-by-step technical details of the conventional cardiography and computed tomography, aggressive
8 median sternotomy (n = 55) and the authors modi- preoperative stabilization, improvements in cardiac
anesthesia, perioperative hemodynamic monitoring and
fication of the left anterolateral thoracotomy (n = 67)
Cardiomyopathy
to achieve radical pericardiectomy without utilizing advances in surgical techniques over the past 100 years,
cardiopulmonary bypass have been alluded to in our pericardiectomy for CCP continues to be associated with
previous publications. 6,20,39,40 The following specific significant mortality (6-19%).2,3,5,6,8,9,18-20,24-36,39,40
maneuvers (Figures 1 and 2) facilitated performance of
radical pericardiectomy via modified left anterolateral POST-PERICARDIECTOMY LOW CARDIAC
thoracotomy: OUTPUT SYNDROME
Development of a new cleavage plane between the
a
The incidence of post-pericardiectomy low cardiac output
sternum and the anterior surface of the pericardium
syndrome is significant and the pathophysiological
di
using cautery and a right angled deep blade sternal
mechanisms responsible are multifactorial in nature,
retractor.
including myopericardial involvement, immobilization
In
Extension of the dissection plane beyond the
atrophy, abnormal diastolic filling characteristics,
midsternum to the right phrenic pedicle.
Development of a new cleavage plane between the
incomplete decortication, remodelling of the ventricle,
worsening tricuspid regurgitation, postoperative mitral
of
diaphragmatic pericardium and diaphragm.
Dissection of the pericardium posterior to the left
regurgitation due to papillary muscle elongation and
phrenic nerve and division of the posterior pericardium massive ascites. 41-45 Several investigators including
ourselves have observed that regardless of the operative
ty
in two halves.
Dissection of the pericardium anterior to the phrenic approach or extent of pericardial resection, a subset of
patients with chronic CCP will develop low cardiac output
18 cie
nerve, division of the anterior pericardium in two
halves and detachment of the anterior pericardium 1
cm away from the right atrioventricular groove.
syndrome.
The hemodynamic hallmark of CCP is impaired
Using these modifications, radical pericardiectomy ventricular diastolic compliance. Following peri-
20 o
was associated with a further reduction of operative cardiectomy, there are major fluid shifts from extravascular
S
mortality as compared to total pericardiectomy of our to intravascular compartments (autotransfusion) which

initial publication (2.9% vs 7.6%) and patients undergoing results in failure of Frank-Starling mechanism causing
total pericardiectomy of our second publication (2.9% acute cardiac dilatation. 6,20 In these patients the use of
al
vs 7.2%). 6,20,39,40 By employing these modifications, we cardiopulmonary bypass allows to control these fluid
have been able to reduce the incidence of postoperative shifts and ultrafiltration.35 So, this may be a concept that
ic
low cardiac output syndrome (LCOS) from 69% (total is not appreciated—the use of cardiopulmonary bypass to
pericardiectomy) to 26.8% (radical pericardiectomy).6,20,39,40 avoid cardiac distension.
og
ol
di
ar
A B C
C
D E F
Figures 1A to F: (A) Intraoperative views of the steps of left modified anterolateral thoracotomy (UKC’s modification) for radical
pericardiectomy. The left pleural cavity is entered through fourth intercostal space; (B) Left lung is retracted posteriorly with a wet sponge
for adequate exposure. Left phrenic pedicle is identified; (C and D) Using cautery, a new cleavage plane is created between posterior surface
of the sternum and anterior surface of the pericardium; (E) The cleavage plane is extended beyond sternum to identify the right phrenic
530 pedicle; (F) Using cautery, a new dissection plane is developed between the diaphragmatic pericardium and diaphragm
KG-64.indd 530 03-11-2018 12:43:22

CHAPTER
64
A B C
a
di
In
of
D E F
ty
Figures 2A to F: (A) Using cautery, two full-length parallel incisions are made 5 mm anterior and posterior to the left phrenic pedicle with
pulmonary artery (PA) as the superior and diaphragm as the inferior extent of the incision; (B and C) Posterior to the phrenic pedicle, the
18 cie
posterior pericardial flap (PPF) is raised to expose the posterolateral surface of left ventricle (LV) and left atrial appendage (LAA). This flap
is further divided into two halves in the center; (D and E) Anterior to the phrenic pedicle, anterior pericardial flap is raised to expose left
ventricle, right ventricle and pulmonary artery. This flap is further divided into two halves. The flap is excised 5 mm anterior to the right
phrenic pedicle extending to pulmonary artery superiorly and inferior vena cava-right atrium inferiorly; (F) The diaphragmatic pericardium
20 o
is dissected along the diaphragm to create a flap and excised
S
There is myo cardial e dema due to rep eate d who suddenly deteriorate after total pericardiectomy and
mechanical compression during surgery which settles are unresponsive to medical therapy. The other subset
al
slowly over time.6,20,39,40 It is indeed impossible to pinpoint include cases of progressive deterioration of ventricular
a specific causative factor for low cardiac output syndrome function and unresponsive to inotropic support.46
ic
following pericardiectomy. Although elevated right

atrial pressure and atrial fibrillation are associated SPECIFIC DISEASE ENTITIES
og
with poor postoperative outcomes, we refrain from

adopting an aggressive surgical approach to treat tricuspid Effusive-Constrictive Pericarditis
regurgitation or atrial fibrillation. If the cardiac output Effusive-pericarditis is a unique clinical-hemodynamic
ol
cannot be sustained by the currently available medical syndrome of multifactorial etiology combining elements
treatment, the next strategy may be to assist the failing of effusion/tamponade and constriction. In this disease,
di
heart by mechanical circulatory assistance.46,47 there is pericardial effusion, pericardial thickening and
Although the use of intra-aortic balloon counter- impaired diastolic cardiac filling.
ar
pulsation (IABC) is universal in adults with acute left The reported incidence in patients presenting with
ventricular dysfunction after myocardial infarction pericardial effusions is 1 to 15%. 2,5,8,11 In developing
C
or cardiac surgery, its use in patients undergoing countries, tuberculosis accounts for approximately
pericardiectomy for chronic CCP remains sporadic.46 70% cases of effusive-constrictive pericarditis. 2,5,8,11
Intra-aortic balloon counterpulsation (IABC) facilitates Penetrating trauma, post-open heart surgery, neoplasia,
recovery of left ventricular function by decreasing left post-irradiation, streptococcal, Salmonella infections
ventricular end-diastolic and left atrial pressure, thus and lasa fever infections are other causes of effusive-
helping the systemic ventricle and indirectly helping the constrictive pericarditis.2,5,6,8,11,50 The clinical course is
pulmonary ventricle by the phenomenon of ventricular insidious and ranges from a month to a year. The clinical,
interdependence.46 The advantage of IABC over left atrial- hemodynamic, radiologic and echocardiographic findings
aortic assist devices, axial flow pumps and veno-arterial are of those associated with effusion and constriction.
extracorporeal membrane oxygenation is the ease of Before surgery, the right atrial, right ventricular end-
application.48,49 diastolic, pulmonary wedge, and intrapericardial pressures
The timing and indications of balloon deployment is are equally increased with a prominent X-descent on
a matter of judgment. It is certainly indicated in patients right atrial pressure tracing. After pericardiocentesis, the
531
KG-64.indd 531 03-11-2018 12:43:23

SECTION intrapericardial pressure declines but the right atrial, TUBERCULOUS PERICARDIAL EFFUSION
right ventricular end-diastolic and pulmonary wedge
8
The disease develops insidiously over time with fever,
pressures remain elevated with a prominent Y-descent fatigue, night sweats and weight loss. The symptoms and
and early diastolic dip in right ventricular pressure. signs include chest pain, cough, breathlessness and right
Cardiomyopathy
Diagnosis is confirmed on pericardial fluid biochemistry

upper abdominal pain. Some patients exhibit evidence
and histopathology.
of chronic cardiac compression mimicking heart failure.
Although there is a marked overlap between the physical
MANAGEMENT signs of pericardial effusion and CCP, the presence of
There are no guidelines on the management of effusive- pericardial friction rub and increased cardiac dullness
constrictive pericarditis in published English language favors a clinical diagnosis of pericardial effusion.51,52
a
literature. The possible reasons are diagnostic difficulty,
varied etiopathogenesis, evolution patterns and lack of Noncalcific and Calcific Constrictive
di
available data.2-6,8-11 Pericarditis
Generally, management is according to the specific
In
The first presentation of tuberculous pericarditis may
etiology. Reaching an etiological diagnosis is a real
be pericardial constriction withour a prior effusive
challenge globally. The results of pericardial fluid culture
stage. Symptoms of systemic venous congestion include
are frequently falsely negative and pericardial biopsy has
of
oedema, abdominal swelling, hepatomegaly and
a higher yield of diagnostic specimens. One therefore
ascites.6,8-11,18-20,51 The incidence of pericardial calcification
has to rely on pericardial tissue biopsy microbiology or
in tubercular constrictive pericarditis ranges between 5%
cytology.2-6,8,11,50
ty
to 76%.6,8-11,18-20,39,40,51 In our previous study on 395 patients
undergoing pericardiectomy between 1985 and 2004,
Treatment Based on Etiology
18 cie
The management of tubercular effusive-constrictive
we observed 4.8% incidence of calcified pericardium, of
which tubercular constriction comprised 88.9% of cases.6
Usually the maximal pericardial calcification occur
pericarditis has been elaborated under tubercular
20 o
pericarditis. In idiopathic and postpericardiotomy cases over the right atrium and right ventricle, diaphragmatic
with tamponade and effusive-constrictive physiology surface and atrioventricular grooves. Fluid displaced by
S
anti-inflammatory treatment with corticosteroids and vigorous LV contraction during resorption of the primary
colchicine has been tried to avoid pericardiectomy. pericardial effusion, preferentially, gravitates towards the
al
Pericardiectomy is ultimately required in many of these right side of the heart where calcium and even bone are
patients.2-6,8,11,39,40,50 slowly deposited in the inspissated fluid.6,8-11,51
ic
Effusive-Constrictive Pericarditis
Treatment Based on Timing of Presentation
og
and Response to Medication This mixed form of tuberculous pericarditis is a common

presentation in India. Clinically, there may be signs of
The following management algorithm has been proposed pericardial effusion along with a diastolic knock and early
ol
by Salami and colleagues. 50 In patients with cardiac third heart sound. Echocardiography reveals loculated
tamponade or imminent tamponade the first step would pericardial effusion between thickened pericardial
di
be pericardiocentesis followed by pericardiostomy and membranes.3-5,50,51

pericardial biopsy for bacteriology and histology. Duration
ar
of illness is the next guide. Patients without tamponade of

more than 1 year duration are advised pericardiostomy Diagnosis of Tuberculous Pericardial Effusion:
A Systematic Approach
C
and biopsy. These authors recommended trial of medical

treatment for 6–8 weeks and operate only when there is The chest radiograph shows an enlarged cardiothoracic
persistent evidence of constriction. Presence of pericardial
ratio in almost all cases, features of active pulmonary
thickening with calcification following pericardiocentesis
tuberculosis in 30% and pleural effusion in 40–60% of
is an absolute indication for pericardiectomy.50
cases. Echocardiography is an accurate and noninvasive
method for the diagnosis of pericardial effusion and
TUBERCULOUS PERICARDITIS constriction.21,22,53,54
CT scan chest demonstrate pericardial effusion along
Clinical Presentation with thickened pericardium and enlarged mediastinal
Clinically, tuberculous pericarditis presents in one of lymph nodes (i.e. enlargement >10 mm with matting and
the three forms: pericardial effusion (80%), effusive- hypodense centers) in almost 100% of cases that resolve
constrictive pericarditis (15%) or as constrictive peri- on treatment. MRI reveals the extent of pericardial and
carditis (5%).3-6,9-11 myocardial involvement.28-30
532
KG-64.indd 532 03-11-2018 12:43:23

Accordingly, a “definite” diagnosis of tuberculous grade of evidence of pulmonary TB). Thrice-weekly dosing CHAPTER
pericarditis is based on the demonstration of tubercle frequency [2(HRZE) 3 4(HR)3] may be an alternative to
bacilli in pericardial fluid or on histologic section of
the pericardium; and a “probable” diagnosis is made
the above recommendation, provided that every dose is
directly observed and the patient is not living with HIV
64
when there is proof of tuberculosis elsewhere in a or living in a HIV-prevalent setting (conditional/high and
patient with unexplained pericarditis; a lymphocytic moderate grade of evidence). Treatment for 9 months or
pericardial exudate with elevated ADA enzyme activity longer gives no better results and has the disadvantages
>40 u/L, IFN-γ >50 pg/L or lysozyme level >6.5 µg/dL of increased cost and poor compliance. Short-course
and/or an appropriate response to antituberculosis chemotherapy is also effective in curing TB in HIV-
chemotherapy.2,5,6,9,10 infected patients.55,56
Antituberculosis chemotherapy increases survival
a
Tuberculous Constrictive Pericarditis dramatically in tuberculous pericarditis. In the
di
The diagnosis of pericardial constriction is made on the preantibiotic era, mortality was 80% to 90%; it ranges
basis of clinical features and confirmed by investigations currently from 8% to 17% in HIV-negative patients and 17%
In
including chest radiography, ECG, and echocardiography, to 34% in HIV-positive individuals.4,9,10,53-56
CT scan, or MRI. The roles of different investigative
modalities for CCP have already been enumerated. Role of Corticosteroids
of
The lymphatic drainage of the pericardium is to the Although adjunctive steroids may have beneficial effects
anterior and posterior mediastinal and tracheobronchial on mortality and morbidity in tuberculous pericardial
lymph nodes. The mediastinal node enlargement of effusion, published studies have not demonstrated
ty
tuberculous pericardial effusion is usually detected any significant beneficial effect on the reaccumulation
on CT scan and/or MRI. If CCP remains doubtful, of pericardial effusion or progression to constrictive
18 cie
endomyocardial biopsy is useful.10,55 pericarditis.4,5,8-10,52,53,55-57
A systematic meta-analysis reported significant
TREATMENT reduction in mortality with corticosteroids when used
20 o
along with rifampicin containing drug combinations. 58
Tuberculous Pericardial Effusion Despite prompt antitubercular treatment and use of
S
Patients living in tuberculosis-endemic regions, corticosteroids, CCP occurs in 30% to 60% of patients with
particularly those infected with HIV, a pericardial effusion tubercular pericarditis.4,5,8-10,52,53,55-57
al
is considered to be tuberculous in origin in the absence Most of the published guidelines recommend the
of an alternative etiology. Approximately two-thirds of use of adjunctive oral corticosteroids for the treatment
ic
these patients have a definite diagnosis of tuberculosis of tuberculous pericarditis. However, the choice of drug
according to microbiological or histologic criteria. In the (prednisone, prednisolone, methylprednisolone), route
og
remainder, an adequate response to antituberculosis (oral, intravenous, and intrapericardial) and dosage is
chemotherapy or other indirect evidence of tuberculous variable.52,53,55,57-59
etiology serves as support for the diagnosis. Even in the
ol
absence of a diagnosis of tubercular pericarditis, anti- Effusive-Constrictive Pericarditis

tubercular treatment should be started in patients from The treatment of effusive-constrictive pericarditis is
di
non-endemic areas.3-6,10,51-53,55 challenging because pericardiocentesis does not relieve

the diastolic cardiac filling and surgical removal of
ar
Antitubercular Drugs: What is the Optimal edematous, friable, thickened epicardium is hazardous
Drug Combination, Dosing Frequency with attendant risks of hemorrhage. It is advisable to initiate
C
and Treatment Duration of Tuberculous antitubercular treatment and decide the optimal time for
Pericarditis? surgical stripping based on serial echocardiogram.2,6,9,37
A controlled clinical trial of complete open surgical
Published literature including our observations over 3
drainage by substernal pericardiotomy and biopsy or
decades suggests that there are no reasons to administer
percutaneous pericardiocentesis on 122 patients by Strang
antitubercular drug treatment for tuberculous pericarditis
and colleagues showed that open drainage obviated the
longer than for extrapulmonary tuberculosis.6,8-10,52,55
need for repeated pericardiocentesis, but not subsequent
The WHO guidelines advocate a regimen consisting of
pericardiectomy.53
isoniazid, rifampicin, pyrazinamide and ethambutol for at
least 2 months followed by isoniazid and rifampicin for a
period of 4 months (total 6 months of therapy).56 Tuberculous-Constrictive Pericarditis
The WHO guidelines suggest that the optimal dosing The timing of pericardiectomy is controversial. There
frequency for new patients with tuberculous pericarditis have been no randomized studies of the practice of early
is daily throughout the course of therapy (strong/high pericardiectomy once antitubercular drugs have been 533
KG-64.indd 533 03-11-2018 12:43:23

SECTION started versus surgery in patients with CCP not responding management of pericardial diseases of the European
to antitubercular drugs. Several investigators including Society of Cardiology. Eur Heart J. 2004;25(7):587-610.
8 ourselves recommend pericardiectomy for persistent

pericardial constriction with hemodynamic deterioration
6. Chowdhury UK, Subramaniam GK, Kumar AS, et al.
Pericardiectomy for constrictive pericarditis: a clinical,
echocardiographic, and hemodynamic evaluation of two
Cardiomyopathy
after 4 to 8 weeks of antitubercular therapy.4-6,8-10,20,36,39,40

surgical techniques. Ann Thorac Surg. 2006;81(2):522-9.
Surger y for calcific constr ictive per icarditis
7. Talreja DR, Edwards WD, Danielson GK, et al. Constrictive
is challenging. A plane of cleavage is created above pericarditis in 26 patients with histologically normal
and below the calcified plaque. The circumferential pericardial thickness. Circulation. 2003;108(15):1852-7.
calcified pericardial patches were then crushed with a 8. Sagrista-Sauleda J, Merce J, Permanyer-Miralda G, et al.
thick hemostat and/or bone cutter and remove them Clinical clues to the causes of large pericardial effusions.
piecemeal avoiding injury to the underlying cardiac Am J Med. 2000;109(2):95-101.
a
chambers, vascular structures, coronaries and phrenic 9. Imazio M, Spodick DH, Brucato A, et al. Controversial issues
di
nerves, while removing calcified pericardial patches in the management of pericardial diseases. Circulation.
over the right atrium, right ventricle and the pulmonary 2010;121(7):916-28.
10. Mayosi BM, Wiysonge CS, Ntsekhe M, et al: Clinical
In
artery. Cardiopulmonary bypass may be required for
characteristics and initial management of patientswith
calcified cocooned pericardium. The risk of death after
tuberculous pericarditis in the HIV era: the investigation
pericardiectomy in patients with tuberculous constrictive
of the management of pericarditis in Africa (IMPI Africa)
of
pericarditis ranges from 3% to 16%.39,40 registry. BMC Infect Dis. 2006;6:2.
11. Roberts WI, Spray TL. Pericardial heart disease: A study
Unresolved Issues and Controversies in of causes, consequences and morphologic features. In:
ty
Management of Tubercular Pericarditis Spodick DH (Ed). Cardiovascular Clinics. Philadelphia: F.A.
Davis; 1976. pp. 11-68.
18 cie
Till date, limited evidence-based data are available
to guide the management of tuberculous pericardial
diseases. The unresolved issues include the difficulty in
12.
13.
Dalvi BV. Kussmaul’s sign: An artIfact?. Lancet. 1989;
1(8650):1337.
Anand IS, Ferrari R, Kalra GS, et al. Edema of cardiac
establishing a bacteriological or histological diagnosis, origin. Studies of body water and sodium, renal function,
20 o
the role of diagnostic pericardiocentesis versus open hemodynamic indexes, and plasma hormones in untreated
S
drainage and biopsy, the use of adjunctive corticosteroids congestive cardiac failure. Circulation. 1989;80(2):299-305.
(particularly in HIV-infected patients), and the timing 14. Bashi VV, John S, Ravikumar E, et al. Early and late results
of pericardiectomy. Furthermore, published literature of pericardiectomy in 118 cases of constrictive pericarditis.
al
Thorax. 1988;43(8):637-41.
addresses the clinical features and outcome of tubercular
15. Lorbar M, Spodick DH. “Idiopathic” pericarditis: the
pericarditis primarily in the pre-HIV era. It is likely that
ic
clinician’s challenge (nothing is idiopathic). Int J Clin Pract.

HIV infection modifies the clinical presentation and 2007;61:138-42.
outcome of tuberculous pericarditis. There are no data on
og
16. Myer TE, Sareli P, Marcus RH, et al. Mechanism underlying

the management of persistent atrial fibrillation in patients Kussmaul’s sign in chronic constrictive pericarditis. Am J
with tuberculous pericardial effusion and normal cardiac Cardiol. 1989;64(16):1069-72.
ol
function. These questions requires examination in large 17. Kothari SS, Roy A , Bahl VK . Chronic constrictive
prospective studies of tuberculous pericarditis. pericarditis:Pending issues. Ind Heart J. 2003;55(4):1-8.
di
18. McCaughan BC, Schoff HV, Piehler JM, et al. Early and late
results of pericardiectomy for constrictive pericarditis. J
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C
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43. Johnson TL, Bauman WB, Josephson RA. Worsening
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a
management of cardiomyopathy and pericarditis in sub-
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Vaitkus PT, Kussmaul WG. Constrictive pericarditis versus
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49. Kiley S, Sofia J, Machuca T. Venoarterial ECMO for recovery
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32. White PD. Chronic constrictive pericarditis (Pick’s disease)
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S
Post Session 2017 (Abstract), No. 1344.

33. Harrington SW. Chronic constrictive pericarditis. Partial
50. Salami MA, Adeoye PO, Adegboye VO, et al. Presentation
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al
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34. Bozbuga N, Erentug V, Eren E, et al. Pericardiectomy for pericarditis in Ibadan. Cardiovasc J Afr Title. 2012;23(4):
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35. Copeland JG, Stinson EB, Griepp RB, et al. Surgical treatment effusion. Postgrad Med J. 2004;80(943):262-6.
og
of chronic constrictive pericarditis using cardiopulmonary 52. Reuter H, Burgess LJ, Louw VJ, et al. Experience with
bypass. J Thorac Cardiovasc Surg. 1975;69:236-8. adjunctive corticosteroids in managing tuberculous
36. Clare GC, Troughton RW. Management of constrictive pericarditis. Cardiovasc J S Afr. 2006;17:233-8.
ol
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37. Merce J, Sagrista-Sauleda J, Permanyer-Miralda G, et al. 54. George S, Salama AL, Uthaman B, et al. Echocardiography
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ar
patients who have a large pericardial effusion without pericardial effusion. Heart. 2004;90:1338-9.
tamponade? Am J Med. 1998;105(2):106-9. 55. Syed FF, Mayosi BM. A modern approach to tuberculous
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38. Kloster FR, Crislip RL, Bristow JD, et al. Hemodynamic pericarditis. Prog Cardiovasc Dis. 2007;50(3):218-36.
studies following pericardiectomy for constrictive
56. World Heart Organization. Treatment of tuberculosis.
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Guidelines WHO/HTM/TB/2009. 420. 4th edition. Geneva:
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chronic constrictive pericarditis. J Operative Tech Thorac
57. Ntsekhe M, Wiysonge C, Volmink JA, et al. Adjuvant
Cardiovasc Surg. 2008;13:14-25.
corticosteroids for tuberculous pericarditis: Promising, but
40. Chowdhury UK, Narag R, Malhotra P, et al. Indications,
timing and techniques of radical pericardiectomy via not proven. QJM. 2003; 96(8):593-9.
modified left anterolateral thoracotomy (UKC’s modi- 58. Critchley JA, Young F, Orton L, et al. Corticosteroids for
fication) and total pericardiectomy via median sternotomy prevention of mortality in people with tuberculosis: A
(Holman and Willett) without cardiopulmonary bypass. J systemic review and meta-analysis. Lancet Infect Dis.
Prac Cardiovasc Sci. 2016;2:17-27. 2013;13(3):223-37.
41. Dines DW, Edwards JE, Burchell HB. Myocardial atrophy 59. Mayosi BM, Ntsekhe M, Bosch J, et al. Prednisolone and
in constrictive pericarditis. Proc Staff Meet Mayo Clin. myocobacterium indicus pranii in tuberculous pericarditis.
1958;33(4):93-9. N Engl J Med. 2014;371(12):1121-30. 535
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An Update on Restrictive
CHAPTER 65
Cardiomyopathy
a
di
INTRODUCTION MRI, cardiac catheterization, and endomyocardial biopsy,
Restrictive cardiomyopathy (RCM) is a group of help in confirming the diagnosis. Certain investigations,
In
heterogeneous myocardial diseases, which is characterized such as skin, liver and muscle biopsy, iron profile, positron
by impaired ventricular filling secondary to increased emission tomography-computed tomography (PET! CT),
genetic analysis, etc. are relevant especially in autosomal
of
myocardial stiffness. Its etiology may vary from infiltrative
and noninfiltrative disorders, storage disorders, and dominant mutations, such as Noonan syndrome and
idiopathic causes. Diagnosis of RCM is often overlooked desminopathy, and some variants of skeletal myopathies.
ty
leading to greater morbidity and mortality, at the time of Autosomal recessive mutations can be associated with
presentation. The prognosis is often guarded, even after RCM and musculoskeletal abnormalities.3
18 cie
a correct diagnosis and appropriate treatment. A detailed
knowledge and understanding of this entity is important
for early diagnosis and management. We hereby briefly
ECHOCARDIOGRAPHIC FINDINGS IN RCM
Biatrial dilation, normal or undersized ventricles, normal
review the etiopathogenesis, clinical presentation,
20 o
or increased wall thickness, normal or near-normal
diagnosis and treatment options of RCM. left ventricular systolic function, mild-to-moderate
S
mitral and/or tricuspid regurgitation are the common

ETIOLOGY echocardiographic findings in RCM. Moderate-to-severe
al
Table 1 describes the various etiologies of RCM.1 pulmonary artery hypertension (PAH) is a feature of RCM
and is due to elevated left ventricle end-diastolic pressures
ic
CLINICAL PRESENTATION (EDP). Concentric thickening of the LV free wall and

Since RCM can involve either or both the left and right septum, right ventricular (RV) free wall and atrial septum
og
ventricles, the clinical presentation may have left and/or thickening with enlarged atria is commonly seen in RCM
right heart failure. The common presentation of diastolic secondary to cardiac amyloidosis. Other features include
thickened valves, the presence of pericardial effusion, and
ol
heart failure is breathlessness, easy fatiguability, lethargy,

and peripheral edema. Palpitations and syncope are characteristic sparkling appearance of the myocardium in
patients with cardiac amyloidosis. Sometimes when there
di
usually due to underlying arrhythmias and heart block.

Children can have poor growth because of underlying RCM. is an overlap between echo features of RCM and CCP,
cardiac biomarkers like BNP can be used to differentiate.5
ar
Cardioembolic stroke and systemic embolization may be

an unusual presentation. Underlying systemic disease The transmitral Doppler spectrum shows a high E-wave
causing RCM can have the predominant symptoms at the with a shortened deceleration time (< 150 ms) and an E/A
C
time of presentation. Table 2 describes the predominant ratio of > 2.6 In chronic constrictive pericarditis (CCP),
symptoms and likely etiology of RCM.2 Characteristic there is 25% respiratory variation in transmitral flow
clinical signs of RCM include elevated jugular venous velocity and 40% respiratory variation in transtricuspid
pressure with Kussmaul! s sign, respiratory rales, ascites, flow velocity; whereas in RCM, there is no such respiratory
hepatomegaly, peripheral edema, and additional heart variation seen. In RCM, the tissue annular Doppler
sounds such as S3 and S4 gallops. velocities (Ea, Aa, and Sa) are reduced but not so in CCP
(Figure 5). In CCP, pericardial thickness is increased;
DIAGNOSIS whereas in RCM, it is normal (Figure 6). The inferior
After a detailed clinical evaluation, routine investigations, vena cava (IVC) can be dilated both in RCM and CCP
such as ECG (Table 3, Figures 1 to 4), X-ray chest, (Figure 7). In cardiac amyloidosis, global longitudinal
echocardiography, and blood investigations (Table 4) strain (GLS) is typically more impaired in the basal and
should be done. Certain investigations, such as cardiac midwall segments than at the apex.7
KG-65.indd 536 03-11-2018 12:43:08

CHAPTER
Table 1: Etiology of RCM
Infiltrative disorders
Idiopathic
65
zz Amyloidosis

zz Sarcoidosis
zz Primary hyperoxaluria
Storage disorders
zz Fabry disease
zz Gaucher disease
zz Hemochromatosis
zz Glycogen storage disorders
zz Mucopolysaccharidosis (Hurler and Hunter syndromes)
a
zz Niemann-Pick disease
di
Noninfiltrative causes
zz Diabetic cardiomyopathy
zz Pseudoxanthoma elasticum
In
zz Myofibrillar myopathies
zz Scleroderma
zz Werner syndrome
of
Endomyocardial causes
zz Carcinoid heart disease
zz Endomyocardial fibrosis
zz Hypereosinophilia
ty
zz Churg Strauss syndrome
zz Acute eosinophilic leukemia
zz Endocardial fibroelastosis 18 cie

zz Drugs: Methysurgide, busulfan, mercurial agents, ergot alkaloids
zz Cancer and cancer-related treatment: Metastatic cancer, lymphoma, multiple myeloma and radiation therapy and chemotherapeutic agents
(Anthracycline)
20 o
Genetic mutations
zz MYH7 Cardiac β-myosin heavy chain (autosomal dominant)
S
zz TNNT2 Cardiac troponin T (autosomal dominant)
zz TPM1 α-tropomyosin (autosomal dominant)
zz MYL3 Myosin light chain 2 (autosomal dominant)

al
zz MYL2 Myosin regulatory light chain 2 (autosomal dominant)
zz TNNI3 Cardiac troponin I (autosomal dominant)
zz DES Desmin (autosomal dominant)

ic
zz MYPN Myopalladin (autosomal dominant)
zz TTR transthyretin (autosomal dominant) amyloidosis

og
Source: Adopted from Eli Muchtar, et al.1

ol
Table 2: Clinical history and relevant association

di
Previous malignancy Metastatic tumors, lymphoma, multiple myeloma, postradiation therapy

Drug history Anthracycline, doxorubicin, antimalarial agents, L-tryptophan, busulfan, mercurial agents
ar
Weight loss Amyloidosis, neuromuscular disorders

Renal dysfunction Cystinosis, scleroderma, mitochondrial myopathy, amyloidosis, Fabry’s disease
C
Gastrointestinal involvement Scleroderma, mitochondrial myopathy, carcinoid, amyloidosis

Lung involvement Scleroderma, carcinoid, Churg-Strauss syndrome
Flushing Carcinoid
Allergic rhinitis and Nasal polyps Churg-Strauss syndrome
Diabetes mellitus Hemochromatosis, mitochondrial myopathy
Hepatic dysfunction Hemochromatosis, amyloidosis
Acroparesthesias Fabry’s disease
Bone pain Multiple myeloma
Fever Reactive arthritis
Source: Adopted from Stollberger et al. Extra-cardiac medical and neuromuscular implications in restrictive cardiomyopathy.2
537
KG-65.indd 537 03-11-2018 12:43:09

SECTION Table 3: ECG findings in RCM4
8
zz Left atrial and/or right atrial enlargement - tall, biphasic P waves
zz Low voltage QRS complexes (in infiltrative causes)
Biventricular hypertrophy
Cardiomyopathy
zz
zz ST segment depression with T wave inversions

zz Obliquely elevated ST-T segments*
zz Late peak T waves and notched biphasic T waves* (due to abnormal repolarisation)
zz Prolonged QT interval
zz Atrial fibrillation, atrial flutter (Figures 1 and 2)
Atrial and ventricular ectopics
a
zz
zz Heart block-AV block (Figure 3), bundle branch blocks, intraventricular conduction delay
di
zz Junctional bradycardia due to sinus node dysfunction (Figure 4)
zz Tachy-bradycardia syndrome
In
*Indicates abnormal diastolic relaxation and ventricular repolarisation abnormalities
of
ty
18 cie
20 o S
al
ic
og
Figure 1: ECG in a patient with restrictive cardiomyopathy showing atrial flutter with variable atrioventricular conduction block.
Courtesy: Dr Yash Lokhandwala, Mumbai
ol
di
ar
C
Figure 2: ECG in a patient with restrictive cardiomyopathy showing atrial flutter with variable atrioventricular conduction.
R/S in V1 >1 is suggestive of right ventricular hypertrophy (RVH)
Courtesy: Dr Ajay Bahl, PGIMER, Chandigarh.
538
KG-65.indd 538 03-11-2018 12:43:10

CHAPTER
65

a
di
In
Figure 3: ECG in a patient with cardiac amyloidosis showing first degree atrioventricular block and pseudoinfarction pattern
of
ty
18 cie
20 o S
al
ic
og
Figure 4: ECG of a restrictive cardiomyopathy patient showing junctional bradycardia due to sinus node dysfunction
ol
Table 4: Blood investigations and RCM etiology

Peripheral blood eosinophilia Hypereosinophilic syndrome, Churg-Strauss syndrome
di
Anemia and thrombocytopenia Gaucher’s disease

ar
Raise hepatic enzymes, renal dysfunction Storage disorders, hemochromatosis, amyloidosis

Elevated serum muscle enzyme levels Neuromuscular disorder
Serum and urine protein electrophoresis Gammapathies-Amyloidosis, POEMS (polyneuropathy, organomegaly, endocrinopathy,
C
M-protein, skin changes) syndrome, Fabry’s disease

Hypothyroidism Mitochondrial myopathy, POEMS syndrome, cystinosis
Raised plasma brain-natriuretic peptide5 To differentiate RCM from constrictive pericarditis
HEMODYNAMIC IN RCM The left atrial hypertension results in large ! v! waves

because of poor atrial compliance. The square root sign
The right and left atrial and ventricular EDP as well as is characterized by a rapid dip and early plateau in the
the pulmonary capillary wedge pressure are increased diastolic ventricular pressure and is due to rapid early
in a majority of the patients with RCM. The left ventricle filling in the end-diastolic pressure tracing. Though square
is commonly more affected than the right ventricle, the root sign is very classical of CCP, it can be seen in about
left ventricle EDP is greater than right ventricle EDP. 43% of patients with RCM.6
539
KG-65.indd 539 03-11-2018 12:43:13

SECTION
8
Cardiomyopathy
a
di
Figure 5: Tissue Doppler velocities (E’, A’, S’) in a patient with chronic
In
Figure 6: Echocardiographic image in subcostal view showing
constrictive pericarditis. In restrictive cardiomyopathy patients,
pericardial thickening in a case of chronic constrictive pericarditis
there is reduction in these velocities
of
vasodilator is an adverse prognostic factor for cardiac
transplantation.
ty
Tissue Biopsy for Diagnostic Evaluation
18 cie of RCM
Endomyocardial biopsy though very rarely performed
has diagnostic implication and at times may be a resort
20 o
to arrive at a confirmative diagnosis of amyloidosis and
S
sarcoidosis. Renal biopsy can confirm the diagnosis in

amyloidosis (Figure 11). Muscle biopsy is useful in RCM
cases associated with musculoskeletal diseases. Liver
al
biopsy can often reveal the diagnosis of glycogen and

lysosomal storage disorders (Figure 12).
ic
Figure 7: Ultrasound upper abdomen showing dilated, noncollapsing

Differentiating RCM from CCP
og
inferior vena cava in a case of restrictive cardiomyopathy

Clinical and hemodynamic features of RCM and CCP
There are elevation and equalization of right and may overlap and share some common features. At
ol
left atrial and ventricular pressures in diastole in CCP times, it may be difficult to differentiate these two
(Figure 8). In RCM, though all four chamber! s diastolic causes of diastolic heart failure (Table 5). However, by
di
pressures are elevated, there is a difference of >5 mm Hg taking into consideration of various findings of clinical
between right vs left ventricle. Dramatic x and y descents examinations, echocardiography, cardiac catheterization,
ar
and Kussmaul! s sign can also be seen in RCM patients radionuclide angiography, computed tomography, cardiac
(Figure 9). Severe PAH can be present in RCM patients magnetic resonance imaging, and cardiac biomarkers,
which is one of the differentiating features between RCM such as plasma brain-natriuretic peptide (BNP) and
C
and CCP. One of the reliable features in differentiating histopathology, one can differentiate between the two
RCM and CCP is the demonstration of interventricular entities. If the Doppler tracings of the transmitral flow
dependence in CCP. In CCP, during inspiration, the do not show respiratory-dependent variations in their
right ventricular filling increases with concomitant amplitudes, CCP is excluded. Plasma BNP levels are
excessive reduction in left ventricular preload due to higher in RCM than in CCP.
exaggerated ventricular interaction. This results in
respirophasic systolic ventricular dissociation in CCP; COMMON CAUSES OF RCM
whereas in RCM, the right and left ventricular systolic
pressures are concordant during respiration (Figures 10A Amyloidosis
and B).8 Pulmonary vascular resistance (PVR) estimation Cardiac amyloidosis is characterized by abnormal
is important for heart transplant workup. A PVR value of misfolded protein deposition in extracellular space
>6 Wood units/m2 after administration of a pulmonary leading to increased cardiac stiffness and RCM. The
540
KG-65.indd 540 03-11-2018 12:43:14

CHAPTER
65

a
di
In
Figure 8: Pressure tracing during cardiac catheterization showing classical elevation and equalization of left ventricular and right ventricular
of
end-diastolic pressure as well as the dip and plateau or square root sign. This type of pattern is classically seen in chronic constrictive
pericarditis, but can be seen in restrictive cardiomyopathy cases also
Courtesy: Dr Yash Lokhandwala, Mumbai.
ty
18 cie
20 o S
al
ic
og
ol
di
Figure 9: Pressure tracing during cardiac catheterization showing rapid x and y descents resembling a ‘W’ pattern. This is classical of
chronic constrictive pericarditis, but can be seen in restrictive cardiomyopathy cases also
Courtesy: Dr Yash Lokhandwala, Mumbai.
ar
three common types of amyloidosis associated with RCM more common in the AL type and is more often due to
C
are light chain immunoglobulin (AL) (74%), wild-type electromechanical dissociation rather than ventricular
transthyretin (ATTRwt) (22%), and mutant transthyretin tachycardia/fibrillation (VT/VF). Amyloidosis of AL
(ATTRm) (4%) amyloidosis. 9,10 Patients with ATTRwt variant carries the poorest prognosis with median survival
usually do not have additional visceral involvement outside of 6 months compared with 24! 66 months in ATTR
the heart, but 5% of patients present with noncardiac variant.11,12 The SCD accounts for approximately one-third
organ damage. In ATTRm and in AL amyloidosis, up to of early deaths in AL amyloidosis. Regarding the heart
40% of patients may have the extra-cardiac disease in failure management, most of the medications, such as
≥2 organs. Other than the clinical manifestation of heart angiotensin-converting enzyme inhibitors, angiotensin
failure and diminished cardiac output, arrhythmias are receptor II blockers, β-blockers, and calcium-channel
frequent in cardiac amyloidosis. Atrial fibrillation is higher blockers, are not well tolerated as they can cause profound
in ATTRwt (45%) than in AL (12%) or in ATTRm (15%) hypotension even with modest doses because of fixed
variant of amyloidosis.10 Sudden cardiac death (SCD) is cardiac output and associated autonomic neuropathy.
541
KG-65.indd 541 03-11-2018 12:43:15

SECTION
8
Cardiomyopathy
a
di
In
A B
Figures 10A and B: Simultaneous pressure tracing of both left and right ventricles. (A) showed respirophasic variation in left ventricular (LV)
and right ventricular (RV) systolic pressures in chronic constrictive pericarditis (CCP). During inspiration, LV systolic pressure decreases while
of
RV systolic pressure increases; and reverse happens during expiration. This respirophasic ventricular disconcordance is absent in restrictive
cardiomyopathy; (B) Greater fall in pulmonary capillary wedge pressure than LV diastolic pressure during inspiration, which leads to greater
expiratory gradient between the two in expiration, in CCP cases
ty
18 cie
20 o S
al
ic
og
Figure 11: Renal biopsy in a case of amyloidosis with multisystem Figure 12: Liver biopsy in a case of restrictive cardiomyopathy with
ol
involvement. Immunofluorescence stain showing kappa light-chain suspected glycogen storage disorder. Periodic acid–Schiff (PAS)
restricted amyloidosis in kidney stain shows intracytoplasmic glycogen confirming glycogen storage
di
Courtesy: Dr Balan Louis, Histopathologist, GKNM, Coimbatore. disorder

Courtesy: Dr Balan Louis, Histopathologist, GKNM, Coimbatore
ar
Loop diuretics and aldosterone antagonists remain the Monoclonal antibodies targeting the amyloid deposits are
mainstay of treatment. Digoxin can bind to amyloid being investigated for therapeutic purposes. Orthotopic
C
fibrils, hence increases the risk of its toxicity. Implantable heart transplantation is the final therapeutic option but
cardioverter defibrillator (ICD) is beneficial in selected infrequently used because of involvement of organs
patients as it does not result in overall survival benefit.13 other than the heart, and the risk of amyloid recurrence
Chemotherapy drugs melphalan and dexamethasone in the transplanted organ. Stabilization of transthyretin
are effective in two-thirds of patients. Bortezomib, a (TTR) in its tetrameric form can halt amyloidogenesis.
proteasome inhibitor, has shown remarkable benefits Two tetramer stabilizers namely diflunisal and tafamidis
when combined with melphalan, cyclophosphamide, are being tested. Doxycycline and tauroursodeoxycholic
and dexamethasone. Immunomodulatory drugs, such acid were shown to disrupt amyloid fibrils and facilitate
as thalidomide, lenalidomide, and pomalidomide, have tissue clearance in ATTR. Orthotopic liver transplantation
antiplasma cell activity but have to be used at lower is designed for ATTRm as a method to replace serum
doses. Daratumumab is an IgGκ monoclonal antibody, amyloidogenic TTR with a more stable wild-type tetramer.
targeting CD38 and hence has antiplasma cell activity and Combined heart and liver transplant is also an option in
542 now being tested in cardiac amyloidosis management. ATTRm.
KG-65.indd 542 03-11-2018 12:43:17

Table 5: Differentiation between chronic constrictive pericarditis (CCP) and restrictive cardiomyopathy (RCM) CHAPTER
65
CCP RCM
Prominent “Y” wave in jugular venous pulse Present Variable
Pulses paradoxus Present in ~1/3rd cases Absent

Pericardial knock Present Absent
Equal right- and left-sided filling pressures Present Left-sided pressure is 3–5 mm Hg more than
right side
Filling pressure >25 mm Hg Rare Common
RV end-diastolic pressure ≥1/3rd RV systolic pressure Present Present in <1/3rd cases
Pulmonary artery systolic pressure > 60 mm Hg Absent Common
a
Square root sign in ventricular diastolic filling pressure Present Variable
di
tracing
Respiratory variation in left and right sided flow Exaggerated Normal
In
Vent wall thickness Normal May increase following infiltration
Enlargement of atrial size Possible left atrial enlargement Biatrial enlargement present
Septal bounce of interventricular septum on echo Present Absent
of
Tissue Doppler velocities Normal Reduced
ty
Sarcoidosis defects may be seen. In the advanced stage, resting
perfusion defects may be seen in the absence of FDG
18 cie
Among patients with systemic sarcoidosis, cardiac
involvement occurs in 2.5! 5% in clinical series14,15 and up
to 25% in autopsy series.16 Noncaseating granulomas, the
uptake, indicating the presence of noninflammatory scar.
Whole-body FDG imaging, typically from the orbits to
the mid-thigh level is increasingly being used to evaluate
histopathological hallmark of cardiac sarcoidosis (CS),
20 o
for extra-CS (Figure 13). In organs with high metabolic
frequently infiltrate LV myocardium, but any other area
activity, a biopsy can be obtained. Hence, PET-CT is
S
of the heart including the right ventricle, atria, papillary

useful for diagnosis, staging, prognosis, and to guide
muscles, valves, pericardium, and coronary arteries
immunosuppressive therapy. The presence of both a
may be involved. The most common presentation is
al
perfusion defect and focal FDG abnormality on baseline

heart failure, but patients may present with syncope,
imaging is a strong predictor of death or VT. Although
palpitations, dyspnea, fatigue, chest pain, or SCD. Any
ic
cardiac magnetic resonance (CMR) images may show

patient of systemic sarcoidosis with cardiac symptoms
thinned walls, aneurysms and segmental wall motion
og
should be thoroughly evaluated as per the guidelines of

abnormalities in a noncoronary distribution, the principal
Japanese Ministry of Health and Welfare (JMHW) criteria method for detecting cardiac involvement is to identify
and the Heart Rhythm Society (HRS) expert consensus areas of late gadolinium enhancement (LGE), usually in
ol
statement (Table 6). 17,18 These criteria include the a subepicardial or transmural distribution. Identifying
presence of noncaseating granulomas on endomyocardial noncaseating granulomas in myocardial tissue is the gold
di
biopsy and either positive extracardiac biopsy or clinical standard for diagnosing sarcoidosis. However, because
diagnosis based on major and minor criteria. Complete of the patchy nature, the sensitivity of endomyocardial
ar
heart block and right bundle branch block are the most biopsy for detecting granulomatous disease is <20%. In
common presenting conduction abnormalities, but all patients with extra-CS, lymph node or lung biopsy is
C
types of conduction abnormalities may occur. Ventricular generally helpful to establish the diagnosis. Standard
tachycardia, supraventricular arrhythmias, frequent medical treatment for heart failure and arrhythmias is
premature ventricular contractions, and ventricular required in cardiac cases. Immunosuppressive therapy is
fibrillation can also occur before the diagnosis of CS. A considered in those with active inflammatory disease and
24-hour Holter recording should be done in any suspected any one of the following cardiac presentations: (a) reduced
case of CS. Cardiac positron emission tomography (PET) left ventricle ejection fraction, (b) high-grade AV block, (c)
imaging involves two different scans: one to assess frequent premature ventricular contractions or frequent
resting myocardial perfusion and areas of fibrosis or scar nonsustained VT, and (d) sustained VT or ventricular
using 82Rubidium or 13N-ammonia; and another scan fibrillation. Corticosteroids are the mainstay treatment for
to image inflammation using F-18 fluorodeoxy glucose patients with CS. Antimetabolites, such as methotrexate,
(FDG) (Figure 13); both of them are acquired in a single azathioprine, leflunomide, mycophenolate mofetil,
session. In the early stages of the disease, focal areas of and cyclophosphamide, have been used as the second-
increased FDG uptake are present and resting perfusion line agents. If the disease progresses despite the use of
543
KG-65.indd 543 03-11-2018 12:43:18

SECTION Table 6: Japanese criteria17 and Heart rhythm criteria18 for the diagnosis of cardiac sarcoidosis (CS)
8
Japanese ministry of health and family welfare 2006 Heart rhythm society 2014
Histological diagnosis EMB: Noncaseating granulomas and histological or clinical EBM: Noncaseating granulomas and
diagnosis of extra-cardiac sarcoidosis No alternative cause identified
Cardiomyopathy
Clinical diagnosis Extra-cardiac sarcoidosis per histological or clinical criteria Probable CS

plus Extra-cardiac sarcoidosis per histological criteria and
≥2 major clinical criteria for CS or ≥1 clinical criteria and
1 major plus ≥2 minor criteria for CS Alternative causes reasonably excluded
Clinical criteria Major
Advanced atrioventricular block or ventricular tachycardia Mobitz type 2 second-degree heart block or third-
degree heart block
a
Thinning of basal interventricular septum Positive gallium-67 uptake in heart
di
Positive gallium-67 uptake in heart Unexplained LVEF <40%
LVEF <50% ECG: Unexplained sustained (spontaneous or
induced) VT
In
CMR: LGE in pattern consistent with CS CMR: LGE in pattern consistent with CS
Minor
of
ECG, ventricular tachycardia, multifocal or frequent FDG-PET: Patchy uptake in a pattern consistent with
premature ventricular contractions, complete RBBB, axis CS
deviation or Q waves
ty
Echocardiogram: RWMA , aneurysm, wall thickening Cardiomyopathy or heart block responsive to
corticosteroid therapy
Nuclear: Perfusion defects on thallium-201 or technetium-99
m SPECT 18 cie
EMB: Moderate interstitial fibrosis or monocyte infiltration
Abbreviations: CMR, cardiac magnetic resonance imaging; ECG, electrocardiogram; EMB, endo-myocardial biopsy; LGE, late gadolinium
20 o
enhancement; LVEF, left ventricular ejection fraction; RBBB, right bundle branch block; RWMA, regional wall motion abnormality; VT, ventricular
tachycardia.
S
Cardiac Hemochromatosis
al
Hereditary hemochromatosis (HH) is characterized by

increased absorption of dietary iron, which accumulates in
ic
various organs leading to their dysfunction. Mutations of

specific genes involved in iron absorption and metabolism
og
are the predominant causes. The most common mutation

involves the gene HFE C282Y in autosomal recessive
fashion. The clinical manifestations include fatigue,
ol
hepatopathy (ranging from hepatomegaly, elevated liver

enzymes to frank cirrhosis, and risk of hepatocellular
di
carcinoma), skin hyperpigmentation (bronze skin),

arthralgia, diabetes mellitus and other endocrinopathies,
ar
male hypogonadism, cardiac conduction defects, and

cardiomyopathy. Increased risk for several infections
C
Figure 13: FDG-PET (F-18 fluorodeoxy glucose-positron emission (Vibrio vulnificus, Listeria monocytogenes, and Yersinia
tomography) scan showing increased uptake in axillary lymph enterocolitica) is another hallmark of the disease. Cardiac
nodes in a case of sarcoidosis
involvement is present in 15! 20% of cases.19 In addition to
Courtesy: Drs Raghava Kashyap, Harishankar, PGIMER, Chandigarh.
infiltration-related restrictive heart failure, there are various
glucocorticoids and a second-line agent, tumor necrosis conduction disturbances in the heart. Echocardiography
helps in confirming restrictive physiology in affected
factor-α inhibition with infliximab or adalimumab and
patients. Cardiac MR imaging (utilizing T2* relaxation
anti-CD-20 monoclonal antibody rituximab should
times) has become a valuable tool to quantify heart and
be considered. Device therapy, such as a permanent liver iron.20 This often obviates the need to perform organ
pacemaker and implantable cardiac defibrillator (ICD), biopsy. Diagnosis is made by mutational analysis, which
is appropriately indicated in patients. Orthotopic heart is usually completed for the two most common HFE gene
transplantation is occasionally indicated in patients with mutations - C282Y and H63D.21 The treatment of choice
intractable arrhythmias or end-stage heart failure. for symptomatic patients is therapeutic phlebotomy.
544
KG-65.indd 544 03-11-2018 12:43:19

It has to be repeated frequently as per the patient 7. Quarta CC, Solomon SD, Uraizee I, et al. Left ventricular CHAPTER
tolerance. Patients with cardiac dysfunction may require structure and function in transthyretinrelated versus
a less aggressive phlebotomy plan with a less frequent
schedule and reduced amount of blood collection
light-chain cardiac amyloidosis. Circulation. 2014;129(18):
1840-9.
65
8. Hurrell DG, Nishimura RA, Higano ST, et al. Value of

during each session. Phlebotomy is generally repeated
dynamic respiratory changes in left and right ventricular
until serum ferritin falls <50 ng/mL and transferrin pressures for the diagnosis of constrictive pericarditis.
saturation is <50%. The use of iron-chelating agents is Circulation. 1996;93(11):2007-13.
usually not required and is poorly tolerated compared 9. Crotty TB, Li CY, Edwards WD, et al. Amyloidosis and
with phlebotomy. Chelation can be considered in patients endomyocardial biopsy: correlation of extent and pattern of
with significant anemia or poor tolerance to phlebotomy deposition with amyloid immunophenotype in 100 cases.
becaus e of low blood pressure or symptomatic Cardiovasc Pathol. 1995;4(1):39-42.
a
hypovolemia not corrected with fluid management. The 10. Longhi S, Quarta CC, Milandri A, et al. Atrial fibrillation in
di
prognosis is driven by the presence of liver disease and its amyloidotic cardiomyopathy: prevalence, incidence, risk
factors and prognostic role. Amyloid. 2015;22(3):147-55.
complications, particularly cirrhosis and hepatocellular
11. Kyle RA, Gertz MA. Primary systemic amyloidosis: clinical
In
carcinoma. Death from cardiac causes has been reported
and laboratory features in 474 cases. Semin Hematol.
in approximately 20% of patients. 22 Iron and vitamin C 1995;32(1):45-59.
supplements should be avoided in them. 12. Castaño A, Drachman BM, Judge D, et al. Natural history
of
and therapy of TTR-cardiac amyloidosis: emerging disease-
CONCLUSION modifying therapies from organ transplantation to stabilizer
and silencer drugs. Heart Fail Rev. 2015;20(2):163-78.
ty
The RCM can present in multiple ways from being
13. Lin G, Dispenzieri A, Kyle R, et al. Implantable cardioverter
asymptomatic detection to heart failure to arrhythmias defibrillators in patients with cardiac amyloidosis. J
18 cie
and stroke. Three common causes of RCM other than
idiopathic RCM include amyloidosis, sarcoidosis, and
hemochromatosis. The CCP can be confused with RCM
Cardiovasc Electrophysiol. 2013;24(7):793-8.
14. Kandolin R, Lehtonen J, Airaksinen J, et al. Cardiac
sarcoidosis: epidemiology, characteristics, and outcome
as clinical and hemodynamic features may overlap, but over 25 years in a nationwide study. Circulation. 2015;
20 o
it is mandatory to delineate between the two as CCP is 131(7):624-32.
S
often curable whereas RCM is not. High index of clinical 15. Newman LS, Rose CS, Bresnitz EA, et al. A case control
etiologic study of sarcoidosis : environmental and
suspicion is required to consider the diagnosis of RCM.
occupational risk factors. Am J Respir Crit Care Med.
al
Earlier the diagnosis is confirmed, better the prognosis.

2004;170(12):1324-30
Treatment differs according to the underlying etiology 16. Uemura A, Morimoto. SI, Hiramitsu S, et al. Histologic
ic
and includes heart failure therapies, immunosuppressive diagnostic rate of cardiac sarcoidosis: evaluation of
agents, device implantation, and heart transplantation. endomyocardial biopsies. Am Heart J. 1999;138(2:1):299-302.
og
17. Hiraga H, Yuwai K, Hiroe M. Diagnostic standard and

REFERENCES guidelines for sarcoidosis. Jpn J Sarcoidosis Granulomatous
Disord. 2007;27:89-102.
1. Muchtar E, Blauwet LA, Gertz MA. Restrictive cardio-
ol
18. Birnie DH, Sauer WH, Bogun F, et al. HRS expert

myopathy: genetics, pathogenesis, clinical manifestations,
consensus statement on the diagnosis and management
diagnosis, and therapy. Circ Res. 2017;121(7):819-37.
di
of arrhythmias associated with cardiac sarcoidosis. Heart

2. Stöllberger C, Finsterer J. Extracardiac medical and Rhythm. 2014;11(7):1304-23.
neuromuscular implications in restrictive cardiomyopathy. 19. Gulati V, Harikrishnan P, Palaniswamy C, et al. Cardiac
ar
Clin Cardiol. 2007;30(8):375-80. involvement in hemochromatosis. Cardiol Rev. 2014;

3. Schwartz ML, Colan SD. Familial restrictive cardiomyopathy 22(2):56-68.
C
with skeletal abnormalities. Am J Cardiol.2003;92(5):636-9. 20. Kondur AK, Li T, Vaitkevicius P, et al. Quantification of
4. Hayashi T, Tsuda E, Kurosaki K, et al. Electrocardiographic myocardial iron overload by cardiovascular magnetic
and clinical characteristics of idiopathic restrictive resonance imaging T2* and review of the literature. Clin
cardiomyopathy in children. Circ J. 2007;71(10):1534-9. Cardiol. 2009;32(6):E55-9.
5. Leya FS, Arab D, Joyal D, et al. The efficacy of brain 21. Bacon BR, Adams PC, Kowdley KV, et al. Diagnosis and
natriuretic peptide levels in differentiating constrictive management of hemochromatosis: 2011 practice guideline
pericarditis from restrictive cardiomyopathy. J Am Coll by the American Association for the Study of Liver Diseases.
Cardiol. 2005;45(11):1900-2. Hepatology.2011;54(1):328-43.
6. Ammash NM, Seward JB, Bailey KR, et al. Clinical profile 22. Niederau CL, Fischer RU, Purschel A, et al. Longterm
and outcome of idiopathic restrictive cardiomyopathy. survival in patients w ith here ditar y hemochromatosis.
Circulation. 2000;101(21):2490-6. Gastroenterology. 1996;110(4):1107-19.
545
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Tropical Endomyocardial
Fibrosis? A Vanishing Curious
CHAPTER 66
Disease
a
di
INTRODUCTION in the fibrotic process, which surprisingly spares the valve
Endomyocardial fibrosis (EMF) is a fascinating cardiac leaflets.
In
disease for several reasons. EMF was first recognized as
a cardiac disease as late as the 1940s, initially at autopsy EPIDEMIOLOGY
of
and later as clinical heart failure. It is prevalent as endemic Pathological features of fibrotic involvement of ventricular
disease predominantly in the tropical region within 15° endocardium was first reported by Arthur Williams in
of the equator in coastal and rain forest regions. Chronic 1938, and recognized at autopsy by Bedford and Konstam1
ty
fibrotic stage of EMF involves only the left ventricular (1946) in African soldiers, but detailed description of
(LV) and right ventricular (RV) endomyocardium sparing the disease and the clinicopathological correlation was
18 cie
other cardiac structures. Though it is postulated that an
acute inflammatory prothrombotic state followed by a
quiescent asymptomatic state precedes the symptomatic
published by Davis in 1948;2 hence, it is often described
as Davis’s disease. Majority of the initial cases were
reported from Uganda, and subsequently from other
chronic fibrotic state, the acute systemic inflammatory countries of the world largely from the tropical regions
20 o
state progressing to chronic fibrotic state has not been namely southern Brazil in South America, southern parts
S
convincingly documented. Symptoms are entirely due of Nigeria, Ghana and Ivory Coast in West Africa, and
to hemodynamic consequence of fibrosis of ventricular southern state of Kerala in India (Figure 1). With the
endomyocardium, which results in ventricular diastolic availability of echocardiographic imaging worldwide,
al
dysfunction and involvement of subvalvular structures several low-income countries from the tropical region
by the fibrotic process causing atrioventricular (AV) have reported EMF in small numbers, e.g. Cameroon,
ic
valve regurgitation. Needless to emphasize, the degree Malawi, Mozambique, Columbia, Vietnam, and South
of diastolic dysfunction and AV valve incompetence
og
China.
determines the severity of hemodynamic consequences Reports from Uganda and Nigeria on necropsy data
and one patient can be entirely asymptomatic while in the 1950s revealed that 15–20% of heart failure patients
ol
another is in end-stage heart failure. Atrial fibrillation had EMF. In 1975, reports from Ivory Coast revealed 15%
(AF) is a common arrhythmia in the more severe cases incidence of EMF by angiography and/or necropsy among
di
and thromboembolism from the atria as well as from the patients with heart failure. In 1993–94, echocardiographic
ventricles is possible, but infrequent. Many regions like study from Uganda revealed 20% incidence of EMF among
ar
Kerala in India, Nigeria and Brazil where EMF was endemic all cardiac patients. Echocardiography study from Ghana
in the 60s and 70s, now report a marked reduction in its reported 4% incidence of EMF in cardiac patients with
prevalence. With wide availability of echocardiographic heart failure. Necropsy study of 734 cardiac cases from
C
imaging, several new regions worldwide are reporting Brazil (1971-91) reported 2% incidence of EMF.3
EMF for the first time. Etiology of EMF continues to be Kutty et al.4 from Kerala in an echocardiography based
elusive, though many risk factors have been proposed as study from 1977-1994 reported 1.5% incidence among
contributing factors. 22,666 cardiac patients. Chelo et al. reported 64 cases of
E M F i s a re s t r i c t i ve ca rd i o myo p at hy ( RC M ) EMF seen over 8 years from 2006 to 2014 from Cameroon
characterized by fibrous tissue deposition on the highlighting geographical distribution with prevalence
endocardium of right, left or both ventricles, preferentially strictly limited to 3 of the 10 provinces in Cameroon.5
at apices and the inflows and sparing the outflows. Severity However, recent reports from Nigeria, Brazil, and Kerala
of hemodynamic derangement is proportional to the in India show a marked decrease in the prevalence of EMF
ensuing impairment of diastolic filling of the ventricles as a cause of heart failure. Only three cases of EMF were
and AV valve incompetence due to involvement of identified in a subset of 7,956 cardiac patients in a study
endocardium, papillary muscles, and chordae tendinae from University in Brazil for a prevalence of 0.04% among
KG-66.indd 546 03-11-2018 12:42:53

CHAPTER
66

a
di
In
Figure 1: Endemic regions reporting endomyocadial fibrosis in the latter half of 20th century
of
all cardiac patients. All the patients with EMF were in the Diagnosis was based on clinical evaluation alone, as 2D
second or third decades of life, and had right ventricular echocardiography and cardiac catheterization studies
EMF (RVEMF) with AF.3 were not available during that period. Majority of patients
ty
The only population-based study on prevalence of were below 30 years, and males and females equally
EMF was reported from rural Mozambique in South East affected. Clinical and autopsy data from other parts of
18 cie
Africa in 2008. The population was from coastal area far
from any major medical facility and less than 1% had
access to medical care. Echocardiographic criteria were
India included 20 cases from North India, 10 autopsy cases
from Western India, and 11 autopsy cases from Tamil Nadu
(Vellore) in South India. The autopsy proven cases had
used and 212 of 1,190 people screened had EMF, 56% similar incidence of RV, LV and biventricular involvement.
20 o
biventricular, 28% RV and 16% LV; 77.5% had mild, 18% In contrast, early clinical studies from Kerala, before 2D
S
moderate, and 4.5% severe disease; 20% were moderately echocardiography was widely available, reported high
symptomatic and <5% severely symptomatic, while the incidence of RVEMF. The age group of pathological series
vast majority had mild or no symptoms. Highest incidence
al
was older as compared to the clinical series from Kerala.

was in the 10–20 age group and average age was 22 years With the availability of 2D Echo and angiographic studies,
with male preponderance. LVEMF was more common
ic
biventricular and left ventricular EMF were detected more

than RV or biventricular EMF in age groups above thirty often, so also milder forms of RVEMF. In 1981, Sree Chitra
years. Familial clustering was also reported.6
og
Tirunal Institute of Medical Sciences and Technology

In general, most reports of EMF are from patients (SCTIMST) presented data of 64 consecutive cases of EMF
attending hospital for heart failure; hence, necessarily are confirmed by angiography. About 70% of patients were
ol
cases of advanced disease. Chance detection of subclinical below 30 years of age (average age 23 years and age range
or asymptomatic EMF in hospital setting in the absence of from 4–50 years). Almost 25 patients had isolated RVEMF,
di
heart failure is rare even when routine echocardiography 4 patients had isolated LVEMF, and 35 had biventricular
is performed for possible cardiac-related symptoms EMF.9 Talwar et al. (2004)10 have reported 30 cases of EMF,
ar
because the ventricular apices are the blind spots during confirmed by echocardiography and angiography, 29 had
routine echocardiographic examination due to near field biventricular disease and one isolated RVEMF.
clutter.
C
A comparative analysis of 295 new cases seen from

1976-1990, and 123 new cases seen from 1991–2001
ENDOMYOCARDIAL FIBROSIS IN INDIA at SCTIMST revealed certain important demographic
The first autopsy report of endomyocardial fibrosis (EMF) variations. The average age of the newly diagnosed cases
in India was by Samuel and Anklesaria7 from Vellore in in 1991–2001 was 33 years, as compared to 25 years in
South India (1960) and by Gopi from Kerala (1962). By 1976–1990 series and only 3% were below 10 years and 12%
1968, EMF was recognized as a common cardiac condition between 11 and 20 years. The number of newly diagnosed
in the southern part of Kerala.8 cases decreased from 20 per year in 1976–1990 to 10 cases
In 1981, a workshop on EMF sponsored by the per year in 1991–2001. The demographic studies revealed
Indian Council of Medical Research (ICMR) was held a trend towards higher age at presentation, with a marked
in Trivandrum (now Thiruvananthapuram), Kerala. 9 decrease in patients presenting below 20 years of age, a
Trivandrum reported 90 cases over 12 years, Kottayam 50 relatively benign course in over 80–90% of patients with
cases and Kozhikode region from north Kerala 25 cases. stable symptoms over several years of follow-up, and
547
KG-66.indd 547 03-11-2018 12:42:53

SECTION mortality of 4% during an average follow-up period of be true always. An occasional patient is seen with severe
36 months. Mortality was limited to patients presenting cavity obliteration and mild mitral regurgitation (MR) and
8 with end-stage heart failure [New York Heart Association
(NYHA) Class IV]. All these findings may be explained
significant PAH due to diastolic LV dysfunction alone. It
is important to recognize this condition, because surgical
Cardiomyopathy
by true reduction in incidence of the disease and less procedure of isolated LV endocardectomy to restore
severe form of the disease presenting late in the natural LV cavity size and normal diastolic function without
history.11,12 valve replacement can result in significant symptomatic
improvement. This, nevertheless, is an extremely rare
ETIOLOGY OF ENDOMYOCARDIAL FIBROSIS situation in our experience. Clinical features of LVEMF are
largely dependent on severity of MR, though diastolic LV
Etiology of EMF is still an enigma. Several factors have
dysfunction can result in further pulmonary hypertension.
a
been associated with occurrence of EMF in a particular
The patient can have increasing grades of dyspnea and
geographical area: exposure to cyanides from high intake of
di
paroxysmal nocturnal dyspnea. LV type cardiomegaly
cassava, serotonins from plantains, deficiency or excess of
is unusual, though LV impulse is often prominent. The
trace elements in soil, e.g. cerium and thorium, deficiency
In
presence of LV S3, evidence of pulmonary hypertension,
of macro- and micronutrients, parasitic infections, such
and a soft pansystolic murmur at apex complete the
as filariasis and schistostomiasis, and malnutrition in a
physical findings.
susceptible population usually from low-socioeconomic
of
strata. Populations with high-socioeconomic status Biventricular EMF: It will have a combination of clinical
improved the state public health facilities and easy access features of RV and LV EMF. Mild RVEMF with moderate-
to health services show epidemiological transition with to-severe LVEMF will have features of LV disease and vice-
ty
remarkable reduction in the prevalence of EMF as in versa. When there is moderate to severe involvement of
Kerala, Brazil, and parts of Nigeria; while EMF has a high both ventricles, detailed hemodynamic and angiographic
18 cie
prevalence in impoverished tropical regions such as
Mozambique in Africa even at the beginning of the 21st
evaluation will guide the surgical strategy as this group of
patients is the most difficult to manage medically.
century.6
LABORATORY INVESTIGATIONS
20 o
In chronic EMF, routine biochemical and hematological
S
CLINICAL PRESENTATION
investigations are done (Figures 2A to E). Chest X-ray,
Symptoms and physical findings closely follow severity
electrocardiogram (ECG) and echocardiogram are
al
of diastolic ventricular dysfunction and AV valve

done in all; and in the modern era, cardiac magnetic
incompetence of RV, LV or both RV and LV.
resonance imaging (MRI) is done in doubtful cases and
ic
RVEMF: Severe form of RVEMF with obliteration of RV occasionally to differentiate EMF from apical hypertrophic
apex and inflow leads to severe nonhypertensive tricuspid cardiomyopathy (HCM). Hemodynamic and angiographic
og
valve regurgitation (TR). The patient complains of study is planned prior to surgical intervention to delineate
fatigue, loss of appetite and weight loss, swelling of legs, chamber morphology, chamber pressure, degree of AV
distension of abdomen, and orthopnea due to respiratory valve incompetence, and PA pressure.
ol
distress from elevated diaphragm. Physical findings

include irregular low volume pulse due to AF and low Chest X-ray and Fluoroscopy
di
stroke output, large expansive ‘V’ waves with rapid ‘VY’ Marked cardiomegaly is seen with severe RVEMF, especially
descent, pulsatile hepatomegaly, pedal edema, ascites with pericardial effusion. Patchy endomyocardial
ar
(often ascites precox), and cachexia. Cardiac examination calcification, better appreciated by fluoroscopy, clinches
reveals cardiomegaly due to right atrial enlargement, often the diagnosis of EMF.
C
associated pericardial effusion, silent precordium with RV

third heart sound (S3) and no murmur or rub. Moderate ECG
RV cavity obliteration (only apical obliteration) with only
ECG features of RVEMF include right atrial (RA)
mild-to-moderate TR results in mild prominent ‘v’ waves
enlargement, right axis deviation of QRS with low voltage
in JVP, mild cardiomegaly due to RA enlargement, faint
QRS complexes, qR pattern with a small R wave in V1 and
S3, and a faint early systolic murmur of TR. There are no
tall R wave in V2. AF is common, and qR pattern in V1 is
features of pulmonary arterial hypertension (PAH) in
believed to indicate RA enlargement.
RVEMF. Mild RVEMF does not produce TR and the patient
ECG features of LVEMF include large R voltage in V5-6,
is asymptomatic though occasionally a prominent ‘a’ wave
and marked ST depression and T wave inversion in lateral
in JVP secondary to RV diastolic dysfunction can be a clue
precordial leads, simulating apical HCM and myocardial
to the diagnosis.
ischemia. The ST & T wave changes can be present in the
LVEMF: Generally, the extent of LV cavity obliteration absence of large R waves and digoxin. LA enlargement is
548 parallels mitral valve incompetence, but this need not often seen.13
KG-66.indd 548 03-11-2018 12:42:53

CHAPTER
66

A B C
a
di
In
D E
of
Figures 2A to E: Imaging modalities depicting features which are diagnostic of EMF: (A) Fluoroscopy showing, the presence of LV apical
calcium; (B) RV angiogram in patient with RVEMF, showing obliteration of the RV apex and body; (C) LV angiogram showing LV apical
obliteration typical of LVEMF; (D) Echocardiogram: Apical 4 chamber view showing the presence of calcium at the LV apex; (E) Perfusion MRI,
ty
4 chamber view in diastole showing fibrosis and obliteration of RV apex
Echocardiography (EMB) is rarely performed to confirm EMF, but may be

18 cie
The sine qua non of EMF is deposition of fibrous tissue
over ventricular endocardium with preserved LV wall
indicated if there is strong suspicion of any other form of
infiltrative RCM.
thickness and LV wall contractility. Secondary effects
20 o
NATURAL HISTORY AND MANAGEMENT
of this can be layered thrombus over the fibrous tissue,
S
AV valve incompetence and atrial enlargement often As most patients come to clinical surveillance late in the
with spontaneous contrast and free-floating thrombi, course of the disease and are usually in functional NYHA
(New York Heart Association) class III-IV, the prognosis is
al
especially in RA. Pericardial effusion may be present in

RVEMF and features of PH in LVEMF.14 dismal with high mortality on medical therapy as for heart
failure of any etiology. Pericardial effusion often seen in
ic
Angiographic Features of EMF severe RVEMF does not benefit from pericardial aspiration
as it does not seem to alter symptoms or clinical outcome.
og
In our experience, angiographic cavity morphology of RV

Surgery, tailored to suit the clinical condition, is an
and LV EMF are fairly characteristic in moderate-to-severe
option: RVEMF, RV endocardectomy with TV repair/
EMF with effacement of normal trabeculae and cavity
replacement with RA reduction surgery to maintain
ol
obliteration. Very mild RV/LV EMF can be missed if fibrous

sinus rhythm, with additional Glenn shunt if indicated.
tissue deposition is insufficient to cause effacement of
Intermediate term outcome with TV prosthesis has been
di
the normal trabecular pattern of RV and LV. AV valve

unsatisfactory with almost all patients reporting back
incompetence is assessed as for AV valve incompetence of
with recurrence of symptoms and valve malfunction. The
ar
other etiologies.15
institute has little experience with bioprosthesis as it was
not easily available in the 80s. Fontan repair, maintaining
Cardiac MRI in EMF
C
sinus rhythm is a logical option for severe RVEMF with

Soft tissue characterization helps differentiate apical HCM poor RV contractile function. LVEMF too has a dismal
from fibrotic deposits of EMF and organizing thrombi of prognosis when in NYHA class IV on optimal medications.
any other etiology. Assessment of RV chamber size and LV endocardectomy with MV replacement is the standard
function can help plan surgical intervention. procedure and long-term outcome is similar to valve
replacement in the young with rheumatic MV disease.
Endomyocardial Biopsy Progression or recurrence of the fibrotic process though
Talwar et al.10 reported 30 cases of EMF, among 50 cases of plausible, has rarely been documented.
idiopathic restrictive cardiomyopathy (RCM) confirmed Natural history study reported from SCTIMST of 206
by angiography and echocardiography. All patients patients seen from 1975 to 1991 (excluding 89 patients
underwent endomyocardial biopsy; 11 had lymphocytic who underwent surgery) and on optimal medical therapy
infiltrates, 13 had fibrosis and myocytolyis, and none revealed survival of 82%, 53% and 37% at 1, 5 and 10
showed eosinophilic infiltrates. Endomyocardial biopsy years, respectively. LV involvement with severe mitral
549
KG-66.indd 549 03-11-2018 12:42:54

SECTION incompetence, PAH, elevated RA mean pressure more diagnosed cases was better, with mortality less than
than 20 mm Hg, and NYHA class III–IV were predictive 10% at 3-year follow-up.
8 of adverse outcome. Of the 206 patients, 179 had
angiography and hemodynamic study, 20 were diagnosed
4. A significant percentage of patients were referred
for abnormal ECG or echo findings, and on further
Cardiomyopathy
by echocardiography, and 7 were diagnosed at autopsy. A evaluation, diagnosed as EMF and these patients
total of 51 patients had RVEMF, 14 had LVEMF and 141 had were often mildly symptomatic. About 12% had
BVEMF. About 28% of patients were below the age of 15 associated other heart diseases such as rheumatic valve
years.12 During this period, 89 patients had surgery (mean disease, coronary artery disease, and hypertrophic
age 25 years) of which 60% were females; 95% patients were cardiomyopathy.
in NYHA class III–IV with an operative mortality of 29% 5. On an average, 5-7 new cases of EMF are seen at the
(within 30 days of surgery) and late mortality of 12%. Among Institute and this number has remained constant from
a
the 43 patients available for follow-up, 50% were in functional 2001.
di
class I and 40% in class II. Surgical intervention included 6. There are no reports of a large number of cases from
MV replacement and/or TV replacement along with LV India in the past 2 decades though there are case
In
and/or RV endocardectomy depending on ventricular reports from several parts of the country.
involvement and AV valve incompetence. All tricuspid It may be inferred that new cases of EMF is decreasing
valve replacement was with mechanical prosthesis. Neither and patients with milder form of the disease are presenting
of
isolated LV endocardiectomy nor bidirectional Glenn shunt later in the natural history of the disease, accounting for
(BDG) was done during this period.15,16 the later age at presentation as well as mild symptoms at
presentation.
ty
IS THE INCIDENCE AND PREVALENCE OF Data from Brazil and Nigeria suggest marked reduction
EMF ON THE DECLINE—A VANISHING AND in the prevalence of EMF among cardiac patients attending
CURIOUS DISEASE? 18 cie
Newly diagnosed cases of EMF confirmed by echo and/
hospitals, but epidemiological survey in Mozambique in a
remote and underprivileged population revealed EMF was
or angiographic study from 2001 to 2008 at SCTIMST endemic with 20% prevalence, 5% of them being severe
20 o
were analyzed to confirm the changing pattern of EMF with symptoms, i.e. 1% of the population.
seen in Kerala.11 There were 54 cases (7–8 cases/year),
S
and majority of cases were above 30 years and only 6% CONCLUSION

below 20 years and none below 10 years. Distribution
Population with better access to health care and public
al
of RV, LV and biventricular EMF was similar to earlier

health services, such as Kerala, Nigeria and Brazil, will
period. Overall mortality over 36 months was 5%. Two
continue to experience a reduction in EMF; while poverty-
ic
patients in NYHA class IV with end-stage heart failure

stricken population with sparse access to health care and
died during follow-up and the rest were stable with mild
og
nonexistent public health services in the tropical and

or no symptoms. Less than 5% of EMF patients were
subtropical regions, especially in Sub-Saharan Africa, such
offered surgery as majority of patients were stable with
as Mozambique, will continue to be endemic to EMF.
mild symptoms (NYHA Class 1-2). Substantial numbers
ol
of cases were detected incidentally by echocardiography,

when evaluated for nonspecific symptoms or abnormal REFERENCES
di
ECG. It is observed that demography of EMF has remained 1. Bedford DE, Korstam GLS. Heart failure of unknown
the same in the past decade. aetiology in Africans. Br Heart J. 1946;8(4):236.
ar
Hospital data from SCTIMST, a tertiary care center 2. Davies JNP. Endomyocardial fibrosis in Uganda. East Afr
taken in isolation, may not reflect the true prevalence of Med J. 1948;25:10-6.
C
the disease in rest of the country or globally. Only the more 3. Akinwusi PO, Odeyemi AO. The changing pattern of
symptomatic patients get preferentially referred. endomyocardial fibrosis in South-West Nigeria. Clin Med
Some important observations from SCTIMST data Insights Cardiol. 2012;6:163-8.
4. Kutty VR, Abraham S, Kartha CC. Geographical distribution
need mention:
of endomyocardial fibrosis in south Kerala. Int J Epidemiol.
1. The average age of EMF at presentation has dramatically
1996;25(6):1202–7.
changed, from a disease predominantly of the young
5. Chelo D, Nguefack F, Mbassi Awa HD, et al. Endomyocardial
during 1976–1990, to disease presenting in the fourth fibrosis in Sub-Saharan Africa: The geographical origin,
to sixth decade of life presently. socioeconomic status, and dietary habits of cases reported
2. There were no cases in the age group less than 10 years in Yaounde, Cameroon. Ann Pediatr Cardiol. 2015;8(3):
in the recent 20 years and only 8% were below 20 years 202-9.
of age. 6. Mocumbi AO, Ferreira MB, Sidi D, et al. A population study
3. Proportion of patients with EMF, presenting in NYHA of endomyocardial fibrosis in a rural area of Mozambique.
class III and IV, decreased and prognosis of newly N Engl J Med. 2008;359(1):43-9.
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7. Samuel I, Anklesaria X. Endomyocardial fibrosis in South Endomyocardial Fibrosis. New Delhi: Oxford University CHAPTER
India. Ind J Path Bact. 1960;3:157. Press. 1993. pp. 20-28.
8. World Health Organization. Idiopathic cardiomegaly. Bull
World Health Organ. 1968;38(6):979-92.
13. Tharakan JA. Electrocardiography in endomyocardial
fibrosis. Indian Pacing Electrophysiol J. 2011;11:129–33.
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9. Sapru RP. Clinical profile of endomyocardial fibrosis. 14. Venkatachalam CG, Balakrishanan KG, Tharakan JM.

ICMR workshop proceedings 1981. In: Sapru RP (Ed). Echocardiographic findings in endomyocardial fibrosis. In:
Endomyocardial Fibrosis in India. Indian Council of Valiathan MS (Ed). Endomyocardial Fibrosis. New Delhi:
Medical Research;1983. Oxford University Press. 1993. pp.153-167.
10. Seth S, Thatai D, Sharma S, et al. Clinico-pathological 15. Tharakan JM, Venkatachalam CG, Balakrishnan KG.
evaluation of restrictive cardiomyopathy (endomyocardial Angiographic features of endomyocardial fibrosis. In:
fibrosis and idiopathic restrictive cardiomyopathy) in ValiathanMS (Ed). Endomyocardial Fibrosis. New Delhi:
India. Eur J Heart Fail. 2004;6(6):723-9. Oxford University Press.1993. p.168-184.
a
11. Tharakan J, B ohora S. Cur rent p erspe ctive on 16. Valiathan MS, Syamkrishanan KG. Surgical treatment of
di
endomyocardial fibrosis. Curr Sci. 2009;97:405–10. endomyocardial fibrosis: Kerala experience. In: Valiathan
12. Balakrishnan KG, Jaiswal PK, Tharakan JM, et al. Clinical MS (Ed). Endomyocardial Fibrosis. New Delhi: Oxford
course of patients in Kerala. In: Valiathan MS (Ed). University Press. 1993. pp. 220-227.
In
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Cardiac Amyloidosis:
CHAPTER 67 Diagnosis and Management
a
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INTRODUCTION The amyloid deposits contain fibrillary and non-
Amyloidosis is a multisystem disorder characterized by fibrillary part. The long, unbranched, beta-pleated, 7–10
In
deposition of extracellular misfolded, homogenous, beta- nm constitutes the fibrillary part. Non-fibrillary component
pleated protein resulting in organ dysfunction. The origin includes amyloid P component, glycosaminoglycan’s
of the word amyloid dates back to 1838 from Latin amylum (GAG), etc.6 Recent clinical research focuses on this non-
of
for starch like material. In 1854 Rudolf Virchow identified fibrillary component as a potential target for dissolution
similar starch like staining with iodine in liver biopsies of deposited amyloid protein.7 Thus, the ensuing organ
dysfunction is due to toxic component and infiltrative
ty
and named it amyloid. Among the systemic involvement
cardiac involvement is major determinant of survival and component.
tenders poor prognosis.1,2 This chapter focuses on clinical
18 cie
presentation and novel advancements in diagnostics and
therapeutics of cardiac amyloidosis.
CLINICAL FEATURES
High suspicion for diagnosis of cardiac amyloidosis is
Rapidly evolving research had identified more than essential for early diagnosis before the end organ damage.
20 o
30 types of amyloid deposition.3 The type of amyloidosis Often the presentation is vague and non-specific. This is
S
is dependent on the precursor protein of origin. Of more challenging in Indian context with increasing super-
particular clinical importance involving the cardiac tissue specialists and more compartmentalization resulting
is primary amyloidosis (AL), which constitutes about
al
in delayed diagnosis. In Mayo clinic data the patients

85%. The remaining 15% constituted by familial (mutant have clinical symptoms for 2 years before diagnosis was
transthyretin), senile (wild transthyretin), senile (serum made.8 The clinical presentation of cardiac amyloidosis
ic
amyloid A), Isolated atrial amyloidosis (atrial natriuretic is that of restrictive cardiomyopathy. The earliest clinical
peptide).4 The incidence of primary amyloidosis is 6–10
og
manifestations are shortness of breath on exertion later

per million population in North America,4 exact incidence followed by features of right sided heart failure with
from India is unknown. edema, ascites and raised jugular pressure. In case of AL
ol
amyloidosis third space fluid accumulation can also be due

PATHOPHYSIOLOGY to renal involvement causing nephrotic proteinuria. Later
di
Cardiac involvement in amyloidosis classically presents as in the disease course, patients may present with syncope,
right-sided or biventricular heart failure with a relatively possibly due to fixed cardiac output or arrhythmia or
ar
normal or decreased cavity size and markedly thickened electromechanical dissociation or co-existing autonomic
ventricular walls and other cardiac structures, consistent neuropathy. Syncope portends a poor prognosis and
advanced disease. Thromboembolic phenomenon could
C
with an infiltrative cardiomyopathy. Small ventricular

cavity produces low cardiac output with resulting elevation also be the initial presentation due to atrial fibrillation.
of intracardiac pressures and pulmonary and systemic A few patients may present with angina which is due to
congestion. This process results from extracellular amyloid deposition in coronary vasculature.
deposition of amyloid proteins, and eventually causes A good general physical examination is important
cellular dysfunction, oxidative stress, and apoptosis of to identify systemic involvement in addition to cardiac
cardiac myocytes via P 38 protein kinase. 5 Abnormal amyloidosis. These include–macroglossia, carpel tunnel
amyloid protein deposition also leads to small vessel syndrome, purpuras (typically–periorbital purpuric
disease and conduction system infiltration. The later is lesions called as raccoon eyes and also subtle petechial
responsible for ventricular arrhythmias. Lastly, there is a lesions over the body, these occur due to fragile blood
direct metabolic dysfunction in the case of AL amyloid that capillaries and also co-existing factor X deficiency).
can occur with light-chain binding to cardiomyocytes that Hepatomegaly secondary to amyloid deposition can
is why not all AL amyloidosis in particular have increased be present in some cases, which is non-pulsatile. In
wall thickness despite symptoms.5 advanced cases congestive hepatomegaly may occur due
KG-67.indd 552 03-11-2018 12:42:16

to right heart failure, where it is pulsatile. There could the extent of deposition in various tissues. Histological CHAPTER
be features of peripheral autonomic neuropathy. In staining of amyloid in the tissue after biopsy is the
some cases amyloid deposition may cause carpel tunnel
syndrome. Sudden cardiac death can occur in 30–40% of
confirmatory gold standard test. The various tests used in
diagnosis of cardiac amyloidosis are elucidated in Table 1.
67

patient with amyloidosis due to ventricular arrhythmias,
Electrocardiogram (ECG): This is the simplest and basic
electromechanical dissociation.9
investigation that gives a clue to the diagnosis. The
presence of low voltage QRS complexes in limb leads
AL AMYLOIDOSIS (< 5 mm) with enlarged left ventricular wall thickness (i.e.
It is due to the deposition of abnormal light chain >1.1 cm) by echo is diagnostic of amyloidosis except for
derived amyloid. It is a multi-systemic disease, although very few infiltrative disorders of heart. The sensitivity of
a
one system predominates the clinical presentation. low voltage complexes in diagnosing amyloid involvent is
These patients present in 5th to 6th decade of life. 63-80%. Other ECG findings are pseudo-infarction pattern
di
Renal involvement is the most common presentation in chest leads and poor r wave progression (Figure 1).
followed by cardiac involvement. The median survival Less than 25% have conduction system abnormalities in
In
in patients with clinically apparent heart failure and form of AV block, atrial fibrillation, and intraventricular
no AL guided treatment is around 8 months. The toxic conduction abnormalities. ECG abnormalities are present
component of amyloid light chain is responsible for even before significant amyloid deposition in heart.12
of
severe cardiac dysfunction without apparent deposition
Echocardiography: While there are many echocardio-
in cardiac muscle. This in contrast to transthyretin
graphic features common in amyloid disease, none
related amyloidosis where the infiltrative component
ty
are highly specific and a combination of several is
causes the damage resulting in massive cardiomegaly at
often needed to make a diagnosis (Figure 2). Features
presentation.10 The presence of macroglossia/peri-orbital
18 cie
petechial lesions is considered pathognomonic of primary
amyloidosis in proper clinical setting.
suggestive of cardiac amyloidosis include normal
biventricular dimensions with concentric left ventricular
wall thickening (especially in the absence of systemic
hypertension), valvular thickening, biatrial enlargement,
20 o
Familial Amyloidosis thickened inter-atrial septum (>7 mm) and interventricular
S
The mutant transthyretin derived amyloid deposits in septum (>12 mm) (ventricular septal thickness greater
tissue. More than 80 types of transthyretin mutations than 15 mm is a poor prognostic marker), pericardial
are found. It presents during 3rd to 6th decade of life effusion.13 The echocardiograph granular or “sparkling”
al
depending on the type of mutation. Certain mutations ventricular wall appearance, a reported classic feature, is
render more amyloidogenic property. The most common
ic
primarily associated with low sensitivity to detect cardiac

mutation responsible is Val122Ile. Neuropathy and renal amyloidosis, can occur in other causes of LV hypertrophy,
og
involvement predominates. Cardiac involvement occurs and is less specific. Left ventricular hypertrophy” is a
in a quarter of patients.11 misnomer given that the histologic pathological hallmark
of cardiac amyloid disease is extracellular infiltration
ol
Senile Systemic Amyloidosis and not myocyte hypertrophy, and pericardial effusion,
Doppler ECHO can identify early diastolic dysfunction in
The wild type of transthyretin derived amyloid is
di
amyloidosis.
responsible in this condition. Extracardiac involvement
is rare in this condition. Presentation is usually late in
ar
7th decade of life. About a quarter of population beyond CARDIAC MAGNETIC RESONANCE AND
the age of 80 years has deposition of wild transthyretin I RADIO-NUCLEAR TESTING
C
their hearts, but the clinical relevance of this is not known. In equivocal cases cardiac magnetic resonance (CMR)
Patients may also have carpel tunnel syndrome associated helps in diagnosis before proceeding with biopsy. Late
with this condition.11 subendocardial gadolinium enhancement is a diagnostic
Other types like secondary amyloidosis, atrial feature of amyloidosis (Figures 3A to C). However, in
natriuric peptide related are associated rarely with cardiac situations of increased heart rates CMR is not useful
involvement. in view of movement artefacts. Diphosphonate (DPD)
based nuclear imaging helps in diagnosis of cardiac
Diagnosis amyloidosis especially transthyretin related. Alternatively
Diagnosis is based upon demonstration of abnormal Pyrophosphate (PYP) can also be used in identification.14,15
amyloid deposition in the involved organ. The initial step The non-fibrillary part of amyloid SAP can be targeted
is the demonstration of monoclonal protein in serum or for identification of amyloid deposits in the body. SAP
urine and a monoclonal plasma cell population in bone scintigraphy is used, but in view of moving myocardium it
marrow. Later imaging techniques help in assessment of cannot accurately identify cardiac amyloidosis.16
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KG-67.indd 553 03-11-2018 12:42:16

SECTION Table 1: Approach to a case of AL amyloidosis
8
Confirmation of presence of amyloid zz Biopsy of suspected site if feasible and safe
zz Fat aspirate or rectal biopsy
(SAP scintigraphy, if available)
Cardiomyopathy
Assessment of patients and monitoring of patients Typing the amyloid fibrils in the biopsy—immunohistochemistry (IHC)
with amyloidosis OR
(laser capture micro-dissection and mass spectrometry, if available)
Supported by the following for confirmation:
Light-chain amyloid (AL), underlying plasma cell dyscrasia
Serum/urine electrophoresis (SPEP/UPEP) and immunofixation
Serum-free light chains
Bone marrow examination
a
Tests of organ function: Liver function tests, serum albumin,
Confirmation of type of amyloid and detecting the serum creatinine, eGFR, 24-h proteinuria
di
underlying disorder Cardiac amyloid:
ECG and 24-h Holter monitor if indicated
Echocardiogram
In
Cardiac magnetic resonance (CMR) with gadolinium contrast
(Suspected transthyretin amyloidosis: 99mTcDPD or PYP scan
Systemic amyloid burden—assess amyloid deposition in liver, spleen, kidneys,
of
adrenals, localised soft tissue deposits and bones
(123I SAP scintigraphy if available)
Hereditary amyloid—appropriate gene sequencing to detect mutations in proteins
known to cause hereditary amyloidosis (fibrinogen alpha chain, transthyretin,
ty
lysozyme, apolipoprotien A1, gelsolin)
Assessment of distribution and degree of organ Cardiac disease stage
dysfunction
18 cie zz NT-proBNP and troponin T/I
Neuropathy
zz Nerve conduction studies
zz Autonomic function studies

20 o
Disease progression and response to treatment Individualized as per assessment of distribution and extent of organ involvement by
monitoring appropriate tests of organ function
S
AL amyloid—monitoring the monoclonal protein by serum-free light chains or SPEP

Appropriate imaging—echocardiography, CMR or 99mTcDPD scintigraphy
Sourece: Adapted from Sachchithanantham S, Wechalekar AD. Imaging in systemic amyloidosis. Br Med Bull. 2013;107:41-56.18
al
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Figure 1 : ECG showing low voltage complexes in limb leads and poor R wave progression
CARDIAC BIOMARKERS for risk stratification of amyloidosis. 17 Elevation of BNP

Brain natriuretic peptide (BNP), NT-ProBNP (N terminal levels in case of amyloidosis implies associated cardiac
fragment of BNP), troponin, serum free light chains involvement. BNP, NT-proBNP have renal clearance and
(FLC) are used in revised ‘Mayo Clinic Prognostic Scale’ can be falsely elevated in renal involvement in case of
554
KG-67.indd 554 03-11-2018 12:42:17

CHAPTER
67

a
di
In
Figure 2: Echocardiography showing the dilated atria, thickened
ventricles and ‘granular sparking’ appearance of the myocardium
of
ty
18 cie
20 o S
A B C
al
Figures 3A to C: (A)CMR cine imaging clearly brings out asymmetric septal hypertrophy; (B) Late gadolinium enhancement imaging
shows discrete linear mid myocardial scar in the basal septum; (C) CMR cine imaging clearly brings out asymmetric septal hypertrophy and
associated apical hypertrophy is also very well appreciated with characteristic spade shape left ventricular cavity at end diastole
ic
og
primary amyloidosis. With successful therapy the levels bone marrow help in diagnosis obviating the need of
of the markers normalize. Novel drugs lenalidomide and endomyocardial biopsy. Fat pad aspirate has a sensitivity
thalidomide can cause transient increase in biomarkers of 70-80% in AL amyloidosis. Immunohistochemistry
ol
during the start of therapy. stain for light chain/serum amyloid-A can be used to
differentiate various types. Proteomic analysis and
di
Serologic testing: Serum protein electrophoresis

mass spectroscopy accurately identifies various types of
(SPEP) and urine protein electrophoresis (UPEP) and
amyloidosis.18,19
ar
immunofixation, serum FLC assay are useful in detection

of abnormal monoclonal protein in primary amyloidosis.
Serum electrophoresis can be normal in 25% of cases, Treatment
C
because light chain is not detected in SPEP test. UPEP with It is a multipronged approach and includes symptomatic
immunofixation combined with serum FLC detects almost management for heart failure, reducing the amyloid
all cases of AL (primary) amyloidosis. Serum FLC is used production, dissolution of amyloid already formed, and
for monitoring response to therapy. organ transplantation.
Cardiac biopsy: It is the gold standard test for diagnosis.
Use of combination of tests mentioned above can MANAGEMENT OF CARDIAC FAILURE
diagnose majority of cases of cardiac amyloidosis. Cardiac Diuretics form the main part of the treatment. ACE/ARB
biopsy is useful to differentiate the type of amyloidosis (angiotensin converting enzyme/angiotensin receptor
especially in setting of isolated cardiac involvement blocker) is poorly tolerated because of the co-existing
and with combination of MGUS and transthyretin renal dysfunction and hypotension. Abnormal affinity of
cardiac amyloidosis. In case of AL amyloidosis biopsy of amyloid to calcium channel blockers and digoxin increases
abdominal fat pad, minor salivary gland, rectal mucosal, the toxicity of these drugs and are poorly tolerated.
555
KG-67.indd 555 03-11-2018 12:42:18

SECTION Presence of pre-syncope/postural hypotension indicates Table 2: Hematologic response criteria17
diuretic overuse/autonomic neuropathy/fixed cardiac
8
Amyloid complete response Negative serum and urine and
output. In low volume circumstances use of midodrine is (ACR) normal FLC ratio
useful especially in patients with co-existing autonomic Very good partial response Difference between involved
Cardiomyopathy
neuropathy and helps in maintaining the vascular tone (VGPR) and uninvolved FLCs [dFLC]
in these patients. Combination of furosemide/torsemide <4 mg/dL
with spironolactone is well tolerated.20 Partial response (PR) dFLC decrease ≥50%
For conduction abnormalities of the heart no specific No response (NR) Less than PR
guidelines are present. For symptomatic bradycardia pace Cardiac response
maker is indicated. Sometimes single chamber pacing Decrease in NT-proBNP by >30% and 300 pg/ml (if baseline NT-proBNP
can deteriorate the cardiac condition because of dys- >650 pg/mL), or a ≥2-point decrease in NYHA class (if baseline NYHA
a
class III or IV)
synchrony. However, the threshold of pacing required is
di
higher in view of amyloid infiltration. The cause of sudden
cardiac death is mostly electro-mechanical dissociation Table 3: Revised mayo staging system for AL amyloidosis
In
and primary intracardiac defibrillator is not always useful. Assigned Relative proportion of patients Median survival in
Amiodarone is tolerated better in these patients. Anti- stage in the assigned cohort months
coagulation in arrhythmias should be used cautiously.21 1 (0 points) 25 94.1
of
2 (1 point) 27 40.3
Decrease in Production of Amyloid 3 (2 points) 25 14
AL amyloidosis: Reduction in production of amyloid is 4 (3 points) 23 5.8
ty
based on antiplasma cell therapy. The treatment strategies A score of 1 is assigned for each of three variables: cardiac troponin T
have evolved and modified from myeloma treatment. ≥0.025 ng/mL, NT-ProBNP ≥1,800 pg/mL and dFLC ≥18 mg/dL
18 cie
Choosing an optimal treatment strategy depends on the
load of the plasma cell clone, organ functions (especially months.22 The Mayo Clinic group was able to demonstrate
that NT-proBNP, troponin (I or C) and serum free light
cardiac and renal) and associated co-existing conditions
20 o
like neuropathy. This can be done by risk adaptation chains could stratify cardiac amyloidosis patients in to
models, ‘Modified Mayo staging’ can be used for this one of four stages with median overall survival ranging
S
purpose. 17 Treatment response assessment tools are from 94 months in stage I disease to 6 months in stage
available for hematologic, renal, cardiac, liver amyloidosis. IV disease (Table 3).17 Severe NT-proBNP elevation in
al
In general achieving a hematologic response is an combination with arterial hypotension carries particularly
important factor predicting the long-term survival. The bad prognosis.17 A recent study involving stanniocalcin 1
ic
hematologic response precedes the organ response. suggests that AL amyloidosis induced cardiotoxicity may
Hematologic response criteria includes the difference not be solely limited to deposition of amyloid protein
og
between involved and uninvolved light chains (dFLC). leading to dysregulation of tissue functions, but also due
Complete response implies normalization of SFLC ratio. to direct cardiotoxic effects of the protein.5, 10 Isolated
Very good partial response (VGPR) decrease in DFLC <40 cardiac involvement is rare, with fewer than 5% of patients
ol
mg/dL and partial response (PR) implies >50% reduction presenting as such.10
in dFLC. Cardiac response criteria considers response Although there are no well conducted RCTs to guide
di
as >30% and >300 ng/L decrease in NTproBNP levels in the initial choice of therapy, based on available evidence
patients with a base line value >650 ng/L. Alternatively bortezomib based regimen is the first choice (except
ar
≥2 class decline in NYHA functional class, with base line in patients with severe neuropathy). Botezomib in
NYHA 3 or 4 (Table 2). combination with dexamethasone has a hematologic
C
From the year 2000 onwards–combination of novel response rate from 68–77%. Combination of this with
anti myeloma drugs such as proteosome inhibitors cyclophosphamide can increase the response rate up
(bortezomib)/immunomodulatory agents (thalidomide, to 94%. Standard dose melphalan based regimens have
lenalidomide), are being used as the standard therapy response rates of 50–71%. In those not tolerating these
for AL amyloidosis. These drugs have replaced the earlier regimens alternative regimens with lenalidomide/
drugs, e.g. melphalan in combination with steroids pomalidomide can be used. Newer drugs recently approved
(prednisolone or dexamethasone). When AL amyloidosis in myeloma such as carfilzomib and daratumomab are
involves the heart, the outcomes are significantly worse. being explored in amyloidosis now. In those patients who
Four large European centers analyzed the outcomes of 346 progress on any regimen alternative regimen should be
patients with cardiac amyloidosis, and the median overall tried for whom patients have not yet been exposed.
survival was reported as 7.1 months, whereas prognosis in For significant amyloid cardiac disease, management
those without cardiac involvement is significantly better, re q u i re s c o o rd i nat i o n b e t w e e n ca rd i o l o g y a n d
with average overall survival ranging between 40 and 94 hematology/oncology. It is advised to first give initial
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induction therapy (bortezomib based) to minimize the followed by ASCT is an acceptable strategy. This approach CHAPTER
burden or to eliminate plasma cells in the bone marrow yields a five-year survival of 60%. Most patients do not
producing light chains. Following induction therapy
patients are considered for heart transplant, the interval
tolerate ASCT prior to cardiac transplantation. Combined
heart and liver transplantation is useful in transthyretin
67

between induction and cardiac transplant is typically amyloidosis.5, 20, 27-28
about 6 months. This may then be followed by high-dose
chemotherapy using melphalan followed by autologous SUMMARY
hematopoietic peripheral blood stem cell transplant
Improved understanding of biology and availability
(ASCT). The interval between heart transplant and ASCT
of novel antimyeloma agents have improved outlook
is also about 6 months. The objective is to replete bone
for patients of cardiac AL amyloidosis. Such patients
marrow with healthy hematopoetic tissue elements and
a
should be carefully screened for presence of extracardiac
minimizes the production of amyloid protein, and hence
involvement. Initial induction therapy followed by cardiac
di
delays further organ deposition and dysfunction.5
transplant followed by high dose chemotherapy and
autologous blood stem cell transplantation is a reasonable
In
TRANSTHYRETIN-RELATED AMYLOIDOSIS option in selected patients. Based on levels of cardiac
The site of production of mutant transthyretin is liver. Before biomarkers and serum-free light chains it is now possible
onset of significant cardiomyopathy liver transplantation to prognosticate and tailor the therapy for patients of
of
can be done. OS at 5 years is 75%. Patients with mutation at cardiac amyloidosis. Recently addition of more drugs is
V122I do not benefit from liver transplantation. In selected likely to translate into improved outcome of this disease.
patients combination of liver and heart transplantation
ty
can be considered. After liver transplantation there is often REFERENCES
progression of cardiomyopathy due to deposition of wild
transthyretin.23
18 cie
type of transthyretin over previous scaffolding of mutant
1. Sipe JD, Cohen AS. Review: history of the amyloid fibril. J
Struct Biol. 2000;130(2–3):88-98.
2. Cohen AS. Amyloidosis. N Engl J Med. 1967;277(10):522-30.
3. Westermark P, Benson MD, Buxbaum JN, et al. A primer
20 o
NOVEL STRATEGIES of amyloid nomenclature. Amyloid Int J Exp Clin Investig.
2007;14(3):179-83.
S
Few phase I and II studies are available of agents which aim 4. Benson MD, Dasgupta NR. Amyloid Cardiomyopathy. J Am
at stabilizing the amyloid. Diflunisal (NSAID), Tafamids are Coll Cardiol. 2016;68(1):25-8.
useful for stabilization of amyloid and showed promising 5. Sousa M, Monohan G, Rajagopalan N, et al. Heart
al
results in transthyretin amyloidosis.24 Few drugs that act at transplantation in cardiac amyloidosis. Heart Fail Rev.
the level of gene expression are under study for decreasing 2017;22(3):317-27.
ic
6. Kisilevsky R. The relation of proteoglycans, serum amyloid

the production of mutant transthyretin. Small interfering
P and apo E to amyloidosis current status, 2000. Amyloid Int
og
RNA (siRNA) has been used in inhibiting the messenger

J Exp Clin Investig. 2000;7(1):23-5.
RNA (mRNA) of transthyretin. 25 Similarly anti sense 7. Bodin K, Ellmerich S, Kahan MC, et al. Antibodies to
oligonucleotides combine and damage the mRNA. Phase human serum amyloid P component eliminate visceral
ol
III studies of these agents are underway.26 amyloid deposits. Nature. 2010;468(7320):93-7.
Few strategies aimed at disrupting the already 8. Kyle RA, Bayrd ED. Amyloidosis: review of 236 cases.
Medicine (Baltimore). 1975;54(4):271-99.
di
deposited amyloid are experimental. Monoclonal

antibodies against SAP, a non-fibrillary constituent of 9. Reisinger J, Dubrey SW, Lavalley M, et al. Electrophysiologic
abnormalities in AL (Primary) amyloidosis with cardiac
ar
amyloid showed promising results in phase I study. There

involvement. J Am Coll Cardiol. 1997;30(4):1046–51.
is also preliminary evidence of role of doxycycline in 10. Merlini G. AL amyloidosis: from molecular mechanisms
disrupting the amyloid.
C
to targeted therapies. Hematol Am Soc Hematol Educ

Program. 2017;2017(1):1–12.
CARDIAC TRANSPLANTATION 11. Ruberg FL , Berk JL . Transthyretin (TTR) cardiac
amyloidosis. Circulation. 2012;126(10):1286–300.
Data on cardiac transplant is still limited, mostly in form 12. Cheng Z, Zhu K, Tian Z,et al. The findings of electrocardio-
of small case series. Donor shortage, high mortality, and graphy in patients with cardiac amyloidosis. Ann
relatively inferior survival compared to other conditions, Noninvasive Electrocardiol Off J Int Soc Holter Noninvasive
cardiac amyloidosis is still not considered a priority in the Electrocardiol Inc. 2013;18(2):157–62.
list of indications for cardiac transplantation. Hematologic 13. Pagourelias ED, Mirea O, Duchenne J, et al. Echo parameters
disease control is essential factor for successful transplant. for differential diagnosis in cardiac amyloidosis clinical
perspective: A head-to-head comparison of deformation
Cardiac transplantation should be preceded by use of
and nondeformation parameters. Circ Cardiovasc Imaging.
induction therapy to reduce the light chain load and 2017;10(3):e005588.
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SECTION 14. Kristen AV, Siepen F aus dem, Scherer K, et al. Comparison 22. Wechalekar AD, Schonland SO, Kastritis E, et al. A
of different types of cardiac amyloidosis by cardiac magnetic European collaborative study of treatment outcomes in
8 resonance imaging. Amyloid. 2015;22(2):132–41.

15. Fontana M, Chung R, Hawkins PN, et al. Cardiovascular
346 patients with cardiac stage III AL amyloidosis. Blood.
2013;121(17):3420–7.
magnetic resonance for amyloidosis. Heart Fail Rev. 23. Gertz MA, Benson MD, Dyck PJ, et al. Diagnosis, prognosis,
Cardiomyopathy
2015;20(2):133–44. and therapy of transthyretin amyloidosis. J Am Coll Cardiol.

16. Hawkins PN. Serum amyloid P component scintigraphy for 2015;66(21):2451–66.
diagnosis and monitoring amyloidosis. Curr Opin Nephrol 24. Maurer MS, Grogan DR, Judge DP, et al. Tafamidis
Hypertens. 2002;11(6):649–55. in transthyretin amyloid cardiomyopathy: effects on
17. Kumar S, Dispenzieri A , Lac y MQ, et al. Revised transthyretin stabilization and clinical outcomes. Circ
prognostic staging system for light chain amyloidosis Heart Fail. 2015;8(3):519–26.
incorporating cardiac biomarkers and serum free light 25. Coelho T, Adams D, Silva A, et al. Safety and Efficacy of
a
chain measurements. J Clin Oncol. 2012;30(9):989–95. RNAi therapy for transthyretin amyloidosis. N Engl J Med.
di
18. Sachchithanantham S, Wechalekar AD. Imaging in systemic 2013;369(9):819–29.
amyloidosis. Br Med Bull. 2013;107:41-56. 26. Ohno S, Yoshimoto M, Honda S, et al. The antisense
In
19. Vrana JA, Theis JD, Dasari S, et al. Clinical diagnosis approach in amyloid light chain amyloidosis: identification
and typing of systemic amyloidosis in subcutaneous of monoclonal Ig and inhibition of its production by
fat aspirates by mass spectrometry-based proteomics. antisense oligonucleotides in in vitro and in vivo models. J
of
Haematologica. 2014;99(7):1239–47. Immunol. 2002;169(7):4039–45.
20. Estep Jerry D, Bhimaraj A, Cordero-Reyes AM, et al. Heart 27. Wechalekar AD, Whelan C. Encouraging impact of
transplantation and end-stage cardiac amyloidosis: a doxycycline on early mortality in cardiac light chain (AL)
review and approach to evaluation and management.
ty
amyloidosis. Blood Cancer J. 2017;7(3):e546.
Methodist Debakey Cardiovasc J. 2012;8(3):8–16. 28. Dubrey SW, Burke MM, Hawkins PN, et al. Cardiac
21. Falk RH, Alexander KM, Liao R, et al. AL (Light-Chain) transplantation for amyloid heart disease: the United
18 cie
Cardiac amyloidosis: A review of diagnosis and therapy. J
Am Coll Cardiol. 2016;68(12):1323–41.
Kingdom experience. J Heart Lung Transplant Off Publ Int
Soc Heart Transplant. 2004;23(10):1142–53.
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CHAPTER 68 Cardiac Sarcoidosis
Ajit Thachil
a
di
INTRODUCTION (2–42%), sudden death (12–65%), and ventricular
Sarcoidosis is a multi-system disease of unknown etiology, dysfunction/heart failure (10–30%). 11 Two features
In
characterized by chronic non-necrotizing granulomatous regarding the morphology of the VT are strongly suggestive
inflammation of the involved organs. In the myocardium, of cardiac sarcoidosis as the etiology of VT, and thus
deserve special mention. Recurrence of monomorphic
of
chronic inflammation usually, but not invariably, leads
to patchy scarring. The inflammatory and scar phases VT of a morphology that is clearly distinct from the index
of the disease often co-exist in the same/different morphology (even if the occurrences are recorded several
months apart) in a patient with apparently idiopathic VT
ty
areas of an involved heart; both phases contribute to
all manifestations of the disease. 1,2 The incidence of is a strong pointer towards cardiac sarcoidosis, especially
in patients with normal or near normal LV function.
18 cie
sarcoidosis, the likelihood of cardiac involvement in
sarcoidosis, and the presentations of cardiac sarcoidosis
all seem to vary in different areas of the world. Familial
This finding was observed in 78% of patients with VT
due to cardiac sarcoidosis, and is extremely rare in true
aggregation has been reported; however, the interactions idiopathic VT.12 Occurrence of pleomorphic VT (defined
20 o
between familial factors, potential inciting pathogens as two distinct monomorphic VT morphologies) within
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and/or triggering environmental stimuli are unclear.3 the same ongoing VT, especially if associated with cycle
length variations of >50 ms in the VT, suggests a complex
VT circuit with multiple exits, a finding typical of cardiac
INCIDENCE AND PREVALENCE
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sarcoidosis (Figure 1). This finding was observed in 49%

The estimated incidence of sarcoidosis is highest among of patients with VT due to cardiac sarcoidosis, as opposed
ic
African Americans in the USA (35.5 per 100,000) followed to 0% of patients with idiopathic VT.13 Subtle fractionations
by the Scandinavian countries (14, 11.5, 11.4 and 7.2 per of the QRS/fragmented QRS complexes (Figures 2A
og
100,000 population respectively in Norway, Sweden, and B) are present during sinus rhythm in up to 60% of
Denmark and Finland respectively). 4,5 Among Asian patients with cardiac sarcoidosis, and provide a diagnostic
countries, Japan has the highest reported incidence clue. QRS fractionation by itself lacks sufficient sensitivity
ol
(1.01 per 100,000 population), with a higher proportion and specificity to be diagnostic of cardiac sarcoidosis.14,15
of patients exhibiting cardiac involvement (reliable Rarely, cardiac sarcoidosis has also been shown to cause
di
incidence and prevalence reports are not available for atrial flutter and atrial fibrillation by direct involvement
Asian countries other than Japan, South Korea and of the atrial myocardium.16,17 Cardiac sarcoidosis usually
ar
Singapore, and for Africa and South America). 6 Sarcoidosis causes left ventricular dysfunction, with/without right
has a slight female preponderance, and usually (~70%) ventricular dysfunction. Occasionally, it can present as
C
presents between the ages of 25 and 60 years.6-8

isolated right ventricular involvement, and masquerade
Pulmonary involvement is present in ~ 90% of patients
as arrhythmogenic right ventricular cardiomyopathy. It
with clinically detectable sarcoidosis. Clinically obvious
can rarely cause patchy myocardial thickening during the
cardiac sarcoidosis has been reported in ~5% of patients
granulomatous inflammatory phase, and thus mimick
with pulmonary/systemic sarcoidosis, whereas subclinical
hypertrophic cardiomyopathy.
cardiac sarcoidosis is present at autopsy in 20–25% of
Case series of cardiac sarcoidosis from India show
patients with pulmonary/systemic sarcoidosis from North
ventricular arrhythmia as the predominant presentation,
America, and in up to 58% of patients from Japan.9,10
with AV block being distinctly uncommon.12 In the author’s
personal experience, out of 43 consecutive patients
PRESENTATIONS diagnosed with cardiac sarcoidosis, 84% presented with
The most common manifestations of cardiac sarcoidosis ventricular arrhythmia, whereas only 2% had AV block
are atrioventricular conduction blocks (26–62%), bundle (unpublished data from CARE Hospitals, Hyderabad,
branch blocks (12–61%), ventricular tachyarrhythmias India). This may be due to referral/investigatory bias,
KG-68.indd 559 03-11-2018 12:42:02

SECTION
8
Cardiomyopathy
a
di
In
Figure 1: Pleomorphic VT in a patient with cardiac sarcoidosis. Note the variations in QRS morphology and cycle length. This was the
fourth different morphology of VT recorded in this patient
of
or may reflect a true geographical variation in the recurrent VT; in contrast, none of the patients with
presentation of cardiac sarcoidosis. A case series from true idiopathic AV block developed these events at follow
ty
Japan reported AV block as a manifestation of the early, up.21
steroid-responsive phase of the disease, and ventricular Two presentations of cardiac sarcoidosis deserve
18 cie
tachycardia as a manifestation of the late (scarred), steroid
non-responsive phase of the disease. 18 Reports from
North America too described that ventricular tachycardia
special attention: cardiomediastinal sarcoidosis, and
isolated cardiac sarcoidosis (ICS). The strong association
of mediastinal adenopathy with cardiac sarcoidosis among
occurred relatively late in the course of disease (mean patients presenting with idiopathic VT was demonstrated
20 o
LVEF 36 ± 14%; right ventricle dysfunction in 16/21 in a case series from India wherein mediastinal adenopathy
S
patients; NYHA ≥2 : 11/21 patients), implying greater role was observed in all 12 patients with cardiac sarcoidosis
for catheter ablation in the management of VT, and poorer presenting with VT.12 In the author’s personal experience,
patient outcomes.19 This contrasts with case series from mediastinal adenopathy was present in 42 out of 43
al
India which report a larger fraction of patients presenting consecutive patients diagnosed with cardiac sarcoidosis
(unpublished data from CARE Hospitals, Hyderabad,
ic
with ventricular tachycardia in the early, inflammatory

phase of the disease (LVEF 53 ± 12%; NYHA I status India). Case series from Japan and Finland have also
og
in 15 out of 18 patients), implying greater response of shown mediastinal adenopathy in 65–100% of patients who
VT to immunosuppressive therapy, and better patient were diagnosed with cardiac sarcoidosis as the cause of
outcomes.1,12 idiopathic dilated cardiomyopathy; sampled mediastinal
ol
Cardiac manifestations may be the first and only nodes showed sarcoid granulomas in 92% patients in one
clinical presentation of sarcoidosis in a significant of these reports.22,23 The finding of significant, unexplained
di
number of patients. One major reason for this is that mediastinal adenopathy in a patient with unexplained VT/
whereas cardiac involvement often causes significant left ventricular dysfunction/AV block should thus trigger
ar
symptoms, extracardiac involvement often causes only a search for cardiac sarcoidosis as the potential etiology.
milder symptoms. Previous case series have reported that True ICS is difficult to diagnose within the current
diagnostic framework (see discussion later) and is, more
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cardiac sarcoidosis was the underlying etiology in 28%

of patients presenting with unexplained monomorphic often than not, an autopsy diagnosis. Autopsy studies
VT; clinically silent extracardiac sarcoidosis was present have shown a 23–30% prevalence of ICS among patients
in 75% of these pateints.20 32 patients presenting with suspected to have cardiac sarcoidosis but did not meet
isolated, unexplained AV block between the ages of 18–60 diagnostic criteria for cardiac sarcoidosis.23-26
years were evaluated for sarcoidosis; cardiac sarcoidosis
was the etiology of AV block in 34% of them; all the PROGNOSIS
patients with cardiac sarcoidosis were detected with In the current era, the most important determinant of
clinically silent extracardiac sarcoidosis.21 A diagnosis prognosis in cardiac sarcoidosis is the ventricular function
of cardiac sarcoidosis as the etiology of AV block also at the time of diagnosis. Earlier reports indicated a
altered the long-term prognosis. Among the patients with median survival of two years after the diagnosis of cardiac
cardiac sarcoidosis as the cause of AV block, 27% went sarcoidosis.27 Subsequently, as we learned to effectively
on to develop heart failure, and 18% went on to develop diagnose and treat the inflammation early on in the course
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CHAPTER
68
Cardiac Sarcoidosis
a
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In
A
of
ty
18 cie
20 o S
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B
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Figures 2A and B: (A) QRS fractionation in inferior leads; (B) QRS fractionation in V1 during sinus rhythm in patients with cardiac sarcoidosis
of disease, and manage the associated arrhythmias, DIAGNOSIS

prognosis has improved remarkably. Currently, patients The diagnosis of cardiac sarcoidosis was previously
diagnosed at the stage of normal ventricular function and made based on the Japanese society guidelines, which
managed appropriately have a near normal long-term were revised in 2006 (Tables 1 and 2).29 Currently, the
survival. 12,28 In contrast, despite administration of the 2014 consensus statement from the heart rhythm society
best available therapy, patients diagnosed at a stage of is preferred for the diagnosis of cardiac sarcoidosis
ventricular dysfunction (LVEF 36 ± 14%; right ventricle (Table 3).30 Angiotensin-converting enzyme levels are
dysfunction in 16/21 patients, NYHA Class ≥2 : 11/21 elevated in 60% of patients with sarcoidosis; however,
patients) had a 43% incidence of death/heart transplant at serum angiotensin-converting enzyme levels lack
two year follow up.19 sensitivity and specificity in diagnosing or managing
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SECTION Table 1: Diagnostic guidelines for cardiac sarcoidosis from the Japanese society, 2007 revision24
8
Criteria for cardiac involvement of sarcoidosis
1. Major criteria
a. High-grade atrioventricular block (including complete atrioventricular block) or fatal ventricular arrhythmia (e.g. sustained ventricular
Cardiomyopathy
tachycardia and ventricular fibrillation)

b. Basal thinning of the ventricular septum or abnormal ventricular wall anatomy (ventricular aneurysm, thinning of the middle or upper
ventricular septum, regional ventricular wall thickening)
c. Left ventricular contractile dysfunction (left ventricular ejection fraction less than 50%)
d. 67Ga citrate scintigraphy or18 F-FDG PET reveals abnormally high tracer accumulation in the heart
e. Gadolinium-enhanced MRI reveals delayed contrast enhancement of the myocardium
2. Minor criteria
f. Abnormal ECG findings: Ventricular arrhythmias (nonsustained ventricular tachycardia, multifocal or frequent premature ventricular
contractions), bundle branch block, axis deviation, or abnormal Q waves
a
g. Perfusion defects on myocardial perfusion scintigraphy (SPECT)
di
h. Endomyocardial biopsy: Monocyte infiltration and moderate or severe myocardial interstitial fibrosis
Cardiac findings should be assessed based on the major criteria and the minor criteria. Clinical findings that satisfy the following 1) or 2)
strongly suggest the presence of cardiac involvement.
In
1. Two or more of the five major criteria (a) to (e) are satisfied .
2. One of the five major criteria (a) to (e) and two or more of the three minor criteria (f ) to (h) are satisfied.
Diagnostic groups in cardiac sarcoidosis
of
1. Histological diagnosis group (those with positive myocardial biopsy findings)
Cardiac sarcoidosis is diagnosed histologically when endomyocardial biopsy or surgical specimens demonstrate non-caseating epithelioid
granulomas.
2. Clinical diagnosis group (those with negative myocardial biopsy findings or those not undergoing myocardial biopsy)
ty
The patient is clinically diagnosed as having sarcoidosis (1) when epithelioid granulomas are found in organs other than the heart, and
clinical findings strongly suggestive of the above-mentioned cardiac involvement are present; or (2) when the patient shows clinical
findings strongly suggestive of pulmonary or ophthalmic sarcoidosis; at least two of the five characteristic findings of sarcoidosis (see
18 cie
below); and clinical findings strongly suggest the above-mentioned cardiac involvement
Characteristic findings of sarcoidosis
1. Bilateral hilar lymphadenopathy
20 o
2. High serum angiotensin-converting enzyme (ACE) activity or elevated serum lysozyme levels
3. High serum soluble interleukin-2 receptor (sIL-2R) levels
S
4. Significant tracer accumulation in 67Ga citrate scintigraphy or18 F-FDG PET

5. A high percentage of lymphocytes with a CD4/CD8 ratio of >3.5 in BAL fluid
al
Table 2: Diagnostic guidelines for isolated cardiac sarcoidosis from the Japanese society, 2006 revision29
ic
Diagnostic guidelines for isolated cardiac sarcoidosis

Prerequisite
og
1. No clinical findings characteristic of sarcoidosis are observed in any organs other than the heart (The patient should be examined in detail
for respiratory, ophthalmic, and skin involvements of sarcoidosis. When the patient is symptomatic, other etiologies that can affect the
corresponding organs must be ruled out)
2. 67Ga scintigraphy or 18F-FDG PET reveals no abnormal tracer accumulation in any organs other than the heart
ol
3. A chest CT scan reveals no shadow along the lymphatic tracts in the lungs or no hilar and mediastinal lymphadenopathy (minor axis
>10 mm)
di
4. Histological diagnosis group: Isolated cardiac sarcoidosis is diagnosed histologically when endomyocardial biopsy or surgical specimens
demonstrate non-caseating epithelioid granulomas
5. Clinical diagnosis group: Isolated cardiac sarcoidosis is diagnosed clinically when the criterion (d) and at least three other criteria of the
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major criteria (a)-(e) are satisfied (Table 1).

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sarcoidosis.31 ACE is produced by activated pulmonary the focal and usually midmyocardial/epicardial location
macrophages. ACE levels are typically increased in of the disease, and reveals noncaseating granulomas in
pulmonary sarcoidosis and have been specifically shown <25% of patients with cardiac sarcoidosis.34 To increase
to be not useful for the diagnosis or monitoring of cardiac sensitivity, electrophysiological (electroanatomic
sarcoidosis without pulmonary involvement. 32 Hence, mapping) or image-guided (PET or CMR) biopsy
studies have focused on finding new biomarkers to procedures may be used. These techniques involve
assess disease activity. Serum levels of neopterin and performing an endomyocardial biopsy from a site that
soluble interleukin-2 receptor levels have been shown demonstrates low voltage on electrophysiology study, or
to be significantly elevated in active disease.33 Although inflammation/scar on PET-CT/MRI respectively. These
promising, none of these biomarkers are ready for clinical techniques have increased positive biopsy rates to up to
use. Endomyocardial biopsy, though the gold standard for 50%.23,35 In general, when concomitant involvement of
diagnosing cardiac sarcoidosis, has low sensitivity due to an extracardiac organ is demonstrated in a patient with
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Table 3: The 2014 HRS consensus statement for diagnosis of cardiac sarcoidosis30 CHAPTER
68
Expert consensus recommendations on criteria for the diagnosis of CS
There are two pathways to a diagnosis of cardiac sarcoidosis:
1. Histological diagnosis from myocardial tissue
Cardiac Sarcoidosis
CS is diagnosed in the presence of non-caseating granuloma on histological examination of myocardial tissue with no alternative cause
identified (including negative organismal stains if applicable)
2. Clinical diagnosis from invasive and non-invasive studies:
It is probable* that there is CS if:
a. There is a histological diagnosis of extra-cardiac sarcoidosis
b. One or more of following is present
Steroid +/– immunosuppressant responsive cardiomyopathy or heart block
Unexplained reduced LVEF (40%)
Unexplained sustained (spontaneous or induced) VT
a
Mobitz type II 2nd degree heart block or 3rd degree heart block
di
Patchy uptake on dedicated cardiac PET (in a pattern consistent with CS)
Late gadolinium enhancement on CMR (in a pattern consistent with CS)
Positive gallium uptake (in a pattern consistent with CS)
In
and
c. Other causes for the cardiac manifestation(s) have been reasonably excluded
*In general, ‘probable involvement’ is considered adequate to establish a clinical diagnosis of CS.
of
cardiac sarcoidosis, biopsy of that organ is more likely to Mantoux test and TB PCR negativity, and an overlap
yield a positive result than an endomyocardial biopsy. syndrome if TB PCR/Mantoux test is positive along
ty
Biopsy results are most likely to be positive if an FDG avid with a negative AFB stain and culture. Other differential
lymph node, preferably from the mediastinum, is targeted diagnoses include giant cell myocarditis (differentiated on
for biopsy.12,23 18 cie endomyocardial biopsy), arrhythmogenic right ventricular
cardiomyopathy, hypertrophic cardiomyopathy and
DIFFERENTIAL DIAGNOSIS idiopathic ventricular tachycardia. Another close mimick
20 o
which is difficult to differentiate is the idiopathic variant
The closest mimick to cardiac sarcoidosis is myocardial
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of “arrhythmogenic inflammatory cardiomyopathy”

tuberculosis, which is indistinguishable from cardiac
(patients presenting with PVCs/VT/VF in whom clinical
sarcoidosis in its clinical and imaging findings.36 Besides,
features and FDG PET findings are consistent with cardiac
al
an overlap syndrome (sometimes called “tuberculous

sarcoidosis, but biopsies do not show non-necrotising
myocarditis”) with mixed features of cardiac sarcoidosis
granulomas), another entity wherein ventricular
ic
and myocardial tuberculosis has also been described; this

arrhythmia responds to immunosuppressive therapy.42 It is
diagnosis would necessitate simultaneous treatment for quite likely that many cases of so-called idiopathic VT and
og
both cardiac sarcoidosis and myocardial tuberculosis.37-39 idiopathic arrhythmogenic inflammatory cardiomyopathy
A positive tuberculin test (induration > 10 mm) in a patient are actually cases of cardiac sarcoidosis wherein the
with a non-caseating granuloma suggests simultaneous site chosen/accessible for biopsy does not harbor a
ol
occurrence of tuberculosis and sarcoidosis, rather than granuloma. It is also possible that some of these are cases
refute the diagnosis of sarcoidosis.40 A negative tuberculin of myocardial tuberculosis.
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test is the norm in sarcoidosis; a negative tuberculin test,

though, can also occur in patients with simultaneous
IMAGING IN CARDIAC SARCOIDOSIS
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tuberculosis and sarcoidosis, where cutaneous anergy due

to sarcoidosis has suppressed the response to tubercular Imaging modalities have a major role to play in the
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antigen.40 A meta-analysis found M. tuberculosis DNA diagnosis, prognostication and monitoring of cardiac
(and occasionally atypical Mycobacterial DNA) positivity sarcoidosis. Echocardiographic abnormalities are
in 26.4% of sarcoid granulomas using polymerase chain described in 30–35% of patients with cardiac sarcoidosis.
reaction (PCR) tests. 41 While the etiological role of Other than systolic and diastolic ventricular dysfunction,
this finding is still debated, it makes a case for NOT the most common finding described is a discrete thinning
diagnosing tuberculosis based on DNA PCR positivity as of the basal anteroseptum, found in 20–30% of patients
the sole criterion. In the light of these confusing findings, (Figures 4A and B). Other findings include areas of focal
cardiac sarcoidosis, myocardial tuberculosis, and the thinning and thickening (during the granulomatous
overlap syndrome can be diagnosed and treated using infiltration phase; Figure 4C), and discrete aneursyms.
a previously described algorithm which has been found None of these findings are sensitive or specific enough to
to be clinically effective (Figure 3). 12 This algorithm be diagnostic on their own. Gallium scans and Technetium
diagnoses tuberculosis in presence of AFB stain or culture scans were previously used to diagnose active cardiac
positivity, sarcoidosis in presence of AFB stain, culture, sarcoidosis, but are currently not recommended due to
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Figure 3: Diagnostic and therapeutic algorithm for VT due to suspected cardiac sarcoidosis or myocardial tuberculosis12
their low sensitivity and specificity.43 The best currently absence of CAD) in the area of high FDG uptake further
available tool for diagnosis of active cardiac sarcoidosis increases the utility of the FDG scan. FDG PET needs to be
seems to F 18-FDG PET-CT showing discrete areas of performed after a specific dietary preparation for up to 72
high FDG uptake (Figure 5). Adding a perfusion scan hours for it to be accurate to diagnose cardiac sarcoidosis.
to the PET-CT to demonstrate perfusion defects (in the The blood glucose level should be normal at the time
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Cardiac Sarcoidosis
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A B
In
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echo in advanced cardiac sarcoidosis; (B) Subtle discrete basal
anteroseptal thinning on 2D echo in early cardiac sarcoidosis; (C)
Focal thickening of the mid-septum in cardiac sarcoidosis. This
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picture can mimick HCM. This patient had inflammation in the thick
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area on FDG PET-CT, and biopsy from this area showed the typical
C granuloma, without evidence of HCM
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C
Figure 5: Use of 18 F-FDG PET-CT to diagnose, and demonstrate treatment response in cardiac sarcoidosis. The upper panel shows discrete
FDG uptake in the apical, lateral and diaphragmatic aspects of myocardium (yellow arrows), and in deep cervical, hilar and subcarinal
lymph nodes (blue arrows) at the time of diagnosis. The bottom panel shows that all these FDG avid areas have become FDG non avid after
treatment
of performing the FDG PET. Besides, significant inter- treatment response in cardiac sarcoidosis. In a study of 14
operator variability calls for an experienced interpreter patients with cardiac sarcoidosis who underwent serial
for the findings.44,45 Reduction in FDG uptake on PET- FDG PET guided therapy, it was noted that at 5.8 months
CT is probably the best available tool for monitoring of therapy, 67% of patients showed reduction and 33%
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A B
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Figures 6A and B: Time course of response of active cardiac sarcoidosis to immunosuppressive therapy, and illustrating the use of serial
FDG PET-CTs to guide therapy32 (see text for further discussion)
of
showed resolution of myocardial inflammation; at 11.6 down a framework for tailoring immunosuppressive
months, 92% had shown reduction and 67% had shown therapy to suit the stage of disease (Figure 8).1 In this
ty
resolution of inflammation; at 20.3 months, no patient regime, patients with VT in the inflammatory phase were
had myocardial inflammation. Reduction in myocardial given oral corticosteroids (prednisolone 1 mg/kg/day,
18 cie
inflammation on PET-CT correlated with quiescence of
arrhythmia and improvement of ventricular function
(Figures 6A and B). 32 Reappearance of FDG uptake
to a maximum dose of 60 mg/day or equivalent dose
of methylprednisolone) for 8 weeks and tapered over
a period of the next 3–4 months before stopping. Oral
in previously non-FDG avid areas has been the most methotrexate (7.5 mg/week) was started concurrently
20 o
promising tool to diagnose relapse of active cardiac with steroids and continued for 2 years (increased up to
S
sarcoidosis.1 Late gadolinium enhancement on cardiac 20 mg/week as tolerated). In the report by Thachil et al.
MRI is the gold standard for diagnosing myocardial scars wherein serial FDG PET-CTs were used to guide therapy,
in cardiac sarcoidosis. Extent of myocardial scarring
al
the mean duration of treatment required was 14.1 ± 4.5

(>18 g) correlates with prognosis of cardiac sarcoidosis. months.32
The LGE is found most commonly in the septum. Mid
ic
Some of the previous studies and analyses have

myocardial and epicardial scars not corresponding to questioned the role of corticosteroid therapy in cardiac
a coronary artery distribution are the usual findings
og
sarcoidosis. All such studies suffer from one major

on DE-CMR.46,47 Cardiac MRI detecting scar, and FDG
limitation: steroids have been used for all patients
PET detecting inflammation thus yield complementary
diagnosed with cardiac sarcoidosis, rather than only for
information in cardiac sarcoidosis.2,48 (Figures 7A and B).
ol
patients diagnosed with cardiac sarcoidosis in the active

More recently, myocardial edema, detected as increased
inflammatory phase. Blanket corticosteroid therapy
signal on T2 weighted cardiac MRI has also been used to
di
for all patients with cardiac sarcoidosis has not been

evaluate inflammation in cardiac sarcoidosis.
shown to be useful.50 Corticosteroids have been found
ar
to be useful in cardiac sarcoidosis provided they are

TREATMENT administered to patients in the active, inflammatory
phase of disease (usually diagnosed by an 18FDG PET-CT
C
Treatment of cardiac sarcoidosis should include disease

specific treatment for the cardiac sarcoidosis per se, showing myocardial inflammation), preferably before the
as well as treatment for the arrhythmias/ventricular onset of severe left ventricular dysfunction.1,12,51,52 There
dysfunction. Immunosuppressant therapy, usually is no standardization of the dose or duration of steroid
using corticosteroids, is effective to manage ventricular therapy. The majority of the sparse literature available
arrhythmia, reverse AV block and to preserve ventricular suggests 20–40 mg/day (or 0.5 mg/kg/day) of prednisolone
function, if initiated during the inflammatory phase for ~ 3months, followed by reduction to 5–15 mg/day
of disease.49 As long-term therapy is usually required, and maintaining this low dose for 9–12 months.51 These
steroid sparing immunosuppressive agents are often recommendations are based on incomplete evidence.
added to avoid the adverse effects of long-term steroid The major evidences behind these recommendations
use. The most commonly used and effective second line are: (i) 30 mg/day was found to have the same effect as
immunosuppressant, used for steroid-sparing effect in 60 mg/day in the only dose finding study, which is an
the long-term, is Methotrexate. Yalagudri et al. has laid older study where steroids were administered without
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Figures 7A and B: Complementary role of DE-CMR and 18FDG PET-CT in cardiac sarcoidosis2
C
evaluating the patients for objective evidence of active clinical response. Myocardial inflammation on FDG
myocardial disease.28 (ii) The regimen simply extends the PET-CT took longer to completely resolve, though most
regimen used for treatment of extracardiac sarcoidosis patients showed reduction in inflammation at 3 months
to cardiac sarcoidosis, without systematic verification itself. Methotrexate was added as a steroid sparing agent in
of whether it may be effective in cardiac sarcoidosis. 31 all of these patients, usually after an initial two months of
In the regime developed at CARE Hospitals, Hyderabad, high dose prednisolone. The initial dose of methotrexate
and described by Yalagudri et al. all 14 patients with was 7.5 mg once/week; the dose was increased (usually
active cardiac sarcoidosis initially responded to oral in increments of 2.5 mg) once every two to four weeks to
prednisolone at a dose of 1 mg/kg/day (maximum 60 reach a maximum dose of 20 mg once/week if tolerated.
mg/day), administered for two months and then tapered Most patients received 18 to 24 months of therapy. In an
and stopped over the next 12 weeks in patients showing analysis by Thachil et al. carried out on patients treated
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Figure 8: Suggested guideline for tailoring therapy for VT in cardiac sarcoidosis according to the stage of disease1
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using this regimen, among patients who underwent serial agent” to avoid the adverse effects of long-term steroid
FDG PET guided therapy, it was noted that at 5.8 months use. 54 It has also been used predominantly for steroid
di
of therapy, 67% of patients showed reduction and 33% resistant cases. There is no standardization of the use of
showed resolution of myocardial inflammation; at 11.6 methotrexate in cardiac sarcoidosis. Birnie et al. used
ar
months, 92% had shown reduction and 67% had shown methotrexate for only steroid refractory cases or in case
resolution of inflammation; at 20.3 months, no patient had of significant adverse effects of steroids. 51 Nagai et al.
myocardial inflammation.32 On this regime, 4 out of 14
C
reported a regime involving lower doses of prednisolone

patients had reactivation of disease, and were managed by and methotrexate for longer durations as compared to
additional immunosuppression, usually by administering the regime reported from CARE Hospitals, Hyderabad.
IV methylprednisolone and/or increasing the dose of They administered 5–15 mg/day of prednisolone along
prednisolone for a brief period.1 IV methylprednisolone with 6 mg/week of methotrexate for all patients for
(up to 1 g/day, for 1–3 days) can be used for more rapid up to 5 years; this was done without serial imaging
control of recurrent VT during the inflammatory phase studies to monitor for active cardiac sarcoidosis.54 Other
of cardiac sarcoidosis, especially during reactivation of immunosuppressive drugs that have been effectively
cardiac sarcoidosis.1,53 This regime was tolerated without used in place of steroids for initial control of disease
serious side effects. Methotrexate is the most common include monthly cyclophosphamide, and infliximab.55,56
second line drug used in cardiac sarcoidosis. It has been Azathioprine has been used in place of methotrexate as a
usually used along with steroids as a “steroid sparing steroid-sparing agent.57
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Table 4: The 2014 HRS consensus statement for management of arrhythmias in cardiac sarcoidosis30 CHAPTER
68
Management of conduction abnormalities
zz Device implantaton can be useful in CS patients with an indicatin for pacing, even if the atrioventricular block reverses transiently IIa
Immunosuppression can be useful in CS patients with second-degree (Mobitz II) or third-degree atrioventricular block IIa
Cardiac Sarcoidosis
zz
zz ICD implantation can be useful in patients with CS and an indication for permanent pacemkar implantations IIa
Management of ventricular arrhythmias
zz Assessment of mycardial inflammation with FDG-PET can be useful in CS patients with ventricular arrhythmias IIa
zz Immunosuppression can be useful in CS patiens with ventricular arrhythmias and evidence of myocardial inflammation IIa
zz Antiarrythmic drug therapy can be useful in patients with ventricular arrhythmias refractory to immunosuppressive therapy IIa
Catheter ablation can be useful in patients with CS and ventricular arrhythmias refractory to immunosuppresive and antiarrhythmic IIa
a
zz
therapy
di
Risk stratification for sudden cardiac death
zz An electrophysiological study for the purpose of sudden death risk stratification may be considered in patients with LVEF >35% IIb
In
despite optimal medical therapy and a period of immunosuppression (if there is active inflammation)
zz CMR for the purpsoe of sudden death risk stratification may be considered IIb
ICD implantation
of
zz Spontaneous sustained ventricuar arrhythmias, including prior cardiac arrest I
zz LVEF <35% despite optimal medical therapy and a period of immunosuppression (if there is active inflammation) I
ICD implantation can be useful in patients with CS, independent of ventricular function and or more of the following: IIa
ty
zz
1. An Indication for permanent pacemakers implantation

2. Unexplained syncope or near-syncope, felt to be arrhythmic in etiology
zz
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3. Inducible sustained ventricular arrhythmias
ICD implantation may be considered in patients with LVEF 36% to 49% and/or an RV ejection fraction <40%, despite optimal
medical therapy for heart failure and a period of immunosuppresion (if there is active inflammation)
IIb
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Management of ventricular arrhythmias in cardiac the guidelines state that an ICD should be considered
S
sarcoidosis is challenging, and often requires a instead of a pacemaker in all patients with cardiac
combination of medical therapy, radiofrequency ablation sarcoidosis who need a pacemaker implant, and that
al
and ICD. In brief, patients presenting with VT due to the ICDs for primary prevention of SCD should be considered
inflammatory phase of the disease are initially treated with strongly in all patients with cardiac sarcoidosis and
ic
corticosteroids and antiarrhythmic drugs for 4–8 weeks an LVEF <35%. The consideration of ICD for primary
before considering radiofrequency ablation if required. prevention should be made only after a reasonable period
og
Patients presenting in the scar phase are considered of immunosuppression.

for ablation if not responding to medical therapy and
antitachycardia pacing via the implanted ICD. Results CONCLUSION
ol
of radiofrequency ablation in cardiac sarcoidosis are

Cardiac sarcoidosis is a global disease, presenting with AV
di
worse than in other arrhythmias, and are even worse

block, ventricular arrhythmias and ventricular dysfunction.
if radiofrequency ablation is performed without initial
Diagnosis and treatment are challenging. However, if
ar
control of inflammation using drugs, or if performed in

diagnosed and treated in the early, inflammatory stage,
the later stage of disease where ventricular dysfunction outcomes are good. Delayed initiation of disease-specific
has set in.1,19 Radiofrequency ablation should be reserved
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therapy leads to poor prognosis.

as the last line of therapy in ventricular arrhythmias due
to cardiac sarcoidosis. The HRS consensus statement
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Imaging and Classification of Takayasu’s Arteritis
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Immunotherapy for Nonspecific Aortoarteritis
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Interventions in Takayasu Arteritis (Nonspecific Aortoarteritis)

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Aortic Diseases: When to Proceed with Surgery?
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Aortic Diseases: When and How to Proceed for Interventional Management?
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Pulmonary Embolism: When to do What?
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Evaluation of Pulmonary Hypertension: A Simplified Algorithm
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Recent Advances in the Management of Idiopathic
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Pulmonary Artery Hypertension

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Kawasaki Disease: What We Should Know?
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Imaging and Classification of
CHAPTER 69 Takayasu’s Arteritis
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INTRODUCTION
Takayasus’s arteritis (TA) was first described by Mikito
In
Takayasu in the 12th Annual Meeting of the Japan
Ophthalmology Society in 1905. He presented there a case
of 21-year-old lady with arteriovenous anastomosis in
of
eye. Later on in English literature TA used to be described
as “pulseless disease”. Takayasus’s arteritis (TA) is a
ty
vasculitis which affects large vessels such as aortic arch,
its branches, pulmonary artery, etc. There is chronic
18 cie
inflammation which leads to thickening of arterial wall
followed by stenosis, occlusion or positive remodeling
in the form of dilatation or aneurysm formation (in up
to one-third of patients). In active phase, there are non-
20 o
specific symptoms such as fever, malaise, anorexia, weight
S
loss, myalgia, arthralgia, vascular pain (e.g. carotidynia), Figure 1: Wavy or scalloped appearance of the thoracic aorta in
etc. In chronic phase, patients generally presents with chest radiograph
limb claudications, abnormalities of pulses, blood
al
pressure discrepancies, hypertension, etc. There may

also be involvement of coronary arteries or AR (aortic
ic
regurgitation). Many a time, patients present with heart

failure, transient ischemic attacks, strokes, mesenteric
og
ischemia, etc.
IMAGING IN TAKAYASU’S ARTERITIS

ol
In TA, most of the imaging modalities including computed

di
tomography (CT) and magnetic resonance (MR) imaging

show arterial wall thickening in early phase. Luminal
ar
changes such as stenosis, occlusion or dilatations are

delineated in late-phase in angiography. In this article,
C
we will briefly discuss the salient imaging features of TA in

chest X-ray, ultrasonography, CT, MRI and FDG-PET.
Figure 2: Hilar enlargement in chest radiograph in a young female
patient of Takayasu’s arteritis
CHEST RADIOGRAPHIC FEATURES
The chest radiographic manifestations include loss of
sharp definition and a scalloped or wavy appearance of ULTRASONOGRAPHY
the descending aorta (Figure 1). Hayashi et al. reported This is a very important tool for monitoring the disease.
that hilar enlargement, although rare, may be a new radio- Duplex Doppler ultrasonography (US) is often used
graphic finding in early-phase TA (Figure 2). Such subtle to identify and measure circumferential vessel wall
findings in a young female patient should alert to the thickening. Sonography of carotids and subclavian
diagnosis of early-phase TA. arteries aids in detection of TA at an early stage,
KG-69 (Sec-9).indd 575 03-11-2018 12:41:31

SECTION where characteristic long segment involvement with Rarely, when the inflammatory changes are severe,
homogeneous, midechoic, circumferential arterial wall granulomatous or diffuse productive inflammation in the
9 thickening, which has been described as the “Macaroni’s
sign” may be found (Figure 3). But one of the main
media and adventitia is associated with marked secondary
intimal hyperplasia, resulting in stenosis of the aortic
Vascular System
limitation of the investigation is that it is operator lumen (Figures 4A and B).

dependent. Suitable acoustic window is also essential
for proper evaluation. Furthermore, it has a low negative CT and MRI
predictive value.
By demonstrating arterial wall changes, cross-sectional
imaging techniques such as CT and MR imaging play an
Angiographic Features important role in early diagnosis of TA. The significant
a
Aortography may not show any intraluminal changes feature of early-phase TA is aortic wall thickening. Hayashi
because the basic pathologic features of early-phase TA et al. reported that a double ring pattern at enhanced CT is
di
are mural changes in the great vessels. On aortograms, the useful for early diagnosis of early-phase TA and evaluation
thickness of the wall of the descending aorta is measured of the effects of steroid therapy. On enhanced CT scans,
In
as the distance between the intraluminal contrast medium the vascular wall is clearly distinguished from the vascular
and the air in the lung. This Measurement includes, lumen by attenuation similar to or higher than that
the thickness of the two pleural layers (which may be of muscle. On enhanced CT scans, the wall shows the
of
negligible) and possibly the thickness should of periaortic double ring pattern: a poorly enhanced in side ring and
infiltration. However, the thickness of the wall of the a well-enhanced outside ring (Figure 5). The inside ring
pulmonary artery is difficult to measure on angiograms. is considered to represent mucoid or gelatinous swelling
ty
18 cie
20 o S
al
ic
og
ol
Figure 3: Macaroni’s sign in Sonography: homogeneous, midechoic, circumferential arterial wall thickening in Takayasu’s arteritis
di
ar
C
A B
Figures 4A and B: Diffuse stenosis of abdominal aorta before (A) and after (B) stent angioplasty in a patient of Takayasu’s arteritis
576
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CHAPTER
69

a
di
In
Figure 5: Double ring pattern in CT angiography: A poorly enhanced Figure 6: Arterial wall thickening in a patient
in side ring and a well-enhanced outside ring in a patient of of Takayasu’s arteritis in MR Imaging
Takayasu‘s arteritis
of
of the intima; the outside ring is considered to represent FDG-PET Scanning
18
active medial and adventitial inflammatory change. The F-fluorodeoxyglucose–positron emission tomography
ty
Inflamed arterial wall enhances at contrast-enhanced CT, (FDG-PET) scanning is emerging as a newer modality
because adventitial vascular structures in the aortic wall for assessing disease activity in TA. This is a noninvasive
18 cie
are probably enlarged vasa vasorum. In all 10 Healthy
adults studied by Park et al. transverse arterial-phase
metabolic imaging modality based on the regional
distribution of 18F-fluorodeoxyglucose, which accumulates
spiral CT angiograms showed an aortic wall that was less in hypermetabolic cells. Some authors have suggested
20 o
than 1 mm thick or even imperceptible; the aortic wall that it could play a role in the management of large-
could not be identified on precontrast and delayed images. vessel vasculitis because of its capacity to detect areas
S
Therefore, the sensitivity and specificity of CT for the of increased glucose metabolism present in the vascular
detection of significant arterial wall thickening are thought wall. Preliminary studies have shown that FDG-PET
al
to be high. scanning had a sensitivity and specificity of 92% and 100%,

Arterial wall thickening can also be demonstrated with respectively, for the assessment of active TA.
ic
MR Imaging (Figure 6). MR imaging has the advantages

of direct imaging in the axial, sagittal, and coronal Classification
og
planes with good contrast resolution, and the spin-echo A classification criterion for TA was first proposed by
technique allows differentiation of the arterial lumen from Ishikawa in 1988. It was based on clinical, laboratory
its wall without contrast medium. An Imaging section
ol
and angiographic parameters. It had obligatory criterion,

perpendicular to the vessel of interest is best suited for two major criteria and nine minor criteria (Table 1). In
assessing wall thickness with MR imaging. In addition, addition to the presence of the obligatory criterion, the
di
MR imaging allows better soft-tissue differentiation and following combinations led to a high probability of TA:
can show signs of inflammation-like edema and increased 1. Two major criteria or
ar
mural vascularity. Avoidance of iodinated contrast and 2. One major criterion and two or more minor criteria or
ionizing radiation are the other advantages of MR imaging. 3. Four or more minor criteria.
C
Dur ing the cours e of early-phas e TA , either Ishikawa’s criteria were evaluated in Japanese
spontaneously or with steroid therapy, the aortic wall population and were found to have 84% sensitivity.
thickening may be reduced, corresponding to a decrease in Characteristic signs and symptoms of TA which were
active inflammation in and around the aortic wall. Steroid included in the obligatory criteria have been enumerated
therapy has resulted in a dramatic improvement in clinical in Table 2. They need to be present for at least one month
and radiologic abnormalities in patients with early-phase to be categorized as obligatory criteria. American College
TA. Hayashi et al. reported the first case of early-phase TA of Rheumatology (ACR) published its classification
in which reduction of aortic wall thickening after steroid criteria for systemic vasculitides in 1990. Objective of
therapy was documented with CT. Follow-up MR imaging these criteria was to identify homogeneous group of
of patients with early-phase TA demonstrated significant patients in epidemiological studies. It was not intended
reduction of thickness of vessel wall in the aorta and initially to be used as a diagnostic tool for clinical practice.
pulmonary artery after steroid therapy. Patients were classified as TA in presence of three out
577
KG-69 (Sec-9).indd 577 03-11-2018 12:41:31

SECTION
Table 1: Ishikawa diagnostic criteria for Takayasu arteritis
9 Criteria
Obligatory Criterion
Definition
Vascular System
Age< 40 years Age <40 years at diagnosis or at onset of “characteristic signs and symptoms” of 1 month
duration in patient history.
Two Major Criteria
1. Left mid-subclavian artery lesion The most severe stenosis or occlusion present in the mid portion from the point 1 cm proximal
to the left vertebral artery orifice to that 3 cm distal to the orifice determined by angiography.
2. Right mid-subclavian artery lesion The most severe stenosis or occlusion present in the mid portion from the right vertebral
artery orifice to the point 3 cm distal to the orifice determined by angiography.
a
Nine Minor Criteria
di
1. High ESR Unexplained persistent high ESR 20 mm/hour (Westergren) at diagnosis or presence of the
evidence in patient history.
In
2. Carotid artery tenderness Unilateral or bilateral tenderness of common carotid arteries by physician palpation; neck
muscle tenderness is unacceptable.
of
3. Hypertension Persistent blood pressure>140/ 90 mm Hg brachial or>160/90 mm Hg popliteal at age< 40
years, or presence of the history at age < 40 years.
4. Aortic regurgitation or annuloaortic By auscultation or Doppler echocardiography or angiography. By angiography or two-
ty
ectasia dimensional echocardiography.
5. Pulmonary artery lesion Lobar or segmental arterial occlusion or equivalent determined by angiography or perfusion
6. Left mid common carotid lesion

18 cie scintigraphy; or presence of stenosis, aneurysm, luminal irregularity or any combination in
pulmonary trunk or in unilateral or bilateral pulmonary arteries determined by angiography.
Presence of the most severe stenosis or occlusion in the mid portion of 5 cm in length from
the point 2 cm distal to its orifice determined by angiography.
20 o
7. Distal brachiocephalic trunk lesion Presence of the most severe stenosis or occlusion in the distal third determined by
S
angiography.
8. Descending thoracic aorta lesion Narrowing, dilation or aneurysm, luminal irregularity or any combination determined by
angiography; tortuosity alone is unacceptable.
al
9. Abdominal aorta lesion Narrowing, dilation or aneurysm, luminal irregularity or any combination and absence of
lesion in aorto-iliac region consisting of 2 cm of terminal aorta and bilateral common iliac
ic
arteries determined by angiography; turtuosity alone is unacceptable.

og
Table 2: Characteristic signs and symptoms of TA included in Classification Criteria and Ishikawa’s diagnostic criteria
Ishikawa’s criteria for Takayasu’s arteritis for TA were applied to angiographically proven TA in
ol
Manifestations Indian patients, sensitivity decreased to 60.4% and 77.4%,

respectively. However, the specificity of both criteria
di
A. Cardinal limb signs or symptoms

1. Pulselessness remained good (more than 95%).
2. Differences in pulses in the arms In 1995, Sharma et al. modified Ishikawa’s criteria.
ar
3. Unobtainable blood pressure They removed the obligatory criterion (age < 40 years). In
4. Significant blood pressure differences in the arms
addition, characteristic signs and symptoms of TA were
5. Easy limb fatigability or pain
C
added as a major criterion. Other modifications included

B. Minor signs or symptoms
the removal of age in the definition of hypertension,
1. Unexplained fever or high ESR (20 mm in the first hour, by
the Westergren method), or both the removal of the absence of aortoiliac lesions, and the
2. Neck pain inclusion of lesions in coronary artery in patients < 30 years
3. Transient amaurosis or blurred vision or syncope of age in the absence of traditional risk factors as a minor
4. Dyspnea or palpitations or both, or hypertension or aortic
regurgitation criterion (Table 4). The presence of either 2 major criteria
or one major and 2 minor criteria or 4 minor criteria are
considered to be diagnostic of TA. The sensitivity of the
of six criteria (Table 3). But the main limitation of these modified Ishikawa’s criteria was 92.5% and the specificity
two criteria (Ishikawa and ACR) was the age restriction was 95.0%.
of less than 40 years for disease onset. Other criticism Considering diagnosis of TA in children and younger
includes limited usefulness in patients with predominant individuals, European League Against Rheumatism
aortic involvement (such as India). When the 1990 ACR (EULAR), the Pediatric Rheumatology European Society
578
KG-69 (Sec-9).indd 578 03-11-2018 12:41:32

CHAPTER
Table 3: The 1990 American College of Rheumatology Classification Criteria for Takayasu arteritis
Criteria
Age at disease onset<40 years

Definition
Development of symptoms or findings related to TA at age <40 years

69

Claudication of extremities Development and worsening of fatigue and discomfort in muscles of 1 or more extremity while in
use, especially the upper extremities
Decreased brachial artery pulse Decreased pulsation of 1 or both brachial arteries
Blood pressure difference >10 mm Hg Difference of>10 mm Hg in systolic blood pressure between arms
Bruit over subclavian arteries or aorta Bruit audible on auscultation over 1 or both subclavian arteries or abdominal aorta
a
Arteriogram abnormality Arteriographic narrowing or occlusion of the entire aorta, its primary branches, or large arteries
di
in the proximal upper or lower extremities, not due to arteriosclerosis, fibromuscular dysplasia, or
similar causes; changes usually focal or segmental
In
The patient is classified to have TA, if at least 3 out of 6 criteria are present. The presence of 3 or more criteria is shown to a have a sensitivity of
90.5% and a specificity of 97.8%.
of
Table 4: Ishikawa’s diagnostic criteria for TA modified by Sharma et al
Criteria Description
ty
Three Major Criteria
1. Left mid-subclavian artery lesion The most severe stenosis or occlusion present in the mid portion from the point
18 cie 1 cm proximal to the vertebral artery orifice up to 3 cm distal to the orifice
determined by angiography
2. Right mid-subclavian artery lesion The most severe stenosis or occlusion present in the mid portion from the
20 o
right vertebral artery orifice to the point 3 cm distal to orifice determined by
angiography
S
3. Characteristic signs and symptoms of at least one These include limb claudication, pulselessness or pulse differences in limbs, an
month duration unobtainable or significant blood pressure difference (>10 mm Hg systolic blood
al
pressure in limb), fever, neck pain, transient amaurosis, blurred vision, syncope,
dyspnea or palpitations
ic
Ten Minor Criteria
1. High ESR Unexplained high ESR >20 mm/hour (Westergren) at diagnosis or evidence in
og
patient’s history
2. Carotid artery tenderness Unilateral or bilateral tenderness of common carotid arteries on palpation. Neck
muscle tenderness is unacceptable
ol
3. Hypertension Persistent blood pressure >140/90 mm Hg brachial or >160/90 popliteal

di
4. Aortic regurgitation or annuloaortic ctasia By auscultation, Doppler echocardiography or angiography
5. Pulmonary artery lesion Lobar or segmental arterial occlusion or equivalent determined by angiography
ar
or perfusion scintigraphy, or presence of stenosis, aneurysm, luminal irregularity

or any combination in pulmonary trunk or in unilateral or bilateral pulmonary
arteries determined by angiography.
C
6. Left mid common carotid lesion Presence of the most severe stenosis or occlusion in the mid portion of 5 cm in
length from the point 2 cm distal to its orifice determined by angiography.
7. Distal brachiocephalic trunk lesion Presence of the most severe stenosis or occlusion in the distal third determined
by angiography.
8. Descending thoracic aorta lesion Narrowing, dilation or aneurysm, luminal irregularity or any combination
determined by angiography; tortuosity alone is unacceptable.
9. Abdominal aorta lesion Narrowing, dilation or aneurysm, luminal irregularity or any combination
10. Coronary artery lesion Documented on angiography below the age of 30 years in the absence of risk
factors such as hyperlipidemia or diabetes mellitus
The presence of two major or one major and two minor criteria or four minor criteria suggests a high probability of TA.
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KG-69 (Sec-9).indd 579 03-11-2018 12:41:32

SECTION Table 5: The EULAR/PRINTO/PRES criteria for childhood Takayasu’s arteritis
9
Criterion Definition
Angiographic abnormality Angiography (conventional, computed tomography, or magnetic resonance imaging) of the aorta or its
(Mandatory criterion) main branches and pulmonary arteries showing aneurysm/dilatation, narrowing, occlusion or thickened
Vascular System
arterial wall not due to fibromuscular dysplasia, or similar causes; changes usually focal or segmental
Pulse deficit or claudication Lost/decreased/unequal peripheral artery pulse(s). Claudication: focal muscle pain induced by physical
activity
Blood pressure discrepancy Discrepancy of four limb systolic blood pressure >10 mm Hg difference in any limb
Bruits Audible murmurs or palpable thrills over large arteries
Hypertension Systolic/diastolic blood pressure greater than 95th percentile for height
Acute phase reactants Erythrocyte sedimentation rate >20 mm per first hour or C-reactive protein any value above normal
a
(according to the local laboratory)
di
Takayasu’s arteritis (TA) is classified when the mandatory criterion is present plus any other criteria.
In
(PRES) and by the Pediatric Rheumatology International 7. Kerr GS, Hallahan CW, Giordano J, et al. Takayasu arteritis.
Trials Organization (PRINTO) in 2005 proposed Ann Intern Med. 1994; 120(11):919-29.
classification criteria. It was further validated in 2008. 8. Luqmani RA, Suppiah R, Grayson PC, et al. Nomenclature
of
This is known as EULAR/PRINTO/PRES criteria and is and classification of vasculitis e update on the ACR/EULAR
meant to be used in individuals younger than 18 years. diagnosis and classification of vasculitis study (DCVAS).
The criteria for childhood TA (c-TA) include angiographic Clin Exp Immunol. 2011; 164:11-3.
ty
9. Maksimowicz-McKinnon K, Clark TM, Hoffman GS.
abnormalities in the aorta or its main branches and
Limitations of therapy and a guarded prognosis in an
pulmonary arteries as a mandatory criterion and five
18 cie
additional features of c-TA (Table 5). When the patient
has the mandatory criterion and at least one of the
American cohort of Takayasu arteritis patients. Arthritis
Rheum. 2007;56(3):1000-9.
10. Mason JC. Takayasu arteritis- advances in diagnosis and
5 other features, c-TA is diagnosed. EULAR/PRINTO/PRES management. Nat Rev Rheumatol. 2010; 6(7):406-15.
20 o
criteria for c-TA are more modern and include CT and MR 11. Matsunaga N, Hayashi K, Sakamoto I, et al. Takayasu
S
imaging techniques. These criteria for diagnosis of c-TA Arteritis: Protean Radiologic Manifestations and diagnosis.
are 100% of sensitive and 99.9% of specific. RadioGraphics. 1997; 17:579-94.
12. Nastri MV, Baptista LP, Baroni RH, et al. Gadolinium-
al
SUGGESTED READING enhanced Three-dimensional MR Angiography of Takayasu

Arteritis. Radiographics. 2004 ; 24(3):773-86.
ic
1. Arnaud L, Haroche J, Malek Z, et al. Is 18F‐fluorodeoxyglucose

13. Ozen S, Pistorio A, Iusan SM, et al. Paediatric Rheumatology
positron emission tomography scanning a reliable way
International Trials Organisation (PRINTO). EULAR/
og
to assess disease activity in takayasu arteritis? Arthritis

Rheum. 2009; 60(4):1193-200. doi: 10.1002/art.24416. PRINTO/PRES criteria for Henoch-Schönlein purpura,
2. de Souza AW, de Carvalho JF. Diagnostic and classification childhood polyarteritis nodosa, childhood Wegener
criteria of Takayasu arteritis. J Autoimmun. 2014; 48-49:79- granulomatosis and childhood Takayasu arteritis: Ankara
ol
83. 2008. Part II: final classification criteria. Ann Rheum Dis.
3. Freitas DS, Camargo CZ, Mariz HA, et al. Takayasu arteritis: 2010;69:798-806.
di
assessment of response to medical therapy based on 14. Rav-Acha M, Plot L, Peled N, et al. Coronary involvement in
clinical activity criteria and imaging techniques. Rheumatol Takayasu’s arteritis. Autoimmun Rev 2007; 6(8):566-71.
ar
Int. 2012; 32:703-9. 15. Ruper to N, Ozen S, Pistor io A , et al. Pae diatr ic
4. Hayashi K, Fukushima T, Matsunaga N, al. Takayasu Rheumatology International Trials Organisation (PRINTO).
EULAR/PRINTO/PRES criteria for Henoch-Schönlein
C
arteritis: decrease in aortic wall thickening following

steroid therapy, documented by CT. Br J Radiol. 1986; purpura, childhood polyarteritis nodosa, childhood
59(699):281-3. Wegener granulomatosis and childhood Takayasu arteritis:
5. Ishikawa K. Diagnostic approach and proposed criteria for Ankara 2008. Part I: overall methodology and clinical
the clinical diagnosis of Takayasu’s arteriopathy. J Am Coll characterisation. Ann Rheum Dis. 2010; 69:790-7.
Cardiol. 1988; 12:964-72. 16. Schmidt WA, Nerenheim A, Seipelt E, et al. Diagnosis of
6. Johnston SL, Lock RJ, Gompels MM. Takayasu arteritis: a early Takayasu arteritis with sonography. Rheumatol. 2002;
review. J Clin Pathol. 2002; 55(7):481-6. 41(5):496-502.
580
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Immunotherapy for
CHAPTER 70 Nonspecific Aortoarteritis
a
di
INTRODUCTION reports have hinted that genetic factors might play a role.
Nonspecific aortoarteritis (NSAA), also known as Takayasu HLAB*52 is the most significant HLA region associated
In
arteritis (TA), is a rare chronic granulomatous primary with TA. The underlying pathophysiology forms the basis
large vessel vasculitis which predominantly involves aorta, of targeted immunosuppressive therapy that is described
in the subsequent section of this chapter.
of
its main branches and pulmonary artery. The disease
can affect any age group right from infancy to adulthood; While administering and optimizing immunotherapy,
however, it predominantly affects young females between knowledge about assessment of disease activity and
severity is essential. This chapter shall illustrate the
ty
20 and 40 years of age. The prevalence of disease varies
various drugs available in the therapeutic armamentarium
according to geographic region. The incidence of TA
for immunotherapy in TA. However, it is important to
geographical region.1 18 cie
varies from 1.2 to 2.6/million/year depending on the
The clinical manifestations var y widely from

mention here that immunotherapy forms only one arm
of the multipronged treatment strategy for TA which
includes other modalities like surgical and endovascular
asymptomatic to life-threatening manifestations
20 o
interventions, anti-platelet agents, supportive care and
depending on the stage of disease and organ
physiotherapy.
S
involvement. The disease has three stages: (1) systemic

inflammation and pre-stenotic/pre-pulseless phase
extending over many years and is characterized by DISEASE ACTIVITY AND SEVERITY
al
nonspecific complains like fever, malaise, anorexia, The aim of immunotherapy is to dampen the ongoing
weight loss and arthralgia (2) stenotic/aneurysmal arterial inflammation and it needs to be tailored depending
ic
stage/late occlusive phase characterized by feeble or on the intensity of ongoing inflammation. However, it
absent pulses, claudication, hypertension and life-
og
is often difficult to predict the underlying inflammation

threatening complications like stroke, seizures, myocardial owing to lack of reliable biomarker, which can define
infarction, aortic regurgitation, mesenteric ischemia and disease activity with precision. Acute phase reactants (ESR
ol
retinopathy (3) fibrotic or burnt out phase. Unfortunately and CRP) are variably associated with disease activity and
owing to the prolonged pre-pulseless phase, blurred are not reliable predictors of disease activity. Elevated
di
transition between three stages and absence of any reliable levels of Pentraxin 3 (PTX3) may be a potential biomarker
biomarker for early diagnosis, there is a considerable of disease activity.
ar
diagnostic delay spanning from months to years which Paucity of sensitive laboratory biomarkers to detect
leads to damage accrual and cardiovascular morbidities. active TA has led to the development of various composite
Characteristic arteriographic findings and existing criteria and scoring systems. In 1994 Kerr et al. proposed
C
classification criteria for both adults and children assist NIH criteria which included four categories (1) ESR more
in diagnosis of TA.2,3 Majority of patients demonstrate than 20 mm/hr, (2) systemic features like fever, malaise (3)
progressive course requiring immunotherapy while 20% features suggestive of vascular ischemia like claudication,
patients can have monophasic self-limiting illness.4 bruits and diminished or absent pulses (4) angiographic
The pathogenesis of TA is yet not well understood features consistent with TA; new onset or worsening of two
but it is assumed to be predominantly a T cell mediated or more out of these four criteria suggest active disease.6
disease. The inflammation is mediated by raised levels of In 2005, the Indian Rheumatology Association Core Group
many inflammatory cytokines like tumor necrosis factor α on Vasculitis (IRAVAS) proposed new set of criteria based
(TNFα), interferon γ (IFN-γ), interleukin (IL)-2 , IL-3, IL-4, on the Birmingham Vasculitis Activity Score (BVAS) called
IL-6 and IL-8. There is also some evidence of involvement Disease Extent Index in TA (DEI.Tak) to assess the disease
of B lymphocytes in the pathogenesis of TA as suggested by activity, which was subsequently modified to Indian
the documentation of antibodies against aortic endothelial Takayasu’s arteritis clinical activity score (ITAS2010),
cells (AAECA) and anti annexin V in patients.5 Several which scores 33 items in six different organ systems.
KG-70.indd 581 03-11-2018 12:40:23

SECTION Further, ITAS-A, an activity version of ITAS2010, takes into with early diagnosis and aggressive treatment (combined
account the acute phase reactants, ESR and CRP may help immunosuppressive agents) had better overall outcome.11
9 in tailoring immunotherapy.7
Various imaging modalities viz. computed tomographic
Approximately 20% of patients with TA have a monophasic
illness, while remaining 80% have a chronic course with
Vascular System
angiography (CTA), magnetic resonance angiography relapsing and remitting disease requiring long term
(MRA) and ultrasonography (USG) have been utilized immunosuppression.12 Although there is no agreement on
to evaluate the disease activity. On CTA, vessel wall optimal preference of the agent and duration of therapy,
thickening with enhancement and low attenuation ring we would summarize the recent evidence and propose an
on delayed phase images is suggestive of disease activity. algorithmic approach (Figure 1) for the management of
Likewise vessel wall thickening and enhancement TA based on the existing literature. The armamentarium
on MRA is consistent with disease activity. On 18F- of various immunotherapeutic drugs in TA includes
a
fluorodeoxyglucose positron emission tomography corticosteroids, non-biological and biological disease
di
(18F-FDG-PET), vessel wall edema and mural contrast modifying drugs.
enhancement is suggestive of disease activity; the pooled
In
sensitivity and specificity of FDG-PET for determining CORTICOSTEROIDS
disease activity remains 70.1% and 77.2%, respectively.
Steroids form the foundation for the long-term
Carotid intima medial thickness (CIMT) of more than 2 mm
management of TA. They are effective in suppressing
of
by USG has shown to have equal concordance with CTA to systemic symptoms and can attenuate vascular changes
predict disease activity. The sensitivity and specificity of in early TA. The European League Against Rheumatism
these imaging modalities in predicting the disease activity (EULAR) recommend high-dose oral glucocorticoids
ty
has varied across studies. 8 Progressive arterial injury (prednisolone, 1 mg/kg/day) as the initial treatment
manifesting as stenosis or dilatation/aneurysm is typically in TA. 13 Usually this dose is continued for 4–6 weeks
18 cie
considered inflammatory and treated with enhanced
immunosuppression.4 However, there remains a caveat
for this approach; in TA, stenosis can also result from non-
(depending on the severity of disease) followed by slow
tapering to lowest possible dose depending on the
clinical response, which is continued over many years.
20 o
inflammatory remodeling response due to myofibroblast Up to two-third of the patients may relapse while tapering
proliferation or resolution of inflammation with fibrosis corticosteroids, necessitating the use of steroid sparing
S
and luminal contraction; wherein the temptation to agents. Also, daily doses are associated with less chance of
increase immunosuppression may not actually translate relapses than alternate day regime.
al
into an evident clinical response.9

In conclusion, Monitoring disease activity in TA is NONBIOLOGICAL DISEASE MODIFYING
ic
a complex process which involves combined inference

ANTIRHEUMATIC DRUGS
derived from clinical assessment, acute phase reactants,
The long-term use of glucocorticoids is often associat-
og
imaging modalities and the use of validated composite

scores. ed with steroid toxicity and therefore, an additional
The manifestation of TA varies from slow simmering immunosuppressive agent is required for sustained
ol
remission. The EUL AR recommends use of 2nd

course with incidentally detected hypertension to
immunosuppressant to achieve control of disease activity
severe life threatening presentations like hypertensive
di
and to facilitate reduction of the cumulative dose of

emergencies. The severity of presentation can guide the
steroids. 13 However, due to lack of large randomized
initial therapy and deciding choice of immunosuppressive
controlled tr ials compar ing the efficac y of one
ar
agent. 10 For the purpose of selecting the initial

immunosuppressant with another, often the choice of
immunosuppressive agent we generally categorise the
disease modifying anti-rheumatic drug (DMARD) is
C
cases as severe TA in presence of either of the following:

variable across physicians and institutions. We usually
life or vital organ threatening conditions (hypertensive
consider methotrexate for mild to moderate disease
emergency), retinal vasculitis, pulmonar y arter y
while more potent immunosuppressive agent like
involvement with or without aneurysm, severe aortic
cyclophosphamide as upfront drug is reserved for severe
regurgitation or myocarditis.
disease manifestations as described above. The duration
of therapy would usually last for many years depending on
IMMUNOTHERAPY the disease course.
There is paucity of good quality data to advocate consensus Methotrexate is widely used as a 1st line immuno-
treatment plans with high quality of evidence for most large suppressive agent for TA and also as steroid sparing
vessel vasculitis. However, there is consensus agreement agent. Although there is paucity of large well designed
that early diagnosis and therapeutic interventions can prospective controlled trials, however, when used in
improve disease outcomes. Oigahsi et al. in their cohort conjunction with corticosteroids it has been found to be
of 106 subjects with Takayasu arteritis showed that those efficacious in achieving remission in addition to allowing
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CHAPTER
70

a
di
In
of
ty
18 cie
20 o S
al
Figure 1: Approach to a patient with non-specific aortoarteritis (NSAA)

ic
*Severe disease: Life or vital organ threatening conditions (hypertensive emergency), retinal vasculitis,
pulmonary artery involvement with or without aneurysm, severe aortic regurgitation or myocardium
og
glucocorticoid dose reduction. 14 Given the long-term (500–750 mg/m2 as monthly pulses) in TA. Stern et al. in
ol
safety profile and affordable cost methotrexate seems a their study of 23 children showed that only 40% could
reasonable initial immunosuppressive agent for TA in our achieve remission with cyclophosphamide while 60%
were shifted to Infliximab.15 Its use is generally reserved
di
setting. The usual dose of methotrextae is 15–25 mg/m2/

week either orally or parenterally. for patients with severe manifestations such as retinal
vasculitis, pulmonary artery involvement with or without
ar
Azathioprine has also been used as an steroid sparing

drug in management of TA. In an Indian study of 15 patients aneurysm, severe aortic regurgitation or myocarditis.16
followed for 1 year, Valaskumar et al. have shown that
C
Mycophenolate mofetil: The results of recent meta-analysis

azathioprine (2 mg/kg/day) in addition to prednisolone to evaluate the efficacy of mycophenolate mofetil MMF
is safe, well tolerated, and effective in controlling systemic in TA has shown that MMF could stabilize the disease
symptoms and laboratory measures of disease activity progression in addition to achieving reductions in steroid
in TA without any progression of angiographic lesions.12 dosage and level of inflammatory markers. 17 MMF
However, further studies with larger sample size are (750–800 mg/m2/day) seems to be an effective alternative
required to conclusively validate the role of azathioprine. immunosuppressant with relatively lower hepatic, renal
Cyclophosphamide is a potent immunosuppressive and bone-marrow toxicity, however larger studies are
agent with established efficacy in vasculitic conditions. required to establish its long-term efficacy.
However, owing to its adverse effect profile including
increased risk of infections it should be used cautiously
and judiciously; more so in adolescent population due OTHER DMARDs
to the associated risk of gonadal toxicity. It has also Leflunomide is effective in controlling disease activity in
been used either orally (2 mg/kg/day) or intravenously the initial stages but is ineffective to sustain remission.18
583
KG-70.indd 583 03-11-2018 12:40:24

SECTION There are anecdotal studies reporting use of other OTHER BIOLOGICAL AGENTS
DMARDs in TA like cyclosporine (CSA) and tacrolimus
9
Abatacept is a fully humanized soluble fusion protein
with successful results.16 Currently, it seems that these compromising the extracellular domain of CTLA-4
agents should be reserved for refractory disease. (cytotoxic T-lymphocyte associated protein-4) and
Vascular System
Fc component of IgG1, which selectively inhibits the

BIOLOGIC DISEASE MODIFYING ANTI- costimulatory signal necessary for T-cell activation has
RHEUMATIC DRUGS failed to maintain sustained remission in newly diagnosed
There is upcoming evidence of use of biological agents in and refractory cases. B-cell dysregulation is thought to
TA. Raised levels of inflammatory cytokines such asTNF- play a role in the pathogenesis of TA, and B-cell depletion
α, IL-6 forms the basis of more specific and targeted using anti CD20; rituximab a monoclonal antibody that
a
binds B-cell CD 20 receptor has been tried in few patients
therapy in TA. The use of biological agents is associated
of refractory TA; however, reports are limited to anecdotal
di
with increased risk of infections and therefore should be
reports or case series. There is evidence of increased
prescribed cautiously in our setting. Additionally, these
Th 17 helper cell in TA which are maintained in active
In
agents are out of reach for most of our patients because of
state by IL-23, accordingly ustekinumab; a monoclonal
exuberant cost, we use these agents for either refractory
antibody against IL12/23p40 was studied in a pilot study
or relapsed disease. Refractory disease is defined as
of 3 patients with active TA showing short-term benefit.
of
increased disease activity following reduction of the
More studies with larger sample size are required before
steroid dose or persistent disease activity despite use of at
recommending the routine use of these novel biological
least one conventional immunosuppressive agent for at
ty
agents in TA.
least 6 months.
At this point we usually reserve use of biological agents
Anti-TNF Agents 18 cie

A recent systematic review describing details of 96 patients
(anti-TNF or tocilizumab) for patients with refractory
TA. The definition of “Refractory disease” is variable but
most studies define refractory disease as a disease with
(77 received infliximab, 17 Etanercept and 5 Adalimumab) increased disease activity following reduction of the
20 o
with TA treated with anti-TNF agents has shown that steroid dose or persistent disease activity despite use of at
S
61% subjects improved in terms of reduction in steroid least one conventional immunosuppressive agent for at
doses and levels of inflammatory markers, however only least 6 months.
al
3 subjects showed an improvement on imaging and a

total of 28 relapses were observed over a follow up of 2 IMMUNOTHERAPY DURING SURGERY
ic
years.19 In an another systematic review of the 75 patients AND PERIOPERATIVE PERIOD

on infliximab: remission was achieved in 74.7%, and In the chronic stages of TA and critical vessel narrowing,
og
steroids were discontinued in 32%, however 28.6% had e.g. cerebrovascular or coronary ischemia or renal artery
relapse during follow up.20 Ten out of 12 patients treated stenosis, surgical interventions are indicated to restore
with Etanercept initially achieved remission but 9 patients the vascular supply and prevent end organ damage.
ol
had a relapse on follow-up. The use of Anti-TNF agents in This can be achieved either by surgery or endovascular
settings like ours where the incidence of tuberculosis is interventions, including balloon angioplasty, stent
di
high should be guarded and close watch for evolution of and stent graft replacement. As a general rule, both
any symptoms suggestive of tuberculosis is warranted. endovascular interventions and surgery should be
ar
tried only after the suppression of inflammation using

Tocilizumab immunotherapy in the vessel wall. Perioperative
C
Raised levels of IL-6 in patients of TA form the basis immunosuppression has resulted in better outcomes
for the use of tocilizumab in TA. In a systematic review and hence immunosuppression should be continued in
including 24 patients tocilizumab could achieve clinical perioperative period.
improvement in 58.3% and steroids could be stopped in
20.8% subjects while 16.6% relapsed during 1 year follow FOLLOW-UP
up period. 18 Interestingly, 71% subjects also showed Patients with TA should be followed up every 3–6
improvement in imaging findings as assessed by FDG- months for assessment of treatment response (using
PET or MRA or CTA. In refractory cases it has helped clinical, imaging and laboratory parameters), disease
in achieving remission by 4th monthly infusion.21 More activity (using instruments like ITAS) and drug toxicity.
robust data is required to make a conclusive statement on If there is suspicion of active disease (e.g. worsening
the efficacy and safety of long-term use of tocilizumab in ITAS with constitutional symptoms) repeat imaging
Takayasu arteritis. (MRA) may be considered.
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KG-70.indd 584 03-11-2018 12:40:24

In case of stable disease for 18-24 months gradual 7. Barra L, Kanji T, Malette J, et al. Imaging modalities CHAPTER
tapering of immunosuppressants may be considered. for the diagnosis and disease activity assessment of
In case of refractory disease; add another immuno-
suppressant whichever is not used earlier or Biological
Takayasu’s arteritis: A systematic review and meta-analysis.
Autoimmun Rev. 2018;17(2):175–87.
70

agent (anti IL-6 or anti-TNF ). 8. Nicolosi PA, Tombetti E, Maugeri N, et al. Vascular
Remodelling and Mesenchymal Transition in Systemic
Sclerosis. Stem Cells Int. 2016;2016:4636859.
CONCLUSION
9. Misra R, Danda D, Rajappa SM, et al. Development and
Ti m e l y d i a g n o s i s a n d o p p o r t u n e i n i t i a t i o n o f initial validation of the Indian Takayasu Clinical Activity
immunotherapy is the key for reduced long-term Score (ITAS2010). Rheumatology. 2013;52(10):1795–801.
complications and the resultant morbidities and mortality 10. Keser G, Direskeneli H, Aksu K . Management of
related to TA. The patients with TA should be regularly
a
Takayasu arteritis: a systematic review. Rheumatology.
followed for comprehensive evaluation of disease activity 2014;53(5):793–801.
di
using clinical, laboratory and imaging modalities. Like 11. Ohigashi H, Haraguchi G, Konishi M, et al. Improved
any other vasculitis, corticosteroids forms the basis of prognosis of Takayasu arteritis over the past decade--
In
immunotherapy in TA, however, owing to accompanying comprehensive analysis of 106 patients. Circ J Off J Jpn Circ
side effects, a steroid sparing second immunosuppressive Soc. 2012;76(4):1004–11.
agent is always required. Methotrextae is the agent of 12. Kerr GS, Hallahan CW, Giordano J, et al. Takayasu arteritis.
of
choice for non-severe disease whereas more potent agent Ann Intern Med.1994:120(11):919–29.
like cyclophosphamide is preferred for severe TA. Due 13. Mukhtyar C , Guillevin L , Cid MC , et al. EUL AR
recommendations for the management of large vessel
to exuberant cost and increased risk of infections use of
ty
vasculitis. Ann Rheum Dis.2009;68(3):318–23.
Biological agents should be reserved for refractory disease.
14. Misra DP, Sharma A, Kadhiravan T, et al. A scoping review of
Long-term prognosis depends on arterial
18 cie
complications and progressive course. 15-year survival for
patients with or without arterial complications was 66.3%
the use of non-biologic disease modifying anti-rheumatic
drugs in the management of large vessel vasculitis.
Autoimmun Rev. 2017;16(2):179–91.
& 96.4% and 58.3% & 92.7% for those with and without 15. Stern S, Clemente G, Reiff A,et al. Treatment of Pediatric
20 o
progressive course respectively.22 However, in a French Takayasu arteritis with infliximab and cyclophosphamide:
study 10 years event free survival (vascular complications,
S
experience from an American-Brazilian cohort study.

relapse and death) was 36.4%.23 J Clin Rheumatol Pract Rep Rheum Musculoskelet Dis.
Perioperative immunotherapy results in better 2014;20(4):183–8.
al
surgical outcomes. There is a need to conduct large, 16. Keser G, Direskeneli H, Aksu K. Management of Takayasu
multicentre randomized controlled trails to generate arteritis: a systematic review. Rheumatology. 2014
ic
high-quality evidence and formulate consensus treatment ;53(5):793–801.

recommendations for the management of TA. 17. Dai D, Wang Y, Jin H, et al. The efficacy of mycophenolate
og
mofetil in treating Takayasu arteritis: a systematic review

REFERENCES and meta-analysis. Rheumatol Int. 2017;37(7):1083–8.
18. de Souza AWS, da Silva MD, Machado LSG,et al. Short-term
ol
1. Fries JF, Hunder GG, Bloch DA, et al. The American

effect of leflunomide in patients with Takayasu arteritis: an
College of Rheumatology 1990 criteria for classification of
observational study. Scand J Rheumatol. 2012;41(3):227–
vasculitis.Summary. Arthritis Rheum. 1990;33(8):1135-6.
di
30.
2. Arend WP, Michel BA, Bloch DA, et al. The American
19. Ferfar Y, Mirault T, Desbois AC, et al. Biotherapies in large
College of Rheumatology 1990 criteria for the classification
ar
vessel vasculitis. Autoimmun Rev. 2016;15(6):544–51.

of Takayasu arteritis. Arthritis Rheum. 1990;33(8):1129–34.
3. Ozen S, Pistorio A, Iusan SM, et al. EULAR/PRINTO/ 20. Osman M, Pagnoux C, Dryden DM,et al. The role of
biological agents in the management of large vessel
C
PRES criteria for Henoch-Schönlein purpura, childhood

polyarteritis nodosa, childhood Wegener granulomatosis vasculitis (LVV): a systematic review and meta-analysis.
and childhood Takayasu arteritis: Ankara 2008. Part II: Final PloS One. 2014;9(12):e115026.
classification criteria. Ann Rheum Dis. 2010;69(5):798–806. 21. Goel R, Danda D, Kumar S, et al.Rapid control of disease
4. Kerr GS, Hallahan CW, Giordano J, et al. Takayasu arteritis. activity by tocilizumab in 10 “difficult-to-treat” cases of
Ann Intern Med 1994;120(11):919-29. Takayasu arteritis. Int J Rheum Dis. 2013;16(6):754–61.
5. Tombetti E, Mason JC. Takayasu arteritis: advanced 22. Ishikawa K, Maetani S. Long term outcome of 120 Japanese
understanding is leading to new horizons. Rheumatology patients with Takayasu disease. Clinical and statistical
(Oxford). 2018 ; doi: 10.1093/rheumatology/key040. [Epub analysis of related prognostic factors. Circulation.
ahead of print] 1994;90:1855-60.
6. Valsakumar AK, Valappil UC, Jorapur V, et al. Role of 23. Comamond C, Biard L, Lambert M, Mekinian A, Ferfar Y,
immunosuppressive therapy on clinical, immunological, Kahn JE et al. Long tern outcomes and prognostic factors of
and angiographic outcome in active Takayasu’s arteritis. J complications in Takayasu arteritis: a multicenter study of
Rheumatol. 2003;30(8):1793–8. 318 patients. Circulation. 2017;136(12):1114-22.
585
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Interventions in Takayasu
Arteritis
CHAPTER 71
(Nonspecific Aortoarteritis)
a
di
INTRODUCTION bark’ appearance, a feature common to many arteritides.
Takayasu arteritis (TA) is a chronic, granulomatous, Chronic inflammation involves all layers of the vessel wall,
In
large-vessel panarteritis with preferential involvement extensive periarterial fibrosis, thickening and adhesions
of the aorta, its major branch arteries and result in tough, noncompliant, rigid vessel walls. This may
be tough to dilate by balloon angioplasty and may require
of
the pulmonary artery. The disease though more common
in Asians and Africans, has worldwide distribution. The high-pressure balloon dilatation.
TA is usually progressive with relapses and remissions.
IMAGING FOR INTERVENTIONS IN
ty
It more commonly affects young with predilection
for females. Early in the disease course, nonspecific TAKAYASU ARTERITIS
18 cie
constitutional symptoms, such as fever, malaise, and
weight loss, may occur. Later on, inflammation of the
involved arteries progresses, resulting in segmental
Due to variations in the pattern of arterial involvement,
accurate imaging is essential for planning interventional
procedure in TA Noninvasive vascular imaging has
stenosis, occlusion, dilatation, and/or aneurysm. This may
20 o
provided new insights into TA. Color Doppler ultrasound
present as extremity pain, claudication, bruits, absent or is useful in initial evaluation of arch and renal arteries.
S
diminished pulses, and inability to record blood pressure. Doppler ultrasound can detect carotid stenosis with
Severe stenosis leads to organ ischemia which may present high sensitivity and specificity (Figure 1). Contrast-
with severe hypertension, heart failure, acute visual loss,
al
enhanced computed tomography angiography (CTA)

or stroke. Endovascular interventions have emerged as and particularly magnetic resonance angiography (MRA)
the treatment of choice for stenotic lesions. The major
ic
can demonstrate arterial anatomy, wall enhancement,

advantages of endovascular interventions include safety, edema, and thickening, which might enable early disease
efficacy, ease of performance, the feasibility of talking
og
detection where luminal diameter is still preserved.

multiple lesions at the same sitting, and the ability to Angiography is nowadays resorted to when intervention
repeat the procedure without any significant morbidity in is planned. Its invasive nature, contrast-requirement, and
ol
cases of recurrence. high radiation dose, limit its use.

di
PATHOPHYSIOLOGY
Takayasu’s disease is a granulomatous vasculitis, with an
ar
acute period of large vessel vasculitis, followed by chronic

phase of fibrosis and scarring.
C
In the acute stage, the adventitial vessels of the arterial

walls become inflamed. Though TA is a panarteritis, the
initial site of inflammation is around the vasa vasora and
at the medioadventitial junction. There is edema and
mononuclear cell infiltration (CD4 and CD8 lymphocytes,
plasma cells, and macrophages) in the outer thirds of the
media and adventitia.1 Rapid or more severe inflammation
leads to loss of smooth muscle cells, medial weakening,
vascular dilatation, and even aneurysm formation.
In the chronic stage, the elastic tissue is replaced
by fibrosis, with thickening of all three layers. There Figure 1: Doppler ultrasound evaluation in a young girl with severe
is luminal narrowing, often affecting multiple sites. arch vessel stenosis shows marked thickening of intima causing
Macroscopically, the intima may be rigid, with a ‘tree severe stenosis of carotid artery in Takayasu arteritis
KG-71.indd 586 03-11-2018 12:40:09

High-resolution Ultrasound of active inflammation in the arterial wall. Some authors CHAPTER
have suggested that arterial wall thickening and more
71
High-resolution color duplex ultrasound (US) is relatively
inexpensive (nonexpensive), well tolerated, can readily intense postcontrast enhancement may reflect active
distinguish the arterial wall from the lumen, measure disease.3,4 The predominant role for MR in the follow-up of

intima-media thickness (IMT), and delineate degrees of patients with TA is to provide a safe, noninvasive mean of
stenosis or aneurysm. It is very useful for assessment of the assessing changes in vascular anatomy over time.
carotid and vertebral circulation, proximal subclavian and
axillary arteries (Figure 1). Angiography
In TA, US reveals concentric arterial wall thickening, Cine angiography and digital subtraction angiography
which may appear bright as a consequence of active arterial (DSA) is performed when intervention is planned. It
wall inflammation and edema. The US may also be used to
a
provides superior spatial resolution and finer detail of
study the abdominal aorta in TA. Doppler evaluation of images compared to those acquired by CT or MR; hence,
di
renal arteries is very useful in initial evaluation and follow-
DSA still represents the gold standard for studying the
up after renal angioplasty.
lumen of the affected arteries. Use of biplane or orthogonal
In
views is very important to assess the severity and extent
CT Angiography of lesions. Sufficiently long runs to be taken so see the
of
Computed tomography (CT) is useful to image the collateral filling in case of total occlusions. In addition
vascular lumen and the arterial wall, allowing diagnosis at to anteroposterior (AP) projection, use of right anterior
an early stage, before significant luminal remodeling has oblique (RAO) projection is strongly recommended while
ty
occurred. Images are acquired in the early arterial phase imaging the right subclavian artery as right subclavian-
following infusion of iodinated contrast medium. Delayed vertebral bifurcation is best seen in this view. Similarly,
18 cie
acquisition is needed to assess late contrast enhancement,
which has the appearance of a double ring, especially in
the venous phase. The hyperplastic intima is seen as inner
aortogram in lateral view is must where visceral arterial
involvement or dissection is suspected. Angiographic
appearance can range from discrete or diffuse long
poorly enhanced rim, while the outer, highly enhanced rim segment stenosis with or without collaterals. Stenotic
20 o
represents vasa vasorum neo-angiogenesis in the actively lesions of aortic branches are often osteal. Angiographic
S
inflamed media and adventitia. 2 Electrocardiogram- appearance helps in planning the intervention and
gating study is needed to see coronary and pulmonary also for definitive sizing of balloon angioplasty and for
involvement. The clinical utility of CT angiography (CTA)
al
deployment of stents. However, important limitations of

in diagnosis, assessment of disease extent, and follow-up DSA are its invasive nature and failure to characterize the
of TA patients is similar to MR.
ic
arterial wall. In addition, patients need hospitalization

CT scores over MR in shorter acquisition times and and there is a low but measurable risk of procedural
provision of images that are typically more intuitive
og
complications.
than MR, with improved anatomical detail. Thus, CTA is
particularly useful for preoperative planning in the event
INTERVENTIONS IN TAKAYASU ARTERITIS
ol
that revascularization is required. However, radiation

exposure and the use of iodinated contrast medium limit
Indications of Endovascular Intervention
di
the use of CTA.

Depending upon the site of arterial obstruction,
Takayasu diseases produce a multiplicity of syndromes.
Magnetic Resonance Imaging
ar
Involvement of the arch with occlusion of stenosis of the

Magnetic resonance (MR) imaging is an important brachiocephalic trunks causes the ‘pulseless’ syndrome
C
imaging technique for TA because of its ability to evaluate with a plethora of visual and cerebral manifestation.
a wide range of vascular territories and lack of radiation Abdominal coarctation is usually associated with renal
exposure, allowing multiple evaluations in young artery stenosis or occlusion. Severe hypertension is usual
patients. MR-angiography (MRA) requires a relatively presentation. Infrarenal aorta stenosis may present with
short acquisition time and generates images of the
leg claudication.
arterial lumen. Specific MRA sequences can be used to
obtain angiographic images without contrast medium.3 Major indications for endovascular/surgical treatment are:
In general, T1-weighted imaging is used to provide Hypertension from stenotic coarctation of the aorta or
anatomical depiction of arterial wall lesions, while T2- renovascular disease
weighted imaging (to assess wall edema) and contrast- End-organ ischemia or peripheral limb ischemia
enhanced T1-weighted imaging (to assess late contrast Cerebral ischemia
enhancement) are used to look for changes suggestive Coronary ischemia
587
KG-71.indd 587 03-11-2018 12:40:09

SECTION Mesenteric ischemia from occlusion of multiple complication rate was of 44%; and (2) biological
branches of abdominal aorta inflammation at the time of revascularization increases
9 Aortic or arterial aneurysms or severe aortic regur-
gitation.
the likelihood of complications by 7 times. A small single
center experience suggested that the use of stent grafts
Vascular System
Revascularization should ideally be performed during may improve patency rates7 due to deprivation of blood
periods of disease remission. There appears to be a clear flow to the inner layers of the vessel. The reasons for
benefit by achieving good control of disease activity with the poor long-term outcomes are: longer lesion length, more
use of immunosuppression both pre- and postoperatively. fibrotic and noncompliant vessels, and persistence of
Intensity and duration of immunosuppressive treatment is vessel wall inflammation despite clinical or laboratory
determined according to each patient’s clinical condition evidence of quiescent disease.
and disease activity. In patients with increased erythrocyte
a
sedimentation rate (ESR) and/or C-reactive protein (CRP), Endovascular Interventional Procedure
di
we start steroids before endovascular intervention adding Endovascular intervention in the form of balloon
methotrexate if the disease activity is not controlled. angioplasty with or without stenting may be undertaken
In
Immunosuppressive treatment usually needs to be continued if indicated by organ ischemia in patients with anatomy
for prolonged period, i.e. 2–3 years. Lifelong follow-up is suitable for endovascular intervention. Informed
required after surgical or endovascular intervention in and written consent explaining procedure, especially
of
TA. This is to monitor any progression of the disease and/ explaining the need of repeated imaging and re-
or restenosis. Prompt escalation of immunosuppressant intervention, should be taken from the patient before
treatment is necessary in patients with increased disease the procedure. Proper planning and availability of all
ty
activity. In a study of 25 patients, who underwent 58 the hardware that may be required during interventions
endovascular procedures, with or without stenting, only after should be ensured prior to intervention procedure.
18 cie
patients were treated with immunosuppressive therapy, and
after the ESR had normalized, there was a 17% restenosis
rate over a mean of 23.7 months.5 However, sometimes,
Appropriate size stent and stent graft should be available to
manage any complication. Usually, the procedure is done
under local anesthesia and sedatives with continuous
20 o
the clinical scenario (e.g. intractable syncope, impending ECG, SPO 2, and blood pressure monitoring. Femoral
loss of vision, resistant severe hypertension) of the patient access is the most common, brachial or radial access is
S
mandates urgent intervention even before complete control used for renal and visceral interventions. Both femoral
of disease activity. and brachial access may be required in cases of aortic
al
Endovascular interventions, particularly for discrete dissection, thoracic aneurysms, and severe stenosis of
stenosis, provide good relief with low morbidity and aorta. Graded dilatation starting with smaller diameter
ic
mortality (Table 1). The procedure provides immediate balloon should be done for severe stenosis. Balloon
symptomatic relief, high initial and intermediate success diameter should not exceed the diameter of adjacent
og
rate with lower morbidity and mortality compared to normal segmented artery. When using high pressure
surgery. A large multicenter study from France analyzed dilation for stenosis resistant to dilatation, balloon size for
the outcome of vascular surgery and endovascular high-pressure dilatation should be less than the diameter
ol
interventions in the management of arterial complications of normal segment of artery. High-pressure dilation for
of TA.6 Among the 104 surgical procedures, 39 (37.5%) resistant lesions increases the success rate of angioplasty;
di
presented a complication, versus 31 (50%) of the 62 however, it also increases the chance of artery dissection
with endovascular repair. Out of the 42 patients, who and rupture, which may be catastrophic. Dilatation should
ar
had endovascular procedure with stenting, 20 (47.6%) stop if the patient complains of severe pain. If stenting
experienced a vascular complication. Main complications is required, then a self-expandable/balloon expandable
C
included restenosis (n = 53, 75.7%), and in a lesser extent stent delivery catheter is advanced over the immobilized
thrombosis in 7 (10 %). The most striking conclusions guide wire. Aggressive postdilation should be avoided and
drawn by this study were: (1) the overall 5-year arterial to be done only when residual stenosis is >30%.
Table 1: Angioplasty/stenting in aortoarteritis at GB Pant Hospital, New Delhi, India

Vessel treated (POBA/Stenting) No. of patients No. of lesions
Aorta 356 387
Renal 236 307
Arch 220 276
Iliac 10 10
Celiac/Mesenteric 11 13
Total 709 963
Abbreviation: POBA, plain old balloon angioplasty
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KG-71.indd 588 03-11-2018 12:40:09

Table 2: Subclavian artery interventions CHAPTER
71
Study/Author Balloon angioplasty Results Complications Follow-up
10
Joseph 1994 n = 24 Technical and clinical success in 81% No major complication Mean F/u 26 months
lesions = 26 Restenosis rate

Angioplasty 28.6%
Tyagi 1998 n = 32 Technical and clinical success 92.8% Complication in 5.4% Mean F/u 43.3 months
in stenosis and 60% in total occlusion Restenosis rate
Angioplasty 19%
ARCH ARTERY INTERVENTIONS Due to chronic nature of the disease, good collateral
Loading doses of aspirin 300 mg and Clopidogrel 600 mg formation is common in TA. Angioplasty for diffuse
a
is given well before percutaneous intervention for aortic long segment stenosis or chronic total occlusion in
di
this disease should be attempted only if the patient
branches. During percutaneous intervention, 5,000
has severe symptoms as the results in these vessels are
IU IV bolus is given followed by 1000 IU an hour later,
In
often suboptimal and restenosis rate is high (Figure 3).
then additional heparin to achieve an activated clotting
However, short segment chronic total occlusions can be
time of 250–350 seconds. Judkins Right guiding catheter
recanalized with the help of hard coronary wires or 035”
8 F or Shuttle sheath 7 F (Cook) is most commonly used
of
hydrophilic straight tip Glide wire (Terumo). Retrograde
both for selective angiography and angioplasty of aortic
approach through ipsilateral brachial or radial artery can
arch arteries. Guiding catheter is introduced into the
also be used in select cases.
proximal portion of the stenotic artery; the stenosis is
ty
Vertebral artery interventions are indicated in cases of
initially crossed with a 0.014˝ soft tip coronary guidewire.
severe cerebral ischemia, where carotid arteries are totally
Monorail balloon of appropriate size is positioned
18 cie
across the stenosis and inflated using diluted contrast.
When using over-the-wire balloons or stents, then a
occluded or diffusely diseased and vertebral arteries are
the sole supply. Since the diameter of vertebral artery
matches with coronaries, coronary balloons and stents
260–300 cm 0.014” coronary guidewire or 018” soft tip
can be readily used.
20 o
peripheral guidewire is used. After balloon angioplasty,
S
if there is flow limiting dissection, then stent needs to

Carotid Interventions
be implanted. Balloon expandable stents to be used in
aorto-ostial locations and self-expandable nitinol stents Carotid angioplasty is indicated for severe cerebral
al
are preferred in extrathoracic portion of subclavian/ ischemia leading to recurrent syncope, transient ischemic
carotid arteries. After the procedure, dual antiplatelet to attacks (TIAs), and visual loss. Usually, multiple arch
ic
be continued for 6 months and then aspirin 75 mg lifelong. arteries are involved. The aim of intervention in such cases
Long-term immunosuppressive is also required in most is to improve cerebral perfusion and provide symptomatic
og
cases to control disease activity. relief.11,12 It is not advisable to target the diffusely diseased
or chronic total occlusion in arch vessels because of limited
success, higher restenosis, and complication rate. Contrary
ol
Subclavian Artery Interventions to subclavian angioplasty, where prolonged balloon

Subclavian arteries are amongst the most commonly inflation is advised, in carotids, the balloon inflation and
di
involved vessels in TA. Surgical revascularization involving deflation has to be quick to prevent worsening of cerebral
bypass of the steno-occlusive lesions is not the preferred ischemia. Serious complications, such as hyperperfusion,
ar
option due to high mortality (5–8%) and complication cerebral hemorrhage, and infarct, may also occur after
rates (up to 23%), comprising of chylothorax, end- arch artery interventions.
C
arterectomy thrombosis, pneumothorax, pleural effusion, Lesions of TA are usually nonthrombotic; hence, use
neck lymph fistula, phrenic nerve palsy, and Horner’s of embolic protection devices is usually not necessary. In
syndrome. In our experience of 126 cases with long-term patients with multiple arch vessel involvement and severe
follow-up, high inflation pressures were required for cerebral ischemia, the blood pressure is often high due to
dilation of these lesions (9.9 ± 4.6 atm).8 The procedure cerebral autoregulation. During angioplasty in such cases,
was successful in 88.8% cases of subclavian artery stenosis sudden hypotension and bradycardia may be seen after
and 50% cases with short segment chronic total occlusion relieving the stenosis, which is treated with intravenous
(Table 2). Restenosis occurred mostly in patients with Atropine and Mephentermine. The experience in carotid
diffuse long segment disease, chronic total occlusion, angioplasty is limited (Table 3, Figures 4 and 5).
or evidence of disease activity. Use of peripheral cutting
balloon angioplasty (Figures 2A to C) is recommended Renal Angioplasty
both for restenosis and native lesions as these lesions are The TA is a common cause of renovascular hypertension in
highly fibrotic.9 children and young adults in Asian countries. Renal lesions
589
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SECTION
9
Vascular System
a
di
A B C
Figures 2A to C: In-stent restenosis in left subclavian artery (A), treated by cutting balloon (CB) angioplasty
In
(peripheral cutting balloon 6 × 20 mm) (B and C)
(Figure 7). For dilatation, a monorail balloon catheter is
of
passed over the wire and positioned across the stenosis.
Balloon is inflated with a pressure gauge until the neck
on the balloon disappears or the patient complains of
ty
pain. Antiplatelets and heparin are given as for arch artery
interventions.
18 cie We reported17 our initial results of renal angioplasty in
54 patients with a success rate of 89.3% (Table 4). Restenosis
was observed in 13.5% cases. In pediatric age group,
20 o
restenosis is higher.24 The higher restenosis rate in children
S
was probably because of small diameter of renal vessels,

and active phase of disease. We observed that although
the disease activity increases the chances of restenosis,
al
not all vessels develop restenosis after angioplasty. In

Figure 3: Long segment chronic total occlusion of left subclavian some patients with severe stenosis, hypertension and
ic
and axillary artery with collateralization. Such lesion has very high congestive heart failure, waiting for disease activity to
restenosis rates and should be managed medically subside, may be risky; and in the intervening period, the
og
artery may become completely occluded so as to preclude

in TA are usually ostial and often bilateral. Revascularization any further procedure. Therefore, in case of severe
is indicated in uncontrolled hypertension, recurrent uncontrolled renovascular hypertension and severe renal
ol
heart failure, or acute decompensated heart failure. artery stenosis, the angioplasty procedure may have to be
Surgical revascularization involves use of aortorenal carried out despite evidence of disease activity while the
di
bypass grafts [saphenous vein or polytetrafluoroethylene patient is on aggressive immunosuppressive treatment.

(PTFE)], direct aortic re-implantation or linorenal shunt. In most angioplasty series of TA, long segment renal
ar
Surgical procedure is made difficult because of extensive artery stenosis, unable to relive the stenosis completely,
perivascular fibrosis and diffuse multifocal disease.
length are associated with higher restenosis rates, stent
C
Some patients with nonfunctioning kidney may require

implantation is used only for flow limiting dissection and
nephrectomy due to uncontrolled hypertension.17
not reduce restenosis. If high pressure balloon dilatation
is not able to completely relive this stenosis, stent
Renal Angioplasty Procedure implantation will not improve result further. Restenosis
The femoral approach is used as a standard, except in is treated by re-intervention preferably by cutting balloon
patients with caudal angulation or occlusion of infrarenal angioplasty with good results.
aorta (Figure 6). Guiding catheter technique is generally In our center, a total of 236 renal angioplasties were
preferred and requires a 6 or 7 F sheath with a hemostasis performed in the last two decades with a cumulative success
valve or guiding catheter with connections like for rate of 90% and restenosis was seen in approximately 25%
percutaneous transluminal coronary angioplasty (PTCA). of the cases (Table 5).
Selective catheterization of the renal artery is usually Stenting of renal artery in TA may have a higher
performed through the guiding catheter using a steerable incidence of restenosis than balloon angioplasty. This may
0.014 inch soft tip PTCA guide wire with a flexible tip be due to reactive fibrosis, intimal thickening, thrombus
590
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Table 3: Carotid interventions13-16 CHAPTER
71
Study/Author Balloon Results Complications Follow-up
angioplasty
Tyagi 2008 n = 10 Technical success 100% No major complication Mean F/u 25 months

lesions = 12 Symptomatic improvement in 80% Restenosis rate 20%
Kim 2011 n = 12 Technical success 91.6% No major complication Mean F/u 39 months
lesions = 21 >50% residual stenosis in 1 patient Restenosis rate
Angioplasty 27.2%
Chen 2015 n = 11 Technical success 82% Complete occlusion of carotid in Mean F/u 31.6 months
2 patients Restenosis 11.1%
Lou 2017 n = 12 Technical success 92% Transient hemiparesis in 1 Mean F/u 40 months
a
lesions = 14 Restenosis 33.3%
di
formation or stent-related exaggeration in intimal tissue of the normal aortic segment, but not to exceed three
In
proliferation. The diameter of renal artery is smaller than times the constricted segment. Graded dilation (i.e. initial
other aortic branches so intimal proliferation may lead to dilatation with a balloon of smaller diameter that was
higher restenosis rate. followed by dilatation with a balloon of larger diameter) is
of
used in patients with severe (<4 mm) stenosis. The balloon
is positioned across the area of stenosis and inflated with
Aortoplasty Procedure
diluted contrast medium. Balloon position was confirmed
ty
Balloon angioplasty offers a relatively simple, cost effective, with fluoroscopy by the appearance of ‘waist’ at the site of
and safe method for the relief of discrete stenotic lesions of constriction. The balloon is inflated sequentially to higher
aorta.
18 cie
Stenosis of aorta is crossed preferably with 0.035”,
flexible tip, exchange length guidewire and aortic
pressures until the waist on balloon disappears or until the
known maximum inflation pressure limit of the balloon
was reached or the patient complains of increasing pain.
angiography performed using a pigtail catheter. A flexible-
20 o
Balloon inflation pressure of 4 to 10 atm is used initially,
tip, 260 cm long exchange guide wire (0.035” in diameter) and this was increased to 11 to 20 atm when high-pressure
S
is passed through the angiography catheter and positioned balloons are required for dilating stenosis that are resistant
above the lesion. In each case, 100 U/kg of heparin to dilatation at lower pressures. Inflations are performed
al
(maximum = 2,500 U) is given intravenously. With the two to four times for 15 to 30 seconds each time. The
exchange guidewire kept in position, the angiography balloon catheter is then replaced by a pigtail catheter;
ic
catheter is replaced by a deflated, air free, balloon aortogram is performed in the same views. Pressure
dilatation catheter. The balloon size is selected as 60-100% gradient across the stenosis is recorded. If there is severe
og
ol
di
ar
C
A B C D E
Figures 4A to E: Selective digital subtraction angiography (DSA) of carotid arteries in a young female with severe cerebrovascular symptoms
shows severe long segment stenosis of left carotid artery (A); Balloon dilatation at high pressure was done followed by long, self-expandable
nitinol, stent implantation with good improvement in lumen (B); DSA at 2-year follow-up shows mild restenosis (C); Right carotid artery also
had severe long segment stenosis of common carotid artery (D); High pressure balloon angioplasty was also done followed by long, nitinol
self-expandable, stent implantation with good improvement in lumen (E).
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SECTION
9
Vascular System
Figures 5A and B: (A) (PRE): Severe stenosis of right common

carotid and vertebral artery ostium in a 22-year-old female with
Takayasu arteritis; (B) (POST): Marked relief of carotid and vertebral
artery stenosis after cutting balloon angioplasty and stenting with
A B improvement in neurological symptoms
a
di
flow-limiting dissection, then the stent is implanted and Pulmonary Artery Angioplasty
postimplant balloon dilatation is performed (Figures 8A
In
Symptomatic pulmonary artery stenosis is a relatively
and B). uncommon manifestation of aortoarteritis in our
country. Such patients usually present with exertional
Results
of
dyspnea and cyanosis. It is usually associated with
We reported our initial experience,27 first in the country, aortic involvement, isolated involvement being rare. The
with percutaneous balloon angioplasty (PTBA) of TA right upper lobe pulmonary artery is most commonly
ty
involving aorta in the Circulation in 1987. In our larger involved than the lobar, segmental and main right and
series,28,29 balloon dilatation was successful in 34 of 38 left pulmonary arteries. We first reported successful
18 cie
cases and resulted in the reduction of mean peak systolic
pressure gradient (PSG) from 75.2 + 29.1 mm Hg to 24.8
± 19 mm Hg (p<0.001). Hemodynamic and angiographic
pulmonary angioplasty in TA.31 Apart from this, there are
only very few case series of percutaneous transluminal
angioplasty (PTA) for pulmonary artery stenosis in TA.
follow-up study was done in 20 cases. In 7 patients, Stent placement helps to patch up the intimal dissection
20 o
gradient further decreased to less than 15 mm Hg; did not improving luminal diameter (Table 8, Figures 11A to C).
S
change in 12 patients, and increased in one case.

In our center, a total of 356 patients underwent PTBA Coronary Angioplasty and Stenting
The results of coronary artery bypass graft (CABG) in TA
al
for stenosis of aorta over the last two decades (Tables 6 and
7). Cardiac catheterization, aortography, and angiography are not satisfactory. It is difficult to construct proximal
anastomosis of the grafts because of extremely thickened
ic
were performed and pressures were recorded both above

and below the site of stenosis. Stenotic lesions with more aortic wall which may contribute to the late proximal
og
than 50% narrowing of the lumen were subjected to occlusion of bypass grafts. As subclavian artery is commonly
aortoplasty. The balloon size was 60-100% of the normal involved, its occlusion may reduce flow to internal mammary
aortic segment but did not exceed three times the stenotic artery which is common conduit in CABG. There are several
ol
segment. Graded dilatation was done, until the waist on case reports, including our own experience, describing
the balloon disappeared or maximum inflation pressure good immediate and long-term results of angioplasty with
di
limit of the balloon was reached or patients started or without stenting of coronary arteries.
complaining of severe backache indicating developing
Mesenteric Angioplasty and Stenting
ar
dissection. Aortic rupture has been reported during

balloon dilatation.30 Rapid implantation of stent graft is Patients with occlusion of multiple arteries of abdominal
lifesaving (Figures 9 and 10). aorta may present with abdominal angina. In our
C
A B C D
Figures 6A to D: Bilateral renal artery stenosis treated with cutting balloon angioplasty
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Table 4: Renal intervention17-23 CHAPTER
Study/Author Balloon angioplasty Results Complications Follow-up
Tyagi 1993 n = 54
lesions = 75
Technical success 89.3% No major complication
HTN improved in 74%
Mean F/u 14 months
Restenosis rate
71

z Angioplasty 13.5%
Sharma 1998 n = 66 Technical success 95% 2 Access site hematoma Mean F/u 22 months
lesions = 96 HTN improved in 89% 1 renal vein injury Restenosis rate
z Angioplasty 16%
Park 2013 n = 13 Technical success 95% No major complications Mean F/u 85 months
Stent-9 HTN improved in 87% Restenosis rate
z Angioplasty 8%
z Stenting 66%
a
Kinjo 2015 n = 11 Technical success 96.7% No major complications Mean F/u 5 years
stent-8 HTN improved in 91.3% Restenosis rate
di
z Angioplasty 9%
z Stenting 62.5%
In
Pang 2016 n = 93 HTN improved in 1 renal artery perforation Mean F/u 2 years
lesions = 125 angioplasty 63.4% 1 access site hematoma Restenosis rate
Stent-64 lesions Stenting 62.1% 1 residual stenosis >30% after stenting z Angioplasty 9.6%
z Stenting 23.8%
of
Abbreviation: HTN, hypertension
ty
experience, there is marked improvement in symptomatic and relapses remain common despite the use of adjunctive
status of a patient presenting with chronic mesenteric immunosuppressants along with corticosteroids. New
ischemia after angioplasty/stenting.34
Aortic Dissection
18 cie therapies, such as tocilizumab, may hold the key to solving
the problem of controlling disease activity in TA; recent
experience suggests that monthly tocilizumab infusions
can halt the restenosis process, at least in the short-term,
20 o
Aortic dissection is regarded to be a markedly rare
in TA patients with recurrent restenosis after endovascular
complication of TA, which may cause cardiac tamponade,
S
intervention.
insufficiency of aortic valves, and malperfusion due to
The second area of progress is in dealing with restenosis
involvement of aortic side branches. 35 Also, vascular
after vascular intervention in TA. Balloon angioplasty
al
inflammation may increase the risk of rupture of the

usually suffices to treat restenotic lesions, and this is
dissection considerably. Aortic dissection as the initial
usually simpler to perform than the original intervention.
ic
presentation is still rarer.36 Endovascular management of

Such procedures have high early success rates and low-
acute aortic dissection in Takayasu arteritis has recently
related risk. At our center, we repeat balloon angioplasty,
og
been reported by us;37 and in select cases, it is safe and

especially cutting balloon angioplasty, in recurrently
effective strategy (Figures 12A to C).
restenosing lesions till sustained success is obtained; most
ol
restenotic lesions require only one or two procedures

RECENT ADVANCES before sustained success is obtained, but a few may need
di
There are three areas where significant progress is more. This usually happens in patients with persisting
occurring. disease activity despite conventional medical therapy, or
in noncompliant patients. Endovascular intervention in
ar
Firstly, persisting disease activity in TA can compromise

intervention outcomes, and also lead to progression of TA should thus be viewed as a potentially multisession
disease, both of which may necessitate re-intervention. treatment and patients should be counseled accordingly
C
Conventional medical treatment for TA is far from effective at the beginning. The key ingredients to a successful
Table 5: Pediatric renal intervention24-26

Study/Author Angioplasty Results Follow-up
Tyagi 1997 n = 31 Technical success 88.6% Mean F/u 14 months
Restenosis rate
z Angioplasty 25.8%
Bayrak 2008 n = 12 Technical success 87.5% Mean F/u 56 months

Restenosis rate
z Angioplasty 42%
Zhu 2014 n = 16 Technical success 94% Mean F/u 7 years

Restenosis rate
z Angioplasty 43.75%
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SECTION
9
Vascular System
A B C D
Figures 7A to D: Left renal angioplasty. Left renal artery chronic total occlusion (A), crossed with 014” Whisper percutaneous transluminal
coronary angioplasty (PTCA) wire and plain old balloon angioplasty (POBA) done (B), leading to dissection (C), which was later stented with
4.0 mm drug-eluting stent (DES) (D)
a
di
In
of
ty
18 cie Figures 8A and B: Digital subtraction angiography (DSA) of thoracic
aorta shows short segment severe stenosis in an 18-year-old female
20 o
patient before balloon angioplasty of thoracic aorta (A), good
A B
S
improvement in aortic lumen after angioplasty (B)

al
ic
og
ol
di
ar
C
A B C D
Figures 9A to D: Thoracoabdominal aortoplasty in Takayasu arteritis. Digital subtraction angiography (DSA) showing long segment stenosis
of thoracic aorta (A) with gradient of 60 mm Hg, balloon angioplasty was done with 10 × 80 mm balloon (B), leading to long segment aortic
dissection (C), which was stented with self-expandable 18 × 90 mm stent followed by postdilatation (D), with final gradient of 16 mm Hg
594
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Table 6: Site of stenotic lesions in the aorta in 356 cases done at CHAPTER
GB Pant Hospital, New Delhi, India
Site Number 71
Descending thoracic 126

Abdominal aorta
z Suprarenal 26
z Infrarenal 78
z Supra- and infrarenal 38
Thoracic and abdominal 88
A B
a
a procedure and proper planning of procedure are
Figures 10A and B: (A) Digital subtraction angiography (DSA) essential for the success of vascular intervention in TA.
di
showing thoracic and abdominal aorta (renal & infrarenal segment)
stenosis in a 9-year-old girl with hypertension and severe heart The third area of progress is in prevention of restenosis.
failure; (B) DSA after angioplasty shows marked improvement in Systemic therapies with immunosuppressive and
In
lumen of aorta after thoracic and abdominal aorta angioplasty. antiproliferative agents (e.g. sirolimus and everolimus) are
The patient had improvement in hypertension and heart failure on
currently in use in cardiac transplant protocols. Sirolimus
follow-up
and everolimus-eluting stents have demonstrated higher
of
efficacy in atherosclerotic coronary artery disease than
final outcome are control of disease activity and use conventional bare metal stents. Considering the same
of appropriate endovascular technique. In patients
ty
hypothesis, both drug-eluting balloons and stents are
with TA, involved arteries have transmural fibrosis which being evaluated in TA patients. At our center, we are using
is difficult to dilate completely despite high balloon
18 cie
inflation pressure. Even moderate improvement in
luminal diameter may improve perfusion to ischemic
both drug-eluting stents and balloons in select cases.
organ and give good symptomatic relief in a large number SUMMARY

20 o
of patients. Disease activity should be assessed with the
S
The recent results of endovascular procedures are combination of clinical manifestations, ESR, CRP, and
encouraging, and we await new technological advances. vascular imaging techniques. Better surrogate markers
Correlation of imaging with symptoms, adherence to are needed.
al
the indications for revascularization in TA, and ensuring Glucocorticoids and other immunosuppressives are
disease activity is controlled prior to and following the key therapy in acute inflammatory phase of TA.
ic
og
Table 7: Hemodynamic and angiographic results of abdominal aortic angioplasty

in 142 patients done at GB Pant Hospital, New Delhi, India
ol
Before PTBA After PTBA

Mean + SD Range Mean + SD Range P value
di
PSG (mm Hg) 79.4 ± 28.2 34–137 16.6 ± 7.3 0–31 <0.001
ar
Aortic diameter at stenosis (mm) 3.9 ± 2.2 0–9.7 10.2 ± 3.6 5.3–19.8 <0.001
Abbreviations: PTBA, percutaneous balloon angioplasty; PSG, peak systolic gradient
C
Table 8: Pulmonary artery interventions31-33

Study/Author Balloon angioplasty Follow-up
Tyagi 2004 n=1 Asymptomatic at 14 year,
Technical and clinical success Follow-up restudy shows well-covered stent struts.
No significant restenosis
Qin 2009 n=1 Max F/u 4 years
Technical and clinical success Angioplasty alone developed restenosis at 18 months.
No restenosis in patients with stenting
Dong 2014 Technical success 92.8% in stenosis & 60% in total occlusion Mean F/u 29 months for 11 patients
No restenosis
595
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SECTION
9
Vascular System
a
A B C
di
Figures 11A to C: Arch aortogram in a young lady showed total occlusion of the left subclavian, left common carotid, and right subclavian
artery at their origin (A); Pulmonary angiogram showed severe (90%) stenosis at the origin of the right pulmonary artery (B); Plain old balloon
angioplasty (POBA) of pulmonary artery stenosis done with 10 × 20 mm balloon, and a 28 mm long Jo stent (Jomed) mounted on a 10 mm
In
diameter balloon was deployed across the stenosis (C)
of
ty
18 cie
20 o S
al
A B C
ic
Figures 12A to C: Computed tomography angiography CTA) and 3-D reconstructed image of the aortic dissection (A and B) and 3-D
reconstructed image (C) showing the completely sealed-off aortic dissection and well-expanded stent graft
og
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Aortic Diseases: When to
CHAPTER 72 Proceed with Surgery?
a
di
INTRODUCTION contains the aortic annulus, the aortic cusps, sinuses
of Valsalva, and the sinotubular junction. Ascending
The aorta commences from the upper part of the left
In
aorta extends from sinotubular junction to the base of
ventricular outflow tract. After ascending for a short
innominate artery. The aortic arch extends from the origin
distance in pericardial cavity, it arches backward and to
of innominate artery to the isthmus. From isthmus to the
of
the left, and then descends down in the thorax and passes diaphragm is the descending thoracic aorta. Aortic root
to the abdomen through aortic hiatus in the diaphragm. and ascending aorta constitute intrapericardial aorta.
It ends opposite the lower border of the fourth lumbar The wall of the aorta is composed of three layers: intima,
ty
vertebra, by dividing into the right and left common iliac media, and adventitia. The intima is a thin layer of ground
arteries (Figure 1). For the purpose of description, aorta substance lined by endothelium. The media is the thickest
18 cie
is divided into root, ascending aorta, arch, descending
thoracic aorta, and abdominal aorta. The aortic root
connects the left ventricle and the ascending aorta. It
of the three layers, and it is made of elastic fibers and
smooth muscle cells. The adventitia is the outermost thin
fibrous layer and contains the vasa vasora.
20 o S
al
ic
og
ol
di
ar
C
Figure 1: Aorta and its branches
KG-72.indd 598 03-11-2018 12:39:18

AORTIC ANEURYSMS CHAPTER
72
Aneurysmal disease is the most common manifestation
of the diseases involving aorta. Aneurysmal disease can
affect any segment of the aorta, but most commonly

affect intrapericardial and abdominal aorta. According to
the location, aortic aneurysms may be thoracic (25.9%),
abdominal (62.7%), thoracoabdominal (8.3%), and
unspecified (3.0%).1 The etiology, natural history, and
treatment of aortic aneurysms differ for various segments.
a
Natural History and Clinical Manifestations
di
The natural history of the aortic aneurysm is that of
continuous expansion and ultimately may present with
In
rupture, dissection, geometric distortion and compression
Figure 2: The timing for intervention is a balance between the risks
of neighboring viscera, and thrombus formation. Incidence
imposed by surgical intervention and that of natural history of the
of rupture and dissection are directly related to the size of aneurysm
of
aneurysm. Once the aneurysm diameter reaches 6 cm,
the risk of rupture and dissection increases steeply. The history, rapid aneurysmal growth, and the presence of
annual risk of rupture or dissection is approximately 2% concomitant dissection in the aneurysm increase the
ty
for thoracic aortic aneurysms between 4.0 and 4.9 cm, risk of complications. Pseudoaneurysm can rupture at a
while reaching nearly 7% for aneurysm >6.0 cm.2 The risk much smaller diameter. On the other hand, associated
18 cie
of expansion/rupture/dissection increases in the presence
of connective tissue disorder, smoking, hypertension,
pregnancy, and positive family history. Pseudoaneurysm
comorbidities, advanced age, more radical procedure,
and surgical inexperience increase the risk of surgical
intervention.
20 o
can rupture at a much smaller diameter.
In present times, most patients with aortic aneurysms Aneurysms of Ascending Aorta and Aortic Root
S
are asymptomatic at the time of diagnosis, and the

Ascending aortic or root aneurysm that manifest in the
aneurysms are typically discovered incidentally on
form of chest pain, aortic regurgitation, tracheobronchial /
al
imaging studies (chest X-ray, CT scan, echocardiogram,

superior vena caval/pulmonary arterial compression need
and ultrasound abdomen) performed for other indications.
surgical intervention irrespective of size. In nonmanifest/
ic
Aneurysms of the root or ascending aorta may distort the

asymptomatic aneurysms, the timing is decided primarily
geometry of the aortic root and can produce secondary
og
by the maximum transverse diameter of the aneurysm

aortic regurgitation, and the patient can present with
(Table 1). The threshold for intervention depends upon
features of aortic regurgitation. When aortic aneurysms
the presence of a connective tissue disorder (bicuspid
are large, patients may suffer a local mass effect and
ol
aortic valve, Marfan’s syndrome), risk factors for dissection

the patient can present, depending upon the site of
(positive family history), condition of the aortic valve
involvement, with features of compression of trachea,
di
(diseased or normal), rate of growth of aorta, size of the

bronchus, pulmonary artery, esophagus, recurrent
patient, and experience of the surgical team.
laryngeal nerve, ureter, or vertebral bodies. Most dreaded
ar
In case of ascending aortic or root aneurysms without

complication of aortic aneurysm is aortic dissection or
aortopathy, the cut-off for intervention is aneurysmal
rupture, which carries very high mortality. Atheromatous
diameter ≥5.5 cm. However, if there is high risk of rupture
C
aneurysms can present with limb ischemia due to

or dissection (connective tissue disorder, family history
atheroembolization or thromboembolization.
of dissection, or rapid enlargement), threshold for
intervention is lowered. Similarly, if the patient needs open
Timing for Intervention in Thoracic heart procedure for valvular lesions, aortic intervention is
Aortic Aneurysms1,2-6 performed at lower diameter. In contrast, among patients
Any aneur ysm, which pres ents w ith symptoms with an increased operative risk (e.g. the elderly or those
and manifestations, needs intervention. In case of with comorbidities), the threshold is raised to 6 cm or
asymptomatic aneurysms, the timing for intervention more for surgery.
is a balance between the risks imposed by surgical Surgery is the mainstay of management inascen-
intervention and that of natural history of the aneurysm ding aortic and root aneurysms. In rare cases of
(Figure 2). The presence of connective tissue disorder, pseudoaneurysms involving midsegment of ascending
smoking, hypertension, pregnancy, positive family aorta, an endovascular option has been reported.
599
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SECTION Table 1: Size criteria for intervention in nonmanifest/asymptomatic ascending aorta/root aneurysm
9
Cut-off diameter for intervention
Condition Normally functioning Aortic valve needs
aortic valve intervention*
Vascular System
Tricuspid aortic valve, no aortopathy 5.5 cm 4.5 cm

Bicuspid aortic valve without risk factors 5.5 cm 4.5 cm
Bicuspid aortic valve with risk factors** 5.0 cm 4.5 cm
Marfan’s syndrome and other connective tissue disorder without risk factor 5.0 cm 4.5 cm
Marfan’s syndrome and other connective tissue disorder with risk factor*** 4.5 cm 4.5 cm
* There is stand-alone indication for aortic valve intervention.
a
** An additional risk factor for dissection is present (e.g. family history of dissection, coarctation of aorta, or aortic growth rate ≥5 mm per year)
or if the patient is low surgical risk and the surgery is performed by an experienced aortic surgical team in a center with established expertise.
di
*** An additional risk factor for dissection is present (e.g. family history of dissection, or aortic growth rate ≥3 mm per year) or desire for
pregnancy.
In
Arch Aneurysms is recommended at an aortic diameter of 5.5 cm or
greater. However, for patients with thoracoabdominal
of
Symptoms associated with aortic arch aneurysms, such as
aneurysms, in whom endovascular stent graft options are
hoarseness resulting from stretching of the left recurrent
limited and surgical morbidity is high, elective surgery is
laryngeal nerve, dysphagia, dyspnea, and chest or back
recommended if the aortic diameter exceeds 6.0 cm.
ty
pain, are indications for intervention in patients with
arch aneurysms unless life expectancy is quite limited. In
Timing of Intervention in Abdominal
18 cie
asymptomatic patients with a dissecting, degenerative or
atherosclerotic aneurysm of the aortic arch, intervention
is reasonable when the diameter of the arch exceeds
Aortic Aneurysm
Abdominal aortic aneurysms are much more common
5.5 cm. Traditionally, open repair has been the procedure
20 o
than thoracic aortic aneurysms. The prevalence of
of choice for arch aneurysms. However, with increasing abdominal aortic aneurysms is approximately 5% among
S
expertise, debranching of arch vessels followed by men ≥65 years of age screened by ultrasound.7 Most of
endovascular repair is emerging as the popular option. abdominal aortic aneurysms have an indolent course and
al
In young, low-risk patients, especially with aortopathies, remain asymptomatic for long time. Later, the aneurysm
surgery still remains the preferred option at established may present with pain and/or pulsatile abdominal
ic
centers of expertise. swelling. It may also present with thromboembolism

or atheroembolism. The terminal event in the natural
og
Descending Thoracic and Thoracoabdominal history of an abdominal aortic aneurysm is rupture and
its associated mortality. The risk of rupture increases with
Aortic Aneurysm
aneurysm size. The UK Small Aneurysm Trial found that for
ol
In current times, endovascular stent-graft is the procedure aneurysms <4 cm, 4 to 4.9 cm, and 5 to 5.9 cm, the annual
of choice for isolated descending thoracic aortic aneu- risk of rupture was 0.3%, 1.5%, and 6.5%, respectively.8
di
rysms. It has the advantage of being far less invasive than For aneurysms 6 cm or greater, the risk of rupture rises
surgery, with potentially fewer postoperative complications sharply, although an exact risk cannot be estimated.
ar
and lower morbidity. However, if morphology is not Although abdominal aneurysms are less prevalent among
suitable, or if access is a problem, surgical replacement women than men, when present, they rupture 3 times
is performed with a Dacron graft. In the presence of more frequently and at a smaller aortic diameter (mean
C
connective tissue disorder, surgery is preferred by many. of 5 versus 6 cm). Rupture is also more common among
In case of thoracoabdominal aneurysms, endovascular current smokers and those with hypertension.9 A rapid
options are limited. De-branching of visceral arteries, rate of expansion predicts aneurysm rupture.
followed by stent graft placement is one of the options. Symptomatic or complicated aneurysm needs
Replacement of thoracoabdominal aorta with a custom inter vention. The management of asymptomatic
made branch graft is yet to become established. Surgery abdominal aortic aneurysm depends on aneurysm
remains the mainstay of management of thoracoabdominal diameter. The indication to repair abdominal aortic
aneurysms. aneurysm needs to balance the risk of aneurysm
Irrespective of size, symptomatic/complicated surveillance and the associated risk of rupture against
aneurysms require intervention. For most uncomplicated the surgical risk at a certain threshold diameter. Today,
descending thoracic aortic aneurysms without any periodic ultrasound surveillance of the aneurysm—until
predisposition for rupture/dissection, intervention it reaches 55 mm or becomes symptomatic or fast growing
600
KG-72.indd 600 03-11-2018 12:39:18

(>10 mm/year)—is regarded as a safe strategy for patients of dissection can proceed antegradely or retrogradely. CHAPTER
with small abdominal aortic aneurysms.4 There is evidence In the presence of dissection, the aorta is weakened and
that in women, abdominal aortic aneurysm rupture at a
smaller aortic diameter than men.10 Even though evidence
can rupture causing cardiac temponade or hemothorax.
Dissection process can compromise the aortic true lumen
72

for threshold diameter in women is scarce, intervention at and can also involve side branches. This may cause various
a smaller diameter (>50 mm) may be justified.4,11 malperfusion syndromes including coronary ischemia,
In recent past, endovascular repair has emerged as cerebral ischemia, spinal cord ischemia, mesenteric
the first choice for management of abdominal aortic and renal ischemia, and limb ischemia. If the dissection
aneurysm. Though the early mortality and morbidity process involves aortic root, aortic valve geometry and
is much less with endovascular repair, secondary support is altered leading to aortic valve insufficiency. If a
interventions in long term are more frequent. Life-long patient survives, acute episode, the false lumen may either
a
imaging surveillance is currently required to monitor for get thrombosed or may dilate aneurysmally.
di
late complications, including endoleaks, migration, and
rupture. Late complications, including secondary sac Classification
In
ruptures, are closely linked to aortic sac enlargement over
Dissection can be classified on the basis of chronological
time.4,12
evolution and anatomically. Chronologically, dissection
Surgical repair continues to be used for patients who
is classified on the basis of time from the onset of initial
of
do not meet the anatomic requirements for endovascular
symptoms to the time of presentation. Acute dissection
repair, including short or angulated landing zones,
is defined as occurring within 14 days of onset of pain;
excessive thrombus, multiple large accessory renal
subacute, between 14 and 90 days from the onset of pain;
ty
arteries, and small and tortuous access vessels with
and chronic, more than 90 days from the onset of pain.4
concomitant occlusive disease. 7 Open surgery may
Anatomically, aortic dissection can be classified
18 cie
also be required for treatment of a persistent endoleak
and aneurysm sac growth after endovascular repair or
for treatment of a mycotic aneurysm or infected graft.7
according to either the origin of the intimal tear or
whether the dissection involves the intrapericardial aorta
(regardless of the site of origin). The two most commonly
20 o
Surgery may also be the preferred option in young patients
used classification schemes are the DeBakey,15 and the
with low operative risk. If there is need to occlude bilateral
S
Stanford systems (Figure 3). 16 The DeBakey system

internal iliac arteries during endovascular repair, or if there
categorizes dissections based on the origin of the intimal
is indication for inferior mesenteric artery implantation,
tear and the extent of the dissection.15
al
surgery is the preferred option.

Type I: Dissection originates in the ascending aorta
and propagates distally to include at least the aortic

ic
ACUTE AORTIC SYNDROMES arch and typically the descending aorta.

Acute aortic syndrome is a term used to describe a Type II: Dissection originates in and is confined to the
og
constellation of life-threatening aortic diseases that ascending aorta.

have similar presentation, but appear to have distinct Type III: Dissection originates in the descending aorta
demographic, clinical, pathological, and survival and propagates most often distally.
ol
characteristics.13 It includes aortic dissection, intramural — Type IIIa: Limited to the descending thoracic
hematoma (IMH), and penetrating aortic ulcer (PAU). aorta.

di
These make up a spectrum of aortic diseases in which one — Type IIIb: Extending below the diaphragm.
entity may evolve into or coexist with another.14 The more commonly used Stanford system groups
ar
The common feature to all these is disruption of the dissections into two categories on the basis of involvement
media layer of the aorta. It may be accompanied with of ascending aorta (intrapericardial aorta):
C
intimal tear. In aortic dissection, there is tearing in the Type A: Dissection involves the ascending aorta
aortic intima and blood enters into the media and causes regardless of the site of origin.
separation of layers. The IMH is defined as a hematoma Type B: Dissection does not involve the ascending
within the medial layer of the aortic wall without the aorta.
presence of intimal injury. The PAU is an ulcer-like lesion
in the intima that erodes through the media of the aortic Natural History
wall and can form localized hematoma within the media.
Untreated acute aortic dissection is a highly lethal
event. The most common causes of death are aortic
Aortic Dissection rupture, stroke, visceral ischemia, cardiac tamponade,
Blood enters through the intimal tear and separates the and circulatory failure.17-19 Lindsay and Hurst20 reported
intima from the media or adventitia. This creates an that one-third of patients sustaining an acute Type
additional false lumen within the layers of aorta. Process A aortic dissection died within 24 hours, 50% within
601
KG-72.indd 601 03-11-2018 12:39:19

SECTION
9
Vascular System
a
di
In
of
Figure 3: Classification of aortic dissection
ty
48 hours, 80% within 7 days, and 95% within the first and patients with advanced features of mesenteric
18 cie
month. In the absence of immediate surgical repair,
medical management of proximal dissection is associated
with a mortality of approximately 20% by 24 hours
ischemia, gangrene, and sepsis.4,28,29 Even if the patient
has got advanced renal failure, or hemiplegia, myocardial
ischemia or limb ischemia, dissection repair should take
after presentation, 30% by 48 hours, 40% by day 7, and the priority. The chances are that the malperfusion will
20 o
50% by 1 month. Patients with uncomplicated Type B resolve with proximal dissection repair in majority.29
S
dissection have a 30-day mortality of 10%.21 However, Postdissection repair, the patient should be re-assessed
patients who develop ischemic complications such as again for persisting malperfusion. If malperfusion persists,
al
renal failure, visceral ischemia, or contained rupture corrective measures are required. The only exception to
have higher mortality. Advanced age, rupture, shock, and this rule is advanced mesenteric ischemia with gangrene
ic
malperfusion are important independent predictors of and sepsis requiring extensive bowel resection.30 Stroke
early mortality.22-25 is also not a contraindication for surgery. The risk of
og
Only about 10% of acute dissections heal hemorrhagic conversion is very small. Sometimes, if
spontaneously, and become chronic dissections. In all the patient undergoes early surgery, there is complete
such cases, distal re-entry sites are present, allowing resolution of neurological deficit.29,31 In patients with coma
ol
decompression of the false lumen.26,27 After acute aortic who present early (<5 hours), surgery yielded favorable
dissection, the false lumen usually remains patent but very results. 4,32,33 However, if a comatose patient presents
di
rarely may thrombose. The patent false lumen is prone to late, surgery is debatable. If pericardial tamponade is
progressive expansion over time, and eventually results in diagnosed, pericardiocentesis as an initial therapeutic
ar
aneurysm formation. step before surgery may be harmful because it reduces

intrapericardial pressure, and, therefore, may convert
C
Treatment of Acute Dissection a sealed leak into a frank rupture leading to sudden
death.4,28,34-36 Fever in the first 48 hours after presentation
Acute Type A dissection is a surgical emergency. In contrast,
is a marker of systemic inflammation in response to
acute Type B dissection is subjected to medical treatment
exposure of aortic media to blood. Hence, it should not
unless complicated by organ or limb malperfusion,
be considered a marker of sepsis and contraindication to
progressive dissection, aortic rupture, intractable pain, or
surgery.
uncontrolled hypertension.28
The mortality is maximum in the first 48 hours after
Surgery for acute type A dissection: The presence of acute initial pain. Hence, if a patient presents within 48 hours
Type A dissection in itself is an indication for surgery and of initial symptoms, emergency surgery should be
all patients with acute Type A dissection should undergo performed. Similarly, the presence of cardiac tamponade,
surgery.1,29 The only exception to this rule are extremely aortic rupture, pulmonary edema, organ malperfusion,
old and moribund patients with significant comorbidities, and hemodynamic instability demand emergency
late presenting (> 5 hours) deeply comatose patients, surgery. If none of these is present, and the patient is
602
KG-72.indd 602 03-11-2018 12:39:20

Table 2: List of complications in Type B dissection hypertension and may require intervention in the form CHAPTER
of surgery or endovascular repair. Currently, because
72
S. no. Complication
of its low early mortality and morbidities, endovascular
1. Rupture/Impending rupture/Leak
repair is the preferred option. In the era of endovascular
2. Rapid aortic expansion

intervention, surgery is the preferred option in limited
3. Hemodynamic instability
circumstances (Table 3).
4. Malperfusion
5. Retrograde ascending aortic dissection
Intramural Hematoma
6. Unremitting pain
Intramural hematoma (IMH) is defined as a hematoma
7. Persistent, uncontrolled hypertension
within the medial layer of the aortic wall without detectable
8. Aneurysmal dilatation (>5.5 cm)
a
intimal injury. Acute IMH accounts for 5–20% of all acute
aortic syndromes, 40 and is considered a precursor of
di
presenting after 48 hours, the patient can be operated on dissection.
urgent basis before next sunset. The current belief is that a majority of radiographically-
In
Management of acute type B dissection: Optimum medical appearing IMH are, in fact, acute dissection with
therapy (OMT), control of blood pressure and pain, undetected intimal tears and thrombosis of the false
lumen.14,41-43 The IMH may progress, dissect, regress, or
of
constitutes a gold standard in management of Type B
dissection.4 Irrespective of clinical stage (acute, subacute, resorb,44-49 with regression in 10%, progression to classic
chronic), OMT is the first line of treatment. Intervention, aortic dissection in 28–47%, and a risk of rupture in 20–
ty
surgery or endovascular, is reserved for complicated or 45%.40 Similar to dissection, depending upon involvement
high-risk Type B dissections (Table 2). Nowadays, surgery of intrapericardial aorta, IMH is also classified into Type
18 cie
is rare in cases of complicated acute Type B dissection,
and has been replaced largely by endovascular therapy.37,38
Lower extremities artery disease, severe tortuosity of the
A and Type B. Several series have shown that 30–40%
Type A IMH evolved into frank dissection and mortality
of Type A IMH was similar to Type A aortic dissection. 4
iliac arteries, a sharp angulation of the aortic arch, and Predictors of IMH complications in acute phase include
20 o
the absence of a proximal landing zone for the stent graft persistent and recurrent pain despite aggressive medical
S
are factors that indicate open surgery for the treatment treatment, difficult blood pressure control, ascending
of acute complicated Type B dissection.4 In the presence aortic involvement, maximum aortic diameter ≥50 mm,
al
of connective tissue disorder, surgery is preferred over progressive maximum aortic wall thickness (>11 mm),
endovascular repair by majority. enlarging aortic diameter, recurrent pleural effusion,
ic
penetrating ulcer or ulcer-like projection secondary to

Subacute and Chronic Dissection localized dissections in the involved segment, and the
og
presence of organ ischemia (brain, myocardium, bowels,

Subacute and chronic type A dissection: The presence of
dissection in intrapericardial aorta, irrespective of clinical kidneys).4,40,43,44
stage (subacute, chronic) is an indication for surgical Similar to Type A and B aortic dissection, surgery
ol
intervention. However, in the absence of complications is advocated for acute IMH of the ascending aorta and
(aneurysmal dilatation, aortic regurgitation, malperfusion, aggressive medical therapy for IMH in the descending
di
and pericardial tamponade), surgery can be planned aorta.4,44,45-48 In the elderly patients or those with significant
electively. In the elderly patients (>80 years) with comorbidities, ‘wait-and-watch strategy’ (optimal medical
ar
comorbidities, the risk of surgery should be balanced therapy and repetitive imaging) may be considered,
against the risk of complications. particularly in the absence of aortic dilation (<50 mm) and
C
IMH thickness <11 mm.4

Subacute and chronic type B dissection: The indications
and choice for intervention in subacute Type B dissection
is similar to that of acute Type B dissection. There is Table 3: Indications for open surgical repair in chronic Type B
growing evidence for beneficial effect of endovascular dissection
repair in uncomplicated subacute Type B dissection. 39 S. no. Indication
However, open surgical repair is not considered for 1. Young patient with connective tissue disorder
prophylactic intervention. 2. Retrograde Type A dissection
Optimal medical therapy is the first line of management 3. Dilated abdominal false lumen with branch vessel
for uncomplicated chronic Type B dissection. A involvement
complicated chronic Type B dissection may present 4. Tortuous aorta (pseudo-coarctation)
with aneurysmal dilatation (>55 mm in diameter), rapid 5. Coarctation with Type B dissection
expansion (>10 mm/year), malperfusion, or resistant 6. Post-endovascular repair complications
603
KG-72.indd 603 03-11-2018 12:39:20

SECTION Penetrating Aortic Ulcer Table 4: Indications for delayed surgical intervention in traumatic
aortic injuries
9
Penetrating aortic ulcer (PAU) is defined as ulceration
of an aortic atherosclerotic plaque penetrating through S. no. Indication
the internal elastic lamina into the media. 4 It can lead 1. Late presenters
Vascular System
to hematoma formation in media and present as acute 2. Prohibitive risk of heparinization

pain syndrome with aortic dissection or perforation.4,40,49 3. Severe hemodynamic instability from concomitant
Usually the patient is elderly, hypertensive, and may injuries (liver, pelvis)
have risk factors that are associated with atherosclerosis 4. Comatose patient
including hyperlipidemia, coronary artery disease, 5. Coagulopathy
and tobacco abuse. In 85-95% cases, it is located in the 6. Sepsis
a
descending thoracic aorta and is much less common in 7. Grossly contaminated wounds
the ascending aorta and arch. 40,50-53 The characteristic
di
finding includes localized ulceration, penetrating through hematoma, TAI is also designated as ‘minimal aortic
the aortic intima into the aortic wall for varying degrees.
In
injury’.
There may be associated hematoma formation within the Grade 1 or minimal traumatic aortic injury (TAI) is
media, pseudoaneurysm or rupture as PAU penetrates managed conservatively. Grade 2 and 3 need urgent
of
through the adventitia. intervention after taking care of other concomitant
Symptomatic ulcers with signs of deep erosion are injuries. Grade 4 TAI demand urgent intervention. If the
more prone to develop dissection or rupture. The aim of expertise and adequate sized stent graft are available,
ty
treatment is to prevent aortic rupture and progression endovascular repair is the first option. When endovascular
to acute dissection. The indications for intervention option is not available, urgent open surgical repair should
18 cie
include recurrent and refractory pain, signs of contained
rupture, rapidly growing aortic ulcer, associated periaortic
hematoma, or pleural effusion.4,40,50 Asymptomatic PAUs
be considered. A delayed surgical intervention, in the
same admission, is also a suitable option in selected
patients (Table 4).
20 o
with diameter >20 mm or neck >10 mm represent a higher
risk for disease progression and may be candidates for ARTERITIS
S
early intervention.4,40 Treatment is based on anatomical

Lesions in arteritis are stenotic in the majority. Less
features, clinical presentation, and comorbidities. In
commonly, the arteries become aneurysmal. Treatment
al
descending thoracic aorta, endovascular stent grafting

is mainly based on the clinical symptomatology,
is emerging as preferred therapeutic modality. 40,50,54,55
complications, and the possible immunologic basis of the
ic
Graft replacement of the ascending aorta is the standard disease. The goals of therapy include: (i) control of clinical
treatment of a PAU of the ascending aorta. Transverse activity by pharmacologic treatment with steroids and/
og
arch PAUs can be managed by open graft replacement or or immunosuppressive therapy, (ii) restoration of blood
endovascular techniques. flow to the stenosed vessel by surgical or endovascular
techniques, (iii) management of aneurysmal disease, (iv)
ol
TRAUMATIC AORTIC INJURY correction of aortic regurgitation, if any, (v) pharmacologic

Blunt aortic injury occurs in less than 1% of motor vehicle control of blood pressure, and (v) supportive management.
di
crashes but is responsible for 16% of the deaths. This In the chronic stages of arteritis, one of the principles
injury is second only to head injury as the leading cause of treatment is revascularization of the affected organs
ar
of death after road traffic accident. About 80% of patients either by surgery or endovascular interventions, including
die before their arrival at a hospital. Of those who survive percutaneous transluminal angioplasty (PTA), stent and
C
stent graft replacement. The success rate and outcome of

the initial injury, a majority will die without definitive
endovascular interventions depend upon the site, length,
treatment. Blunt aortic injury most often occurs after
and stage of the arterial stenosis. Though satisfactory
sudden deceleration, usually in automobile crashes. The
results are obtained in lesions involving thoracic aorta,
descending aorta is fixed to the chest wall, whereas the
infra-renal aorta, and renal artery, the outcomes of
heart and great vessels are relatively mobile. Traditional endovascular interventions in the supra-aortic branches
views have held that sudden deceleration causes a tear at are less rewarding. Due to the presence of diffuse lesions
the junction between the fixed and mobile portions of the and increased wall thickening, the stenosis in the carotid
aorta, usually near the isthmus. and subclavian arteries responds less well to balloon
Based on imaging, TAIs were classified into grade 1–4 angioplasty. In aortic involvement, patients with short
in severity. These included: grade 1, intimal tear; grade 2, segment (<4 cm long) stenosis show better overall results
intramural hematoma; grade 3, aortic pseudoaneurysm; than those with long segment (>4 cm long) stenosis.
and grade 4, free rupture. When intimal flap is less than Eccentricity of the stenosis, presence of diffuse adjacent
604 10 mm in length without any accompanying periaortic disease, location of the stenosis in juxtadiaphragmatic
KG-72.indd 604 03-11-2018 12:39:21

segment of the aorta, and presence of calcification prospective measurement program. J Vasc Surg. 1996; CHAPTER
adversely affect the outcome of PTA. 23(2): 213-20.
All lesions are not amenable to PTA . Surgical
procedures are required for total aortic occlusion, severe
10. Lederle FA, Wilson SE, Johnson GR, et al. Immediate repair
compared with surveillance of small abdominal aortic
72

aortic incompetence, critical central nervous system aneurysms. N Engl J Med. 2002;346(19):1437-44.
ischemia, coronary ischemia, aneurysmal dilatation, 11. Brewster DC, Cronenwett JL, Hallett JW Jr, et al. Joint
ostial lesions, tight stenosis, extensive renal segmental Council of the American Association for Vascular Surgery
artery involvement, and, occasionally, in case of failure of and Society for Vascular Surgery. Guidelines for the
treatment of abdominal aortic aneurysms: report of
angioplasty.
a subcommittee of the Joint Council of the American
Association for Vascular Surgery and Society for Vascular
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20 o
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of Acute Aortic Dissection (IRAD), Circulation. 2006;114:
S
3. Nishimura RA, Otto CM, Bonow RO, et al. 2014 AHA/ACC

guideline for the management of patients with valvular I357-64.
heart disease. J Am Coll Cardiol. 2014;63(22):2438-88. 18. Mehta RH, Suzuki T, Hagan PG, et al. Predicting death in
al
4. Erbel R, Aboyans V, Boileau C, et al. 2014 ESC Guidelines on patients with acute type A aortic dissection. Circulation.
the diagnosis and treatment of aortic diseases: Document 2002;105(2):200-6.
ic
covering acute and chronic aortic diseases of the thoracic 19. Tsai TT, Fattori R, Trimarchi S, et al. Long-term survival
and abdominal aorta of the adult The Task Force for the in patients presenting with type B acute aortic dissection:
og
Diagnosis and Treatment of Aortic Diseases of the European insights from the International Registry of Acute Aortic
Society of Cardiology (ESC). Eur Heart J. 2014;35(41):2873- Dissection. Circulation. 2006;114(21):2226-31.
926. 20. Lindsay J, Hurst JW. Clinical features and prognosis
ol
5. Riambau V, Böckler D, Brunkwall J, et al. Editor’s choice– in dissecting aneur ysm of the aorta. Circulation.
management of descending thoracic aorta diseases: 1967;35(5):880-8.
di
clinical practice guidelines of the European Society for 21. Hagan PG, Nienaber CA, Isselbacher EM, et al. The
Vascular Surgery (ESVS). European Journal of Vascular and International Registry of Acute Aortic Dissection (IRAD):
Endovascular Surgery. 2017;53(1):4-52. new insights into an old disease. JAMA. 2000;283(7):897-
ar
6. Hiratzka LF, Creager MA, Isselbacher EM, et al. Surgery 903.

for aortic dilatation in patients with bicuspid aortic 22. Suzuki T, Mehta RH, Ince H, et al. Clinical profiles and
C
valves: a statement of clarification from the American outcomes of acute type B aortic dissection in the current
College of Cardiology/American Heart Association Task era: lessons from the International Registry of Aortic
Force on Clinical Practice Guidelines. J Am Coll Cardiol. Dissection (IRAD). Circulation. 2003;108(Suppl 1): II312-7.
2016;67(6):724-31. 23. Nallamothu BK, Mehta RH, Saint S, et al. Syncope in acute
7. Chaikof, EL, Brewster DC, Dalman RL, et al. The Society for aortic dissection: diagnostic, prognostic, and clinical
Vascular Surgery practice guidelines on the care of patients implications, Am J Med. 2002;113(6):468-71.
with an abdominal aortic aneurysm. J Vasc Surg. 2018;67: 24. Nienaber CA, Zannetti S, Barbieri B, et al. Investigation of
2-77. Stent grafts in patients with type B aortic dissection: design
8. Mortality results for randomised controlled trial of early of the INSTEAD trial: a prospective, multicenter, European
elective surgery or ultrasonographic surveillance for small randomized trial. Am Heart J. 2005;149(4):592-9.
abdominal aortic aneurysms. The UK Small Aneurysm 25. MacKenzie KS, LeGuillan MP, Steinmetz OK, et al.
Trial Participants. Lancet. 1998;352(9141):1649-55. Management trends and early mortality rates for acute type
9. Brown PM, Pattenden R, Vernooy C, et al. Selective B aortic dissection: a 10-year single-institution experience.
management of abdominal aortic aneurysms in a Ann Vasc Surg. 2004;18(2):158-66.
605
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SECTION 26. Eagle KA, DeSanctis RW. Aortic dissection. Curr Probl 41. Uchida K, Imoto K, Karube N, et al. Intramural haematoma
Cardiol. 1989;14(5):225-78. should be referred to as thrombosed-type aortic dissection.
9 27. Fann JI, Miller DC. Aortic dissection. Ann Vasc Surg.
1995;9(3):311-23.
Eur J Cardiothorac Surg. 2013;44(2):366-9.
42. Park KH, Lim C, Choi JH, et al. Prevalence of aortic
28. Tsai TT, Nienaber CA, Eagle KA. Acute aortic syndromes.
Vascular System
intimal defect in surgically treated acute type A intramural

Circulation. 2005;112(24):3802-13. hematoma. Ann Thorac Surg. 2008;86(5):1494-500.
29. Bonser RS, Ranasinghe AM, Loubani M, et al. Evidence, 43. Kitai T, Kaji S, Yamamuro A, et al. Detection of intimal
lack of evidence, controversy, and debate in the provision defect by 64-row multidetector computed tomography
and performance of the surgery of acute type A aortic in patients with acute aortic intramural hematoma.
dissection. J Am Coll Cardiol. 2011;58(24):2455-74. Circulation. 2011;124(11):S174-8.
30. Girdauskas E, Kuntze T, Borger MA, et al. Surgical risk of 44. von Kodolitsch Y, Csosz SK, Koschyk DH, et al. Intramural
preoperative malperfusion in acute type A aortic dissection.
a
hematoma of the aorta: predictors of progression to
J Thorac Cardiovasc Surg. 2009;138(6):1363-9.
dissection and rupture. Circulation. 2003;107(8):1158-63.
di
31. Estrera AL, Garami Z, Miller CC, et al. J Thorac Cardiovasc
45. Moizumi Y, Komatsu T, Motoyoshi N, et al. Clinical
Surg. 2006;132(6):1404-8.
features and long-term outcome of type A and type B
32. Pocar M, Passolunghi D, Moneta A, et al. Coma might not
In
intramural hematoma of the aorta. J Thorac Cardiovasc
preclude emergency operation in acute aortic dissection.
Surg. 2004;127(2):421-7.
Ann Thorac Surg. 2006;81(4):1348-51.
33. Fujii H. Is coma an absolute contraindication for emergency 46. Evangelista A, Mukherjee D, Mehta RH, et al. Acute
of
central aortic operation? J Thorac Cardiovasc Surg. intramural hematoma of the aorta: a mystery in evolution.
2004;128(5):749-50. Circulation. 2005;111(8):1063-70.
34. Song JK, Kim HS, Kang DH, et al. Different clinical features 47. Chirillo F, Salvador L, Bacchion F, et al. Clinical and
ty
of aortic intramural hematoma versus dissection involving anatomical characteristics of subtle-discrete dissection of
the ascending aorta. J Am Coll Cardiol. 2001;37(6):1604-10. the ascending aorta. Am J Cardiol. 2007;100(8):1314-9.
18 cie
35. Iss elbacher EM, Cigar roa JE, Eagle K A . Cardiac
tamponade complicating proximal aortic dissection. Is
pericardiocentesis harmful? Circulation. 1994;90(5):2375-8.
48. Nienaber CA, Richartz BM, Rehders T, et al. Aortic
intramural haematoma: natural history and predictive
factors for complications. Heart. 2004;90(4):372-4.
36. Kaji S, Nishigami K, Akasaka T, et al. Prediction of 49. Nienaber CA, Powell JT. Management of acute aortic
20 o
progression or regression of type A aortic intramural syndromes. Eur Heart J. 2012;33(1):26-35.
S
hematoma by computed tomography. Circulation. 1999; 50. Eggebrecht H, Plicht B, Kahlert P, et al. Intramural hematoma
100:281-6. and penetrating ulcers: indications to endovascular
37. Grabenwoger M, Alfonso F, Bachet J, et al. Thoracic treatment. Eur J Vasc Endovasc Surg. 2009;38(6):659-65.
al
Endovascular Aortic Repair (TEVAR) for the treatment of 51. Coady MA, Rizzo JA, Hammond GL, et al. Penetrating ulcer
aortic diseases: a position statement from the European of the thoracic aorta: what is it? How do we recognize it?
ic
Association for Cardio-Thoracic Surgery (EACTS) and the

How do we manage it? J Vasc Surg. 1998;27(6):1006-15.
European Society of Cardiology (ESC), in collaboration with
52. Cho KR, Stanson AW, Potter DD, et al. Penetrating
og
the European Association of Percutaneous Cardiovascular

atherosclerotic ulcer of the descending thoracic aorta and
Interventions (EAPCI). Eur Heart J. 2012;33(13):1558-63.
arch. J Thorac Cardiovasc Surg. 2004;127(5):1393-9.
38. Fattori R, Tsai TT, Myrmel T, et al. Complicated acute type
53. Nathan DP, Boonn W, Lai E, et al. Presentation,
ol
B dissection: is surgery still the best option? A report from

complications, and natural history of penetrating
the International Registry of Acute Aortic Dissection. JACC
atherosclerotic ulcer disease. J Vasc Surg. 2012;55:10-5.
di
Cardiovasc Interv. 2008;1(4):395-402.

39. Nienaber CA, Kische S, Rousseau H, et al. Endovascular 54. Eggebrecht H, Herold U, Schmermund A, et al. Endovascular
repair of type B aortic dissection: long-term results of the stent-graft treatment of penetrating aortic ulcer: results
ar
randomized investigation of stent grafts in aortic dissection over a median follow-up of 27 months. Am Heart J.
trial. Circ Cardiovasc Interv. 2013;6(4):407-16. 2006;151(2):530-6.
C
40. Ganaha F, Miller DC, Sugimoto K, et al. Prognosis of aortic 55. Botta L, Buttazzi K, Russo V, et al. Endovascular repair
intramural hematoma with and without penetrating for penetrating atherosclerotic ulcers of the descending
atherosclerotic ulcer: a clinical and radiological analysis. thoracic aorta: early and mid-term results. Ann Thorac
Circulation. 2002;106(3):342-8. Surg. 2008;85(3):987-92.
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Aortic Diseases: When and How
to Proceed for Interventional
CHAPTER 73
Management?
a
di
INTRODUCTION The goals of imaging broadly, are:
The aorta is composed of different segments, namely the
Establish the diagnosis and its location.
In
Anatomical description with respect to its extent and
aortic root, ascending aorta, arch, descending thoracic
and abdominal aorta. Each of these segments is affected by morphological features like presence of thrombus
a variety of disease pathologies which may be congenital, and/or calcification.
of
Identify complications (aor tic regurgitation,
traumatic, inflammatory, neoplastic or atherosclerotic
in etiology. In addition, certain disease pathologies have coronary artery involvement, pericardial effusion/
hemopericardium, aortic rupture or leaking, branch
ty
a predilection or affinity for specific aortic segments
(Table 1). Symptomatically, there is a wide spectrum of vessel involvement and malperfusion syndromes)
Chest radiograph is a widely used and easily accessible
18 cie
clinical presentation across the various disease states
ranging from clinically asymptomatic and detected as
incidental finding, to acutely life-threatening clinical
examination. In addition to assessing for suitability for
surgery, it may provide subtle clues in selected clinical
manifestations. With regards to the temporal sequence conditions like presence of aortic wall calcification/
20 o
of events, the disease states may have a hyperacute (<24 aortic enlargement in Takayasu arteritis or widening of
S
hours), acute (<2 weeks), subacute (<90 days) or chronic mediastinum, obliteration of aortic knob, displacement of
presentation depending on the time to development of intimal calcification in aortic dissection.
symptoms. The imaging options available for assessment Transthoracic echocardiography (TTE), though
al
are: operator dependent, is useful in identifying the aortic valve

Plain radiography
pathologies and screening for the proximal ascending
ic
Transthoracic echocardiography (TTE)

aorta. Transesophageal echocardiography (TEE) is accurate
Transesophageal echocardiography (TEE)
og
for the detection of acute aortic syndromes with ability to

Multidetector CT
visualize both ascending and descending aorta in real time.
Magnetic resonance imaging
Nuclear imaging with fluorine-18-flurorodeoxyglucose
Invasive catheter angiography
ol
positron emission tomography is useful in assessment of

inflammatory activity in aortitis. Beyond this, it has limited
IMAGING OF AORTIC DISEASES
di
role.
Diagnosis and treatment planning with regards to aortic The best way to visualise the aorta is orthogonal
ar
diseases requires optimized imaging of both, the aorta imaging with computed tomography (CT) and magnetic
and accessory organs. Irrespective of the location of the resonance imaging (MRI), due to their ability to scan the
disease process, it is imperative to image the whole of
C
entire aorta. Multislice/multidetector CT angiography with

aorta because of multifocal involvement with skipped its orthogonal imaging capability is the most commonly
areas of normalcy. In addition, vascular access evaluation used imaging technique for the aorta, its branch vessels
is essential for planning therapy. and accessory organs. Its field of view is large with,
Table 1 : Disease predilections of different segments of aorta

Aortic root and ascending aorta Aortic arch Thoracic aorta Abdominal aorta
Vasculitis Atherosclerosis Vasculitis Atherosclerotic
Aneurysmal aortic root dilatation in bicuspid aortic Vasculitis Atherosclerotic Vasculitis
valve, Marfans, Loeys Dietz, Turners syndrome
Atherosclerotic Coarctation and Turners Mid aortic syndrome, Mid aortic syndrome,
syndrome (pseudocoarctation) neurofibromatosis neurofibromatosis
Traumatic, dissection Traumatic, dissection Traumatic, dissection Dissection
KG-73.indd 607 03-11-2018 12:39:08

SECTION in addition, excellent spatial, temporal and contrast of gradients along with visualization of collateral vessels
resolution. Its disadvantages however include the risk and associated heart defects. Echocardiography will not
9 of radiation, exposure to iodinated contrast and limited
functional evaluation.
depict collateral vessels. CT angiography provides all
information except calculation of gradients. It is useful for
Vascular System
MRI is also capable of multiplanar imaging with treatment planning and follow ups.
3D reconstruction. Cine MRI can visualize blood flow, Midaortic dysplastic syndrome, a disorder with
differentiate slow flow and clot, diagnose and quantify unknown etiology presents usually in the second decade
aortic regurgitation. Magnetic resonance angiography can of life with hypertension and absent femoral pulses. 2
identify branch vessel morphology. CT angiography characterizes the location (thoracic
This overview is not exhaustive but generic for and abdominal aorta with involvement of renals and
commonly encountered aortic pathologies which can mesenteric vessels), extent and collaterals. The differential
a
be characterized broadly into steno-occlusive lesions, diagnosis is late stage of Takayasu arteritis from which it
di
aneurysmal lesions, aortitis, non-traumatic acute can be differentiated only by histopathology.
conditions like dissection, intramural hematoma and Severe atherosclerotic disease of the iliac arteries or
In
penetrating aortic ulcer. aorta may result in stenosis or occlusion of the aorta below
the renal arteries. Leriche syndrome (Figures 2A and B)
STENO-OCCLUSIVE LESIONS OF AORTA is one of the manifestations occurring due to complete
of
Coarctation of the aorta is a congenital anomaly. Preductal occlusion of the infrarenal aorta. 3 CT angiography
coarctation (obstruction proximal to ductus arteriosus) diagnoses and prognosticates the condition in terms
presents in infancy. Arch hypoplasia and dilatation of of location, severity, extent, involvement of branches,
ty
the arch vessels is associated in more than 50% of the presence of collaterals and assessment for amenability to
cases. (1) Post ductal coarctation (Figure 1) presents after endovascular intervention.
18 cie
the neonatal period. Affected individuals can either be
asymptomatic, or hypertensive. They may suffer lower
Many inflammatory vasculitis can produce aneurysms
in many portions of the aorta and its branches, but only
limb claudication or are seen to have radiofemoral delay Takayasu arteritis produces stenosis in the thoracic aorta.4
20 o
on examination. Bicuspid aortic valve being the most The disease has an early or systemic or prepulseless phase
S
common association is seen in upto three fourth of the when only cross–sectional imaging can depict the mural
cases. Ventricular septal defect, sinus venosus type atrial thickening and contrast enhancement as no apparent
septal defect, hypoplastic left heart syndrome, mitral changes are produced intraluminally to be seen on
al
valvular abnormalities, truncus arteriosus, right sided angiography. This early or systemic phase characterized
aortic arch, supravalvular pulmonary stenosis, aneurysms by systemic symptoms like fever and elevated acute
ic
of the ascending aorta, ductus, intercostal arteries, and phase reactants like C-reactive protein is responsive to
circle of Willis, stenosis of the left subclavian artery and steroid therapy.5 Untreated, there may steno-occlusive
og
aberrant right subclavian artery are its other associations.1 lesions with wall calcifications or aneurysmal lesions.
Aortography shows the length, caliber and hemodynamic CT angiography is more effective in the early phase
significance of the obstructed segment with measurement
ol
and certainly better than angiography in depicting wall

calcification and luminal thrombus. In addition, it shows
di
contiguous involvement of the aortic valve cusps and

presence of pericardial effusion. Pulmonary arteries
ar
can also be evaluated. Any endovascular intervention

should be done only after control of disease activity
unless pressing indications are present in the form of
C
cardiac failure, flash pulmonary edema, hypertensive

encephalopathy and retinopathy. Gradients across
stenosis (functional significance of a particular lesion) can
be measured during angiography, however, caution needs
to be exercised as gradients may be masked or attenuated
in presence of cardiac failure. MR imaging has become
significant since it can demonstrate early wall thickening
before luminal narrowing becomes apparent. Gadolinium
enhanced fat suppressed images show the thickened
Figure 1: CT angiography sagittal oblique maximum intensity (ring like or concentric thickening of more than 3 mm)
projection (MIP) images show segmental narrowing of the aorta
(arrow) distal to the origin of left subclavian artery (LSCA) suggestive enhancing wall. Also, high signal intensity on T2 weighted
of coarctation of aorta images suggest edema.6
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CHAPTER
73

a
di
In
of
A B
ty
Figures 2A and B: Sagittal MIP and virtual reconstructed (VR) images show non opacification of the abdominal aorta
(black solid arrow) starting just inferior to the renal artery origin (white solid arrow)
DILATATIVE OR ANEURYSMAL LESIONS

18 cie branches through multiplanar reconstructions (MPR)
and maximum intensity projection (MIP) images. In
20 o
Expected normal dimensions for ascending aorta,
descending thoracic aorta, abdominal aorta are 4, 3 addition, it is useful in detection of calcifications and
S
and 2 cm respectively. 7 An aneurysm is defined as a accurately images the coronary arterial tree. Knowledge
permanent dilatation of the aorta exceeding the normal of the relationship between the aortic aneurysm and
the aortic branches is necessary to assess the adequacy
al
measurements at a particular anatomic level.

of the “landing zone”. The risk of rupture or dissection
Atherosclerosis is the cause of approximately 70%
increases at 6 cm for the ascending and 7 cm for the
ic
of all thoracic aortic aneurysms, annuloaortic ectasia

descending aorta. 10,11 Rupture is indicated by active
from cystic medial necrosis is the most common cause
contrast extravasation hyperdense collections in the
og
of an aneurysm involving to the ascending aorta.8 Other

pleura, pericardium, mediastinum or retroperitoneum.
causes are aortic dissection, trauma, infection, systemic
A draped aorta sign may be seen in a contained rupture
inflammatory diseases, vasculitis and congenital (rare).
of the posterior aortic wall and crescent sign may be
ol
There is male predominance with prevalence increasing

indicative of impending rupture.12
with age. Aneurysms can also be classified as true or false
A mycotic aneurysm is a wide necked saccular
di
depending on whether they are contained by the three

aneurysm (Figures 4A and B) with a tendency to involve
layers of aortic wall (true and generally fusiform in shape)
the ascending aorta.9 The lesion is in close proximity to
ar
or there is disruption of intima with blood surrounded and

the structures affected by endocarditis or there can be
contained by adventitia and periadventitial tissue (false or
hematogenous spread (septicemia). Another possibility
C
pseudoaneurysms and generally saccular with a narrow

is direct spread of infection from vertebral osteomyelitis
neck).9 Pseudoaneurysms can be caused by trauma (most
and psoas abscess. The majority of infected abdominal
commonly located at aortic isthmus), penetrating aortic
aortic aneurysms occur in the suprarenal abdominal
ulcer (descending aorta).9
aorta. Specific imaging findings include the presence of
Most abdominal aortic aneurysms (Figures 3A and B)
periaortic inflammation and gas and adjacent vertebral
are true (80%) with atherosclesotic etiology and involve
abnormalities.
the infrarenal aorta (90%).
Orthogonal imaging describes the type of aneurysm
with its size (diametier and length), involvement of AORTITIS
branch vessels, relationship to airway and other vessels Many autoimmune diseases and inflammatory vasculitis
and occurence of thrombus and calcifications. There can involve portions of the aorta and its branches like
is clear advantage of CT angiography over MRI in this Takayasu arteritis (as described above), rheumatoid
respect with its superior ability to show the relationship to arthritis, ankylosing spondylitis, Giant cell arteritis (GCA),
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SECTION
9
Vascular System
a
di
In
A B
of
Figures 3A and B: CT angiography sagittal and coronal MIP images show a large fusiform aneurysm involving the abdominal aorta
ty
18 cie
20 o S
al
ic
og
A B
ol
Figures 4A and B: (A) CT angiography oblique sagittal MIP image shows a wide neck saccular pseudoaneurysm arising from the proximal
descending thoracic aorta with surrounding hematoma; (B) CT angiography axial images shows peripherally enhancing lymph nodes in the
di
pretracheal location (arrow)

ar
relapsing polychondritis, Reiter’s disease, systemic lupus In rheumatoid arthritis, aortitis is rare, though the aortic
erythematosus, scleroderma, psoriasis, ulcerative colitis valve and annulus may be affected with inflammation.
and Behcets disease to name a few. Patients on long-term steroid therapy may have multiple
C
Large and medium-sized vessels and usually superficial aortic aneurysms.21-23

cranial arteries are affected in GCA. Aortic involvement Aortitis is uncommon in patients with SLE.
(15%) occurs as annuloaortic ectasia or ascending aortic In Behcets, wall-enhancing saccular pseudoaneurysms
aneurysm with propensity to extend into the aortic arch, may develop in the aorta and its branches24
acute dissection, aortic valve insufficiency, abdominal
aortic aneurysm or thoracic aortic aneurysm.13-17
Valve thickening and nodularity leading to insuffiency
AORTIC DISSECTION
or regurgitation are common manifestations of ankylosing Aortic dissection is the result of a tear in the intima as a result
spondylitis and are associated with significant mortality.18 of which blood penetrates the aortic wall. Death can be the
This increases with disease duration. result inspite of optimal treatment. Its annual occurrence
Relapsing polychondritis may lead to aortic dilatations is in the range of 3–5 per 1,00,000 cases per year, however,
and aneurysms.19,20 the incidence has been increasing.25 Dissection can be of
610
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two types: Stanford type A involves the ascending aorta CHAPTER
whereas type B involves the descending aorta distal to the
left subclavian artery. The mortality rate can be as high as
80% within 2 weeks for Type A dissection.26 However, in
73

recent times there has also been a concomitant increase
in the avenues for managing and treating this condition in
the form of best medical management and endovascular
repair techniques with promising in hospital survival
rates as high as 90–98% especially for Type B acute aortic
dissection with best medical management alone.27
Type A dissection constitutes 60% of aortic dissections
a
and affects the ascending aorta and arch. Complications
di
include coronary artery occlusion, acute aortic regurgita-
tion and rupture leading to cardiac tamponade. Type B
In
dissection begins beyond brachiocephalic vessels and Figure 5: Noncontrast CT image shows hyperdense cresentric
thickening of the ascending aortic wall (white arrows) suggestive of
accounts for 40% of aortic dissections. Type A dissections
intramural hematoma
require primary surgical repair whereas type B dissections
of
are treated medically with interventions in cases of CT also can depict other pathologic entities with similar
complication. clinical manifestations, such as intramural hematoma
Complicated dissection is associated with refractory
ty
(IMH) (Figure 5) and penetrating atherosclerotic ulcer.
pain, malperfusion, free or contained rupture, refractory/ Chest radiography may be normal or demonstrate
persistent hypertension or hypertension associated with
18 cie
malperfusion and features suggesting imminent rupture
on two consecutive CT examinations. Mortality in patients
a number of suggestive findings, including a widened
mediastinum (>8.0–8.8 cm at the level of the aortic
knob), double or irregular aortic contour and inward
with refractory pain and hypertension is high compared to displacement of intimal calcification.
20 o
patients without these associated signs.28 A bedside transthoracic echo is most useful for
S
This condition is seen in the age group of 50–70 years ascending aortic dissections, ventricular and valvular
with male predominance. Four-fifths of the patients have function, pericardial effusion and mediastinal hematoma.
associated hypertension. Trauma, connective tissue Transesophageal echo (TEE) can be performed in the
al
disorders (Turner’s, Marfan’s, Ehler Danlos, Loeys-Dietz emergency for unstable patients.
syndrome), vasculitis, tertiary (cardiovascular) syphilis, A CT typical protocol includes a non-contrast scan
ic
coarctation, bicuspid aortic valve are few other less to look for intramural hematoma. Scan in the arterial
common causes of AD. Cocaine use and pregnancy, phase with ECG gating assesses the ascending aorta and
og
especially third trimester or postpartum period are also coronary involvement. A delayed scan is required in post-
known risk factors. treatment cases to look for endoleaks. Magnetic resonance
ol
Effective antihypertensive therapy results in survival imaging (MRI) can also be used but is best reserved for
rates of 90%–98% in acute Type B dissection. Three-fifths follow up imaging. A duplex ultrasound of the groin is
required for measuring the calibre of access vessels.
di
of the survivors have an uncomplicated or benign course

thus questioning the widespread use of endovascular The classic intimal flap is seen in approximately
70% of cases of aortic dissection (Figures 6 and 7).
ar
therapy.27
Aortic aneurysm formation occurs in 25-30% within Differentiation of the true lumen from the false lumen
four years despite initial stabilisation. Aneurysmal is important for planning endovascular interventional
C
degeneration is thus inevitable with medical therapy only procedures (Table 2).
delaying its occurence. Also, around 24% of patients with
Type B dissection with require surgical intervention within DISEASES SPECIFIC TO AORTIC ROOT
14 days for early complications mentioned above.29 AND ASCENDING AORTA
Imaging is necessary for diagnosis, define the extent Bicuspid aortic valve (BAV) is the most common congenital
of dissection and to identify the complications. Multislice heart disease and affects 2% of the population.30 It is an
computed tomography (CT) is imaging modality of choice autosomal dominant disease with variable penetrance
for accurate pre-procedure planning for graft sizing and expressivity. Various morphologies of BAV are
and evaluating the landing zones. Radiation dose and associated with patterns of aortic dilatations (50% of the
its potential for nephrotoxicity should be kept in mind patients) and coarctation.31
because patients will need a catheter angiography and Aortic dilatation can be seen in connective tissue
treatment as well as multiple follow up imaging. disorders like Marfans (mutation in fibrillin gene) and
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SECTION
9
Vascular System
a
di
A B
Figures 6A and B: (A) Computed tomography angiography coronal images show presence of dissection flap (arrow) in the ascending aorta;
In
(B) Computed tomography angiography axial images show that the dissection flap is extending into the left main coronary artery (*). Note is
made of the presence of bilateral pleural effusion with underlying atelectasis
of
ty
18 cie
20 o S
al
ic
A B
Figures 7A and B: (A) Computed tomography angiography oblique sagittal images show the dissection flap (black solid arrow) originating
og
just distal to the left subclavian artery (LSCA); (B) Computed tomography angiography axial images show the presence of flap in the
descending thoracic aorta
ol
Table 2 : Differences between true and false lumen on CT angiography

di
True lumen False lumen

Continuity with undissected aorta No continuity
ar
Smaller cross-sectional area Larger cross-sectional area

Thrombosis rare May become thrombosed
C
Intimal calcification may be present Calcified false lumen can be seen in chronic dissections with mural
calcification
COBWEB SIGN (fine linear areas of low attenuation)-not present 100% specific for false lumen
BEAK SIGN (wedge of hematoma)-not present Present
Penetrating atherosclerotic ulcer is seen as a collection of contrast material is seen outside the aortic lumen on contrast enhanced scans.
Loeys Dietz Syndome (mutation in transforming growth Dietz syndrome with aortic dissection occuring earlier
factor b receptor. There is dilatation of the annulus and at a smaller aortic diameter.32 Turners syndrome
with effacement of sinotubular junction in annuloaortic is associated pseudocoarctation and dilatation of the
ectasia due to Marfans disease (Figures 8A and B). ascending aorta with increased risk of dissection at non
Aneurysmal aortic root dilatation also occurs in Loeys- aneurysmal ascending aortic diameters.33
612
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CHAPTER
73

a
di
A B
In
Figures 8A and B: CT angiography reconstructed MIP images show dilated aortic root
with effaced sinotubular junction and ascending aortic aneurysm
of
Some vasculitides (such as giant cell arteritis) can also 3. Ruehm SG, Weishaupt D, Jörg F, et al. Contrast-enhanced
cause ascending aortic aneurysms. MR angiography in patients with aortic occlusion (Leriche
Echocardiography is particularly helpful for both syndrome). J Magn Reson Imaging. 2000;11(4):401-10.
ty
diagnosis and follow up, but provides only two dimensional 4. Miller SM. Thoracic aortic diseases. In: Miller SM, (Ed).
imaging. CT and MRI with ECG gating provide much Cardiac radiology. St Louis, Mo: Mosby; 1996. pp. 386-435.
18 cie
more precise measurements with the disadvantage of
radiation exposure with CT studies. Younger patients
5. Matsunaga N, Kuniaki H, Sakamoto I, et al. Takayasu
arteritis: protean radiologic manifestations and diagnosis.
Radiographics. 1997;17(3):579-94.
with connective tissue disorder should be offered MRI for
20 o
6. Desai MY, Stone JH, Foo TKF, et al. Delayed contrast-
regular surveillance. Newer sequences even not require
enhanced MRI of the aortic wall in Takayasu’s arteritis: initial
contrast administration for assessment of ascending aorta.
S
experience. AJR Am J Roentgenol. 2005;184(5):1427-31.

The cut off for surgery in absence of any other
7. Scott RA, Ashton HA, Kay DN. Abdominal aortic aneurysm
cardiovascular abnormality is 55 mm. In BAV, this cutoff is
al
in 4,237 screened patients: prevalence, development, and

40 mm and for Marfans, this cutoff is 50mm or growth rate
management over 6 years. Br J Surg. 1991;78(9):1122–5.
more than 5 mm/yr.
ic
8. Lemon DK, White CW. Anuloaortic ectasia: angiographic,

hemodynamic and clinical comparison with aortic valve
CONCLUSION
og
insufficiency. Am J Cardiol. 1978;41(3):482–6.

Aorta is affected by a myriad of pathologies each 9. Desai MY, Stone JH, Foo TKF, et al. Delayed contrast-
having specific anatomic predilection and imaging enhanced MRI of the aortic wall in Taka yasu’s arteritis: initial
ol
features. Optimal imaging is essential for prompt and experience. AJR Am J Roentgenol. 2005;184(5):1427-31.
comprehensive diagnosis and goes a long way in identifying 10. Elefteriades JA . Natural history of thoracic aortic
di
right treatment strategies. Multislice CT is usually best aneurysms: indications for surgery, and surgical versus
suited for fast and comprehensive imaging of the aorta but nonsurgical risks. Ann Thorac Surg. 2002;74(5):1877–80.
ar
11. Elefteriades JA, Tranquilli M, Darr U, et al. Symptoms plus

provides only limited functional evaluation. MRI provides
family history trump size in thoracic aortic aneurysm. Ann
functional evaluation but has its inherent limitations. In
Thorac Surg. 2005;80(3):1098-100.
C
our setting, CT angiography is regarded as the standard

12. Halliday KE, Al-Kutoubi A. Draped aorta: CT sign of con-
of care when it comes to evaluating aortic diseases, with
tained leak of aortic aneurysms. Radiology.1996;199:41–4.
MRI being used only when CT is contraindicated or when
13. Bley TA, Uhl M, Venhoff N, et al. 3-T MRI reveals cranial and
functional evaluation is required.
thoracic inflammatory changes in giant cell arteritis. Clin
Rheumatol. 2007;26(3):448–50.
REFERENCES 14. Zehr KJ, Mathur A, Orszulak TA, et al. Surgical treatment
1. Philips RR, Gordon JA. Coarctation of the aorta. In: Bawm of ascending aortic aneurysms in patients with giant cell
S (Ed). Abrams’ angiography. 4th edition. Boston, Mass: aortitis. Ann Thorac Surg. 2005;79(5):1512–7.
Little, Brown; 1997.pp.434-63. 15. Lie JT, Failoni DD, Davis DC Jr. Temporal arteritis with giant
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a 2 to 18 years follow-up and selective histopathological 16. Gelsomino S, Romagnoli S, Gori F, et al. Annuloaortic ectasia
study. Eur J Vasc Surg. 1990;4:75-82. and giant cell arteritis. Ann Thorac Surg. 2005;80:101–5.
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arteritis of the aorta: catastrophic complications without a Study. Circulation.2013;127(20):2031–7.
9 preexisting aneurysm. Eur J Intern Med. 2008;19(7):59-60.

18. Roldan CA, Chavez J, Wiest PW, et al. Aortic root disease
26. Mehta RH, Bossone E, Evangelista A, et al. Acute type
B aortic dissection in elderly patients: clinical features,
outcomes, and simple risk stratification rule. Ann Thorac
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and valve disease associated with ankylosing spondylitis. J

Am Coll Cardiol. 1998;32(5):1397–404. Surg. 2004;77(5):1622–8.
19. G i o rd a n o M , Va l e nt i n i G, S o d a n o A . R e l a p s i n g 27. Ziganshin BA, Dumfarth J, Elefteriades JA. Natural history
polychondritis with aortic arch aneurysm and aortic arch of Type B aortic dissection: ten tips. Ann Cardiothorac Surg.
syndrome. Rheumatol Int. 1984;4(4):191–3. 2014;3(3):247–54.
20. Manna R, Annese V, Ghirlanda G, et al. Relapsing 28. Trimarchi S, Eagle KA, Nienaber CA, et al. Importance of
refractory pain and hypertension in acute type B aortic
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a
Aortic Dissection (IRAD). Circulation. 2010;122(13):1283–9.
21. Levine AJ, Dimitri WR, Bonser RS. Aortic regurgitation in
29. Fattori R, Montgomery D, Lovato L, et al. Survival after
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rheumatoid arthritis necessitating aortic valve replacement.
endovascular therapy in patients with type B aortic dissection:
Eur J Cardiothorac Surg. 1999;15(2):213–4.
a report from the International Registry of Acute Aortic
In
22. Hoshina K, Koyama H, Miyata T, et al. Aortic wall cell
Dissection (IRAD). JACC Cardiovasc Interv. 2013;6(8):876–82.
proliferation via basic fibroblast growth factor gene transfer 30. Vallely MP, Semsarian C, Bannon PG. Management of
limits progression of experimental abdominal aortic the ascending aorta in patients with bicuspid aortic valve
of
aneurysm. J Vasc Surg. 2004;40(3):512–8. disease. Heart Lung Circ. 2008;17:357–63.
23. Smith DC, Hirst AE. Spontaneous aortic rupture associated 31. Siu SC, Silversides CK. Bicuspid aortic valve disease. J Am
with chronic steroid therapy for rheumatoid arthritis in two Coll Cardiol. 2010;55:2789–800.
cases. AJR Am J Roentgenol. 1979;132(2):271–3.
ty
32. Van Hemelrijk C, Renard M, Loeys B. The Loeys-Dietz
24. Ko GY, Byun JY, Choi BG, et al. The vascular manifestations syndrome: an update for the clinician. Curr Opin Cardiol.
of Behçet’s disease: angiographic and CT findings. Br J 2010;25(6):546–51.
Radiol. 2000;73(876):1270–4. 18 cie
25. Howard DPJ, Banerjee A, Fairhead JF, et al. Population-
Based Study of Incidence and Outcome of Acute Aortic
33. Hjerrild BE, Mortensen KH, Sørensen KE, et al. Thoracic
aortopathy in Turner syndrome and the influence of
bicuspid aortic valves and blood pressure: a CMR study. J
20 o
Dissection and Premorbid Risk Factor Control Clinical Cardiovasc Magn Reson. 2010;12:12.
S
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Pulmonary Embolism:
CHAPTER 74 When to do What?
a
di
INTRODUCTION for recurrent VTE (are hospitalized or have reduced
Pulmonary embolism (PE) is a dreaded disease with a mobility for another reason, have active cancer, or have no
In
vast spectrum of presentation varying from asymptomatic reversible risk factor for VTE such as recent surgery) and
subsegmental emboli to massive PE with hemodynamic those with poor cardiopulmonary reserve are suggested
collapse. The management options include clinical anticoagulation over clinical surveillance.
of
surveillance, anticoagulations, systematic thrombolysis,
surgical embolectomy, catheter-directed thrombolysis ANTICOAGULATION
(CDT) and other endovascular interventions. Though the
ty
Anticoagulation is the crucial in management of acute PE.
guidelines aptly describe the role of each of these treatment
Once the bleeding risk has been assessed, anticoagulation
modalities, there are gray areas and borderline zones
18 cie
where patient individualization and clinical experience
play a major role in decision making. Team work with
should be promptly initiated by the treating physician. In
cancer patients, low-molecular-weight heparin (LMWH)
is preferred to unfractionated heparin (UFH) in both
physicians from varied disciplines of medicine has been
20 o
formed in many tertiary care center so as to deal promptly treatment as well as thromboprophylaxis. For the rest,
and aggressively with the varied spectrum of PE—so- factor Xa antagonists and direct thrombin inhibitors
S
called pulmonary embolism response team (PERT). The [together known as novel oral anticoagulants (NOACs)]
present review focuses on when to utilize each of these are the upcoming modalities of anticoagulation. The
al
treatment modalities across varied spectrum of PE with NOACs are now placed as the first-line therapy in several
special emphasis on catheter-directed techniques. guidelines and the use of these agents may alleviate
ic
Clinical follow-up is suggested in patients with drawback of vitamin K antagonists (VKA) therapy, i.e.
sub-segmental PE with no proximal deep venous to have subtherapeutic international normalized ratios
og
thrombosis (DVT) and a low risk for recurrent venous (INRs). Several factors may be decisive in the choice of
thromboembolism (VTE). Patients who have high risk anticoagulant chosen (Table 1).
ol
Table 1: Choice of anticoagulant for treatment of pulmonary embolism

Issue Favored anticoagulant Comments
di
Malignancy LMWH Recently diagnosed, widespread VTE, metastatic cancer, markedly

symptomatic; vomiting; on chemotherapy
ar
To avoid parenteral therapy Rivaroxaban; apixaban VKA, dabigatran, and edoxaban; may require parenteral therapy
initially
C
Once a day oral therapy Rivaroxaban; edoxaban; VKA

Hepatic involvement with coagulopathy LMWH NOACs contraindicated in deranged INRs due to hepatic
involvement. Not easy to manage INRs with VKAs and INR may
not be reflective of anticoagulant effect
Renal involvement with creatinine VKA In severe renal derangement, NOACs and LMWH are
clearance <30 mL/min contraindicated. Dose adjustments of NOACs are needed with
varying levels of renal impairment
Dyspepsia or history of GI bleed VKA, apixaban More dyspepsia with dabigatran. Higher probability of GI bleeds
with dabigatran, rivaroxaban, and edoxaban vs VKA
Thrombolyzed patients UFH More experience in thrombolyzed patients
Need of reversal agent VKA, UFH
Pregnancy LMWH Remaining therapeutic options cross the placental barrier
Abbreviations: INR, international normalized ratio; VKA, vitamin K antagonists; UFH, unfractionated heparin; LMWH, low-molecular-weight
heparin; GI, gastrointestinal; NOAC, novel oral anticoagulants; VTE, venous thromboembolism
KG-74.indd 615 03-11-2018 12:38:28

SECTION SYSTEMIC THROMBOLYTIC THERAPY bleeding risk with systemic thrombolysis and surgical
embolectomy. Moreover, surgical procedures are
9
It has long been established that systemic thrombolytic
therapy accelerates resolution of PE as evidenced by more dependent on available expertise and resources. This is
rapid lowering of pulmonary artery pressure, increases an ideal situation where catheter-based therapy can be
Vascular System
in arterial oxygenation, and resolution of perfusion scan life-saving.

defects, and that this therapy increases bleeding. The net
mortality advantage of thrombolysis in acute PE is the CATHETER-BASED THERAPY
ultimate outcome of patients bleeding risk vs the risk of The term ‘catheter-based therapy’ (CBT) refers to the use
death from acute PE. Patients with the maximum risk of of any of several devices and techniques in the pulmonary
mortality from PE and the lowest risk of bleeding obtain artery (PA) with or without low-dose thrombolytic therapy.
the greatest net advantage from thrombolysis. Patients
a
The term ‘catheter-directed thrombolysis’ (CDT) refers
with the lowest risk of dying from PE and the highest risk to the infusion of thrombolytics into the PA via an infusion
di
of bleeding obtain the least net benefit from thrombolysis catheter with multiple exit ports, placed into the PA,
and may be harmed. preferably into the embolus.
In
Most of the new evidence comes from the PE Pharmacomechanical thrombolysis (PMT) refers
thrombolysis trial (n = 1,006). The PE patients with to low-dose thrombolysis combined with additional
RV (right ventricle) dysfunction were randomized to mechanical measures (i.e. more than simply direct
of
tenecteplase and heparin or to heparin therapy alone intraembolic infusion) such as fragmentation to aid in
(with placebo). It was found that thrombolysis prevented eliminating the emboli.
cardiovascular collapse at the cost of increased major There is a decrease in use of systemic thrombolysis
ty
(including intracranial) bleeding. Hence, there was no due to continued concern regarding devastating bleeding
definite net benefit from thrombolysis. However, ‘rescue complications, particularly intracranial hemorrhage
18 cie
thrombolytic therapy’ seemed to be of advantage in
patients with cardiovascular collapse after initially being
(ICH), as well as the results of recent studies suggesting
relative safety and efficacy of CBT. Unfortunately, as
treated with anticoagulant therapy alone. effective as systemic thrombolysis can be, the incidence
20 o
Systemic thrombolysis is recommended in patients of major bleeding and ICH is clearly higher than
with acute PE associated with hypotension (e.g. systolic BP
S
with anticoagulation alone. This persisting obstacle

<90 mm Hg) who do not have a high bleeding risk. It is not together with advances in surgical techniques and
recommended in acute PE patients without hypotension. catheter technology has prompted alternate treatment
al
Systemic thrombolysis may also be administered in options, including lower-dose systemic fibrinolysis,
some patients with low bleeding risk who deteriorate after surgical embolectomy, and a number of catheter-
ic
initiating anticoagulation, but have not yet developed based approaches. In spite of several promising studies
hypotension. For instance, there may be a progressive heart suggesting the improved safety and acceptable efficacy of
og
rate increase, a decrease in systolic blood pressure (BP) lower doses of systemic thrombolytic agents, for example,
(which remains >90 mm Hg), an increase in jugular venous 50 mg of IV tissue-type plasminogen activator (tPA), an
pressure (JVP), worsening gas exchange, signs of shock acceptable reduction in the risk of major bleeding and ICH
ol
(e.g. cold sweaty skin, reduced urine output, confusion), has not been satisfactorily proven.
progressive RV dysfunction on echocardiography, or A recent analysis of the National Inpatient Sample
di
an increase in cardiac biomarkers warranting systemic

(NIS) database indicates that utilization of CBT has
thrombolysis.
increased since 2010. It was shown, based on a propensity-
ar
matched analysis of a cohort of 352 in patients with PE

Case who underwent CBT compared with 352 in patients who
C
A 28-year-old male, a multisubstance abuser referred to had systemic thrombolysis that the in-hospital mortality
tertiary care center with history of massive PE after being rate was approximately 10% which was significantly lower
thrombolyzed with streptokinase 10 days ago. He was in than the rates for systemic thrombolysis (20%). There
cor pulmonale with sinus tachycardia (heart rate 126/ were very low rates of ICH (0.28%) and no ICH after
min), hypotension (BP = 90/60 mm Hg on inotropes), 2010. This was, however, at the expense of higher rates
shock index 1.4. Echocardiography revealed dilated of acute renal failure requiring hemodialysis and higher
right atrium (RA) and RV with pulmonary artery systolic cost. The gradually decreasing major bleeding rates may
pressure of 48 mm Hg. Troponin-T and BNP were raised. reflect increasing experience and use of lower doses of
thrombolytic agents with newer catheter-based devices.
Issues in Management Data available and clinical experience with certain
This case reflects a patient of failed thrombolysis with techniques, strongly suggest there can be benefit and that
hemodynamic compromise. There are issues of increase these approaches should continue to be pursued.
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KG-74.indd 616 03-11-2018 12:38:28

Potential Indications for attempt to deliver it within the embolus. Thrombolytic CHAPTER
Catheter-based Therapy agents are usually administered as a continuous infusion; a
High-risk PE with mild hypotension, or intermediate-
bolus may be considered at the time of catheter placement
in patients who are hemodynamically unstable or appear
74
risk PE with more severe degrees of RV dysfunction and

to be worsening. Many of these studies have suggested
positive biomarkers and/or more severe hypoxemia are
improvement but without comparison anticoagulation
feasible scenarios for CBT. Given the low risk for major
arms. There is no standard thrombolytic agent, infusion
complications, it is reasonable to consider CBT, in patients
duration, or drug dose utilized in CDT, although tPA has
with massive PE who have been reasonably stabilized
been most commonly utilized and approximately 20 mg of
and with contraindications to systemic thrombolysis and
tPA has been delivered over approximately 12–24 hours in
in patients on the more severe end of the intermediate
larger studies.
a
risk spectrum (patients with severe RV dysfunction by
Mohan et al. found improved short- and long-term
echocardiography and positive biomarkers). Other special
di
outcomes in 50 consecutive high-risk patients of PE
subgroups include failed thromobolysis, thrombolysis
with pigtail rotational mechanical thrombectomy and
with PE after 7–10 days, severely compromised patients,
In
intraembolus thrombolysis with urokinase.
and age more than 65 years. The potential advantages
Combined modality of mechanical breakdown and
of a catheter-based procedure include the use of either
intralesional thrombolysis is a potential alternative to
no thrombolytic agent or low-dose thrombolysis, thus,
of
high-risk surgical procedures in patients with subacute
offering the possibility of more rapidly reducing the clot
massive PE. In a study 11% patients with massive PE
burden with what appears to be a reduced risk of major
presenting subacutely were administered mechanical
bleeding including ICH.
ty
fragmentation and intrapulmonary lysis with urokinase
(4,400 IU/kg over 10 min followed by 4,400 IU/kg per
Catheter-based Therapeutic Options
18 cie
Several percutaneous catheter-based techniques have
been utilized for treatment of high-risk and intermediate-
hour over 24 h). Patients documented noteworthy
improvement in immediate hemodynamics with 100%
survival at 30 days and 6 month follow-up. Patients with
risk PE as shown in Box 1 and Figures 1A to I. massive PE presenting subacutely (>2 weeks) have high
20 o
mortality and organized grown up clots which may be
S
Catheter-directed, Low-dose Thrombolysis less amenable to thrombolysis with increased likelihood

of recurrence and development of thromboembolic
Although anticoagulation with heparin alone has little
pulmonary hypertension.
al
effect on improvement of RV size and performance within

The subgroup of patients of massive PE who were
the first 24 to 48 hours, the extent of early RV recovery after
treated with intravenous (IV) thrombolysis but failed to
ic
low-dose CDT appears comparable to that after standard-

respond to treatment poses a therapeutic challenge in
dose systemic thrombolysis. Bleeding complications
og
view of high-risk bleeding and mortality during surgery.

appear to occur less frequently with CDT than with full-
Mechanical thrombosuction and intraembolus lysis
dose systemic thrombolysis; and thus, this procedure has
in such patients has been shown to be a promising
been commonly performed in patients with intermediate-
ol
alternative strategy.
and high-risk PE with relative contraindications to
In acute PE recanalization should be done using pigtail
systemic thrombolysis. The thrombolytic agent is infused
di
followed by thrombosuction and lysis using thrombolytic

into the PA, with or without ultrasound assistance in an
agent (Figure 2). For older organized clot, increased
ar
clot surface by mechanical fragmentation followed by

Box 1: Catheter-based techniques thrombolysis causes increased velocity of thrombolysis as
Catheter-directed, low-dose thrombolytic infusion, shown in Figures 3A and B.
C
without ultrasound assistance The thrombolytic agent, urokinase (UK), specifically

Ultrasound-facilitated, catheter-directed therapya catalyzes the cleavage of the ArgVal bond in plasminogen
Embolus fragmentation with pigtail or balloon catheter
to form plasminogen which breaks down the fibrin
polymers of blood clots. Urokinase is nonantigenic
Suction/vortex embolectomy with aspiration of emboli
(unlike streptokinase), more potent as compared to
Catheter-directed extraction embolectomy tissue plasminogen activator and may be a preferred
Rheolytic embolectomy with hydrodynamic catheter devices option amongst plasminogen activators. It has direct
Rotational embolectomy catalytic activity against fibrinogen and renders it less
A combination of the above
clottable by thrombin by releasing fibrinopeptide B,
a a potent chemoattractant. Henceforth, urokinase has
This is the only catheter-based therapy technique studied in a
randomized controlled trial and Food and Drug Administration effects beyond just fibrinolysis, which might be applicable
approved specifically for the treatment of acute pulmonary embolism. in patients with subacute PE and relatively organized
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SECTION
9
Vascular System
a
di
In
A B C D
of
ty
18 cie
20 o S
al
E F G H
ic
og
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di
ar
C
I
Figures 1A to I: Devices utilized for catheter-based therapy
older thrombi. Furthermore, in a randomized controlled Preparation for the Procedure

multicenter trial of urokinase vs rt-PA in the treatment This consists of risk stratification, and an understanding of
of acute PE, it was found that in spite of swift clot lysis who will perform the procedure, where it will be done, and
within two hours by rt-PA; at 24 hours both the drugs the precise technique(s). A specialist in PE, or PE team,
were equivalent in terms of effective reperfusion. Also, in for example, a PE response team (PERT), can facilitate
developing nations, urokinase can be a preferred option the decision process and more rapid deployment of a
due to low cost and availability. treatment plan. Anticoagulation should be initiated in
618
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CHAPTER
74

a
di
In
of
ty
18 cie
Figure 2: Thrombosuction and lysis using thrombolytic agent
20 o S
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ic
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ol
di
ar
C
A B
Figures 3A and B: Schematic drawing demonstrating the effect of mechanical fragmentation of a total occlusive central thrombus in the pulmonary
artery, before (A) and after (B) mechanical fragmentation and dispersion of the smaller clots into the peripheral branches of the pulmonary artery.
Fragmentation and distal dispersion is likely to reduce pulmonary artery pressure and increase total pulmonary perfusion
all PE patients unless it is contraindicated. When CBT laboratory is crucial, if more critically ill PE cases are to be
is considered, IV heparin is often utilized since it has considered.
a short half-life and is reversible. Rapid access to the After giving local anesthesia, 6 F sheath is introduced
cardiac catheterization or interventional radiology in the femoral vein for procedure. The 6 F standard
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SECTION
9
Vascular System
a
di
A B C
Figures 4A to C: Pulmonary angiography. (A) Total cut off of right pulmonary artery; (B) Mechanical breakdown and intrapulmonary
In
urokinase administration; (C) Postprocedural pulmonary angiography revealing restoration of pulmonary flow in right pulmonary artery and
its branches
of
Table 2: Thrombolytic therapy in PE and deep venous thrombosis (systemic and catheter directed)
Drug Loading dose Maintenance dose Duration of infusion Concurrent heparin
ty
Systemic thrombolytic doses in pulmonary embolism
tPA (Alteplase) None 100 mg 2 hours Optional
Urokinase
Streptokinase
(STK)
18 cie
4,400 U/kg/hr
250 000 IU as a loading
dose over 30 minutes
4,400 U/kg/hr
100 000 IU/hr
12–24 hours
12–24 hours
No
20 o
Catheter-directed thrombolysis dose in pulmonary embolism
Loading dose
S
tPA (Alteplase) Each treated lung at a rate of 1 mg/hr, to a total dose of 24 mg (over 12 hr for bilateral lung infusions)
Urokinase 1. 4,400 IU/kg body weight is given intralesionally over 10 minutes and followed by 2,200-4,400 IU/kg /hr for 12
al
hours
2. 120,000–240,000 IU/hr by McNamara protocol graded infusion 4,000 IU/min for 2 hours or up to restoration
ic
of antegrade flow followed by 2,000 IU/min for 12–24 hours or until complete lysis. Intrathrombus lacing
60,000 IU followed by McNamara protocol 250,000 IU followed by 50,000 IU/hr. Pulse spray 5,000 IU every 30
seconds for 20 minutes 2,000 IU/cm occlusion length. Intraoperative thrombolysis 1000–2000 IU/min in distal
og
thrombus.
(Tenecteplase is being used in different study groups and as an off-level indication)
ol
pigtail catheter is used to obtain initial pulmonary intraoperative thrombolysis 1000–2000 IU/min in distal
angiography for confirmation of massive PE (Figures thrombus (Table 2).
di
4A to C). Mechanical recanalization of thrombus is done

with multipurpose catheter followed by fragmentation Ultrasound-facilitated, Catheter-directed
ar
and thrombus suction with 6 F pigtail. After ensuring

Therapy
flow across affected pulmonary artery, urokinase in
C
dose of 4,400 IU/kg body weight is given intralesionally The low-dose CDT technique with the most controlled
over 10 minutes and followed by 2,200–4,400 IU/kg/hr supportive clinical trial data involves a local, slow infusion
for 12 hours through pigtail catheter kept in pulmonary of a thrombolytic agent through low-profile catheters
artery with maximum thrombus burden in our center placed in the obstructed PA using the high-frequency low-
now we are using 2,200 IU/kg/hr dose. There are other power EkoSonic ultrasound technique, i.e. ultrasound-
protocols for urokinase, and have been mentioned. assisted CDT (USCDT), ultrasound exposure causes a
Continuous infusion 120,000–240,000 IU/hr by McNamara reversible disaggregation of uncross-linked fibrin fibers,
protocol graded infusion 4000 IU/min for 2 hours or up which may create additional binding sites and facilitate
to restoration of antegrade flow followed by 2,000 IU/min the thrombolytic effect. Furthermore, ultrasound pressure
for 12–24 hours or until complete lysis. Intrathrombus waves may increase thrombus penetration of thrombolytic
lacing 60,000 IU followed by McNamara protocol 250,000 drugs by ‘acoustic streaming.’
IU followed by 50,000 IU/hr. Pulse spray 5,000 IU every The 5.2 F infusion catheter contains three lumens
30 seconds for 20 minutes 2,000 IU/cm occlusion length with one for the inner ultrasound cable, one for the drug
620
KG-74.indd 620 03-11-2018 12:38:31

infusion, and one for the coolant (normal saline). Most Rheolytic Embolectomy CHAPTER
commonly, an ultrasound/ infusion catheter is placed in
74
Repeated injections of saline into large proximal emboli
each lung. A commonly used tPA dose is 0.5 to 1.0 mg/ have been performed analogs to catheter fragmentation.
hr per catheter. The total tPA dose is typically between A more formal approach has employed a high-pressure

12 and 24 mg, delivered over 12–24 hours. A low-dose, saline jet generating a pressure gradient via Bernoulli’s
weight-based heparin infusion is continued during the principle, enabling the dissolution and removal of emboli.
thrombolytic infusion, with a target partial thromboplastin This AngioJet device also permits the local injection of
in the low-therapeutic range (e.g. 40–60 seconds). The
thrombolytic agents by the ‘power pulse’ spray technique,
coolant is infused at approximately 35 mL/hr. In Ultima
forcing the drug into the emboli. Massive hemoptysis,
trial of intermediate-risk PE, a standardized ultrasound-
renal failure, and death from bradycardia and apnea have
assisted catheter-directed thrombolysis (USAT) regimen
a
been reported. This resulted in a black-box warning from
was better than anticoagulation with heparin alone in
the FDA for the use of AngioJet in acute PE.
di
reversing RV dilatation at 24 hours, without increased
bleeding. Similarly, in SEATTLE II trial of acute massive
Catheter-directed Extraction Embolectomy
In
and submassive PE, ultrasound-facilitated, catheter-
directed, low-dose fibrinolysis reduced RV dilation, The FlowTriever device is a catheter-based mechanical
pulmonary arterial hypertension, clot burden, and also device for percutaneous endovascular retrieval of emboli
of
minimized intracranial hemorrhage. and is intended for use in the proximal (lobar and main)
pulmonary arterial system. The device is composed of
the FlowTriever catheter with an integral self-expanding
Aspiration/Suction/Vortex Embolectomy
ty
wire form consisting of three nitinol disks, an aspiration
Several aspiration techniques have been employed and guide catheter, and a retraction aspirator. Clinical
18 cie
can be attempted using regular 8 F or larger guide catheters
or more specialized catheters. The earliest experience was
obtained with the 10 F Greenfield suction embolectomy
improvement may result from both clot extraction and
improved perfusion via penetrating the emboli. The
device is intended for use without thrombolytic agents,
catheter. The device allowed extraction of the centrally
20 o
but thrombolytics (and contrast dye) can be infused
located emboli by using sustained suction with a large through the aspiration-guided catheter. Successful use
S
syringe. The device proved effective but was somewhat of the FlowTriever device in a critically ill massive PE
cumbersome based on the requirement for a surgical cut patient who failed systemic thrombolysis has been
down for access and the need to retrieve the device and
al
reported.
the emboli as a unit. Manual suction embolectomy has
been utilized alone or as an adjunct to other techniques. Catheter-based Therapy: Complications
ic
The guide catheter is advanced into the embolus in the

There are several potential complications of CBT
og
right or left PA. Suction is applied with a 20- to 50-mL

techniques for acute PE. Some involve access to the
syringe while the catheter is moved slowly back and forth
right heart and PAs, and manipulation of catheters
over several centimeters within the clot.
once access is accomplished. Also included are major
ol
The AngioVac cannula is a 22 F venous catheter that

access site bleeding, significant arrhythmias, pulmonary
removes emboli utilizing a centrifugal pump and venous
arterial dissection or perforation, pericardial tamponade,
di
reinfusion cannula with the latter minimizing blood worsening hypoxemia and hemodynamics, recurrent
loss. The device is Food and Drug Administration (FDA) PE, and distal clot embolization. Others may relate to the
ar
approved for the ‘removal of undesirable intravascular specific procedure, such as hemolysis/hemoglobinuria, as
material’ including fresh, soft thrombi, or emboli. The described earlier with rheolytic therapy
C
AngioVac catheter consists of a balloon-expandable,

funnel-shaped distal tip, which improves removal of large Catheter-based Therapy: Caution
emboli from the right heart chambers or proximal PAs.
The selection of one of the above techniques for
management of acute PE needs a careful thought and
Embolus Fragmentation/Dissolution experience. For instance, a proximal massive PE shall
Fragmentation of emboli is a relatively simple and rapid warrant recanalization of proximal pulmonary arteries
technique and does not require complex resources. (mechanical as well as thrombosuction) in addition to
The theory is that by mechanically disrupting occlusive administration of local thrombolytic agent. The operator
proximal emboli into smaller fragments, improved should be cautious of distal embolization in a pre-existent
peripheral flow can be achieved. This has been successfully state of hemodynamic compromise. Moreover, in a
achieved with manual rotation of a pigtail catheter or by relative distal and segmental subacute and submassive
employing a balloon angioplasty catheter. PE catheter-based thrombolysis alone might be sufficient.
621
KG-74.indd 621 03-11-2018 12:38:31

SECTION Postintervention modality holds a promise for management of PE in times
to come.
9
Effective continued anticoagulation postintervention is
crucial to avoid recurrent clot formation. Patients with
recent catheter-based intervention may develop access SUGGESTED READING
Vascular System
site bleeding. One of the methods to reduce bleeding is to 1. Brady AJB, Crake T, Oakley CM. Percutaneous catheter
hold the heparin drip for 1 to 2 hours after sheath removal, fragmentation and distal dispersion of proximal pulmonary
then restart without a bolus. Oral anticoagulation or embolus. Lancet. 1991;338(8776):1186–9.
LMWH can be initiated once clinical evaluation. However, 2. Chechi T, Vecchio S, Spaziani G, et al. Rheolytic
no guidelines point as to when or how anticoagulants thrombectomy in patients with massive and submassive
should be initiated post-CBT, especially if thrombolysis acute pulmonary embolism. Catheter Cardiovasc Interv.
has been given. Unfractionated heparin alone for the first 2009;73(4):506–13.
a
24–48 hours postintervention with initiation of a direct 3. Donaldson CW, Baker JN, Narayan RL, et al. Thrombectomy
di
oral anticoagulant (DOAC) or warfarin subsequently (or using suction filtration and veno-venous bypass: single
LMWH in active cancer patients) is the usual followed center experience with a novel device. Catheter Cardiovasc
In
Interv. 2015;86(2):81-7.
strategy. The IVC filters are not recommended for routine
4. Greenfield LJ, Kimmell GO, McCurdy WC 3rd. Transvenous
use in patients with PE.
removal of pulmonary emboli by vacuum-cup catheter
of
technique. J Surg Res. 1969;9(6):347–52.
Consensus Statements 5. Jaff MR, McMurtry MS, Archer SL, et al. Management of
In management of acute PE, the catheter-directed massive and submassive pulmonary embolism, iliofemoral
ty
treatment has varying levels of recommendations in deep vein thrombosis, and chronic thromboembolic
the guidelines. In American College of Chest Physicians pulmonary hypertension: a scientific statement from the
American Heart Association. Circulation. 2011;123(16):
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(ACCP) guidelines 2016, catheter-directed treatment
has grade 2 level of recommendation in patients with
hypotension, increased bleeding risk, failed systematic
1788-830.
6. Kabrhel C, Rosovsky R, Channick R, et al. A multidisciplinary
pulmonary embolism response team: initial 30-month
thrombolysis, and shock with impending death. Similarly,
20 o
experience with a novel approach to delivery of care
the European Society of Cardiology (ESC) 2014 endorse to patients with submassive and massive pulmonary
S
catheter-directed treatment at class 2A level as an embolism. Chest. 2016;150(2):384–93.

alternative to surgical embolectomy in patients with 7. Kearon C, Akl EA, Ornelas J, et al. Antithrombotic therapy
al
failed thrombolysis or contraindication to systematic lysis. for VTE disease: CHEST Guideline and Expert Panel
Probably, the guidelines are in need of more evidence with Report. Chest. 2016;149(2):315-52.
ic
larger randomized trials in studies. 8. Konstantinides SV, Torbicki A, Agnelli G, et al. 2014 ESC
guidelines on the diagnosis and management of acute
og
pulmonary embolism. Eur Heart J. 2014;35(43):3033-69.

CONCLUSION
9. Kucher N, Boekstegers P, Müller OJ, et al. Randomized,
Strict vigil and at the same time thoughtful management by controlled trial of ultrasound-assisted catheter-directed
an astute physician mind is warranted in management of PE.
ol
thrombolysis for acute intermediate-risk pulmonary

Decision making is largely dependent on risk stratification embolism. Circulation. 2014;129(4):479–86.
via clinical, hemodynamic, cardiac biomarkers, and
di
10. Kuo WT, Banerjee A, Kim PS, et al. Pulmonary embolism

echocardiographic parameters in association with response to Fragmentation, Embolectomy, and Catheter
estimation of bleeding risk. Anticoagulation should be Thrombolysis (PERFECT): Initial results from a prospective
ar
initiated when PE is strongly suspected and the bleeding multicenter registry. Chest. 2015;148(3):667-73.
risk is perceived to be low. Low-risk patients with acute PE 11. Laporte S, Mismetti P, Décousus H, et al. Clinical predictors
C
are continued on anticoagulation. Severely ill patients with for fatal pulmonary embolism in 15,520 patients with
high-risk (massive) PE require aggressive therapy, and venous thromboembolism: findings from the Registro
Informatizado de la Enfermedad TromboEmbolica venosa
if the bleeding risk is acceptable, systemic thrombolysis
(RIETE) Registry. Circulation. 2008;117(13):1711-6.
should be considered. Catheter-based therapy, consisting
12. Meyer G, Vicaut E, Danays T, et al. Fibrinolysis for patients
of various devices and techniques, with or without low-
with intermediate-risk pulmonary embolism. N Engl J Med.
dose thrombolytic therapy has a role in gray areas and
2014;370(15):1402-11.
borderline zones such as thrombolytic contraindication, 13. Mohan B, Aslam N, Mehra AK, et al. Impact of catheter
failed thrombolysis, subacute presentation, elderly fragmentation followed by local intrapulmonar y
patients, high-risk submassive PE or in patients with thrombolysis in acute high-risk pulmonary embolism as
severely compromised cardiopulmonary reser ve. primary therapy. Indian Heart J. 2014;66(3):294-301.
With progression of catheter-directed techniques and 14. Mohan B, Chhabra ST, Aslam N, et al. Mechanical
development of expertise over the years, endovascular breakdown and thrombolysis in subacute massive
622
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pulmonary embolism: A prospective trial. World J Cardiol. catheter-directed thrombolysis. Catheter Cardiovasc Interv. CHAPTER
2013;5(5):141-7. 2015;86(7):1219-27.
15. Mohan B, Mahajan V, Chhabra ST. Combined modality of
mechanical breakdown and intraembolus thrombolysis
18. Piazza G, Hohlfelder B, Jaff MR, et al. A prospective, single-
arm, multicenter trial of ultrasound-facilitated, catheter-
74
in failed systemic thrombolysis of subacute pulmonary directed, low-dose fibrinolysis for acute massive and

embolism patients. J Interv Cardiol. 2010;23(5):479–84. submassive pulmonary embolism: The SEATTLE II Study.
16. Müller-Hülsbeck S, Brossmann J, Jahnke T, et al. Mechanical JACC Cardiovasc Interv. 2015;8(10):1382-92.
thrombectomy of major and massive pulmonary embolism 19. Sharifi M, Bay C, Skrocki L, et al. Moderate pulmonary
with use of the Amplatz thrombectomy device. Invest embolism treated with thrombolysis (from the “MOPETT”
Radiol. 2001;36(6):317–22. Trial). Am J Cardiol. 2013;111(2):273–7.
17. Patel N, Patel NJ, Agnihotri K, et al. Utilization of catheter- 20. Weinberg AS, Dohad S, Ramzy D, et al. Clot extraction
directed thrombolysis in pulmonary embolism and with the FlowTriever device in acute massive pulmonary
a
outcome difference between systemic thrombolysis and embolism. J Intensive Care Med. 2016;31(10):1-4.
di
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Evaluation of Pulmonary
CHAPTER 75 Hypertension: A Simplified
Algorithm
a
di
INTRODUCTION while a mean PAP of 21–24 mm Hg at rest is considered
borderline which requires further evaluation and follow-
Pulmonary hypertension (PH) is a heterogeneous group
In
up. Invasive measurement of PAP is considered gold
of disorders which results in increase in pulmonary artery
standard. Many cases can often be diagnosed with
pressure (PAP) due to increased pulmonary vascular
noninvasive methods such as 2D-echo and CT chest [high
of
resistance. The PH is defined as mean PAP of 25 mm Hg
rest (HRCT), CT pulmonary angiography]. Whenever in
or greater at rest during right heart catheterization (RHC).
doubt, invasive studies must be performed since PH has
The PH may be difficult to recognize since common
dismal prognosis, if not timely diagnosed and treated. The
ty
symptoms, such as exertional dyspnea and fatigue, are
PH has been classified into 5 groups by current European
nonspecific. These symptoms are often thought to be due
Society of Cardiology (ESC 2015) guidelines. Entities
18 cie
to other comorbidities and diagnosis is delayed. A high
index of suspicion is required to make a timely diagnosis.
Despite of improved understanding of pathogenesis
included in individual group share common clinical
presentation, pathology, and hemodynamics. The current
updated clinical classification is given in Table 1.
and significant advancement in imaging modalities,
20 o
Classification of PH associated with congenital heart
work-up of PH remains a laborious process. A systematic disease is given in Table 2.
S
multidisciplinary approach is advocated when PH is

suspected. ALGORITHMIC APPROACH TO PULMONARY
al
HYPERTENSION (FIGURE 1)
DEFINITION AND CLASSIFICATION
Clinical Symptoms and Signs
ic
The definitive diagnosis of PH is made on RHC. The PH

is diagnosed when the mean PAP is ≥25 mm Hg at rest. A Both NIH registry and REVEAL registry showed that average
og
mean PAP below 20 mm Hg at rest is considered normal, delay between onset of symptoms and final diagnosis of
Table 1: Updated clinical classification of pulmonary hypertension (ESC guidelines 2015)

ol
1. Pulmonary arterial hypertension 3. Pulmonary hypertension caused by lung diseases and/or

1.1 Idiopathic PH hypoxia
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1.2 Heritable PH 3.1 Chronic obstructive pulmonary disease (COPD)

1.2.1 BMPR2 mutation 3.2 Interstitial lung disease (ILD)
1.2.2 Other mutations 3.3 Other pulmonary diseases with a mixed restrictive and
ar
1.3 Drugs and toxins induced obstructive pattern

1.4 Associated with: 3.4 Sleep-disordered breathing
1.4.1 Connective tissue disease 3.5 Alveolar hypoventilation disorders
C
1.4.2 Human immunodeficiency virus (HIV) infection 3.6 Chronic exposure to high altitude
1.4.3 Portal hypertension 3.7 Developmental lung diseases
1.4.4 Congenital heart disease 4. Chronic thromboembolic pulmonary hypertension and other
1.4.5 Schistosomiasis pulmonary artery obstructions
1’. Pulmonary veno-occlusive disease and/or pulmonary capillary 4.1 Chronic thromboembolic pulmonary hypertension
hemangiomatosis 4.2 Other pulmonary artery obstructions
1’’. Persistent pulmonary hypertension of the newborn (PPHN) 5. Pulmonary hypertension with unclear pulmonary
2. Pulmonary hypertension caused by left-sided heart disease multifactorial mechanisms
2.1 Left ventricular systolic dysfunction 5.1 Hematological disorders
2.2 Left ventricular diastolic dysfunction 5.2 Systemic disorders
2.3 Valvular disease 5.3 Metabolic disorders
2.4 Congenital/acquired left heart inflow/outflow tract 5.4 Others
obstruction and congenital cardiomyopathies
2.5 Other
Abbreviation: ESC, European Society of Cardiology
KG-75.indd 624 03-11-2018 12:38:13

Table 2: Pulmonary hypertension associated with congenital PH was 2 years. Delay in diagnosis was more common in CHAPTER
heart disease young individuals. This is due to the fact that symptoms
Eisenmenger
syndrome
Systemic to pulmonary shows resulting in
severe elevation in PVR leading to reverse
are often nonspecific and there is lack of suspicion on
part of treating physician. Symptoms include exertional
75

or bidirectional shunting. dyspnea, lethargy, and fatigue. As the disease progress,
PH associated with Moderately to large systemic to additional symptoms such as syncope and manifestations
prevalent systemic to pulmonary defects. PVR is mildly to
of right heart failure (abdominal distention, pedal edema)
pulmonary shunts moderately increased with left-to-right
shunting. appear. Other less common manifestations include cough,
PH with small/ Marked elevation in PVR in presence of hemoptysis, and hoarseness of voice (Ortner’s syndrome).
coincidental defects small cardiac defects which themselves Common physical signs include loud P2 component of
are not responsible for elevated PVR. This second heart sounds (S2), narrow split or single split S2,
a
entity behaves similar to idiopathic PH. parasternal heave, raised jugular venous pressure (JVP),
PH after defect PH persists or develops latter after
di
and holosystolic murmur of tricuspid regurgitation.
correction correction of congenital heart disease in
the absence of significant postoperative
Advanced disease is associated with clinical signs of right
In
hemodynamic lesions. heart failure.
Abbreviations: PH, pulmonary hypertension; PVR, pulmonary vascular
resistance
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Figure 1: Algorithmic approach for evaluation of pulmonary artery hypertension 625
KG-75.indd 625 03-11-2018 12:38:14

SECTION ECG and Chest X-ray right atrial pressure. The PH is suspected if TRV is ≥2.8
m/sec or estimated PASP is ≥35-40 mm Hg. Classification
9
Basic investigations, such as ECG and chest X-ray, may
provide clue to the presence of PH. However, a normal of PH based on PAP is given in Table 4. There are
ECG and X-ray do not rule out PH. The ECG findings are limitations with TRV measurements. Both overestimation
Vascular System
neither sensitive nor specific. Common findings include and underestimation of PH occurs frequently with
P-pulmonale, right axis deviation, right ventricular echocardiography. Whenever in doubt, the patient should
hypertrophy, right ventricular strain, and right bundle undergo RHC as discussed subsequently.
branch block (RBBB). Supraventricular arrhythmias, Other echocardiography parameters that may
such as atrial flutter and fibrillation, are usually seen in increase the suspicion of PH should also be looked into
advanced stage. (Table 2). Due to caveats in measurement of PH by
Chest X-ray provides valuable information since it is echocardiography, the ESC guidelines suggest grading
a
abnormal in significant proportion of patients at the time the probability of PH on the basis of TRV measurement at
di
of diagnosis. Chest X-ray findings include enlarged main rest and on the presence of additional echocardiographic
and hilar pulmonary arteries with peripheral pruning of features suggestive of PH. The probability of PH is then
In
pulmonary vasculature. Right ventricular enlargement judged as high, intermediate, or low (Table 5).
may be present which is best seen on lateral view. Echocardiography is often helpful in determining the
etiology. Left heart disease, mitral valve disease, and shunt
of
lesions can be easily diagnosed by echocardiography.
Echocardiogram
If PH is suspected based on clinical features, ECG and
Right Heart Catheterization
ty
chest X-ray, echocardiography is often the next step in
evaluation of PH. Echocardiography provides valuable The RHC has a crucial role in evaluation of PH. It firmly
severity of PH.
18 cie
information regarding the presence or absence and
Doppler echocardiography provides hemodynamic

establishes or excludes diagnosis of PH since it directly
measured PAP as compared to echocardiography which
relies on indirect calculations. The RHC also provides
assessment of PAP. Various echocardiographic parameters useful information on the degree of hemodynamic
20 o
of PH are shown in Figures 2A and B and Table 3, impairment, determines response to pulmonary arterial
S
respectively. Measurement of pulmonary artery systolic hypertension (PAH) therapy, and establishes prognosis.
pressure (PASP) is the most validated criteria. Its Indications of RHC are given in Table 6.
measurement is based on peak tricuspid regurgitation The RHC plays a pivotal role in the management of
al
velocity (TRV) (Bernoulli equation) taking into account group 1 PH. Vasodilator testing must be performed in all
ic
og
ol
Figure 2A: Various Doppler echocardiographic indices for the evaluation of PH

di
Abbreviations: SPAP, systolic pulmonary artery pressure; TRV, tricuspid regurgitation velocity; RAP, right atrial pressure; IVC, inferior vena cava;
MPAP, mean pulmonary artery pressure; DPAP, diastolic pulmonary artery pressure; PRV, peak pulmonary regurgitation velociy; TVI, time-velocity
ar
integral; PVR, pulmonary vascular resistance

C
B1 B2 B3
Figure 2B: Calculation of PH by Doppler parameters. (B1) Measured TRV is 3.68 m/s, calculated PASP is 54 mm Hg; (B2) IVC diameter is 2.2 cm
with <50% collapsibility suggesting a high RAP (15–20 mm Hg); (B3) MPAP as measured by PRV (yellow arrow) and DPAP as measure by PRV
ED (red arrow) were 31 mm Hg and 10 mm Hg respectively
626
KG-75.indd 626 03-11-2018 12:38:15

Table 3: Indirect echocardiographic signs suggesting pulmonary hypertension in addition to Doppler parameters (ESC guidelines 2015) CHAPTER
75
A: The ventricles B: Pulmonary artery C: Inferior vena cava and right atrium
Right ventricle/ left ventricle basal diameter Right ventricular acceleration time Inferior cava diameter >21 mm with decreased
ratio >1.0 inspiratory collapse (50% with a sniff or <20%

with quiet inspiration)
Flattening of the interventricular septum (left Early diastolic pulmonary regurgitation Right atrial area (end-systole) >18 cm2
ventricular eccentricity index >1.1 in systole velocity >2.2 m/sec
and/or diastole)
PA diameter >25 mm.
Abbreviation: ESC, European Society of Cardiology
a
patients of group 1 PH unless contraindicated. Agents used CT Scan
di
for acute vasodilator testing include inhaled nitric oxide
Chest CT is invaluable noninvasive imaging modality
(NO), intravenous (IV) epoprostenol and IV adenosine.
In
which is gaining importance as one of the frontline test
An acute response is defined as a decrease in mean PAP by
for evaluation of PH. It provides multifold benefits in
at least 10 mm Hg to an absolute value lower than 40 mm
evaluation of PH in the form of:
Hg in the absence of decreased cardiac output. Calcium-
of
Assessment of cause of PH
channel blockers are found to be very effective in patients
Allows comprehensive evaluation of pulmonary
who show a robust response to acute vasodilator testing.
vasculature and lung parenchyma
The RHC is also helpful in differentiating patients
ty
Additional evaluation of cardiovascular changes for
who have PH due to left heart disease (group 2 - systolic
dysfunction, diastolic dysfunction, or valvular heart assessment of disease severity.
18 cie
disease). This group is defined as postcapillary PH on the
basis of hemodynamics (Figure 3). It is characterized by
The CT signs suggestive of PH include pulmonary
artery dilatation (PA diameter ≥29 mm) and pulmonary
mean PAP ≥25 mm Hg and pulmonary capillary wedge ascending aorta diameter ratio (≥1.0). A segmental artery
20 o
pressure (PCWP) of >15 mm Hg. Rest of the PH groups bronchus ratio >1:1 in three or four lobes is highly specific
for PH.
S
(1, 3, 4, and 5) are included in precapillary group in which

PCWP is ≤15 mm Hg. It is the best method for evaluation of PH due to lung
Although chronic thromboembolic pulmonary parenchymal diseases (group 3). Diseases that involve
al
hypertension (CTEPH) can be diagnosed by CT pulmonary pulmonary microvasculature, such as pulmonary veno-
angiography and ventilation/perfusion lung scan (V/Q occlusive disease (PVOD) and pulmonary capillary
ic
scan), presurgical work-up of CTEPH requires RHC and hemangiomatosis (PCH) (group 1); and miscellaneous
traditional pulmonary angiography in most of the patients. causes, such as sarcoidosis, hematological disorders,
og
ol
Table 4: Grading of pulmonary hypertension based on pulmonary artery pressures

Severity of PH PASP (mm Hg) Mean PAP (mm Hg)
di
Mild 30–49 25–34

Moderate 50–70 35–49
ar
Severe >70 >50

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Abbreviations: PH, pulmonary hypertension; PASP, pulmonary artery systolic pressure; PAP, pulmonary artery pressure
Table 5: Echocardiographic probability of pulmonary hyperten-sion in symptomatic patients with a suspicion of pulmonary
hypertension (ESC guidelines 2015)
Peak tricuspid regurgitation velocity (m/s) Presence of other echo ‘PH signs Echocardiographic probability of pulmonary hypertension
≤2.8 or not measurable No Low
≤2.8 or not measurable Yes Intermediate
2.9–3.4 No
2.9–3.4 Yes High
>3.4 Not required
Abbreviation: PH, pulmonary hypertension

627
KG-75.indd 627 03-11-2018 12:38:15

SECTION
Table 6: Indications of right heart catheterization in pulmonary hypertension
9 z
Indications
To confirm the diagnosis of pulmonary arterial hypertension and for treatment decisions
Vascular System
z Vasodilator testing should be performed in all patients of pulmonary hypertension (group 1)

z To assess the treatment effect of drugs in pulmonary arterial hypertension (group 1) and follow up
z RHC is recommended in patients with congenital cardiac shunts to look for operability
z RHC is helpful when PH is suspected due to left heart disease (post capillary hypertension). It reliably differentiates postcapillary
hypertension from precapillary hypertension
z RHC is indicated in patients with CTEPH (group 4) for diagnosis and treatment purpose
a
Abbreviations: RHC, right heart catheterization; CTEPH, chronic thromboembolic pulmonary hypertension
di
neoplastic obstruction, and Langerhans cell histiocytosis In the randomized SERAPHIN trial, patients with a
In
(LCH) (group 5), are easily diagnosed with chest CT. 6MWD >400 m versus ≤400 m at month 6 had a reduced
The contrast-enhanced computed tomography (CECT) risk of PAH-related death or hospitalization (hazard ratio
performed with multiple detector computed tomography 0.48; 95% confidence interval 0.33-0.69).
of
(MDCT) scanners is the reference standard for diagnosis Exercise testing is helpful in the following ways:
of CTEPH as already discussed. Patients who have moderate-to-high probability of PH
and normal pulmonary artery pressure at rest should
ty
Ventilation/Perfusion Lung Scan be subjected to exercise to look for exercise induced PH.
To define the World Health Organization (WHO)
18 cie
The V/Q scan is useful in the patient with suspected
CTEPH. It has a higher sensitivity as compared to CT
pulmonary angiography. A normal or low probability V/Q
functional class on which treatment algorithm is
based.
Deterioration or improvement exercise in capacity on
20 o
scan effectively rules out CTEPH. However, CT scan is the
follow-up further guides changes in treatment therapy.
preferred modality now since it is easily available in most
S
To rule out other alternative diagnosis.

of the centers. Single photon emission CT could be better
modality than V/Q scan and CT pulmonary angiography;
Overnight Oxymetry and Polysomnography
al
however, more studies are needed to prove its superiority.

Overnight oxymetry can recognize patients who develop
ic
Exercise Testing and 6-minute Walk Test significant nocturnal desaturation. Such patients require
supplemental oxygen therapy during sleep. Formal
Exercise tests have predictive abilities for both diagnosis
og
polysomnography is indicated for sleep-related breathing

and prognosis. Evaluation of exercise capacity is
disorder (obstructive sleep apnea).
recommended in the recent guidelines for the assessment
of PH. The recommendations have relied on 6-minute
ol
Pulmonary Function Test

walk test (6MWT) distance (6MWD) and particular key
variables obtained from cardiopulmonary exercise testing Role of pulmonary function test (PFT) in evaluation of PH
di
(CPET). Whilst less frequently used than the 6MWT is limited. The PFT are done when significant pulmonary
to assess functional capacity, CPET remains the gold disease (restrictive or obstructive) is suspected. However,
ar
standard for assessing cardiorespiratory fitness and is PH has a variable association with the degree of lung
part of various PH specialty centers. However, CPET is not damage as assessed radiologically and by lung function.
C
easily available. The PH is usually seen in more advanced chronic

The 6MWT is an important test to quantify functional obstructive pulmonary disease (COPD) and interstitial
capacity. It is a useful prognostic indicator in all major lung disease (ILD).
trials of PH. A lower 6MWT test is associated with poor Moreover, mild-to-moderate abnormalities in PFT
prognosis The subject is instructed to walk as far as may be seen in group 1 PH and other groups since
possible in six minutes in a 30-meter walkway or corridor. many patients of PH have mild-to-moderate reduction
Oxygen saturation, breathlessness, and heart rate are in various PFT parameters. Thus, PFT offers little help
measured before, during, and at the completion of the in differentiating various groups of PH unless grossly
6MWT. Rest is permissible and if walking aids are used, abnormal.
it is noted in the report. The 6MWT has been found to
be reliable, with intraclass correlation coefficient values Additional Investigations
ranging between 0.72 and 0.99. The outcome of the test is Additional blood tests are indicated when a specific
expressed in total distance covered. etiology of PH is suspected. Routine hematology and
628
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CHAPTER
75

Figure 3: Differentiation of pulmonary hypertension due to left heart disease from other groups
a
di
thyroid function test should be performed in all the parenchyma and vasculature (group 3 and group 4). The
patients. Various investigations include: RHC remains gold standard for evaluation. It should be
In
Liver function test (LFT) when portopulmonary performed, whenever indicated since risk of RHC is minimal.
hypertension is suspected. However, LFT may be Role of basic investigations, such as PFT, oxymetry, and
abnormal due to advanced disease because of hepatic polysomnography, is equally important. Hence, a step-wise
of
congestion, cardiac cirrhosis, or use of endothelin systematic approach is advisable.
receptor antagonist.
Serological testing for connective tissue disorders
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[such as antinuclear antibody (ANA)], viral hepatitis,
and human immunodeficiency virus (HIV). 1. Bossone E, D’Andrea A, D’Alto M, et al. Echocardiography
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Laboratory studies for hemolytic anemia.
Thrombophilia screening for CTEPH such as

in pulmonary arterial hypertension: from diagnosis to
prognosis. J Am Soc Echocardiogr. 2013;26(1):1–14.
2. Dunlop B, Weyer G. Pulmonary Hypertension: Diagnosis
antiphospholipid antibodies, anticardiolipin anti-
and Treatment. Am Fam Physician. 2016;94(6):463-9.
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bodies, and lupus anticoagulant.
3. Farber HW, Gibbs S. Under pressure: pulmonar y
N-terminal pro-brain natriuretic peptide (NT-pro-
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hypertension associated with left heart disease. Eur Respir

BNP)/BNP may be elevated in both left and right heart Rev. 2015;24(138):665-73.
failure. Thus, it does not have any diagnostic value. 4. Galiè N, Humbert M, Vachiery JL, et al. 2015 ESC/ERS
al
However, raised NT-pro-BNP/BNP is an indicator of Guidelines for the diagnosis and treatment of pulmonary
poor prognosis. hypertension: The Joint Task Force for the Diagnosis and
ic
Treatment of Pulmonary Hypertension of the European

Society of Cardiology (ESC) and the European Respiratory
CONCLUSION
og
Society (ERS): Endorsed by: Association for European

Diagnosing PH in timely manner offers a significant challenge Paediatric and Congenital Cardiology (AEPC), International
to clinicians. A high index of suspicion is always required. Out Society for Heart and Lung Transplantation (ISHLT). Eur
of various diagnostic modalities appropriate investigations is
ol
Heart J. 2016;37(1):67-119.
based on clinical profile of the patient and echocardiographic 5. Grignola JC. Hemodynamic assessment of pulmonary
findings. The CT chest is quite useful while evaluating using hypertension. World J Cardiol. 2011;3(1):10-7.
di
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Recent Advances in the
Management of Idiopathic
CHAPTER 76
Pulmonary Artery Hypertension
a
di
INTRODUCTION available for years and macitentan is the new addition.
Idiopathic pulmonary hypertension (PAH) is a rare Sildenafil, tadalafil, bosentan, and ambrisentan have
In
disease with poor prognosis. Though there have been been available in India for many years. Macitentan and
advances in pharmacotherapy in the last few years, the riociguat are recently introduced in India.
prognosis for this condition remains poor with estimated
of
5-year survival of about 7–8 years at present. Patients in COMBINATION THERAPY
India are further disadvantaged due to the fact that some It has been a common practice to introduce targeted
ty
of the proven medications are not available and are very therapy sequentially as per the clinical response. The
expensive to import. When the patient continues to be in Ambrisentan and Tadalafil in Patients with Pulmonary
18 cie
functional class IV despite maximum medical therapy, the
only viable option available is heart-lung transplantation.
It is prohibitively expensive with uncertain outcomes in
Arterial Hypertension (AMBITION) trial has shown that
upfront combination therapy with ambrisentan and
tadalafil is superior to sequential administration. Upfront
Indian scenario. In this chapter, we will review some of the combination therapy is advised to patients especially
20 o
recent advances in the management of idiopathic PAH. those who present with severe symptoms or advanced
S
disease.1
PHARMACOTHERAPY
al
Most important mechanism for development of PAH is ORAL ANTICOAGULANTS

endothelial dysfunction and/or injury, which leads to Small retrospective studies but not randomized controlled
ic
imbalance in production of endogenous vasodilators trials have shown the benefit of oral anticoagulants in
(prostacyclin & nitric oxide) and vasoconstrictors PAH patients. In two large contemporary registries, the
og
(endothelin & serotonin). Current pharmacotherapy question has been addressed. In a European PAH registry,
(selective pulmonary vasodilators) mainly involves Comparative, Prospective Registry of Newly Initiated
working on these molecular pathways involved in the Therapies for Pulmonary Hypertension (COMPERA), oral
ol
maintenance of pulmonary vascular tone. These drugs anticoagulants have shown survival benefit in patients
basically decrease the pulmonary artery muscle tone with idiopathic PAH but not in other forms of PAH. In
di
thereby decreasing the resistance and pressure. The basic contrast, the Registry to Evaluate Early and Long-term
pathogenic hall mark of endothelial and smooth muscle PAH Disease Management (REVEAL) from the USA did
ar
proliferation is not targeted. Hence, in spite of the so-

not show any survival advantage with oral anticoagulants
called targeted therapy, the progression of underlying
and was actually harmful in patients with systemic
C
disease is relentless.
sclerosis-associated PAH.2,3
The three molecular pathways that are involved
include nitric oxide pathway, prostaglandin pathway,
and endothelin pathway. The existing drugs for Riociguat
nitric oxide pathway include inhaled nitric oxide or Riociguat is a soluble guanylate cyclase (sGC) stimulator.
phosphodiesterase-5 (PDE-5) inhibitors, sildenafil, The sGC converts guanosine triphosphate (GTP) to
and tadalafil. Riociguat is a new drug in this pathway. cyclic guanylate monophosphate (cGMP) which causes
The existing drugs in prostaglandin pathway include vasodilatation and decreases smooth cell proliferation.
intravenous epoprostenol, inhaled iloprost, and treprostinil Administration of riociguat leads to increased production
that can administered through oral, subcutaneous or of cGMP and pulmonary vasodilatation. In the pivotal
intravenous routes. Oral treprostinil and selexipag are the phase 3 study, Pulmonary Arterial Hypertension Soluble
recent additions in this pathway. Bosetan and ambrisentan Guanylate Cyclase–Stimulator Trial 1 (PATENT-1),
are endothelin receptor antagonists (ERA) that have been the maximum tolerated dose of riociguat (0.5–2.5 mg)
KG-76.indd 630 03-11-2018 12:38:02

thrice a day was compared to placebo in group 1 PAH significant side effects and proven efficacy in preventing CHAPTER
patients. 4 Patients could be drug naïve or could be morbidity and mortality events.6
taking background ERA or prostaglandins excluding
intravenous prostanoids). Patients taking PDE-5 inhibitors
76
Selexipag
Recent Advances in the Management of Idiopathic Pulmonary Artery Hypertension

are excluded. It is a 12-week study and change in six-
Selexipag is a prostacyclin receptor agonist that can be
minute walk distance (6MWD) was the primary end
administered orally. Structurally, it is different from other
point. At the end of 12 weeks, there was a 30-meter
prostanoids used in the treatment of PAH. It decreases
increase in riociguat arm compared to 6-meter decrease
PVR and increases cardiac output. In an event-driven
in placebo arm which is statistically significant. There
phase-3 clinical trial, the Prostacyclin (PGI2) Receptor
was significant improvement in other parameters such
Agonist In Pulmonary Arterial Hypertension (GRIPHON),
as pulmonary vascular resistance (PVR), N-terminal
a
it was studied in 1,156 patients. Selexipag was given
pro-b-type natriuretic peptide (NT-proBNP) levels, and
at a maximum tolerated dose (beyond which patients
di
functional class. The drug was well tolerated without any
will have intolerable prostaglandin-related side effects)
major side effects. The benefit was noted irrespective of
ranging from 200 to 1,600 mg twice a day. Patients were
In
the background therapy. Riociguat is the only drug that
permitted to take background medication ERA or PDE-5
was shown to be beneficial in the management of chronic
inhibitors but not prostanoids. The primary end point
thromboembolic pulmonary hypertension.5 It has been
is morbidity and mortality composite end point. There
of
approved by the US Food and Drug Administration (FDA).
was a significant 40% reduction in the primary end point.
Selexipag is consistently effective at each maximally
Macitentan tolerated dose, which means a maximum tolerated dose
ty
Macitentan is an endothelial receptor antagonist. Unlike of 200 mg twice a day is as effective as maximum tolerated
ambrisentan, macitentan is a dual endothelin receptor dose of 1,600 mg twice a day.7 It is important to up titrate
18 cie
antagonist working on both ETA and ET B receptors. It
has increased affinity for receptors with long-lasting
the dose to maximum tolerated dose. Prostaglandin-
related side effects are dose dependent and include
occupancy. In preclinical studies, it has shown better headache, diarrhea, nausea, jaw pain, flushing, myalgia,
20 o
efficacy compared to other ERA. Unlike bosentan, it arthralgia, and extremity pain. However, over a period of
does not interact with bile salt export pump and does time, the severity of the side effects decreased and the drug
S
not cause any hepatotoxicity. It was evaluated in a global became more tolerable. It is noteworthy that selexipag was
event-driven outcome randomized controlled trial, Study beneficial over and above the background therapy with
al
with an Endothelin Receptor Antagonist in Pulmonary ERA and PDE-5 inhibitors.

Arterial Hypertension to Improve Clinical Outcome
ic
(SERAPHIN), the primary end point of which was time to Treprostinil

clinical worsening. It was a novel end point for a clinical
og
Oral trepostinil is being developed by United Therapeutics

trial in PAH. All earlier drug trials in PAH utilized change
which had successfully developed injectable treprostinil
in 6MWD over a short period ranging from 12 to 16
that can be administered subcutaneous or intravenous
weeks. The study was conducted in patients with Group
ol
route. However, until today, oral treprostinil is not a very

1 pulmonary hypertension (PH). Patients could be drug
successful drug in PAH treatment. Oral treprostil is less
naïve, or using background therapy with PDE-5 inhibitors
di
effective and poorly tolerated due to its side effects. In

or inhaled or oral prostanoids. They should not be using
short-term clinical trials, it has improved 6MWD in drug
other ERAs. Macitentan 3 mg or 10 mg once a day dose
ar
naïve patients but has no significant effect on 6MWD in

was compared with placebo in 1:1:1 ratio. The study was
patients who have been taking ERAs or PDE-5 inhibitors.8,9
done in 742 patients with median treatment duration
A large multicenter trial is underway that has a combined
C
of 115 weeks. Over the study period, patients receiving

morbidity and mortality end point. Results are expected
macitentan had a 45% relative risk reduction in morbidity
soon and its exact role can be defined. However, like
and mortality events. There was significant improvement
selexipag, exact dosing for each patient will be a challenge
in functional class, 6MWD and quality of life. Drug was
in clinical practice.
well tolerated. Unlike bosentan, there was no signal for
hepatotoxicity; and unlike ambrisentan, there was no
incidence of pedal edema. Nasopharyngitis is a common Ranolazine
side effect and occasionally anemia may be seen. From the Right ventricular (RV) systolic function is an important
available evidence, it cannot be commented whether the prognostic determinant of survival in PAH. Ranolazine is
drug is superior to bosentan or ambrsentan since head- a metabolic modulator that improves systolic function.
to-head comparative studies are not done. However, the In short-term studies, administration of ranolazine
major advantage of this drug seems to be the absence of to patients with RV dysfunction, due to PAH, led to
631
KG-76.indd 631 03-11-2018 12:38:02

SECTION improvement in RV systolic function indices such as was done in 13 patients and 8 patients who refused the
tricuspid annular plane systolic excursion (TAPSE), RV procedure served as controls. They reported sustained
9 free wall longitudinal strain, and fractional area change. Its
role in improving clinical outcomes, if any, is not known.10
clinical and hemodynamic benefit and improvement in
6MWD. Interestingly, there are no other publications on
Vascular System
this treatment modality.

Spironolactone
Activation of endothelial cell ETA receptors on pulmonary POTTS SHUNT
artery endothelial cells is associated with pulmonary Potts shunt is creation of anastomosis between left
vasodilatation. Hyperaldosteronism as seen in PAH pulmonary artery and descending thoracic aorta. It can be
results in increased oxidative stress which in turn done by surgery, transcatheter route or by stenting a probe
a
results in inhibition of ETA receptors. Spironolactone, an patent PDA.15,16 Conceptually, it works when the patient
aldosterone antagonist, decreases the inhibitory effect has suprasystemic PA pressures. By shunting into lower
di
of oxidative stress thus enhancing vasodilatation. In a pressure aorta from PA with suprasystemic pressures,
short-term clinical trial, combination of spironolactone RV afterload is decreased. In balloon atrial septostomy,
In
to ambrisentan led to more decrease in brain natriuretic there is shunting of desaturated blood at atrial level and
peptide (BNP) concentrations and more increase in coronary and cerebral circulations get hypoxic blood;
6MWD compared to treatment with ambrisentan alone.11 while in Potts shunt, desaturated blood is shunted to lower
of
body. Multiple publications have reported good midterm
Imatinib clinical benefits and probable survival advantage.17-19 This
ty
Imatinib inhibits platelet-derived growth factor receptors, can be considered in patients who are not candidates for
a tyrosine kinase, that is strongly upregulated in small heart-lung transplantation. Surgical correction is easier in
18 cie
pulmonary arteries leading to pulmonary vascular
remodeling and subsequently pulmonary hypertension.
In a small randomized, double blind, placebo-controlled
childhood. In adults, the surgery can be challenging due to
the fact that the distance between pulmonary artery and
aorta increases. Transcatheter Potts shunt is technically
trial, Imatinib in Pulmonary Arterial Hypertension, a challenging and only a few cases are reported till date.
20 o
Randomized, Efficacy Study (IMPRES), 202 patients with These procedures, both surgery and transcatheter route,
S
PVR ≥ 800 Dynes sec cm–5 symptomatic on more than 2 PAH carry high mortality and there is steep learning curve. In
therapies were randomized to imatinib vs. placebo and patients with subsystemic PA pressures, a valved conduit
followed up for 24 weeks. Imatinib showed improvement
al
may be used to direct right-to-left shunting and prevent

in exercise capacity and hemodynamics, but serious left-to-right shunt.20 Its role in patients with subsystemic
adverse events and drug discontinuations were limitations
ic
PAH needs to be established. Theoretically, it is possible

of the study. 12 There could be an occasional patient that even in patients with subsystemic PA pressures, there
og
who would respond to imatinib. It is not recommended can be intermittent right-to-left shunt depending upon
for routine use but can be tried in a rare patient who is relative pulmonary and systemic vascular resistance.
worsening and has no other treatment option. Close Further, measured PA pressures reflect both the pulmonary
ol
monitoring for efficacy and side effects is warranted. vascular resistance as well as the right ventricle systolic
Patients should not receive concomitant anticoagulants as function. Failing right ventricle may not be able to generate
di
there is increased incidence of subdural hematomas with suprasystemic pressures, even in the presence of very high
this combination. pulmonary vascular resistance. In such situations, Potts
ar
shunt may still shunt right to left in the presence of what

STEM CELL THERAPY appears to be subsystemic PA pressure. This therapy
C
Many clinical trials are going on in animal models; but, should be developed further in countries like India, where
to date, there is only one small published study in seven heart-lung transplantation is prohibitive.
patients. There was some improvement in 6MWD but not
in hemodynamic parameters. There is no proven clinical EXPERIMENTAL THERAPIES
efficacy.13 There are many molecules that are shown to be effective
in rat model of PAH but not in human beings. There
PULMONARY ARTERY DENERVATION are many promising new treatment targets currently in
C h e n e t a l . h av e d e s c r i b e d p u l m o n a r y a r t e r y experimental stages.21 Some of the drugs being evaluated
denervation therapy in patients with PAH. 14 They have are listed below:
done radiofrequency ablation similar to renal artery Nuclear factor eryrythroid 2–related factor 2 (Nrf2)
denervation at pulmonary artery bifurcation, at the activator and Nuclear Factor Kappa B (NFkB)
ostia of right and left pulmonary arteries. The procedure suppressor: Bardoxolone methyl.
632
KG-76.indd 632 03-11-2018 12:38:02

Bone morphogenetic protein (BMP) signaling REFERENCES CHAPTER
activator: FK 506 (tacrolimus)
76
1. Hoeper MM, McLaughlin VV, Barberá JA, et al. Initial
Interleukin-6 (IL-6) pathway (tocilizumab) combination therapy with ambrisentan and tadalafil and
Glutamine-N-methyl-D-aspartate (NMDA) receptor mortality in patients with pulmonary arterial hypertension:
Recent Advances in the Management of Idiopathic Pulmonary Artery Hypertension

axis. a secondary analysis of the results from the randomised,
controlled AMBITION study. Lancet Respir Med.
2016;4(11):894-01.
Nuclear Factor Erythroid 2–related Factor 2
2. Hoeper MM, Huscher D, Ghofrani HA, et al. Elderly
(Nrf2) Activator and Nuclear Factor Kappa B patients diagnosed with idiopathic pulmonary arterial
(Nfkb) Suppressor hypertension: results from the COMPERA registry.
Bardoxolone methyl is an oral, once-daily antioxidant International journal of cardiology. 2013;168(2):871-80.
a
inflammation modulator. It activates Nrf2, a protein that 3. Badesch DB, Raskob GE, Elliott CG, et al. Pulmonary
arterial hypertension: baseline characteristics from the
induces molecular pathways that protect against oxidative
di
REVEAL Registry. Chest. 2010;137(2):376-87.
damage due to inflammation and injury. A Dose-Ranging
4. Ghofrani H, Galie N, Grimminger F, et al. Riociguat for
Study of the Efficacy and Safety of Bardoxolone Methyl
In
the treatment of pulmonary arterial hypertension: a
in Patients with Pulmonary Hypertension (LARIAT) is randomized, double-blind, placebo-controlled study
an ongoing phase 2 study examining safety, tolerability, (PATENT-1). Chest. 2012;142(4):1027.
of
and efficacy of bardoxolone methyl for the treatment of 5. Ghofrani HA, D’Armini AM, Grimminger F et al. CHEST-1
patients with pulmonary hypertension.22 Study Group. Riociguat for the treatment of chronic
thromboembolic pulmonary hypertension. N Engl J Med.
ty
2013;369(4):319-29.
BMP Signaling Activator: FK 506 (Tacrolimus)
6. Pulido T, Adzerikho I, Channick RN, et al.. Macitentan
Dysfunctional BMP signaling is a general feature of PAH and morbidity and mortality in pulmonary arterial
18 cie
and tacrolimus, an inhibitor of nuclear factor of activated
T-cells (NFAT) family, was reported to reverse severe PH
hypertension. N Engl J Med. 2013;369:809-18.
7. Sitbon O, Channick R, Chin KM, et al. Selexipag for the
in the hypoxia model by restoring bone morphogenetic Treatment of Pulmonary Arterial Hypertension. N Engl J
20 o
protein receptor type 2 (BMPR2) signaling. Tacrolimus has Med. 2015;373(26):2522-33.
been studied in the single center randomized controlled 8. Jing ZC, Parikh K, Pulido T, et al. Efficacy and safety of oral
S
phase 2 safety and efficacy trial, FK506 (Tacrolimus) treprostinil monotherapy for the treatment of pulmonary
arterial hypertension: a randomized, controlled trial.
in Pulmonary Arterial Hypertension (TransformPAH).
al
Circulation. 2013;127(5):624-33.
Early experience with compassionate use in end-stage
9. Tapson VF, Jing ZC, Xu KF, et al. Oral treprostinil for the
patient appears promising but further clinical trials are treatment of pulmonary arterial hypertension in patients
ic
warranted.23 receiving background endothelin receptor antagonist

and phosphodiesterase type 5 inhibitor therapy (the
og
Inflammatory Pathway FREEDOM-C2 study): a randomized controlled trial. Chest.

2013;144(3):952-8.
Tocilizumab, an anti-IL-6 monoclonal antibody is being
10. Mardi Gomberg-Maitland, Robert Schilz, Anuj Mediratta,
ol
studied in an open label phase 2 study, TRANSFORM-UK, et al. Phase I safety study of ranolazine in pulmonary
to assess the safety and efficacy of the drug in WHO group arterial hypertension Pulm Circ.2015;5(4):691–700.
di
1 PAH with WHO functional class 2 to 4. Final results of the 11. Maron BA, Waxman AB, Opotowsky AR, et al. Effectiveness
study are awaited.24 of spironolactone plus ambrisentan for treatment of
ar
pulmonary arterial hypertension (from the [ARIES] study 1

Glutamine-NMDA Receptor Axis and 2 trials). Am J Cardiol. 2013;112:720-5.
12. Frost AE, Barst RJ, Hoeper MM et al. Long-term safety and
C
Glutamine-NMDA (N-Methyl-D-aspartate) receptor axis efficacy of imatinib in pulmonary arterial hypertension. J

is dysregulated in PAH. Vascular NMDA receptors could Heart Lung Transplant. 2015;34(11):1366-75.
be potential targets for antiremodeling in PAH.25 13. Granton J, Langleben D, Kutryk MB, et al. Endothelial
NO-Synthase Gene-Enhanced Progenitor Cell Therapy for
CONCLUSION Pulmonary Arterial Hypertension: The PHACeT Trial. Circ
Res. 2015;117(7):645-54.
Treatment of PAH (Group 1 of PH diseases) continue to be 14. Chen SL, Zhang FF, Xu J, et al. Pulmonary artery denervation
frustrating. While the recent drug discoveries have made a to treat pulmonary arterial hypertension: the single-center,
significant change in patients’ outcome, a lot more needs prospective, first-in-man PADN-1 study (first-in-man
to be done. pulmonary artery denervation for treatment of pulmonary
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SECTION artery hypertension). Journal of the American College of 20. Keogh AM, Nicholls M, Shaw M, et al. Modified Potts shunt
Cardiology. 2013;62:1092-100. in an adult with pulmonary arterial hypertension and
9 15. Kula S, Atasayan V. Surgical and transcatheter management

alternatives in refractory pulmonary hypertension: Potts
recurrent syncope - three-year follow-up. Int J Cardiol.
2015;182:36-7.
shunt. Anatol J Cardiol. 2015;15(10):843-7. 21. Hu J, Xu Q, McTiernan C, et al. Novel targets of drug
Vascular System
16. Latus H, Apitz C, Moysich A, et al. Creation of a functional treatment for pulmonary hypertension. American Journal
Potts shunt by stenting the persistent arterial duct in of Cardiovascular Drugs. 2015;15(4):225-34.
newborns and infants with suprasystemic pulmonary 22. Bardoxolone methyl evaluation in patients w ith
hypertension of various etiologies. J Heart Lung Transplant. pulmonary arterial hypertension (PAH)—LARIAT. Reata
2014;33:542-6. Pharmaceuticals. Available from: http://clinicaltrials.gov/
17. Baruteau AE, Belli E, Boudjemline Y, et al. Palliative Potts ct2/show/NCT02036970. Accessed May 2018.
shunt for the treatment of children with drug-refractory 23. Spiekerkoetter E, Sung YK , Sudheendra D, et al.
a
pulmonary arterial hypertension: updated data from the Randomised placebo-controlled safety and tolerability trial
di
first 24 patients. Eur J Cardiothorac Surg. 2015;47:105-10. of FK506 (tacrolimus) for pulmonary arterial hypertension.
18. Boudjemline Y, Patel M, Malekzadeh-Milani S, et al. Eur Respir J. 2017;50(3).
Patent ductus arteriosus stenting (transcatheter Potts 24. Hernández-Sánchez J, Harlow L, Church C, et al. Clinical
In
shunt) for palliation of suprasystemic pulmonary arterial trial protocol for TRANSFORM-UK: A therapeutic open-
hypertension: a case series. Circ Cardiovasc Interv. label study of tocilizumab in the treatment of pulmonary
2013;6:18-20. arterial hypertension. Pulm Circ. 2018;8(1).
of
19. Gorbachevsky SV, Shmalts AA, Barishnikova IY, et al. Potts 25. Dumas SJ, Bru-Mercier G, Courboulin A, et al. NMDAtype
shunt in children with pulmonary arterial hypertension: glutamate receptor activation promotes vascular
institutional experience. Interact Cardiovasc Thorac Surg. remodelling and pulmonary arterial hypertension.
ty
2017;25:595-9. Circulation. 2018;137:2371–89.
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Kawasaki Disease:
CHAPTER 77 What We Should Know?
‘It licks the skin and mucosal membrane, and bites the coronaries.’
a
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INTRODUCTION commonly expressed in Japanese and Asian children.
Kawasaki disease (KD) is a disease of the young, frequently It occurs throughout the year with occasional seasonal
In
affecting children below 5 years. Adult population may clustering and is not likely to be communicable. The
have coronary artery disease (CAD) as a consequence of youngest age of KD worldwide is 2 weeks and the oldest
is in the thirties. Neonates have KD very rarely and also
of
childhood KD. KD is now considered to be the second
adults. KD is particularly uncommon beyond 8 years. An
most common cause of acquired heart illness in India,
older child may have atypical KD and late diagnosis; and,
next only to rheumatic fever/rheumatic heart disease (RF/
hence, increased prevalence of coronary lesions.
ty
RHD). In Kerala, it has, probably, overtaken RF/RHD. KD
The slow emergence of KD in India is due to many
is now established as a ‘novel’ risk factor for CAD in adults;
reasons. Underdiagnosis, under-reporting, late diagnosis,
18 cie
and, hence, the pediatricians, pediatric cardiologists, and
cardiologists should know about this enigmatic illness.
lack of awareness, geographic localization, and lack of
specific tests are some of them. In addition, sequential
evolution of various clinical criteria, multiple physicians
HISTORICAL PERSPECTIVE
20 o
involved (e.g. pediatricians, ophthalmologists and
The first case of KD was reported in a 4-year-old child in dermatologists), atypical presentation, less sensitization
S
Japan by Tomisaku Kawasaki in 1964. In 1974, the first among pediatric community and lesser number of
English language report was published. In the 1990s, pediatric cardiologists may be other reasons.
al
diagnostic criteria were refined, role of echocardiography

was defined, and use of intravenous immunoglobulin Prevalence
ic
(IVIG) was initiated. Single-dose IVIg was introduced in

The prevalence in various countries is as follows:
the 1990s. This century saw the development of new drugs
og
Japan: 240/100,000—Children < 5 years

and re-emergence of steroids in the therapeutics of KD.
USA: 25/100,000—Children < 5 years
When the first case of KD in India was reported by
UK: 5-10/100,000—Children < 5 years
Taneja from Delhi in 1987, it was greeted with skepticism
ol
Kerala with 3.5 million population of children below

but later the disease seems to have become widespread in
5 years is presumed to have a prevalence of 5–10/100,000
varying regions of India. Acceptance arrived later. The first
di
(Table 1).
major series on KD was published from Kerala in 1997.
Host susceptibility may be genetically mediated.
ar
Twins have a 13% incidence in KD. However, the sibling

EPIDEMIOLOGICAL PERSPECTIVE risk is only 2% and offspring risk 1%. Genetic influence
Kawasaki disease is a disease of infants and young children, is suggested by the presence of high prevalence in Japan,
C
80% of KD occurs below five years; more than half (60%) Asia, and in the USA. Not only KD susceptibility but also
occurs before 2 years, and the peak age is around one year. the outcome may depend on genetic influence. Various
It is more common in boys than girls (1.5:1) and is more human leukocyte antigens (HLA) are being implicated.
Table 1: Epidemiological profile of KD

UK USA India Kerala
Prevalence/100,000 5–10 10–20 ? 5–10?
Rank in acquired HD 1 1 2 1
Below 5 years 75% 80% 80% 70%
M/F ratio 1.5:1 1.5:1 2:1 1.5:1
Peak age 6–12 mon 18–24 mon 18–24 mon 18–30 mon
Seasonality ? + ? 0
KG-77.indd 635 03-11-2018 12:37:31

SECTION Kawasaki Disease Table 2: Possible causative agents
9
Recurrence: Bacteria: Staphylococci Corynebacterium
Japan: 5/1000 patient years Streptococci Yersinia
Propionibacteria
USA; 2/1000 patient years
Myobacteria
Vascular System
Death: 0.015 to 0.1%

Chlamydia
Virus: Measles
PATHOLOGY EBV
Adeno
Possible causative agents postulated include bacteria, Parainfluenza
viruses, dust mite, and certain noninfectious agents such Parvovirus
as carpet shampoo, insecticides, and mercury. Recently,
a
bacterial superantigens (staphylococcal or streptococcal)
Polymorphous exanthema
di
have been strongly implicated in the genesis of KD. Virus
Bilateral nonpurulent conjunctival congestion.
may be having a helper role in immune-mediated vascular
Changes in the lips of oral cavity
injury. None have been directly implicated. Of late,
In
Acute nonsuppurative cervical lymphadenopathy.
possible prenatal insults like advanced age of mother and
If five principal features are present or if four are
maternal group B Streptococcus (GBS) colonization and
present with echocardiographic coronary artery lesions
of
infant with history of bacterial infection are implicated in
(CAL) demonstrated, the diagnosis of KD is made
the genesis of KD (Table 2 and Figure 1).
(Figure 2).
Cardiac pathology in KD passes through four stages I to
ty
IV. They are stages of:
Microvascular angitis (0–10 days)
Other Significant Findings
The other significant findings include:
18 cie
Panvasculitis with aneurysm development (12–25 days)
Granulation of coronaries (28–31 days)
Scarring (40 days to 4 years).

Cardiovascular: S3 gallop, murmur, soft S1, ECG
abnormalities, cardiomegaly, myocardial infarction,
and pericarditis
20 o
Gastrointestinal: Vomiting, diarrhea, colic, hydrops of
CLINICAL DIAGNOSIS
S
gallbladder, paralytic ileus, and mild hepatitis

The diagnosis of KD is still essentially clinical, supported Hematological: Polymorphonuclear leukocytosis,
by laboratory findings and echocardiography. In the thrombocytosis, elevated erythrocyte sedimentation

al
absence of a specific diagnostic gold standard, clinical rate (ESR), C-reactive protein (CRP), hypoalbuminemia,
diagnosis is the major tool. and anemia
ic
Urinary: Proteinuria, pyuria, and nephrotic syndrome
American Heart Association (AHA) Guidelines Re s pi rat o r y : Pu l m o na r y n o d u l e, c ou g h, a n d

og
(2017) pneumonia
I. > 5 days of fever plus Joints: Arthralgia and polyarthritis
Neurological: Aseptic meningitis and seizures.

ol
II. 4/5 of principal clinical features

a. Changes of the extremities Fever is usually high grade, abrupt in onset and can
spike. It may last for 10–14 days. Conjunctival congestion
di
b. Rashes
c. Conjunctival congestion is nonpurulent and occurs within 1–3 days, oral mucosal
d. Oral changes changes occur within 2 days, causing changes in lips,
ar
e. Lymphadenopathy oral mucosa, and a ‘strawberry’ tongue. These changes

may last for 10 days. Extremity changes include palmar
C
and plantar erythema with induration which starts on

Japanese Kawasaki Disease Research
the 3rd to 5th day with desquamation occurring by 2nd
Committee Criteria
and 3rd week. Polymorphous exanthematous rashes
We can also follow the Japanese Kawasaki Disease occur predominantly on trunk within 3–4 days and lasts
Research Committee (JKDRC) fourth revision diagnostic for 1 week. Lymph node enlargement occurs in 75% and
guidelines to diagnose KD. appears within 3 days of illness (Figure 3).
Principal Symptoms Laboratory Findings

Fever Hb <11 g 65%
Changes in extremities TLC > 11000 70%
— Acute – red palm/sole with indurative edema. Platelet count >4–5 L 45%
— Subacute – desquamation of fingers, toes, sole and ESR >30 98%
palm. CRP +ve 72%
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KG-77.indd 636 03-11-2018 12:37:32

CHAPTER
77

a
di
In
of
ty
Figure 1: Pathogenesis model
18 cie
20 o S
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ic
og
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Figure 3: Clinical features of KD (n = 69)

Source: SAT Hospital, Thiruvananthapuram
di
ar
Figure 2: Kawasaki disease—time sequence of principal findings LABORATORY EVALUATION

Blood Counts
C
Differential Diagnosis
A carefully done blood count is extremely useful. There
A number of childhood illnesses mimic KD. They include could be mild anemia. Polymorphonuclear leukocytosis
measles, staphylococcal scalded skin syndrome (SSSS), is present in more than half. A very high count (>30,000)
drug rashes, IMN, and other viral exanthems in infants. is perhaps a risk factor/marker for coronary artery lesion
In toddlers and children, Steven-Johnson syndrome (SJS), (CAL). A raised ESR is almost always present, as is an
measles, toxic shock syndrome, SSSS, systemic juvenile elevated CRP. An ESR beyond 100 mm/hr or persistently
high ESR or CRP could be indicators of development of
rheumatoid arthritis, drug reactions, scarlet fever and
CAL. Elevated ESR and CRP will become normal in 6–8
RF can be part of differential diagnosis. A careful history weeks. ESR may remain high for variable period if IVIg is
taking, clinical examination, and findings of clinical administered. Thrombocytosis (platelet count >500,000)
accompaniments, will more or less sort out the issue with occurs in 60%. This occurs in the second week and may
the help of laboratory evaluation (Table 3). persist for 4–6 weeks.
637
KG-77.indd 637 03-11-2018 12:37:33

SECTION Table 3: Differential diagnosis of KD
9
KD SSSS SJA Measles Drug rash RF
Age <5 years <5 years Any <5 years Any 5-15 years
Fever +++ +++ + ++ + +
Vascular System
Toxic + ++ + + 0 0
Conjunctivitis ++ + + ++ 0 0
Lymph nodes ++ + + + 0 0
Limb involvement ++ + 0 0 0 ++
Joints + + 0 0 0 ++
Clinical CVS involvement + 0 0 0 0 ++
a
Abbreviations: KD, Kawasaki disease; SSSS, staphylococcal scalded skin syndrome; SJA, systemic onset juvenile arthritis; RF, rheumatic fever; CVS,
di
cardiovascular system
In
Biochemistry ST-T changes
Liver function tests may be abnormal. Raised transaminases
Prolonged QTc
Acute myocardial infarction (STEMI).
of
can be common without jaundice. It was found in 20% in
our series. Elevated alanine aminotransferase (ALT) level
is more crucial. Serum albumin is decreased and globulin Echocardiography
ty
level is increased. Hepatitis can occasionally be due to It is extremely useful in acute phase, convalescing phase
aspirin. Reye syndrome has been reported with the use of and in late follow-up in KD. In acute phase, it can pick
aspirin.
18 cie up pericardial effusion, left ventricular (LV) dysfunction,
MR, less commonly AR; and, of course, possible coronary
artery lesions (CAL). It must be done using the highest
Other Investigations (Biomarkers)
20 o
frequency transducer available, ideally 7.5–10 MHz.
Cardiac Troponins: troponin T or I could be elevated in
S
KD. It could indicate myocardial involvement.

Parameters Studied
N-terminal pro-brain natriuretic peptide (NTpBNP)
may be useful in indicating myocardial involvement. Coronary artery size
al
Coronary artery morphology

Additional findings: Ejection fraction (EF), MR, AR,
CARDIOVASCULAR MANIFESTATIONS IN KD
ic
pericardial effusion.
Clinical Findings
og
Seven segments are selected for echocardiography of the

Physical findings of cardiovascular involvement may be coronaries:
variable and are not very common. The findings include Left main coronary artery (LMCA) and bifurcation
ol
tachycardia, accentuation of an already existing innocent Left anterior descending coronary artery (LAD)—
murmur, S3 gallop, and pericardial rub. Murmurs of mitral proximal, distal

di
regurgitation (MR) and aortic regurgitation (AR) are rare. Right coronary artery (RCA)—proximal, mid, distal
Circumflex (Cx)/posterior descending artery (PDA).

Heart failure can occur rarely.
ar
Most commonly involved segments are:

Chest X-ray Proximal LAD
C
Proximal RCA
Chest X-ray can show mild cardiomegaly and incidence
LMCA
can be 10%. The cardiomegaly may be either due to
Circumflex
myocardial dysfunction or due to pericardial effusion.
Distal RCA.
Pulmonary venous congestion could be seen.
Vi su a l i z at i o n o f c o ro na r i e s i nvo l ve s ca re f u l
visualization of both proximal and if possible distal
Electrocardiography segments of both left coronary artery system and right
The findings include: coronary system. The views are parasternal short axis with
Sinus tachycardia tilted views, apical 4-chamber view and subcostal views.
Supraventricular or ventricular tachyarrhythmias The overall sensitivity of echocardiography in picking
Atrioventricular (AV) blocks: Prolonged PR, second- up CAL is 95% and specificity is nearly 100%. If stenosis
degree AV block. is present, sensitivity may be around 85% and specificity
638
KG-77.indd 638 03-11-2018 12:37:33

Table 4: Sensitivity and specificity of echocardiography in Table 5: Normative data of normal coronaries in infants and CHAPTER
coronary artery lesion children SAT Study 2002
Sensitivity Specificity Coronary artery
1. LMCA
BSA
<0.5
Mean mm
1.6
97th centile mm
2.5
77
Dilatation 95% 99%

Stenosis RCA 85% 98% 0.5–1.0 1.8 2.5
> 1.0 1.9 2.5
LMCA/LAD 80% 98%
2. LAD <0.5 1.4 2.0
Abbreviations: RCA, right coronary artery; LMCA, left main coronary
artery; LAD, left anterior descending coronary artery 0.5–1,0 1.5 2.3
>1.0 1.6 2.2
3. RCA <0.5 1.2 2.0
98% (Table 4). Sensitivity decreases with distal coronary 0.5–1.0 1.4 2.0
a
segments but most coronary lesions are in the proximal >1.0 1.6 1.6
segments. The echocardiography is done traditionally in
di
4. Circumflex <0.5 1.2 1.6
the acute phase, at 6–8 weeks of illness and at 6 months 0.5–1.0 1.2 1.7
and 1.0 year in our institution, using a 5-MHz probe. In
In
> 1.0 1.3 1.6
addition to size, morphology is also studied.
Abbreviations: BSA, body surface area; LMCA, left main coronary artery;
Coronary artery lesion can be: LAD, left anterior descending coronary artery; RCA, right coronary
of
artery
Aneurysms: Saccular, fusiform, sacculofusiform, and
tubular.
Dilatation
Table 6: Coronary artery lesion—classification according to
ty
Stenosis. diameter
Up to 4 mm: Mild dilatation
What is Abnormal? 18 cie
According to JKDRC 1984 recommendations, a coronary
z
z
z
4–8 mm: Moderate dilatation
>8 mm: Giant aneurysm
artery is abnormal if the internal diameter of either

20 o
coronary artery is >3 mm in children below 5 years or >4 Z-score Classification
S
mm in children above 5 years or if a segment measures 1.5

Less than 2 Z Normal
times the adjacent coronary segment; or if the coronary
2.0–2.5 Z Dilatation only
lumen is irregular. This had been widely followed for
al
> 2.5–5.0 Z Aneurysm (small)

assigning CAL in KD. Later, normative data appropriate
> 5–10.0 Z Medium aneurysm
for body surface area (BSA) were used; like de Zorzi 1998.
ic
More than 10 Z Giant aneurysm

There are now many normative data for assessment, from
og
the USA to Canada to Japan.

In our institution, we assessed coronary artery size Echocardiography (Other than CAL)
(internal diameter) in normal healthy infants and children Low LV ejection fraction may be observed, especially
ol
up to 12 years and calculated centiles and arrived at a in early phase of KD. Most of LV dysfunction recovers
normative data. Instead of age, we decided to measure Pericardial effusion
di
coronary artery size according BSA and plotted the mean MR: 10–15%
and the 97th centiles. A total of 158 children were studied AR: <5%
ar
(Tables 5 and 6). Aortic root dilatation.

So, irrespective of age and BSA, any value above 2.5
mm (LMCA), 2.3 mm (LAD), 1.7 mm (Cx), and 2.0 mm Echocardiography in KD
C
(RCA) could be abnormal. We now have arbitrarily defined

if LMCA, LAD or RCA are above 2.5 mm and Cx is above SATH Series
2.0 mm in our cases. This is a significant departure from EF: 70.2 + 6%
the JKDRC criteria which might miss out minor dilatation MR: 8%
of coronaries and underestimate cardiovascular morbidity AR: 0%
in KD. Pericardial effusion: 2%
To analyze abnormality, various normative data linked Coronary lesion: 24%
to BSA can be utilized. The various methods include those Arteries: LAD, LMCA, RCA, Cx
from de Zorzi, McCrindle, Kobayashi, Dallaire, and many
others. Predictors of CAL
The original JKDRC criteria using absolute values have Age less than 1.0 year
been replaced by Z-scores using normative data. Male Sex
639
KG-77.indd 639 03-11-2018 12:37:33

SECTION TLC >30,000/mm3 weeks; even without treatment. Response to IVIg is often
ESR > 100 mm/hr dramatic—within 24 hours.
9 Persistently high ESR
ECG showing acute Ml pattern SPECIAL CONCERNS IN KD
Vascular System
Low Hb
Hypoalbuminemia Incomplete KD/Atypical KD (10%)
Late IVIg administration. Both these diagnostic terms have been occasionally used
with overlap. However, incomplete KD is defined as
OTHER ABNORMALITIES presentation of KD in those who do not fulfill the clinical
criteria, with or without CAL. The term atypical KD is used
Muscle Enzymes for those who present with atypical presentation, but have
a
Creatine phosphokinase-MB (CPK-MB), could be elevated CAL usually. Those situations would require the proactive
di
in KD, especially if an infarct or micro infarct has occurred role of a cardiologist for resolution of dilemma.
or if significant myocarditis develops. Trop T and Trop Incomplete KD (ICKD) will have less of lymphadeno-
In
I results in KD are variable and may not be very useful. pathy, rashes, and extremity changes, while mucosal
Recently, BNP estimation has been touted as marker for changes will be very common (90%). ICKD may lead to late
risk of developing CAL, as also plasminogen activator diagnosis and late initiation of IVIg treatment. This may
of
inhibitor-1 (PAI-1), urinary neopterin, and cytokines- lead to higher incidence of CAL.
interleukin-6 (IL-6), IL-8, and IL-2. Some of the presentations in atypical KD include
meningitis, sensory neural deafness, pleural effusion, and
ty
acute lymphadenitis.
Lipid Profile Laboratory evaluation will be helpful in decision
18 cie
There has been documentation of mildly elevated total
cholesterol, low-density lipoprotein (LDL)-cholesterol
and triglyceride (TG) and low high-density lipoprotein
making. Concomitant elevation of ESR, CRP, and platelet
count will be quite useful. Newer markers like troponins,
procalcitonin and pro-N-BNP could be useful.
(HDL) following KD, especially in convalescence. This
20 o
could be due to IVIg-induced protein fraction changes in Diagnosis
S
plasma or a primary phenomenon.

Figure 4 shows incomplete kawasaki disease (AHA
Algorithm 2004).
al
OTHER INVESTIGATIONS
Coronary Angiogram Supplementary Laboratory Criteria
ic
They are usually indicated in prognostication and The supplementary laboratory criteria is used in decision
og
therapeutic strategy planning in KD with CAL. The making in incomplete KD

S. albumin <3 g/dL
children who need angiography are those with large
Hb <11 g/dL
coronary aneurysms, multiple aneurysms and who have
ol
Elevated ALT (ALT used to be called serum glutamic-

clinical, ECG, or scintigraphic evidence of ischemia.
pyruvic transaminase, or SGPT)
di
Platelet count >4.5 lac

Stress Studies TLC >15,000/mm3
ar
Exercise treadmill test (TMT), dobutamine stress Sterile pyuria.
echocardiography, and stress thallium have been used in

the assessment of ischemia in children.
C
Acute Myocardial Infarction

In acute stage
Others During convalescence
These include PET, MRI, spiral CT, intravascular ultrasound Remote (Adult).
(IVUS), and endomyocardial biopsy. They are limited to Acute myocardial infarction (AMI) in KD has higher
mostly research centers. MRI can characterize all cardiac mortality and most often has a large thrombus load.
abnormalities but has logistic issues such as cost, time Rupture as a cause of STEMI is unusual.
taken, and need for anesthesia. IVUS can assess coronary
lesions which are subtle and can also prognosticate. Future Atherosclerosis
There have been studies showing increasing BP, adiposity
NATURAL HISTORY and TG levels following KD which may cause accelerated
Kawasaki disease is a self-limiting disease. The mean atherosclerosis. Hence, there is an intriguing possibility
640 duration of fever is 12 days. The maximum duration is four of premature coronary artery disease (CAD) in KD
KG-77.indd 640 03-11-2018 12:37:33

CHAPTER
77

a
di
In
of
ty
18 cie
20 o S
Figure 4: Incomplete Kawasaki disease (AHA Algorithm 2004)

al
survivors due to interplay of multiplicity of factors such

ic
as gross coronary artery lesions, endothelial dysfunction,

og
abnormal flow reserve, dyslipidemia, and possible

adiposity and hypertension (Figure 5).
ol
TREATMENT OF KD
Even though etiology is unknown, current therapeutic
di
strategy for KD is more or less standard. The goals are:

To treat acute inflammation and prevent CAL.
ar
To prevent thrombosis.
Figure 5: Coronary artery disease in Kawasaki disease

C
Intravenous Immunoglobulin
Landmark trials in the 1980s in Japan and the USA have doses are less efficacious. IVIg should be at least given as
established the role of IVIg in reducing CAL and current two doses (1 g/kg/day × 2) if there is a feasibility problem
recommendation of administration of 2.0 gm/kg/IVIg in administration. Harada scores have been used to assess
is based on major trials in the 1990s. IVIg should be the requirement of IVIg in KD in Japan.
administered within 10 days of illness and preferably
within 6 days of illness. Very early IVIg may further reduce Mechanism of IVIg in KD
CAL. IVIg was first given in KD in 1983. IVIg with aspirin Downregulation of cytokine production
can bring down the percentage of CAL at 6 weeks from 25% Fc receptor blocking
to 5% that is a five-fold reduction. Late administration of Neutralizing antibodies
IVIg is a risk factor for giant aneurysm formation. Multiple Suppress T cell induction
641
KG-77.indd 641 03-11-2018 12:37:34

SECTION Concerns Regarding IVIg Late KD (>10 days)
— Full dose aspirin is given
9
It has a high osmolality and can cause fluid overload.
— IVIG administration is individualized, depending
Hence, it has to be given over 12 hours; starting with 0.03
mg/kg/min and building up to 0.1 mg/kg/min. Adverse on risk factors, cost, etc.
Vascular System
reactions are rare (<5%). The usual problems are chills,

shivering, hemolytic anemia, and liver injury. There KD—Other Modalities of Therapy
have been also concerns regarding spread of hepatitis Steroids
and HIV, and also on the efficacy of different commercial
They are generally either not indicated or possibly
preparations of IVIg.
contraindicated in acute KD as a primary therapy.
This is based on a major initial trial of steroids in KD in
Aspirin
a
the 1980s. However, there have been recent reports of
Relatively high doses of aspirin are started once the administration of steroids in KD in selected cases. Drug
di
diagnosis is made. The AHA recommends a dose of used is methylprednisolone 30 mg/kg/IV × 3 doses - pulse
80–100 mg/kg/day/4 divided doses till fever subsides, methylprednisolone. The indications may be:
In
acute symptoms subside, and acute phase reactants Recrudescent or persistent clinical features.
become normal. However, most centers in Japan give IVIg failure and re-treatment (20%).
of
a dose ranging from 30–60 mg/kg/day. We follow this In 2003, a randomized controlled trial comparing
strategy in our institution. Salicylate-induced hepatitis is a IVIg alone vs IVIg + methylprednisolone showed reduced
cause for concern in KD treated with a large dose aspirin fever, shortened duration of illness, and rapid reduction
ty
with moderately elevated transaminases, vomiting, and of ESR and CRP, but no significant difference in coronary
mild icterus. This could be more common in Japanese or dimension. So, steroids are still not widely used in the
18 cie
Asians. So, there is a minor debate on what is the optimal
dose of aspirin in acute phase. During convalescence, the
antiplatelet dose of 5 mg/kg is given for 6–8 weeks till the
initial treatment of KD.
Steroids are used:
As primary therapy—Not indicated
next echocardiography is performed. As adjuvant with IVIg—Could be useful in reducing.

20 o
CAL
S
In refractory KD—Useful in reducing refractoriness in

STANDARD PROTOCOL FOLLOWED IN OUR
high-risk KD.
INSTITUTION
al
IVIg 2 g/kg /IV infusion over 12 hours.

Antioxidants

Aspirin (Enteric coated): 60 mg/kg/day; 4 divided

The α tocopherol and vitamin C may mitigate the clinical
ic
doses till the child is:

— Afebrile
features of KD. So far there have been no genuine trials on
og
— Acute symptoms abate.

these.
Subsequent therapy:
— Aspirin 5 mg/kg/day once daily for 6–8 weeks.
Cyclopsprine A
ol
— Echocardiography is done at 6–8 weeks There have been isolated reports of using cyclosporine A
— If echo is normal, aspirin is discontinued in IVIg failure in KD.
di
— If echo is abnormal, aspirin is continued indefin-
itely with follow-up echo. Oral Prednisolone

ar
Recrudescence or persistent symptoms: They have been used in a few centers with variable success.
— Continue full dose aspirin
C
— IVIg 2 g/kg/single dose.

Abciximab/tPA/Streptokinase
Large aneurysm (>6 m):
They have been used in acute coronary events in children
— In acute phase
with KD and also in large aneurysm in acute or subacute
Low molecular weight heparin x 5 days
stage.
Add clopidogrel 1.5 mg/kg.
— In convalescent phase: Clopidogrel with aspirin.
— In giant aneurysm (>8 mm): Anticoagulant added

Ticlopidine/Clopidogrel
to low dose aspirin to keep INR 1.5–2.0 with This could be an alternative to dipyridamole in large CAL,
warfarin especially in giant aneurysms.
Atypical KD: 10%
Treat as KD with full complement of IVIg and aspirin Pentoxyphylline
if echocardiogram is abnormal or borderline normal/ It is a TNF alpha inhibitor and may have a role in reduction
higher number of risk factors present. of CAL.
642
KG-77.indd 642 03-11-2018 12:37:34

Plasma Exchange Refractoriness could be predictable. There have been CHAPTER
various scoring systems for this prediction – Egami, Sano,
77
This could be used in resistant KD.
and Kobayashi. Most of them have sensitivity of 80-85%
Ulinastatin and specificity of 75%.

T h e s t a n d a rd re g i m e n f o r re f r a c t o r y K D i s
This is a trypsin inhibitor used as an adjunct to treating
administration of one more dose of IVIg, 2 g/kg. Usually,
IVIG resistant KD.
80% will respond favorably. The nonresponders may
Rest have to be given either methylprednisolone or infliximab.
Other drugs/modes which could be used are ulinastatin,
It is advised for 2 to 3 weeks. More prolonged rest may be
methotrexate, and plasmapheresis.
offered in the presence of giant aneurysm.
a
Doses of Pharmacological Agents New Strategy
di
IVIg: 2 g/kg over 12 hours A new strategy in KD could be as given in Figures 6 and 7.
Aspirin: 30–60 mg/kg/day in divided doses
In
Low-dose aspirin: 5 mg/kg/day LONG-TERM MANAGEMENT
Methylprednisolone: 30 mg/kg/ dose × 3 day Long-term management of a child or infant who has
2–3 hours infusion recovered from KD is based on risk stratification.
of
Infliximab: 5 mg/kg/IV infusion over 2 hours Risk stratification in turn depends primarily on CAL.
Prednisolone: 2 mg/kg/PO/day to begin with and then Echocardiography is the primary tool in assessing CAL
taper
ty
stratification.
Recombinant tissue plasminogen activator (rtPA): 0.5 I. KD. Normal coronaries
mg/kg/hr for 6 hours IV

infusion
18 cie
Streptokinase: 1000 IU/kg/bolus; 1000 IU/kg/hour
Z-score < 2.0
II. KD. Dilatation only
Z-score 2–2-5
Unfractionated heparin: 50 U/ kg loading IV. 20 U/kg/ III. KD. CAL. Small aneurysm
20 o
hour infusion Z-score 2.5–5.0
S
Low-molecular-weight heparin (LMWH): 2 mg/kg/day 1. Current/persistent

BD SC 2. Decreased/Normal
Warfarin: 0.1 mg/kg/day to start IV. KD CAL. Medium aneurysm
al
Maintain International Normalized Ratio Z-score 5.0–10

(INR) 2 1. Current/Persistent
ic
Clopidogrel: 1.5 mg/kg/day 2. Decreased to small

3. Decreased to normal (Z score < 2.5).
og
Refractory KD V. KD. Large/Giant aneurysm

After IVIg, if fever does not respond beyond 36 hours, one Z-score > 10
can suspect refractory KD. It is usually seen in 5–10%. 1. Current/Persistent
ol
Other reasons for fever could be intercurrent infection, 2. Decreased to medium

other diseases like systemic juvenile idiopathic arthritis 3. Decreased to small
di
(SJIA), viral fever, etc. 4. Decreased to normal/dilatation.

ar
C
Figure 6: New strategy in Kawasaki disease

643
KG-77.indd 643 03-11-2018 12:37:35

SECTION
9
Vascular System
a
di
In
Figure 7: Initial phase of Kawasaki disease and follow-up
of
PROTOCOL FOR MANAGEMENT (TABLE 7) Lifestyle modification
Restriction of physical activity
Level I Normal
ty
Empirical statin (11b)
Stop aspirin at 8 weeks Empirical β-blockers (11b)

18 cie
Ongoing follow-up: 6 months–12 months
No follow-up later. Lifestyle modification.
Assess for inducible ischemia and if needed imaging.
INTERVENTIONS IN KD
Level II
20 o
Intervention can be either percutaneous or surgical.
Continue aspirin–Low dose for 6-8 weeks It is offered in both acute situations (acute coronary
S

Ongoing follow–up up to 12 months. syndrome) or in chronic CAD.

Lifestyle modification.
al
Acute Coronary Syndrome

Level III STEMI: It is a medical emergency and needs restoration
ic

Continue aspirin indefinitely of coronary circulation. The standard approach is

Reassess CAL at 6 months and 12 months
og

intravenous thrombolysis with intravenous/oral
Yearly follow-up antiplatelet agents. Coronary artery bypass grafting
Lifestyle modification (CABG) is not indicated. Percutaneous coronary
ol
No restriction of physical activity: intervention (PCI) may not be ideal as the reason for
Empirical statin – IIb – controversial occlusion is thrombus rather than plaque rupture.
di
Clopidogrel if child is intolerant to aspirin. NSTEMI: Pharmacological therapy with intravenous

antiplatelets and LMWH is advocated.
ar
Level IV STEMI in an adult with distant KD, immediate coronary

Continue aspirin indefinitely angiography and PCI may be the preferred option,
unlike a child with STEMI. Pharmacotherapy can be
C
Reassess CAL at 3, 6, 9, 12 months

Ongoing follow-up 6 monthly contemplated in appropriate situations.
Lifestyle modification
Some restriction of physical activity Chronic CAD
Assess for inducible ischemia It can be either by catheter intervention or by CABG.
Imaging if indicated Catheter intervention can be by percutaneous
Empirical statin therapy (IIb) transluminal coronary angioplasty (PTCA), with stent
Dual antiplatelet (especially, if CAL > 6 mm (IIb).
or rotablation.
CABG is preferred in the left main CAD and multivessel
Level V CAD.
Assess at 1, 2, 3, 6, 9, 12 months and later at 3–6 months PCI is preferred in single vessel disease or two-vessel
Continue aspirin indefinitely disease amenable to PCI. Plain balloon angioplasty
Add warfarin to keep INR to 2–3 should not be used.
644
KG-77.indd 644 03-11-2018 12:37:35

Table 7: Protocol for management CHAPTER
77
Freq visit LDA DAPT Warf Statin BB TMT
I No 0 0 0 0 0 0
II Yearly 0 0 0 0 0 0

+
III Yearly + 0 0 + 0 +
IV 6 months + + 0 + 0 +
V 3 months + + = + + +
Abbreviations: DAPT, dual antiplatelet therapy; LDA, low dose aspirin; Warf, warfarin; BB, beta-blockers; TMT, treadmill test
a
NATURAL HISTORY Table 8: What matters to whom—diagnosis
di
Features Pediatrician Cardiologist
KD is a self-limiting disease. The mean duration of fever is
Clinical recognition +++ +
12 days. The maximum duration is four weeks; even without
In
Predictors of CAL ++ +
treatment. Response to IVIg is often dramatic–within 24
Optimization of laboratory work ++ +
hours. Death in KD is now rare. It was 1–3% in the 1970s
and now it has become < 0.1%. It occurs due to acute Incomplete KD ++ ++
of
infarction and rarely due to aneurysm rupture. Atypical KD ++ ++
Late mortality is again due to infarction or intervention Newer imaging 0 +
related events. Coronary involvement is usually between CAG 0 +
ty
Stress testing + ++
20 and 30%. In our institution the CAL occurred in 24%.
Usually, CAL regresses within 1 year in 50% children.
18 cie
Endothelial dysfunction is near universal in CAL and it
could possibly occur in coronaries identified as normal by Methods
Table 9: What matters to whom—treatment
Pediatrician Cardiologist
1. IVIg dosing +++ +
echocardiography. Hence, accelerated atherosclerosis is a
20 o
2. Treat refractory KD +++ ++
potential risk in KD. In spite of apparently normal looking
3. Dosing of aspirin, clopidogrel, ++ ++
S
coronaries, carotid intima media thickness (CIMT) is DAPT, warf

altered in KD. 4. New pharmacological agents ++ ++
ESR initially may go up after IVIg and will fall gradually. 5. STEMI management + +++
al
It will take 6–10 weeks to reach normal value. CRP will fall
to normal by 4–6 weeks. Platelet count will become normal
ic
Table 10: What matters to whom—prognosis/follow-up

by 4–8 weeks, after peaking at 3 weeks. Pediatrician Cardiologist
Regression of CAL occurs in approximately half. About
og
1. Follow-up ++ +++
40% will develop aneurysm. Stenosis can occur in 5–10%. 2. Regression of CAL ++ +++
Giant aneurysm occurs in 5%. Aneurysm rupture less 3. Prevention CAD ++ ++
ol
common. Regression is more likely when child is >1–0 4. Management of CAD + +++
year, female and the lesions are fusiform and less than 6 5. Interventions O +++
mm in diameter.
di
KD with no initial CAL will have no CAL at the end of Even though KD is primarily a vasculitis, all layers of
10 years. KD with giant aneurysm is unlikely to become
ar
heart can be involved.

normal. About 50% KD with CAL of > 6 mm will develop Myocardial involvement can be as high as 75% by biopsy.
stenosis. Pericardial effusion can occur in 10–20%; valvulitis could be
C
cause of MR and AR. AR can occur due to root dilatation also.

LONG-TERM CARDIAC DAMAGE Papillary muscle dysfunction and ischemia can cause MR.
Coronary: CAD
Noncoronary: Interventions (Tables 8 to 10)
— LVd ysfunction
Catheter (PCI)
— MR, AR
CABG.
— Aortic root dilation
The indications are not data driven. Mostly they are
empirical and derived from adult experience. The choice
INDICATIONS FOR CORONARY ANGIOGRAPHY of catheter interventions is as given below:
Stress test positive Plain balloon angioplasty: Not optimal
Giant aneurysm Stent placement: Older children
Ischemic symptoms Rotablator: Better?
645
KG-77.indd 645 03-11-2018 12:37:35

SECTION CABG is reserved for LMCA lesion, 3-vessel disease 8. Burns JC, Kushner HI, Bastian JF, S et al. Kawasaki disease:
with/without LV dysfunction. A brief history. Pediatrics. 2000;106(2):E27.
9 In significant occlusive coronary lesions, CABG is

traditionally offered. Initially, saphenous vein grafts (SVG)
9. Dajani AS, Taubert KA, Takahashi M,et al. Guidelines
for long-term management of patients with Kawasaki
disease. Report from the Committee on Rheumatic
Vascular System
were used but now current bilateral internal mammary

Fever, Endocarditis, and Kawasaki Disease, Council on
artery (IMA) graft is preferred. Restenosis seems to be
Cardiovascular Disease in the Young, American Heart
earlier in KD children or adults who undergo CABG. PTCA Association. Circulation. 1994;89(2):916-22.
have been used with or without stent in children or adults 10. Dale RC, Saleem MA, Daw S, et al. Treatment of severe
with distant KD. Restenosis rate may be higher. complicated Kawasaki disease with oral predinosolone and
The 10-year patency in KD is 80%. aspirin. J Pediatr. 2000;137(5):723-6.
11. de Zorzi A, Colan SD, Gauvreauk, et al. Coronary artery
a
CONCLUSION dimensions may be misclassified as normal in Kawasaki
di
disease. J Pediatr. 1998;133(2):254-8.
Kawasaki disease is emerging as an important acquired 12. Durongpisitkul K, Gururaj VJ, Park JM, et al. The prevention
heart disease in children, probably next only to RF/RHD of coronary artery aneurysm in Kawasaki disease: a meta-
In
in our country. The regional variation occurs at national analysis on the efficacy of aspirin and immunoglobulin
level also wherein a large number have been reported treatment. Pediatrics. 1995;96(6):1057-61.
from Kerala. Even though etiology remains an enigma, 13. Fujiwara H, Hamashima Y. Pathology of the heart in
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effective acute therapy is currently available which can Kawasaki disease. Pediatrics. 1978;61(1):100-7.
reduce coronary involvement five-folds. Some sort 14. Gopika SR, Ahamed MZ. Coronary artery diameter in
of long-term surveillance is warranted. Occasionally, normal infants and children of Kerala by two-dimensional
ty
revascularization may be required. Many features of echocardiography. Participants’ Handbook. Pedheart 2012.
Department of Pediatric Cardiology, GMC, Trivandrum.
KD–both mechanical and biochemical, might predispose
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to accelerated atherosclerosis and hence increased
CAD occurrence in the future. Even though KD is a
15. Hiracshi S, Misawa H, Takeda N, et al. Transthoracic
ultrasonic visualisation of coronary aneurysm, stenosis,
and occlusion in Kawasaki disease. Heart. 2000;83(4):400-
disease of young children and the chief stakeholder is the 5.
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pediatrician, pediatric cardiologist and cardiologist have 16. JCS Joint Working Group. Guidelines for diagnosis and
an integral role in diagnosis and management. There
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management of cardiovascular sequelae in Kawasaki

must be a synergy between three of them to prevent death, disease (JCS 2013). Digest version. Circ J. 2014;78(10):2521-
prevent development of CAL, long-term follow-up and 62.
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management – both in acute setting and chronic setting. 17. Kato H, Ichinose E, Kawasaki T. Myocardial infarction in
Interventional and surgical practices may have to be used Kawasaki disease: clinical analysis in 195 cases. J Pediatr.
ic
in selective cases. 1986;108(6):923-7.

18. Kato H, Inoue U, Kawasaki T, e t a l . Adult coronar y ar ter
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y dis eas e probably due to childhood Kawasaki disease.

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Kawasaki disease: high dose or low dose? Eur J Pediatr. of Kawasaki disease. A 10- to 21-year follow-up study of 594
1991;150(9):642-6. patients. Circulation. 1996;94(6):1379-85.
2. Akagi T, Kato H, Inoue O, et al. Valvular heart disease in 20. Kawasaki T, Kosaki F, Okawa S, et al. A new infantile acute
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Kawasaki syndrome: incidence and natural history. Am febrile mucocutaneous lymph node syndrome (MLNS)
Heart J. 1990;120(2):366-72. prevailing in Japan. Pediatrics. 1974;54(3):271-6.
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3. Akagi T, Ogawa S, Ino T, et al. Catheter interventional 21. Kim M, Kim K. Elevation of cardiac troponin I in the acute
treatment in Kawasaki disease: A report from Japanese stages of Kawasaki disease. Pediatr Cardiol. 1999;20(3):184-8.
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Pediatric Interventional Cardiology Investigation group. J 22. Kitamura S. The role of coronary bypass operation
Pediatr. 2000;137(2):181-6. on children with Kawasaki disease. Coron Artery Dis.
4. Akagi T, Rose V, Benson LN, et al. Outcome of coronary 2003;14(1):95.
artery aneurysms after Kawasaki disease. J Pediatr. 23. Kobayashi T, Saji T, Otani T, et al. Efficacy of immunoglobulin
1992;121(5):689-94. plus prednisolone for prevention of coronary artery
5. Arjunan K, Daniels SR, Meyer RA, et al. Coronary artery abnormalities in severe Kawasaki disease (RAISE study): a
caliber in normal children and patients with Kawasaki randomised, open-label, blinded-endpoints trial. Lancet.
disease but without aneurysms: an echocardiographic and 2012;379(9826):1613-20.
angiographic study. J Am Coll Cardiol. 1986;8:1119-24. 24. Kurotobi S, Nagai T, Kawakami N, et al. Coronary diameter
6. Baer AZ, Rubin LG, Shapiro CA, et al. Prevalence of coronary in normal infants, children and patients with Kawasaki
artery lesions on the initial echocardiogram in Kawasaki disease. Pediatric Int. 2002;44(1):1-4.
syndrome. Arch Pediatr Adolesc Med. 2006;160(7):686-90. 25. Liang CD, Huang SC, Su WJ, et al. Successful intravenous
7. Barron KS. Immune abnormalities in Kawasaki disease: streptokinase treatment of a child with Kawasaki disease
prognostic implications and insight into pathogenesis. complicated by acute myocardial infarction. Cathet
646 Cardiol Young. 1991;1:206-11. Cardiovasc Diagn. 1995;35(2):139-45.
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classification of coronary artery abnormalities based on gammaglobulin. Pediatr Cardiol. 2001;22(5):419-22.
coronary artery. Z-scores after Kawasaki disease. Pediatr
Cardiol. 2010;31(2):242-9.
37. Shulman ST. IVG G therapy in Kawasaki disease:
mechanism(s) of action. Clin Immunol Immunopathol.
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27. McCrindle BW, Rowley AH, Newburger JW, et al. Diagnosis, 1989;53(2):S141-6.

treatment, and long-term management of Kawasaki 38. Silva AA, Macno Y, Hashmi A, et al. Cardiovascular risk
disease: a scientific statement for health professionals factors after Kawasaki disease: a case-control study. J
from the American Heart Association. Circulation. Pediatr. 2001;138(3):400-5.
2017;135(17):e927-99. 39. Stanley TV, Grimwood K. Classical Kawasaki disease in
28. Ministry of Health and Welfare, Research Committee a neonate. Arch Dis Child Fetal Neonatal Ed. 2002;86(2):
on Kawasaki Disease. Report of the Subcommittee on F135-6.
Standardization of Diagnostic Criteria and Reporting of 40. Sundel R. Refractory Kawasaki disease. UpToDate 2015.
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Coronary Artery Lesions in Kawasaki Disease. Tokyo: 41. Sundel RP, Baker AL, Fulton DR, et al. Corticosteroids
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Japan: Ministry of Health and Welfare, 1984. in the initial treatment of Kawasaki disease: report of a
29. Neches WH. Kawasaki disease. In: Anderson RH, Baker randomized trial. J Pediatr. 2003;142(6):611-6.
EJ, MaCartney FJ, Rigby ML, Shinebourne EA, Tynan M, 42. Suzuki A, Kamiya T, Ono Y, Kinoshita Y, Kawamura
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editors. Paediatric Cardiology. 2nd edn. London: Churchill S, Kumura K. Clinical significance of morphological
Livingstone. 2002;1683. classification of coronary arterial segmental stenosis due to
30. Newburger JW, Burns JC, Beiser AS, et al. Altered lipid profile Kawasaki disease. Am J Cardiol. 1993;71(13):1169-73.
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after Kawasaki syndrome. Circulation. 1991;84(2):625-31. 43. Suzuki A, Tizard EJ, Gooch V, et al. Kawasaki disease:
31. Newburger JW, Takahashi M, Beiser AS, et al. A single echocardiographic features in 91 cases presenting in the
intravenous infusion of gamma globulin as compared United Kingdom. Arch Dis Child. 1990;65(10):1142-6.
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with four infusions in the treatment of acute Kawasaki 44. Takahashi M, Mason W, Lewis AB. Regression of coronary
syndrome. N Engl J Med. 1991;324(23):1633-9. artery aneurysms in patients with Kawasaki syndrome.
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32. Newburger JW, Takahashi M, Gerber MA, et al. Diagnosis,
treatment, and long-term management of Kawasaki disease:
a statement for health professionals from the Committee
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Circulation. 1987;75(2):387-94.
Takahashi M. Kawasaki syndrome (mucocutaneous lymph
node syndrome). In: Allen HD, Gutgesell HD, Clark EB,
on Rheumatic Fever, Endocarditis and Kawasaki Disease, Driscoll DJ, editors. Moss and Adams’ Heart Disease in
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Council on Cardiovascular Disease in the Young, American Infants, Children, and Adolescents including the Fetus and
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Heart Association. Circulation. 2004;110(17):2747-71. Young Adults. 6th edn. Philadelphia: Lippincott Williams &
33. Onouchi Z, Kawasaki T. Overview of pharmacological Wilkins Co. 2001. p. 1216-25.
treatment of Kawasaki disease. Drugs. 1999;58(5):813-22. 46. Tatara K, Kusakawa S. Long-term prognosis of giant
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34. Research Committee of the Japanese Society of Pediatric coronary aneurysm in Kawasaki disease: an angiographic
Cardiology; Cardiac Surgery Committee for Development study. J Pediatr. 1987;111(5):705-10.
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of Guidelines for Medical Treatment of Acute Kawasaki 47. Taubert KA. Epidemiology of Kawasaki disease in the
Disease. Guidelines for medical treatment of acute United States and worldwide. Prog Pediatr Cardiol.
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Kawasaki disease: report of the Research Committee of 1997;6:181-5.

the Japanese Society of Pediatric Cardiology and Cardiac 48. Tse SM, Silverman ED, McCrindle BW, et al. Early treatment
Surgery (2012 revised version). Pediatr Int. 2014;56(2): with intravenous immunoglobulin in patients with
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135-58. Kawasaki disease. J Pediatr. 2002;140(4):450-5.

35. Satomi G, Nakamura K , Narai S, et al. Systematic 49. Williams RV, VM, Tani LY, Minich LL. Does Abciximab
enhance regression of coronary aneurysms resulting from
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visualization of coronary arteries by two-dimensional

echocardiography in children and infants: evaluation in Kawasaki disease? Pediatrics. 2002;109(1):E4.
Kawasaki’s disease and coronary arteriovenous fistulas. Am 50. Yamakawa R, Ishii M, Sugimura T, et al. Coronary
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Heart J. 1984;107(3):497-505. endothelial dysfunction after Kawasaki disease: evaluation

36. Shen CT, Wang NK. Antioxidants may mitigate the by intracoronary injection of acetylcholine. J Am Coll
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deterioration of coronary arteritis in patients with Cardiol. 1998;31(5):1074-80.
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Common Pitfalls and Artifacts in ECG Interpretation

SB Gupta
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Computerized ECGs: Strengths and Limitations
O
Kartikeya Bhargava
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ECG Assessment of Supraventricular Tachycardia

Amit Vora, Samhita Kulkarni
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ECG Assessment of Wide QRS Tachycardia

Binay Kumar, Yash Lokhandwala
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Atrioventricular Block: Diagnosing the Level of Block

Avinash Anantharaj, Anandaraja Subramanian
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STEMI Equivalents
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Arun K Chopra
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CHAPTER 78
Common Pitfalls and Artifacts
in ECG Interpretation
SB Gupta
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INTRODUCTION The ECG is a very important diagnostic tool in the
The invention of electrocardiography (ECG) is more than armamentarium of clinicians for patients suffering from
In
100 years old and the use of ECG has become a standard cardiovascular disorders, especially from acute coronary
medical practice. Sometimes, ECG is considered a syndrome (ACS) or from various arrhythmias. However,
ECG may be normal in episodic arrhythmias such as
of
reliable tool to diagnose or rule out medical problems as
compared to bedside diagnosis. However, ECG has many paroxysmal supraventricular tachycardia and in the early
limitations which have not been adequately emphasized. stages of acute coronary syndrome. The ECG may be
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To minimize the limitations, ECG has to be read in abnormal with structurally normal hearts, especially with
clinical context. If ECG is interpreted in view of clinical athletes or in the early repolarization syndromes.
adequate than otherwise.

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history and examination, the interpretations will be far
NORMAL ECG IN PATHOLOGICAL
CONDITIONS
LIMITATIONS
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Paroxysmal arrhythmias:
1
The various limitations are as follows: — Paroxysmal supraventricular tachycardia (SVT)/
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1. Lack of normal standards: There are tremendous atrial fibrillation (AF)

variations in the ECG from person to person. However, — Idiopathic ventricular tachycardia (VT)/cate
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the normal standards have been prescribed for reading cholinergic polymorphic ventricular tachycardia
ECG, but still lots of variation beyond these limits are (CPVT)/paroxysmal ventricular fibrillation
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considered normal. — Paroxysmal atrioventricular (AV) blocks.
2. Clinical and electrocardiographic correlations: The Coronary artery disease (CAD):

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ECG cannot correlate the severity of cardiac disease — Acute ACS

and the degree of the abnormality in the record. — Stable CAD
Most simple example will be a normal ECG in a case — Right ventricular or postwall myocardial
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of acute coronary syndrome (ACS) or acute evolving

infarction (MI).
myocardial infarction (AMI).
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Intermittent syndromes:
3. Functional reserve: Though ECG can give information
— Brugada syndrome
a b o u t h e a r t ’s r hy t h m i c i t y , e x c i t a b i l i t y , a n d
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— LQTS (long QT syndrome)

conductivity, but it cannot give much information
— Intermittent preexcitation.
about its functional reserve.
Cardiomyopathies:
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4. Diagnostic information: The ECG cannot reliably give

— Dilated
diagnostic information as there are so many overlap
— Hypertrophic
of ECG findings that one cannot come to a conclusion
— Infiltrative.
regarding one diagnosis just on the basis of ECG. For
example, ST depression on ECG will have umpteenth The ECG may be absolutely normal in various episodic
differential diagnosis. arrhythmias when the patient has no symptoms. History
5. Certain specific patterns: Many patterns have been taking is very important in such situations; and if there
specified on ECG to diagnose various disorders; but are episodic symptoms of palpitations, which are sudden
in clinical context, these criteria are disappointing. in onset and offset; and if associated with giddiness or
For example, Q1S3T3 criteria of pulmonary embolism shortness of breath, such patients must be evaluated
may only be seen in 20–30% of the cases. P mitrale of very carefully. The ECG at the time of episode may clinch
mitral stenosis is not specific for mitral stenosis, but it the diagnosis; else, stress test, Holter monitoring, event
denotes left atrial abnormalities because of any cause. recording, external loop recording for longer periods,
KG-78 (Sec-10).indd 651 03-11-2018 12:37:20

SECTION internal loop recording, or electrophysiological (EP) study Conduction Defects
may be required to come to conclusive diagnosis.
10
i. Left bundle branch block (LBBB) may mimic or
While evaluating syncope, one should always remember mask acute MI. Criteria have been laid down to
that AV blocks or sinus pauses may be paroxysmal and
diagnose acute MI in the presence of LBBB. One of
Electrocardiology
may not be picked on single ECG. Carotid hypersensitivity

the limitations of ECG is to diagnose acute MI in
or vasovagal syncope will show sinus bradycardia during
the presence of LBBB. The LBBB presents with QS
the episode only. Hence, to evaluate syncope, when we
complexes in right and midprecordial leads with ST
come across normal ECG, we need to take the help of other
elevation leading to confusion to diagnose additional
tests as mentioned above is essential.
MI. Sgarbossa criteria6 should be applied to diagnose
The ECG is the most common test for evaluation
MI in the presence of LBBB. The ST elevation more
of chest pain by the clinicians. However, ECG may be
than 5 mm in limb leads and precordial leads showing
a
perfectly normal in anginal episodes and even in early
QS complexes, ST elevation of 1 mm or more in Lead
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phases of evolving acute MI. Up to 10% of patients
I, aVL, V5, and V6 leads showing R wave and ST
presenting with ACS, may have normal ECG. 2,3 Right
depression, where ST elevation is expected, will favor
In
ventricular MI and postwall MI may also present with
the diagnosis of acute MI. The Q waves in LI, aVL, V5,
normal ECG. A large number of patients with stable CAD
and V6 in the presence of LBBB favors the old anterior
will also have normal ECG. It needs to be reemphasized
wall MI.
of
that normal ECG does not rule out CAD. And, serial ECGs
ii. Left anterior fascicular block (LAFB) may again mask
will be able to clinch the diagnosis.
inferior wall MI or mimic anterior wall MI.
So, many cardiac disorders may present intermittently,
iii. WolffParkinsonWhite (WPW) syndrome type A may
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such as Brugada syndrome, LQTS, or preexcitation with
mimic lateral wall MI and type B may mimic inferior or
normal ECG in between the episode.4 Similarly, so many
anterior wall MI.
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cardiomyopathies may present with normal ECGs and
high index of suspicion will only clinch the diagnosis.
Conditions, such as pulmonary embolism, may also
iv. Left ventricular hypertrophy: The QS complex in V1 and
V2, tall T waves seen in precordial leads, and poor R
wave progression may suggest anterior wall infarction.
present with almost normal ECG except may be with
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v. Acute pericarditis : The ECG changes of acute
subtle sinus tachycardia and history taking and again
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pericarditis confuse the physicians the most with

high index of suspicion will be helpful in reaching to a
the changes with acute MI. The ECG showing ST
conclusive diagnosis.
segment elevation (though downsloping) is sometimes
The CAD is one of the most dreadful diseases in
al
confused with evolving acute MI until unless properly

cardiology and a lot of emphasis has been laid on its
interpreted in the light of history and looking for the
diagnosis based on ECG. There are so many conditions
ic
subtle signs on ECG of pericarditis (Figure 1).

which may mimic like CAD and mislead us in diagnosing
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the event correctly and erroneous diagnosis will be made

leading to unnecessary treatment.5 Pulmonary Diseases
Poor R wave progression and loss of R waves in the right
COMMON PITFALLS IN DIAGNOSIS OF
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sided and midprecordial leads in chronic obstructive

CORONARY ARTERY DISEASE ON ECG lung disease (COLD) may mimic anterior wall infarction.
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The common pitfalls in the diagnosis of CAD on ECG are Vertical heart in emphysematous lung lead to Q waves in
discussed below: inferior leads mimicking inferior wall MI. Spontaneous
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pneumothorax can also mimic MI because of displacement

Cardiac Conditions and rotation of heart showing poor R wave progression,
low voltage ECG, and symmetrical T wave inversion
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Myocardial Diseases (Figures 2 and 3).

i. P r i m a r y m y o c a r d i a l d i s e a s e : Hy p e r t r o p h i c
cardiomyopathy, especially apical cardiomyopathy Intracranial Causes
mimic myocardial infarction showing Q waves in
The intracranial (IC) bleeds are known to produce ECG
inferior and anterior leads. Poor R wave progression
changes—deep symmetrical T wave inversion, prolonged
and STT wave changes are common features in dilated
QT and Q waves, and mimic acute MI (Figure 4).
cardiomyopathy mimicking anterior wall MI.
ii. Secondary myocardial disease: Myocarditis, various
infiltrative disorders, such as sarcoidosis and muscular Metabolic Abnormalities
dystrophies, and autoimmune conditions, such as Various metabolic abnormalities, especially hyperkalemia
scleroderma and cardiac tumors, may show STT wave and hypothermia, show ECG changes difficult to
changes which mimic CAD. distinguish from ACS (Figure 5).
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CHAPTER
78

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Figure 1: ECG in a patient of acute pericarditis mimicking acute myocardial infarction
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Figure 2: Poor R wave progression mimicking anteroseptal infarction (ASMI)

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Figure 3: ECG in a case of chronic obstructive pulmonary disease (COPD) mimicking anteroseptal infarction (ASMI)
653
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SECTION
10
Electrocardiology
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Figure 4: ECG changes in a patient of subarachnoid hemorrhage mimicking acute myocardial infarction
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ABNORMAL ECG WITH NORMAL HEARTS 1. Normal variants: Early repolarization syndrome is
Early repolarization syndrome (ERS) sometimes too difficult to differentiate from acute
al

evolving MI (Figure 6).
Juvenile T wave pattern
Left ventricular hypertrophy (LVH) pattern
2. Miscellaneous causes: Certain genetic conditions, such
ic
Poor progression of R wave.

as Brugada syndrome, may mimic anterior wall MI.
3. WolffParkinsonWhite syndrome, hypertrophic
Early repolarization is one of the most common
og
cardiomyopathy, amyloidosis, myocarditis, pulmonary

abnormalities noted, especially in young adults. The
embolism and rarely hyperkalemia may present with Q
ECG shows raised J point with notched downstroke of
waves and/or ST elevation mimicking acute MI.
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QRS complex, most commonly in the rightsided and

4. One of the most confusing findings in the ECG is the
midprecordial leads. It is seen in almost 1–2% of normal
STT waves changes because it may be nonspecific,
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population. It is quite commonly confused with evolving

may represent various medical disorders, drug side
acute MI. Historically, it is considered to be benign
effects, or as serious as myocardial ischemia.
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condition, and some recent studies have related ERS to

be associated with sudden cardiac death (SCD) or VT/
COMMON ARTIFACTS IN ECG
ventricular fibrillation (VF).7
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In children, T waves are inverted in precordial leads

INTERPRETATION
up to V4; while in adults, T waves are inverted up to The ECG artifacts are defined as ECG abnormalities
V2 only. Sometimes, inverted T waves up to V4 continue recorded as cardiac potentials, but are not related to
in adulthood, and it is known as persistent juvenile electrical activity of the heart. Normal components of
pattern. the ECG are distorted because of these artifacts. These
Sometimes, LVH pattern is noted in thin individuals. artifacts need to be recognized; else, it may lead to
The R wave of less than 3 mm in Lead V3 is considered unnecessary testing and wrong treatment.
as poor progression of R wave and seen in dextrocardia,
pneumothorax, pectus excavatum, and as normal variant. Causes
Sometimes, it is confused with anterior wall MI. These could be:
Abnormal lean Q waves can be noticed in LII and aVF Internal
and not considered as sign of old inferior wall MI. External.
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CHAPTER
78

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Figure 5: ECG in case of hyperkalemia mimicking extensive anterior wall myocardial infarction and ECG after correction of hyperkalemia
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Figure 6: ECG showing early repolarization mimicking acute anteroseptal infarction (ASMI)
Internal — Power line electrical disturbances

Patients’ motion: 8 — Electrical cautery, other electrical devices,
— Tremors and shiveringinduced motion artifacts
radiofrequency products, etc.
— Simple movements.
Cable and electrode malfunction:
— Insufficient electrode gel
Muscular activity.
— Misplaced leads
External — Broken wires
Electromagnetic interference:9 — Inappropriate filer settings
— Improper earthing — Loose connections.

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KG-78 (Sec-10).indd 655 03-11-2018 12:37:24

SECTION The ECG interpretation is valid only;10 12 patients wrongly diagnosed as VT
If electrodes are placed in correct anatomic locations Unnecessary cardiac catheterization in 3 patients
10 Lead wires are attached to appropriate leads
The recording is of good technical quality
Unnecessary medical therapies including intravenous
(IV) antiarrhythmic agents in 9 patients

Electrocardiology
Proper filtering Precordial thumps in 2 patients
Absence of extraneous electrical noise Prosthesispatient mismatch (PPM) in 1 patient
Serial ECG interpretation can be perfect only if ECG is Automated implantable cardioverterdefibrillator
taken with consistent technique, i.e. (AICD) in 1 patient.

Electrodes in same location Differentiation of electrocardiographic artifact from
The patient’s body in same position real disease:
Using the same lead configuration. Absence of symptoms or hemodynamic variation
a
The ECG artifacts can be due to: during the event
Normal ventricular complexes appearing among
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Inaccurate lead placement
Lead wire reversals dysrhythmic beats

Association with body movement
In
Noisy ECG signals
Instability of baseline tracing during and immediately
Inappropriate filter settings
Serial comparison with inconsistent lead sets.

following the alleged arrhythmia
Synchronous, visible notching consistent with the
of
The ECG artifacts because of electrical noise (Figure 7).
The ECG artifacts because of tremors: Sometimes, ECG underlying ventricular rhythm marching through the
is recorded in extreme cold conditions and the patient is pseudoarrhythmia.
ty
shivering or the patient is having disease with tremors as
Parkinsonism, giving rise to artifacts (Figures 8 to 10). LEAD MISPLACEMENTS
(Figure 11).
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The ECG wrongly interpreted at ventricular tachycardia
Clinical implications of wrong interpretation of ECG

The most common artifacts in the ECG are because of limb
lead reversals:12,13
In a standard ECG, limb leads are attached as follows
artifacts in one study:11 (Figure 12).
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Figure 7: ECG artifacts because of electrical noise

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New Delhi, India

Rakesh Yadav MD DM Nitish Naik MD DM S Ramakrishnan MD DM

Professor Professor Professor

New Delhi, India

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Netaji Subhash Place, Pitam Pura

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Prelims_Kewal C Goswami (40 pgs).indd 6 05-11-2018 18:04:52

Aayush Goyal Ajay Bahl Anandaraja Subramanian

Department of Cardiovascular and Postgraduate Institute of Medical

All India Institute of Medical Sciences Chandigarh, India

Abhinav Singhal Department of Cardiology

Department of Nuclear Medicine Medical Education and Research

New Delhi, India MGM Medical College and MY Hospital

Abhishek Goyal ICMR RF/RHD Registry

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Department of Cardiology Jawaharlal Institute of Postgraduate Pediatric Cardiologist

Consultant Interventional Cardiologist

Kolkata, West Bengal, India

Arun K Chopra New Delhi, India

Fortis Escorts Hospital Bijesh Viswambaran CM Nagesh

Pediatric Cardiology Department of Cardiology

Department of Cardiovascular Bengaluru, Karnataka, India

New Delhi, India Sri Jayadeva Institute of

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New Delhi, India Bengaluru, Karnataka, India

Jaganmohan A Tharakan Medanta-The Medicity

All India Institutes of Medical Sciences Trivandrum, Kerala, India

Girish Kumar Parida

Department of Nuclear Medicine

New Delhi, India

Professor Bengaluru, Karnataka, India

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Medical Sciences and Technology Department of Cardiology Cardiologist

Lakshmi Gopalakrishnan Chandigarh, India

All India Institute of Medical Sciences

Lakshmi Kumari Sankhyan Tufts Medical Center

New Delhi, India

Lalit Kumar Coordinator and Head

Laxmi H Shetty Mohit Bhutani

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Nobuyuki Kagiyama Raghav Bansal Rishi Sethi

Rishikesh, Uttarakhand, India

Professor and Head Cardiology

Education and Research Chennai, Tamil Nadu, India

Department of Cardiology Rajiv Ananthakrishna

Sri Jayadeva Institute of

Consultant Pediatric Cardiologist

Kokilaben Dhirubai Ambani Hospital Department of Cardiology

New Delhi, India

Prelims_Kewal C Goswami (40 pgs).indd 11 05-11-2018 18:04:54

Institute of Cardiology Department of Cardiology All India Institute of Medical Sciences

Sanjiv Sharma Lucknow, Uttar Pradesh, India

Department of Cardiovascular Shiv Kumar Choudhary

Interventions Department of Cardiovascular and

Associate Professor of Cardiology Southern Railway Headquarters Hospital

Department of Cardiology Department of Cardiology

Practical Points in Blood Pressure Measurement 13

Blood Pressure Measurement in Special Populations 14

Typical Arterial Pulse of Significant Aortic Regurgitation 17

Three Components of Rheumatic Fever Pathogenesis 46

Controversies in Pathogenesis of Acute Rheumatic Fever/

Evolution into Chronic Rheumatic Heart Disease 50

Estimated Burden of Disease 57

Acute Aortic Regurgitation 69

Is Early Recognition Beneficial? 74

Targets for Screening 77

The Natural History of Subclinical RHD 77

Natural History of Mitral Stenosis in the

Indications for BMV 92

Clinical Anatomy of Tricuspid Valve 106

Etiology of Tricuspid Valve Abnormalities 107

Tricuspid Stenosis 107

Symptoms of Tricuspid Valve Disease 110

Effect of Various Maneuvers 112

Common Case Scenarios in Routine Clinical Practice 131

Mitral Stenosis and Regurgitation 133

Tricuspid Stenosis and Regurgitation 141

Mitral Valve Anatomy 180

Pathophysiology of Aortopathy 192

Natural History 192

Balloon Valvuloplasty 194

Indications of Surgery for Aortopathy 196

Pregnancy and BAV 196

Antimicrobial Therapy 207

IE in Special Subgroups 208